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Resistance or Endurance Training is Efficacious in Decreasing Central Blood Pressures, Improving Endothelial Function an...

Permanent Link: http://ufdc.ufl.edu/UFE0042458/00001

Material Information

Title: Resistance or Endurance Training is Efficacious in Decreasing Central Blood Pressures, Improving Endothelial Function and Vasoactive Balance in Young Prehypertensives
Physical Description: 1 online resource (132 p.)
Language: english
Creator: Beck, Darren
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2010

Subjects

Subjects / Keywords: arterial, endothelium, endurance, exercise, prehypertension, pressure, resistance, stiffness
Applied Physiology and Kinesiology -- Dissertations, Academic -- UF
Genre: Health and Human Performance thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) proposed a new classification of blood pressure level termed prehypertension. Support for the creation of this new classification was based on the greater risk of developing clinical hypertension amongst prehypertensives when compared to normotensives. Prehypertensives are 11 times more likely to develop essential hypertension and the resulting cardiovascular risks associated with clinically high blood pressure. Lifestyle modifications, such as the adoption of an appropriate exercise regimen, are the sole recommendations for the treatment and prevention of prehypertension and to prevent the progression to stage one essential hypertension. Resistance and endurance exercise training are common and efficacious exercise modalities recommended by the American Heart Association and the JNC 7 for treatment and prevention of hypertension. Prehypertensives exhibit marked vascular stiffness when compared to normotensive counterparts. The effect of exercise training on arterial function in prehypertensives is grossly underinvestigated. The purpose of this study was to examine the effect of resistance and endurance aerobic exercise training on conduit arteries, muscular arteries, and microvascular vessels in prehypertension. This study was conducted at the Center for Exercise Science, College of Health and Human Performance, University of Florida. The study was designed to be a prospective randomized and controlled study. A total of 45 healthy prehypertensive (SBP = 120 ? 139 mmHg; DBP = 80 ? 89 mmHg) men and women (n=45) 18-35 years of age met screening requirements and participated in the intervention phase of the study. Subjects were randomly assigned to either a resistance exercise training group (n=15), endurance exercise training group (n=15) or a control group (n=15). The training groups (n=30) performed exercise training 3 days per week. The control group (n=15) was instructed to refrain from initiating structured exercise training programs during the study. Duration of the exercise program was 8 weeks. We hypothesized that 8 weeks of resistance or endurance training alone would decrease arterial stiffness, increase limb blood flow, and reduce both central and peripheral blood pressure in young healthy prehypertensive subjects. To test our hypothesis, pulse wave velocity in the aorta, femoral, and brachial arteries and aortic augmentation index was measured using applanation tonometry at study entry and after 8 weeks of resistance or endurance exercise training. Large artery endothelial function was measured in the brachial artery using ultrasound and the flow mediated dilation technique. In addition, the endothelial function of the micro vascular arterioles was assessed using reactive hyperemia and venous occlusion plethysmography.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Darren Beck.
Thesis: Thesis (Ph.D.)--University of Florida, 2010.
Local: Adviser: Braith, Randy W.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2012-12-31

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2010
System ID: UFE0042458:00001

Permanent Link: http://ufdc.ufl.edu/UFE0042458/00001

Material Information

Title: Resistance or Endurance Training is Efficacious in Decreasing Central Blood Pressures, Improving Endothelial Function and Vasoactive Balance in Young Prehypertensives
Physical Description: 1 online resource (132 p.)
Language: english
Creator: Beck, Darren
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2010

Subjects

Subjects / Keywords: arterial, endothelium, endurance, exercise, prehypertension, pressure, resistance, stiffness
Applied Physiology and Kinesiology -- Dissertations, Academic -- UF
Genre: Health and Human Performance thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) proposed a new classification of blood pressure level termed prehypertension. Support for the creation of this new classification was based on the greater risk of developing clinical hypertension amongst prehypertensives when compared to normotensives. Prehypertensives are 11 times more likely to develop essential hypertension and the resulting cardiovascular risks associated with clinically high blood pressure. Lifestyle modifications, such as the adoption of an appropriate exercise regimen, are the sole recommendations for the treatment and prevention of prehypertension and to prevent the progression to stage one essential hypertension. Resistance and endurance exercise training are common and efficacious exercise modalities recommended by the American Heart Association and the JNC 7 for treatment and prevention of hypertension. Prehypertensives exhibit marked vascular stiffness when compared to normotensive counterparts. The effect of exercise training on arterial function in prehypertensives is grossly underinvestigated. The purpose of this study was to examine the effect of resistance and endurance aerobic exercise training on conduit arteries, muscular arteries, and microvascular vessels in prehypertension. This study was conducted at the Center for Exercise Science, College of Health and Human Performance, University of Florida. The study was designed to be a prospective randomized and controlled study. A total of 45 healthy prehypertensive (SBP = 120 ? 139 mmHg; DBP = 80 ? 89 mmHg) men and women (n=45) 18-35 years of age met screening requirements and participated in the intervention phase of the study. Subjects were randomly assigned to either a resistance exercise training group (n=15), endurance exercise training group (n=15) or a control group (n=15). The training groups (n=30) performed exercise training 3 days per week. The control group (n=15) was instructed to refrain from initiating structured exercise training programs during the study. Duration of the exercise program was 8 weeks. We hypothesized that 8 weeks of resistance or endurance training alone would decrease arterial stiffness, increase limb blood flow, and reduce both central and peripheral blood pressure in young healthy prehypertensive subjects. To test our hypothesis, pulse wave velocity in the aorta, femoral, and brachial arteries and aortic augmentation index was measured using applanation tonometry at study entry and after 8 weeks of resistance or endurance exercise training. Large artery endothelial function was measured in the brachial artery using ultrasound and the flow mediated dilation technique. In addition, the endothelial function of the micro vascular arterioles was assessed using reactive hyperemia and venous occlusion plethysmography.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Darren Beck.
Thesis: Thesis (Ph.D.)--University of Florida, 2010.
Local: Adviser: Braith, Randy W.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2012-12-31

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2010
System ID: UFE0042458:00001


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1 RESISTANCE OR ENDURANCE TRAINING IS EFFICACIOUS IN DECREASING CENTRAL BLOOD PRESSURES, IMPROVING ENDOTHELIAL FUNCTION AND VASOACTIVE BALANCE IN YOUNG PREHYPERTENSIVES By DARREN THOMAS BECK A DISSERTATION PRESENTED TO THE G RADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 20 10

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2 2010 Darren Thomas Beck

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3 To my family

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4 ACKNOWL EDGMENTS First and foremost, I thank my advisor Dr. Randy W. Braith. I would also like to thank Dr. Darren P. Casey and Jeffrey S. Martin. I would like to thank Blaze D. Emerson, Bryan D. Brown, and Kaitlin J. Murphy for their assistance in training the participants for this research project. Lastly, I would like to thank the other members of my committee, Dr. Stephen L. Dodd and Dr. Scott K. Powers, and Dr. Wilmer W. Nichols, for their suggestions and guidance.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ ............... 4 LIST OF TABLES ................................ ................................ ................................ ........................... 8 LIST OF FIGURES ................................ ................................ ................................ ......................... 9 LIST OF ABBREVIATIONS ................................ ................................ ................................ ........ 11 ABSTRACT ................................ ................................ ................................ ................................ ... 14 CHAPTER 1 INTRODUCTION ................................ ................................ ................................ .................. 16 Background ................................ ................................ ................................ ............................. 16 Prehypertension Defined ................................ ................................ ................................ 16 Exercise and Prehypertension ................................ ................................ .......................... 17 Anatomy of the Arterial System ................................ ................................ ...................... 19 Consequences of Arterial Stiffness ................................ ................................ ................. 19 Endurance Exercise and Arterial Function ................................ ................................ ...... 21 Resistance Exercise Training and Arterial Function ................................ ....................... 22 Specific Aims and Hypotheses ................................ ................................ ............................... 24 2 LITERATURE REVIEW ................................ ................................ ................................ ....... 26 Prehypertension ................................ ................................ ................................ ...................... 26 Prehypertension and Resistance Training ................................ ................................ ....... 28 Shear Stress ................................ ................................ ................................ ..................... 34 Mechanical Transduction ................................ ................................ ................................ 35 Nitric Oxide ................................ ................................ ................................ ..................... 36 Oxidative Stress and Redox Balance ................................ ................................ ............... 38 Reactive Oxygen Species ................................ ................................ ................................ 38 Antioxidants ................................ ................................ ................................ .................... 40 ADMA/DDAH/BH 4 /Homocysteine ................................ ................................ ................ 41 Inflammation ................................ ................................ ................................ ................... 42 C Reactive Protein ................................ ................................ ................................ ........... 42 RAAS ................................ ................................ ................................ .............................. 45 ANGII ................................ ................................ ................................ .............................. 45 AT1 Receptors ................................ ................................ ................................ ................. 46 AT2 Receptors ................................ ................................ ................................ ................. 47 Cholesterol ................................ ................................ ................................ ....................... 48 Muscle Contraction and Exercise ................................ ................................ .................... 50 Endurance Aerobic Exercise ................................ ................................ ........................... 51 Resistance Exercise ................................ ................................ ................................ ......... 51

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6 Summary ................................ ................................ ................................ ................................ 53 3 MATERIALS AND METHODS ................................ ................................ ........................... 55 Group Assignments ................................ ................................ ................................ ................ 55 Prehypertensive Participant Eligibility Crit eria ................................ ................................ ...... 56 Inclusion Criteria: ................................ ................................ ................................ ............ 56 Exclusion Criteria: ................................ ................................ ................................ ........... 56 Normotensi ve Control Participant Eligibility Criteria ................................ ............................ 56 Inclusion Criteria: ................................ ................................ ................................ ............ 56 Exclusion Criteria: ................................ ................................ ................................ ........... 56 Laboratory Measurements ................................ ................................ ................................ ...... 57 Visit #1 ................................ ................................ ................................ ............................ 57 Screening ................................ ................................ ................................ .................. 57 Arterial stiffness testing ................................ ................................ ........................... 57 Venous occlusion plethysmography ................................ ................................ ......... 59 Brachial artery flow mediated dilation ................................ ................................ ..... 61 Blood sampling ................................ ................................ ................................ ........ 62 Visit #2: ................................ ................................ ................................ ........................... 63 Skeletal muscle strength testing ................................ ................................ ............... 63 Aerobic capacity testing ................................ ................................ ........................... 63 Resistance exercise training ................................ ................................ ..................... 64 Aero bic exercise training ................................ ................................ ......................... 65 Criteria for termination of exercise tests: ................................ ................................ 65 Possible discomforts and risks ................................ ................................ ................. 66 Vascular measurements ................................ ................................ ............................ 66 Blood draw ................................ ................................ ................................ ............... 67 Biochemical Analyses ................................ ................................ ................................ ............ 67 Vasodilator Production ................................ ................................ ................................ .... 67 Vasoconstrictor Measurement ................................ ................................ ......................... 68 Lipid Peroxidation ................................ ................................ ................................ ........... 68 Antioxidant Capacity ................................ ................................ ................................ ....... 69 Inflammatory Markers ................................ ................................ ................................ ..... 69 Plasma Renin Activity ................................ ................................ ................................ ..... 69 Statistical Considerations ................................ ................................ ................................ ........ 70 Statistical Analysis. ................................ ................................ ................................ ......... 70 Sample S ize Calculation. ................................ ................................ ................................ 71 4 RESULTS ................................ ................................ ................................ ............................... 75 Subject Characteristics before and after Exercise Training or Time Control ......................... 75 Brachial Artery Endothelial Function after Exercise Training ................................ ............... 75 Blood Pressure and Pulse Wave Analysis after Exercise Training ................................ ........ 76 Central and Peripheral Artery Stiffness after Exercise Training ................................ ............ 77 Forearm and Calf Resistance Artery Blood Flow after Exercise Training ............................. 77 Vasoactive Balance ................................ ................................ ................................ ................. 78 Oxidative and Reductive Stress Balance ................................ ................................ ................ 79

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7 Vas odilation and Vasoconstriction Factors ................................ ................................ ............ 80 5 DISCUSSION ................................ ................................ ................................ ......................... 94 Main Findings ................................ ................................ ................................ ......................... 94 Peripheral Resting Systolic and Diastolic Blood Pressure ................................ ..................... 94 Brachial Artery Endothelial Function and Exercise Training ................................ ................ 95 Shear Stress and Mechanical Transduction ................................ ................................ ............ 99 Arterial Stiffness, Pulse Wave Characteristics, and Central Blood Pressure ....................... 101 Peripheral Resistance Artery Endothelial Function and Exercise Training ......................... 106 Vasoactive Balance ................................ ................................ ................................ ............... 107 Conclusions ................................ ................................ ................................ ........................... 111 Limitations and Future Directions ................................ ................................ ........................ 112 LIST OF REFERENCES ................................ ................................ ................................ ............. 113 BIOGRAPHICAL SKE TCH ................................ ................................ ................................ ....... 132

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8 LIST OF TABLES Table page 4 1 Baseline subject characteristics before and after exercise training and time control ........ 81 4 2 Brachial artery flow mediated dilation before and after exercise training and time control ................................ ................................ ................................ ................................ 81 4 3 Pulse wave analysis before and after exercise trai ning and time control .......................... 82 4 4 Pulse wave velocity before and after exercise training and time control .......................... 83 4 5 Forearm and calf ven ous occlusion plethysmography before and after exercise training or time control ................................ ................................ ................................ ...... 83

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9 LIST OF FIGURES Figure page 3 1 Ascending aortic pressure wavefo rm. ................................ ................................ ................ 72 3 2 Hemodynamic parameters derived from pulse wave analysis ................................ ........... 73 3 3 Determination of the pulse wave transit distances from body surface measurements. ..... 74 4 1 Brachial artery flow mediated dilation (FMD) at baseline and after exercise training or time control. Data are expressed as meanSEM; *P<0.05. ................................ .......... 84 4 2 Aortic Augmentation index (AIx) at baseline and after exercise training or time control. Data are expressed as meanSEM. P*<0.05. ................................ ...................... 84 4 3 Aortic augmentation index normalized for heart rate at 75 bpm at baseline and after exercise training or time control. Data are expressed as meanSEM. P*<0.05. .............. 85 4 4 Wasted left ventricu lar energy (LVEW) at baseline and after exercise training or time control. Data are expressed as meanSEM. P*<0.05. ................................ .............. 85 4 5 Carotid femoral pulse wave velocity (PWV) at baseline and after exer cise training or time control. Data are expressed as meanSEM. P*<0.05. ................................ .............. 86 4 6 Carotid radial pulse wave velocity (PWV) at baseline and after exercise training or time control. Data are expr essed as meanSEM. P*<0.05. ................................ .............. 86 4 7 Carotid radial pulse wave velocity (PWV) at baseline and after exercise training or time control. Data are expressed as meanSEM. P*<0.05. ................................ .............. 87 4 8 Resting calf blood flow at baseline and after exercise training or time control. Data are expressed as meanSEM. P*<0.05. ................................ ................................ ............. 87 4 9 Peak cal f blood flow at baseline and after exercise training or time control. Data are expressed as meanSEM. P*<0.05. ................................ ................................ ................... 88 4 10 Total calf blood flow at baseline and after exercise training or time co ntrol. Data are expressed as meanSEM. P*<0.05. ................................ ................................ ................... 88 4 11 Resting forearm blood flow at baseline and after exercise training or time control. Data are expressed as meanSEM. P*<0.05. ................................ ................................ .... 89 4 12 Peak forearm blood flow at baseline and after exercise training or time control. Data are expressed as meanSEM. P*<0.05. ................................ ................................ ............. 89 4 1 3 Total forearm blood flow at baseline and after exercise training or time control. Data are expressed as meanSEM. P*<0.05. ................................ ................................ ............. 90

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10 4 14 NOx, ET 1, and NOx/ET 1 at baseline and after exercise tra ining or time control. Data are expressed as meanSEM. P*<0.05. ................................ ................................ .... 91 4 15 8 expressed as meanSEM. P*<0.05. ................................ ................................ ................... 92 4 16 Trolox Equivalent Antioxidant Capacity (TEAC) at baseline and after exercise training or time control. Data are expressed as meanSEM. P*<0.05. ............................ 92 4 17 6 expressed as meanSEM. P*<0.05. ................................ ................................ ................... 93 4 18 Angiotensin (ANG II) at baseline and after exercise training or time con trol. Data are expressed as meanSEM. P*<0.05. ................................ ................................ ............. 93

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11 LIST OF ABBREVIATION S 1RM one repetition maximum 8 iso PGF 8 isoprostane A23187 calcimycin, calcium ionophore A23187 ADMA N G ,N G dimethylarginine Akt Akt/pro tein kinase B ATP adenosine triphosphate ATPase adenosine triphosphatase BH4 tetrahydrobiopterin Ca 2+ calcium ion c Src tyrosine protein kinase CRF cardiorespiratory fitness CRP C reactive protein DDAH d imethylarginine dimethylaminohydrolase DETA NO diet hylenetriamine NONOate DMSO dimethyl sulfoxide EDTA ethylenediaminetetraacetic acid eNOS endothelial nitric oxide synthase ET 1 endothelin FAK focal adhesion kinase FOXO forkhead box O GXT graded exercise test hsCRP high sensitivity C reactive protein HM G CoA 3 hydroxy 3 methyl glutaryl coenzyme A IGF 1 insulin like growth factor 1

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12 IL 6 interleukin 6 iNOS inducible nitric oxide synthase LCAT lecit hin cholesterol acyltransferase L NMMA L N G monomethyl arginine citrate MAP mitogen activated protein MAFbx mu scle atrophy F box MCP 1 monocyte chemoattractant protein 1 MuRF1 muscle ring finger 1 B nNOS neuronal nitric oxide synthase NO nitric oxide NOS nitric oxide synthase NOx nitrate/nitrite NOx4 NADPH oxidase 4 O superoxide radical ONOO peroxynitrate PAPA NO propylamine propylamine NONOate p130Cas Crk associated substra te PBS phosphate buffered saline PECAM 1 platelet endothelial cell adhesion molecule 1 PEH post exercise hypotension PI3K phosphoinositide 3 kinase PVDF polyvinylidene difluoride Ras small GTPase related to Ras SH 2 Src homology 2 domain

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13 SOD superoxide dism utase sVCAM 1 soluble vascular cell adhesion molecule 1 TBS tris buffered saline TNF tumor necrosis factor VE cadherin vascular endothelial cadherin VEGFR2 vascular endoth elial growth factor receptor 2

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14 Abstract of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy RESISTANCE OR ENDURANCE TRAINING IS EFFICACIOUS IN DECREASING CENTRAL BLOOD PRESSURES, IMPROVING ENDOTHELIAL FUNCTION AND VASOACTIVE BALANCE IN YOUNG PREHYPERTENSIVES By Darren Thomas Beck December 201 0 Chair: Randy W. Braith Major: Health and Human Performance The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) proposed a new classification of blood pressure level termed prehypertension. Support for the creation of this new classification was based on the greater risk of developing clinical hypertension amongst prehypertensives when compared to normotensives. Prehypertensives are 11 times more likely to develop essentia l hypertension and the resulting cardiovascular risks associated with clinically high blood pressure. Lifestyle modifications, such as the adoption of an appropriate exercise regimen, are the sole recommendations for the treatment and prevention of prehyp ertension and to prevent the progression to stage one essential hypertension. Resistance and endurance exercise training are common and efficacious exercise modalities recommended by the American Heart Association and the JNC 7 for treatment and preventio n of hypertension. Prehypertensives exhibit marked vascular stiffness when compared to normotensive counterparts. The effect of exercise training on arterial function in prehypertensives is grossly underinvestigated. The purpose of this study was to exa mine the effect of resistance and endurance aerobic exercise training on conduit arteries, muscular arteries, and microvascular vessels in prehypertension. This study was

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15 conducted at the Center for Exercise Science, College of Health and Human Performanc e, University of Florida. The study was designed to be a prospective randomized and controlled study. A total of 45 healthy prehypertensive (SBP = 120 139 mmHg; DBP = 80 89 mmHg) men and women (n=45) 18 35 years of age met screening requirements and participate d in the intervention phase of the study. Subjects were randomly assigned to either a resistance exercise training group (n=15), endurance exercise training group (n=15) or a control group (n=15). The training groups (n=30) performed exercise training 3 days per week. The control group (n=15) was instructed to refrain from initiating structured exercise training programs during the study. Duration of the exercise program was 8 weeks. We hypothesized that 8 weeks of resistance or endurance tr aining alone would decrease arterial stiffness, increase limb blood flow, and reduce both central and peripheral blood pressure in young healthy prehypertensive subjects. To test our hypothesis, pulse wave velocity in the aorta, femoral, and brachial arte ries and aortic augmentation index was measured using applanation tonometry at study entry and after 8 weeks of resistance or endurance exercise training. Large artery endothelial function was measured in the brachial artery using ultrasound and the flow mediated dilation technique. In addition, the endothelial function of the micro vascular arterioles was assessed using reactive hyperemia and venous occlusion plethysmography.

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16 CHAPTER 1 INTRODUCTION Background Prehypertension Defined Hypertension is a ma jor antecedent to stroke, heart failure, and end stage renal disease. It is estimated that one in every three U.S. adults has high blood pressure, and approximately 25% of the U.S. population 20 yr or older has prehypertension. 1, 2 The estimated direct cost of the high blood pressure for 2009 was $73.4 billion U.S. do llars. 1 Of the adults with hypertension, only 31% h ad it under control with pharmacological treatments. 1, 3 Prehypertension is a categorical description used by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institute of Health (NIH) the American Heart Association, and the Center for Disease Control to categorize people with an increased resting blood pressure slightly above normal (<120/80). 4 Prehypertension is defined as untreated systolic blood pressure of 120 to 139 mmHg or diastolic blood pressure of 80 to 89 mmHg and not having been told on tw o occasions by a doctor or other health care professional that one has hypertension 3 Recent publications estimate there are currently 54 million Americans over the age of 20 that can be classified a s prehypertensive and are 11 times more likely to develop essential hypertension. 5 8 Prehypertension is associated with a 27 % increase in all cause mortality and a 66% increase in cardiovascular disease mortality when compared to normotensives. Compared with normal blood pressure (<120/80 mm Hg), prehypertension was associated with a 1.5 to 2 fold risk for major cardiovascular disease events in those <60, 60 1, 3, 9 Prehypertension is considered a self accelerating condition in which development of arteriolar hypertrophy and endothelial dysfunction hasten the transition to essential hypertension (EH). 10 Individual s with prehypertension demonstrate marked vascular stiffness. 10 It has also been

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17 reported that prehypertension is associated with increased abn ormal blood lipid profiles, c contribute to increased arterial stiffness and endothelial dysfunction. 8, 11, 12 In a recent public ation, Wang et al. report a stepwise increase in the vasoconstrictors (ANGII, AVP, ET) and a stepwise decrease in the vasodilators (CGRP and SOD) across three blood pressure categories from normotensive to prehypertensive and finally hypertension 13 Vascul ar stiffness is a known precursor to development of EH and isolated systolic hypertension (ISH) similarly, vascular stiffnes s is implicated as one of the major contributing factors for the development of hypertension in prehypertensives. 14, 15 According to the NHLBI report from the Joint National Committee on Prevention, Detection, Evaluation, and Treatme nt of High Blood Pressure (JNC7), prehypertension is not a disease category and individuals with prehypertension are not candidates for drug therapy. 4 Rather the JNC 7 recommends that people with prehypertension practice lifestyle modifica tion to prevent the progressive rise in blood pressure and increased risk of cardiovascular disease. 4 The cornerstone of these modifications is the participation in structured and regular physical activity for the treatment of prehypertens ion and prevention of hypertension. Exercise and Prehypertension Endurance exercise training has been shown to reduce both systolic and diastolic blood pressure 8 to 17 mmHg and 6 to 13 mmHg in hypertensives respectively and continues to be recommended to all people as a primary intervention to maintain normal blood pressure and reduce risk of future cardiovascular disease. 16 Higashi et al. reported tha t aerobic exercise improves endothelial function in humans with hypertension. 17 E ndurance exercise results in impr oved expression and activity of vascular eNOS and antioxidant enzymes influencing nitric

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18 oxide bioavailability and improves endothelial function in coronary arteries and peripheral resistance vessels. 18, 19 While the study of exercise and blood pressure has been overwhelmingly focused on endurance training, the effects of resi stance training and blood pressure remains underinvestigated. The American Heart Association and the American College of Sports Medicine recommend resistance exercise but only as a compliment to a regular aerobic training program. Resistance exercise tr aining is a common and well accepted exercise modality that has been implemented into exercise prescriptions in various populations to help improve muscular strength and increase muscle mass. 20 It is efficacious in attenuating osteoporosis and sarcopenia 21, 22 Levels of muscular strength and cardiorespiratory fitness were examined in prehypertensives and the incidence of developing hypertension decreased by 45% with increased muscular strength and cardiorespi ratory fitness when compared to low fitness. 23 Further, muscular strength is inversely associated with the development of essenti al hypertension in prehypertensives regardless of cardiorespiratory fitness level. 23 Moreover, it has been shown to effectively reduce cardiovascu lar risk factors, such as hyperinsulinemia, dyslipidemia, and hypertension. Indeed, in a study by Carter et al. 24 8 weeks of resistance exercise training resulted in decreases in both systolic and diastolic blood pressure by 9 and 8 mmHg respectively in young prehypertensive subjects In a recent study of the effect of resistance exerc ise training on the blood pressure response during a submaximal aerobic exercise test it was shown that not only was the blood pressure response to increasing workloads attenuated but cardiovascular function during the test was improved. 25 Resistance exercise also reduces central blood pressure, improves microvascular function, and increases blood flow to muscles. 26 Acutely, a single bout of mild to moderate exercise can lead to a postexercise decrea se in blood pressure in

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19 hypertensive individuals, called postexercise hypotension (PEH). PEH can last for up to 13 hours in humans and could be an effective nonpharmacologic antihypertensive strategy. 27 Anatomy of the Arterial System The arterial system is composed of arteries that vary in size and function that work together to maintain blood flow throughout the body. Large elastic arteries of the central circulation, such ejected from the left ventricle during systole. The ability of the aorta to expand allows for a temporary storage of blood during systole. In turn, the elastic recoil durin g diastole allows for a continuous blood flow in the peripheral circulation. Blood flow pushed into the peripheral circulation is transported through muscular conduit arteries, such as the femoral and brachial arteries. M uscular conduit arteries have the ability to alter smooth muscle tone and therefore, modify the speed of the pressure waves. This is commonly referred to as pulse wave velocity. Lastly, the small arterioles or resistance vessels, transport and control bl ood flow into tissues. These vessels are thought to control mean arterial pressure by altering their diameter. Overall, the various types and regions of arteries function to maintain a relatively constant perfusion pressure and flow at the capillary leve l. Consequences of Arterial Stiffness Large artery stiffness is an important determinant of cardiovascular risk, including myocardial infarction and heart failur e and has recently been related to cardiovascular mortality. 28 Increased central arter ial stiff eness occurs with agin g and in certain disease states including diabetes, hypertension, atherosclerosis, and end stage renal failure. 29 Aortic stiffness measured by pulse wave velocity is i ncreased by approximately 2 fold between the ages of 20 and 80 years. 30 Interestingly, the stiffening seen with aging appears to be limited to the central large elastic arteries (i.e. aorta), as muscular peripheral arteries do not seem to b e affected with

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20 aging. 30, 31 However, stiffening throughout the arterial system m ay occur in various disease states. Changes in arterial stiffness can be detected before the appearance of overt vascular disease, and may act as a marker for the development of future atherosclerotic disease. Arterial stiffening in either elastic or musc ular vessels can lead to altered blood flow. Additionally, increased vessel stiffness increases the propagation velocity of pressure (and flow) waves in the arterial system. When the primary or forward pressure wave encounters changes in vessel stiffness or diameter, such as at branch points or at the interface with the resistance vessels, a portion of the wave is reflected back toward the heart. Augmentation index is the augmented pressure divided by the pulse pressure. In young healthy individuals the resulting closure, where it augments coronary perfusion pressure. However, with increased arterial stiffness, the reflected wave returns to the heart prematurely w here it progressively overlaps systole. Increases in arterial stiffness, regardless of etiology, cause the reflected wave to return progressively earlier and with greater amplitude during systole resulting in augmentation of left ventricular and aortic pr essure, and cardiac work. 32 The measurement of this increased time under pressure is referred to as the augmentation index and this relationship is altered by changes i n heart rate. Augmentation index decreases approximately 5.6% for every 10 bpm increase in heart rate. This decrease is due to the decrease in left ventricular ejection duration which accompanies the rise in heart rate. Augmentation index is increased w ith a reduction in heart rate. An increase in central aortic stiffness alone causes only minor changes in ascending aorta pressure wave contour when compared to increases in stiffness in peripheral arteries. 32 Movement of the reflected wave from diastole into systole does not affect mean arterial pressure

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21 when averaged across the entire cardiac cycle, but it does result in a higher average pressure during systole and a lower average pressure during diastole. The increased systolic pressure loads the heart and is reported as an increase in augmentation index. Furthermore, the late pressure peak produces a proportionate decrease in ventricular outflow and a reduction i n stroke volume. This necessitates an increase in heart rate, which further limits the coronary perfusion pressure time integral resulting in the unfavorable combination of increased LV work load and myocardial oxygen consumption, and diminished perfusion pressure. Endurance Exercise and Arterial Function Strategies that lower arterial stiffness include pharmacological management and lifestyle changes such as weight reduction, dietary modifications, and exercise. The role of endurance exercise on arteria l function has received a considerable amount of attention. Cross sectional studies have suggested that regular endurance exercise has a beneficial effect on arterial function in various populations. 33 35 The first prospective study to examine the effect of endurance exercise on arterial function demonstrated that 30 minu tes of cycling at 65% of VO 2max three times per week for 4 weeks resulted in a 30% improvement in systemic arterial compliance (opposite of stiffness) in healthy young males. 36 Likewise, Tanaka et al. 35 showed that regular endurance exercise over a 3 month period restores central arterial compliance levels in previously sedentary healthy middle aged and ol der men. Three months of endurance exercise training has also been shown to decrease arterial stiffness in clinical populations such as patients with coronary artery disease 37 and in hemodialysis patients. 38 Interestingly, after one month of detraining, arterial stiffness reverted to pre exercise levels. These results as well as others indicate that endu rance exercise training likely has a positive effect on arterial stiffness. Aerobic exercise decreases the sensitivity of norepinephrine induced contraction in aortic rings directly related to increased levels of AT2 receptors. 39 Adams et al. reports a concomitant decrease in

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22 AT1 and an increase in AT2 receptor mRNA following 4 weeks of exercise training as w ell as a diminished mRNA expression of oxidases involved in large amounts of ROS production including gp91phox, Nox4, and p22phox. 40, 41 The combination of these factors resulted in a decrease in the vasoactive net effect of angiotensin II, a reduction in radical oxygen species production, and improv ed endothelial function. Resistance Exercise Training and Arterial Function The effects of resistance training on the arterial vasculature are underinvestigated and largely unknown. Notwithstanding, the American Heart Association, American Diabetes Assoc iation, American College of Sports Medicine, and the JNC 7 all recommend resistance training but only as a compliment to a regular aerobic training program. Some researchers report very promising beneficial effects of a resistance exercise training progra m on blood pressure and blood vessel function. A strong, inverse and graded association between exercise capacity and all cause mortality was observed in prehypertensive individuals. 42 Moreover, it was reported that the protective effects of increased exercise capacity in preventing all cause mortality was greater in the younger prehypertensives versus the older group. 42 Resistance exercise training improves exercise capacity, attenuates the blood pressure response to the increasing workloads, and improves cardiovascular function during graded exercise testing. 25 Blood pressure variation (BPV) is increased with hypertension. Four weeks of Resistance exercise training reduced blood pressure variation significantly from baseline and reductions in blood pressure were equal to those reported for the endurance aerobic training group. 43 Prehypertensives exhibit markedly increased central blood pressures significantly greater than age and gender mat ched normotensives. 10 These increased central pressures can be accounted for, in large part by the increased arteriolar hypertrophy and arterial stiffness reported with prehypertension. 10

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23 Significant reductions in central blood pressure, both carotid and aortic were reported after 6 weeks of resistance exercise training in normotensives. 26 Heffernan et al. also report significant increases in fo rearm blood flow and shear rate as well as reductions in forearm vascular resistance following 6 weeks of resistance training. 26 Further, these positive vascular effects remained after 4 weeks of detraining. This study demonstrates that resistance training not only improves microv ascular function and increases limb blood flow but the improvements are maintained following at least 4 weeks of detraining. 26 These data may suggest that the beneficial effects of resistance training are not transient but rather a lasting adaptation. Evidence to support the cl aim of vascular adaptation in the microvasculature has been reported following only 4 weeks of resistance training in prehypertensives 44 Prehypertensive men with lower high density lipoprotein (HDL C) levels present with increased carotid artery st iffness, fasting blood glucose, body fat, and lower cardiorespiratory fitness when compared to prehypertensive men with higher HDL C. 45 Further, the detrimental effects of lower HDL C levels on large art ery stiffness appear to be mediated by inflammation and not cardiorespiratory fitness or body fat levels. 45 When comparing chronic resistance exercisers to matched non resistance trained subjects there i s no difference in carotid artery stiffness and carotid compliance when normalized for relative mean arterial blood pressure. 46 Resting carotid medial thickness and car otid diameter were not different between groups. However, high density lipoprotein (HDL C) was increased in the resistance training group, while all other cholesterol values remained similar when compared to their matched peers. It should also be noted t hat bodyfat percentage of the resistance training group was significantly reduced. 46 Both low levels of HDL C and increased body fatness have been implicated as increas ed risk factors for increased vascular stiffness.

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24 To date and to our knowledge, only two prospective interventional studies have examined the effect of both endurance and resistance exercise on vascular function in prehypertension subjects The noninv asive techniques of vascular measurement utilized in our cardiovascular laboratory offer the unique ability to further characterize and determine the common mechanisms responsible for improved vascular function antihypertensive effects of resistance traini ng. For the first time, to our knowledge, we will study the separate effects of 8 weeks of resistance exercise training and endurance aerobic exercise training on arterial function in a group of y oung healthy prehypertensives and compare these results to a n age and gender matched group of normotensives Specific Aims and Hypotheses Specific aim 1 : Determine whether resistance exercise training alone results in decreases in aortic, femoral, and brachial stiffness and arterial wave reflection after 8 weeks of training in prehypertensives. Hypothesis 1: W hole body resistance training 3 day s per week for 8 weeks will decrease large artery stiffness resulting in altered arterial wave reflection and reductions in pulse wave velocity in prehypertensives Speci fic aim 2: Determine whether changes in arterial stiffness are similar after 8 weeks of resistance exercise when compared to 8 weeks of endurance training in prehypertensives Hypothesis 2: W hole body resistance training 3 days per week for 8 weeks will be equally beneficial to reducing arterial stiffness as measured using pulse wave analysis when compared to equal amounts of endurance training in prehypertensives Specific aim 3: Determine whether resistance or endurance exercise training causes chang es in limb blood flow after 8 weeks of training in prehypertensives.

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25 Hypothesis 3: W hole body resistance training as well as endurance training 3 days per week for 8 weeks will increase resting and peak limb blood flow in prehypertensives. Specific aim 4: Determine whether changes in arterial stiffness are accompanied by commensurate changes in central and peripheral blood pressures. Hypothesis 4: W hole body resistance training as well as endurance training 3 days per week for 8 weeks will red uce both central and peripheral blood pressures. Specific aim 5: Determine whether changes in arterial stiffness are accompanied by commensurate changes in vasoactive agents, inflammat ory factors, and lipid profile. Hypothesis 5: W hole body resistance training as well as endurance training 3 days per week for 8 weeks will have beneficial effects on the plasma levels of vasoactive agents, inflammatory factors, resting glucose, and lipid profile.

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26 CHAPTER 2 LITERATURE REVIEW Prehypertension The st udy of prehypertension in the young and otherwise healthy offer s the unique opportunity to study the effects of hypertension without the complicating factors associated with aging, chronic and persistent hypertension, and the structural and physiological c hanges as sociated with chronic disease. Prehypertension is a categorical description put forth by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institute of Health (NIH) describing people with an increased resting blood pressure sl ightly above normal (<120/80). Prehypertension is defined as untreated systolic blood pressure of 120 to 139 mmHg or untreated diastolic blood pressure of 80 to 89 mmHg. 4 People with prehypertension are more prone than normotensive subject s to develop diabetes, and this proclivity may reflect the decreased ability of insulin to promote vascular smooth muscle cell relaxation and glucose transport to skeletal muscle tissue respectively. 47 Recent publications estimate there are currently 70 million Americans over the age of 20 that can be classified as prehypertensive and are 11 times more likely to develop essential hypertension. Prehypertension is associated with a 27% increase in all cause mortality and a 66% increase in cardiovascular disease mortality when compared to normotensives. 5, 6, 8 Prehypertension is considered a self accelerating condition in which development of arteriolar hypertrophy and endothelial dysfunction facilitates the transition to essential hypertension (EH). Individuals with prehypertension demonstrate marked vascular stiffness. 10 Vascular stiffness is a known precursor to development of EH and isolated systolic hypertension (ISH) and has been implicated as one of the major contributing factors for the development of hypertension in prehypertensives. 14, 15 It has also been reported that prehypertension is

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27 associated with increased abnormal blood lipid profiles, c rea ctive protein (CRP), tumor nerosis stiffness and endothelial dysfunction. 8, 11, 12 In a recent publication, Wang et al. reported a stepwise increase in the vasoconstrictors (ANGII, AVP, ET 1) and a stepwise decrease in the vasodilators (CGRP and SOD) across three blood pressure categories (normotensive, prehypertensive, and hypertensive) 13 According to the NHLBI report from the J oint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7), prehypertension is not a disease category and individuals with prehypertension are not candidates for drug therapy. 4 Further, the JNC 7 report advises all people with prehypertension to practice lifestyle modification to prevent the progressive rise in blood pressure and increased risk of cardiovascular disease. 2, 4 The greater prevalence of risk factors of a large cohort from the NH ANES study in prehypertensive vs. normotensives suggests the continued need for early clinical detection and intervention of prehypertension and comprehensive preventative and public health efforts. 5 In 2004, Greenlund et al. repeated this call for an increase in the need for early clinical detection and intervention of prehypertension and comprehensive preventative and pub lic health efforts following a study of prehypertensive and normotensive subjects in a study that tracked increased risk factors associated with prehypertension in a large cohort (n=1088) from the NHANES trial. 5 The cornerstone of these modifications is the participation in structured and regular physical activity for the treatment of prehypertension an d prevention of hype rtension. Most studies designed to elucidate the beneficial effect of exercise and physical fitness have focused on those which are brou ght about by aerobic exercise. What follows is a current review of the effect of resistance training on blood pressure and arterial function.

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28 Prehypertension and Resistance Training Prehypertensives not only have an increased risk of hypertension and future cardiovascular disease but are also at an increased risk for developing Type II Diabetes. 48 Increased physical fitness reduces the likelihood of prehypertensives developing essential hypertension. 23 A strong, inverse and graded association between e xercise capacity and all cause mortality was observed in prehypertensive individuals. The protective effects of increased fitness were more pronounced in younger than older individuals. 42 Moreover, they reported that the effects of increased exercise capacity in preventi ng all cause mortality were greater in the younger prehypertensives versus the older group. L evels of musc ular strength and cardiorespiratory fitness were examined in prehypertensives and the incidence of developing hypertension decrease d by 45% with incr eased muscular strength and cardiorespiratory fitness when compared to low fitness 23 Further, muscular strength is inversely ass ociated with the development of essential hypertension in prehypertensives regardless of cardiorespiratory fitness level. 23 A study of therapeutic lifestyle modification in prehypertensives supports the JNC7 recommendations for lifestyle modification as the first line intervention to reduce blood pressure and the risk factors associated with prehypertension. 49 In that study, a large cohort of prehypertensives (n=2478) participated in community based programs implementing therapeutic lifestyle changes. These community pr ograms targeted changes in nutrition, weight management, stress management, smoking cessation, and exercise training interventions. Resting blood pressures were reduced in both resting systolic and diastolic blood pressure by an average of 7 and 6 mmHg r espectively. 49 Prehypertensives exhibit markedly increased central blood pressures when compared to matched normotensives. I ncreased central pressures can be attributed to, in large part, the increased arteriolar hypertrophy and arterial stiffness re ported with prehypertension. Blood pressure variation (BPV) is increased with hypertension. Four weeks of Resistance exercise

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29 tr aining reduced blood pressure variation significantly from baseline and equal to the reductions reported for the endurance aerobic training group. 43 It should also be noted that peripheral systolic and diastolic blood pressures were also significantly decrea sed in both groups but the decreases wer e not different between groups. Significant reductions in central blood pressure, both carotid and aortic were reported after 6 weeks of resistance exercise training. 26 Heffernan et al. also report significant increases in forearm blood flo w and shear rate as well as reductions in forearm vascular resistance following 6 weeks of resistance training. Further, these positive vascular effects remained after 4 weeks of detraining. Resistance training not only improves microvascular function an d increases limb blood flow but the improvements are maintained at least 4 weeks of detraining. 26 These data suggest that the beneficial effects after resistance training are not a trans ient but a lasting adaptation. T he results of Heffernan and coworkers were replicated in the b lood flow and microvasculature data reported in prehypertensives following only 4 weeks of resistance training. 23, 26, 44 An increased vasodilatory capacity was observed following 4 weeks of resistance training in previous ly sedentary subjects. 44 Peak blood flow and total blood flow, measured using plethysmograph, was increased in the resistance training group. These improvements were significantly greater than the increases reported in the aerobic endurance trainin g group. Since these blood flow measurements are indicative of the vasodilatory capacity of the resistance vessels and are due to factors such as nitric oxide availability, it is possible that resistance training may upregulate nitric oxide signaling to a greater extent than aerobic training leading to a greater increase in limb blood flow after four weeks of training. The present study is designed to help answer this question.

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30 There is evidence that resistance training can elicit vascular adaptations sim ilar to changes that were previously found primarily following chronic aerobic endurance training. Resting brachial diameter and peak blood flow after occlusion increased following 12 weeks of resistance exercise. 50, 51 In a study of unilateral strength training in previously sedentary subjects brachial artery resting diameter was increased an average o f 5.5% in the trained arm with no change in the untrained arm following 12 weeks of isometric resistance training. 51 In this study b rachial artery diameter and cros s sectional area of the biceps brachii were measured using magnetic resonance imaging (MRI). 51 The increase in resting diameter suggests a unique adaptation cause d by resistance training that may be mediated by persistent chemical stimuli that affect arterial tone (NO, ET 1, ANGII). 51, 52 Increased post occlusion blood flow suggests increased capillary or arteriolar proliferation, or enhanced resistance vessel endothelial function. It should also be noted t hat peak and average shear rate were unchanged suggesting that the increase in blood flow maintains the tonic shear rate in the face of increased resting vessel diameters 52 L arger resting diameters results in less diameter change post occlusion and not necessarily a lack of improvement in endothelial function Further, endothelial function seems to b e improved due to increa sed flow and baseline diameters. 52 This is not surprising cons idering the subjects were young healthy, and normotensive and were already exhibiting normal, some may consider, optimal endothelial function at baseline Brachial arteries are large conduit arteries and may not necessarily represent the increase in endothelial fu nction of smaller arteries and arterioles which are more responsib le for blood pressure changes. Simply, f low mediated dilation, peak shear rate, and average shear rate did not change from baseline. It could be said that endothelial function did not chan ge following 12 weeks of resistance exercise. Brachial artery diameter change due to re active hyperemia is determined relative to the resting diameter

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31 and the lack of change may be a result of the larger relative resting vessel caliber. Endothelial funct ion did not increase after 12 weeks of resistance training in young, healthy, normotensive males possibly due to the fact that these subjects optimally dilate because they exhibit good endothelial function. In a study by Ray et al. isometric handgrip train ing improved endothelial function and decreased resting arterial blood pressure without altering sympathetic nerve activity or resting heart rate 53 This improvement in endothelial function may have been due to the upregulation of eNOS and the subsequent increase in the production and release of endothelial derived NO This is important in prehypertension because arterial stiffness and decreased endothelial function both lead to increased blood pressure in this group. Carter et al. found that 8 weeks of resistance exercise training in previously untrained prehypertensives resulted in decreases in both systolic and diastolic blood pressure by 9 and 8 mmHg respectively. 24 These peripheral blood pressure reductions were not accompanied by changes in muscle sympathetic nerve acti vity (MSNA) This is contrary to the belief that chronic resistance training results in an increased basal level of sympathetic outflow and noradrenalin. It should be noted that nitric oxide decreases sympathetic outflow at the prejunctional level and NO may exert a tonic inhibitory influence on the discharge of sympathetic efferents. 54, 55 Kawano reported no differences in the vasoactive response of the carotid arteries to a cold pressor test between chronic resistance trained and the no n resistance trained subjects. 46 The response of conduit arteries to systemic cold may be a result of the balance between adrenergic vasoconstriction and vasodilation, with the latter being mediated by en dothelial function. 56 Therefore, the endothelial function, via NO, may play an important role

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32 in changing the conduit artery diameter response to a sympathetic st imulation by cold pressor test. Further support for the improvement of e ndothelial function following resistance training was found by Vona et al. in a study of coronary artery disease patients with endothelial dysfunction. 57 Four weeks of Resistance exercise training significantly improved endothelial function measured using the flow mediated dilation technique. 57 Moreover the large significant beneficial effects of resistance exercise did not differ from the improvements reported for the endurance aerobic training group. 57 When comparing chronic resistance exercisers to matched non resistance trained subjects there is no difference in carotid beta stiffness and carotid compliance when normalized for relative mean arterial blood pressure. 46 Resting carotid medial thickness and carotid diameter were not different between groups. However, high density lipoprotein (HDL C) was increased in the resistance training group, while all other cholesterol values remained similar when compared to their matched peers. It should also be noted that bodyfat percen tage of the resistance training group was significantly reduced. 46 Prehypertensive men with low HDL C levels have increased carotid artery stiffness, fasting blood gluc ose, body fat, and lower cardiorespiratory fitness when compared to prehypertensive men with high HDL C. 45 Further, the detrimental effects of lower HDL C levels on large artery stiffness appear to be me diated by inflammation and not cardiorespiratory fitness or body fat levels. 45 Resistance training significantly increases HDL C levels greater than endurance training. 58 CRP levels were decreased significantly following 10 weeks of resistance training in previously sedentary subjects without changes in IL 6 o r body composition. 59 Levels of CRP were unchanged in the endurance trained group. In this study of sedentary but otherwise healthy

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33 subjects (n=102) baseline CRP and IL 6 concentrations were elevated where as blood lipid and glycemic index we re both normal. 59 Presumably the increases in the markers of chronic systemic inflammation were a result of the sedentary lifestyle of the subjects as opposed to another as yet und iagnosed disease or condition. In this study, there was a tre nd towards an increase in HDL C in the resistance trained but not the endurance trained group Hypertension as determined from standard brachial artery sphygmomanometry is a well established cardiovascular risk factor However, peripheral blood pressur e measurements, obtained by standard brachial artery (cuff) techniques, are not always a reliable measure of ascending aorta pressure. 60 In fact, data from The Strong Heart Study have shown that non invasively obtained central arterial pressure is more strongly related to cardiovascular outcomes. 61 The noninvasive techniques and technologies for vascular measurement utilized in our cardiovascular laboratory will provide the unique ability to further characterize and determine the com mon mechanism of the improved vascular function responsible for the blood pressure reducing effects associated with chronic resistance training. Resistance exercise training improves exercise capacity, attenuates the blood pressure response to the increas ing workloads, and improves cardiovascular function during graded exercise testing. 25 When comparing chronic resistance traine rs to age, gender, and blood pressure matched non resistance traine rs an acute bout of resistance exercise impaired the endothelial function in the unconditioned subjects whereas, the chronic resistance trained subjects endothelial function remain ed unchanged. This suggests th at chronic resistance training protects against this transient vascular dysfunction and that training protects against the adverse affects of a resistance load in hypertensives. 62 This study also suggests a period of adjustment when beginning a resistance exercise training program and this early period may represent the steep part of the benefits curve

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34 in terms of increased vascular functio n and inexact measurements made of arterial function during this period may represent them as being similar to arterial stiffness. Sinoway et al. reported an attenuated sympathetic response and decreased arterial pressure during dynamic handgrip exercise after forearm resistance training. 63 This may also explain the transient arterial stiffness reported, by a few investigators, when measurements are made in previously sedentary subjects, especially after beginning a high intensity resistance training program an d having measurements of arterial stiffness after a short period following baseline. In this proposal, we hypothesize that one p ossible mechanism for improved blood pressure changes in prehypertensives is due to increase d resting vessel diameter and improv ed blood flow due to increased endothelial function and a decrease in tonic vasoconstriction following 8 weeks of resistance training. Shear Stress The intermittent increase in pressure during resistance training results in an increase in shear stress alon g the intimal wall of the arteries. It may be this increased shear stress which is the mechanism by which resistance training is efficacious in lowering blood pressure by improving arterial function similar to the effects of endurance training. Recently, a study of the acute pressure effects of resistance training, with and without breath holding, reported an increased range of blood pressures during resistance training similar to those of endurance exercise. 64 In fact, according to Tinken and Green, resistance exercise induced alterations in shear stress are responsib le for the improved endothelial function and vascular remodeling associated with in response to resistance exercise in human subjects. 65 Improvement in endothelial dysfunction with exercise is not mediated by changes in cardiovascular risk factors but is, in fact, an independent adaptation to exercise and shear stress. 66 Shear rate during leg exercise in the young is nearly twice that which is produced in the old. 67 Increased conduit

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35 artery wall thickness, a rapid adaption to physical inactivity, is abolished with resistance exercise in humans during 60 days of bedrest. 68 Mechanical Transduction The cytoskeleton has a c entral role in the transmission of tension changes mediated by shear stress, throughout the cell in the decentraliz ed model of endothelial mechanotransduction 69 Direct signaling can occur through deformation of the luminal surfac e. L ocalized activation of potassium, sodium and calcium ion channel s, phospholipase activity leading to calcium signaling, G protein activation and caveolar signaling all work in concert Mechanotransduction is also mediated via junctional signaling Junctional signaling is the transmission of forces to intercellular jun ction protein complexes via the cortical and/or filamentous cytoskeleton. Vascular endothelial growth factor ( VEGFR2 ) located at the luminal surface or near the ju nction can associate with VE catenin, and p hosphatidylinositol 3 kinase to phosphorylate Akt and the primary transmem brane protein at this location. Cytoskeletal forces are also transmitted to adhesion sites. Transmembrane integrins bound to t he extracellular matrix serve as a focus for deformation. This deformation results in autophosphorylation of FAK, which binds the SH2 domain of c Src, a kinase family that phosphorylates paxillin and p130cas and leads to integrin dependent activation of MA P kinases via Ras GTPase. A second parallel integrin mediated pathway involves the activation of Shc, which binds Src family kinases through SH2 domains. Shc phosphorylation leads to Ras MAP kinase activity.81 Ras releases the trans acting NF s cytosolic inhibitor, and thus enables its translocation to the nucleus where it binds to the promoters of multiple target genes. A third integrin mediated pathway involves rhoA activation, wh ich profoundly influences actin assembly and, theref ore, transmission of mechanical stimuli. Nuclear deformation is also likely to result in mechanically induced signaling

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36 Nitric Oxide The free radical Nitric Oxide (NO ) is one of the most ubiquitous signaling molecules in mammalian biology and particip ates in virtually all cellular and organ function in the body. Physiological levels of NO produced in endothelial cells are essential for regulating the relaxation and proliferation of vascular smooth muscle cells, leukocyte adhesion, platelet aggregat ion, angiogenesis and thrombosis. The role of NO in the cardiovascular system has been extensively studied. NO regulates cell metabolism, insulin signaling and secretion, vascular tone, and immune system function. Therefore, the synthesis of NO is es sential for vasodilation, the maintenance of blood pressure and glucose uptake, and, if levels of NO are decreased, insulin resistance and hypertension will result. In addition, NO serves as a neurotransmitter, decreases sympathetic outflow at the preju nctional level, and may exert a tonic influence on the discharge of sympathetic efferents. 54, 55 Endothelium derived NO is continuously synthe sized from one of the guanidine nitrogen atoms of the amino acid L arginine utilizing the endothelial isoform of nitric oxide syntha se (eNOS) in two successive reactions 70 The principal mechanism for the production of NO is shear stress along the wall of endothelial cells Agonists such as acetylcholine and bradykinin bind to receptors on endothelial cells causi ng the release of NO 71 73 Both shea r stress mediated and agonist mediated production of NO function by increasing endothelium intra cellular calcium, which binds to an inactive eNOS complex releas ing the active eNOS molecule. Shear stress activates tyr osine kinase (TK). TK activates phosphoinositide 3 kinase (PI 3 kinase). Akt is phosphorylated and activated by PI3 kinase. Akt kinase activates eNOS by directly phosphorylating the enzyme Ser1179. This non receptor dependen t reaction utiliz es constitu tive Ca 2+ /calmodulin dependent enzymes and is therefore a calcium dependent reaction. 70 This substrate/enzyme reaction yields one NO molecule and L citrulline as a byproduct. (See Figure 1 1) NO is a labile cytotoxic messenger

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37 mol ecule with primarily paracrine functions and has a short half life of roughly 10 seconds in vivo. 74 NO is rapidly oxidized forming nitrite and then nitrate by oxygenated hemoglobin and is eventually excreted in the urine. 74 Because NO is a free radical itself, and readily undergoing change and breakdown it is extremely reactive and susceptible to scavenging by other reactive oxygen species (ROS). Therefore, NO production/turnover/bioavailability is assessed by measuring nitrates and nitrates in human plasma. Nitric oxide synthase (NOS) inhibition in the brachial artery of hypertensive patients is less effective on basal forearm flow compared with normotensive subjects. 75 This evidence suggests that the basal release of NO by the endothelial cells is deficient in those with hypertension. Further, NOS inhibition in type 2 diabetics versus healt hy controls demonstrated that NO is required for glucose uptake during exercise. 76 Moreover, glucose uptake was increased in primary skeletal muscle cells from healthy individuals when the NO donor sodium n itroprusside was administered. 77 Endothelial dysfunction is associated with increased cardiovascular events and is defined by decreased NO bioavailability and endothelial dependent vasodilation. Decreased NO bioavailability can be due both to a decrease in NO synthesis and a n increase in the formation of the superoxide radical (O ) which react s with NO forming the extremely reactive radical peroxinitrate (ONOO ). Proper functioning endothelium continuously produces NO which is important in maintaining resting vascular tone 71 Increased production above basal levels is stimulated in 2 ways: shear stress mediated and agonist mediated. Mechanical shear stress or pulsatile laminar flow along the endothelial wall causes the synt hesis and release of NO and is an important local mechanism for the maintenance of vascular tone 78

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38 Endothelial dysfunction is often a term used to define a decrease in NO bio availability. As well as being an important vasodilator, NO also plays a role in preventing plaque formation by suppr essing leukocyte and platelet activity and inhibiting smooth muscle proliferation. Decreased levels of NO would promote a vascular environment more prone to plaque formation as well as vasoconstriction. Endothelial dysfunction is seen in patients with c oronary and peripheral vascular disease as well as people with conventional cardiovascular risk factors 79, 80 and is an independent predictor of cardiac events 80 We expect NO production to be increased after 8 weeks of e xercise training and this improvement in NO and plasma NOx will be measureable using commercially available kit (Cayman Chemical, Inc.), which converts plasma nitrate to nitrite using nitrate reductase. Oxidative Stress and Redox Balance Reactive Oxygen Species Although the exact mechanism involved in the development of hypertension in prehypertensives is not well understood, oxidative stress may play an important role and elevated markers of oxidative stress can provide indirect evidence for increased production of oxygen free radicals. 81, 82 Reduced availability of NO may occur due to its incre ased breakdown by reactive oxygen species (ROS) especially superoxide ( O 2 ), to form the highly reactive peroxynitrate (OONO ) and leads to increased levels of oxidative stress. ROS is produced in the vasculature by multiple sources including, mitochondr ial electron transport chain (mETC) arachidonic acid pathway enzymes cyclooxygenase and lipoxygenase, cytochrome p450s, xanthine oxidase (XO) nicotinamide dinucleotide (phosphate) oxidase (NAD(P)H) nitric oxide synthase (NOS) peroxidases, and other hemopro teins. Vascular cell production of ROS appears to be predominantly in the XO, NAD(P)H oxidases, and NOS systems. Of these, NAD(P)H oxidases appear to be the predominant source of O 2 production. NAD(P)H oxidase complexes are

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39 membrane bound enzymes presen t in vascular endothelial, smooth muscle, and adventitial cells. They are multi subunit enzymes made up primarily of five phagocytic oxidase (phox) subunits: p47phox, p67phox, p40phox, p22phox, and gp91phox (also termed Nox2). 83 NAD(P)H oxidase catalyzes O 2 production by reducing O 2 by one electron. O 2 is produced in vascular smooth muscle cells in re s ponse to angiotensin II through the stimulation of NAD(P)H oxidases via both angiotensin AT(1A) and AT(1B) receptors and these receptors appear to play a predominant role in the O 2 production induced by ANG II 84 A potent role in the regulation of NAD(P)H ox idase production of O 2 occurs through transcriptional regulation of oxidase subunits and stimulation of signaling pathways involving c Src p21 Ras protein kinase C, phospholipase D, and phospholipase A 2 83 Prehypertension has been associated with oxidative stress markers which are linked to the atherosclerotic process and endothelial dyfunction 82, 85, 86 Endothelial dysfunction correlates well with the production of superoxide anions and this increase in ROS precede d the onset of hypertension in a study of young prehypertensive spontaneously hypertensive rats. 87 Prehypertension has been identified as one of the risk factors for developing hypertension and oxidative stress may be the common denominator in the development of hypertension in pr ehypertensives. 4, 82 Oxidative stress has been reported to enhance arteriolar tone and elevation of arterial resistance and pressure. 88 Indeed, Sathiyap riya et al., reported increased oxidative stress in prehypertensive non obese males. 86 Levels of malondialdehyde, protein carbonyl, and erythrocyte catalase activities are significantly increased and whole blood reduced glutathione and erythrocyte catalase a ctivities are significantly reduced among the prehypertensive subjects compared to normotensive controls. 86 Th e increase in malondialdehyde and protein carbonyl suggest that oxygen free radicals may already have exerted their cytotoxic effects in

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40 prehypertensives and the decreased levels of catalase observed can result in an increased accumulation of oxygen free r adicals 89 The elevated glutathione peroxidase activity in prehypertensives may be upregulated to combat the excess production of free radicals. 86 We speculate that there will be a decrease in ROS production and that this alteration can be assessed by quantifying the oxidative stress induced lipid peroxidation using an ELISA kit (Assay Designs) which measures 8 iso PGF in human plasma using Antioxidants A ntioxidant s are substance s when present in a low concentration, capable of significantly delaying or preventing oxidation relative to an oxidizable substrate Superoxide dismutase (SOD), catalase, and gluta thione peroxidase are the major enzymatic antioxidants pres ent in the vasculature. SOD catalyzes the dismutation of O 2 to hydrogen peroxide (H 2 O 2 ) and O 2 Extracellular SOD plays an important role in the regulation of oxidative stress in the vascular in terstitium. Produced and secreted by the vascular smooth muscle cells, extracellular SOD works by binding to glycosaminoglycans in the vascular extracellular matrix on the endothelial cell surface and is the main SOD of the different vascular isoforms. R educed glutothione provides reducing equivalents for many biochemical pathways and is largely responsible for the regulation of t he intracellular redox state of vascular cells 90 Glutathione peroxidase reduces H 2 O 2 to H 2 O, lipid peroxides to lipid alcohols and oxidi zes glutathione to glutathione disulfide. Another intracellular antioxidant enzyme, catalase, also reduces H 2 O 2 to H 2 O and molecular oxygen. Catalase is primarily located in cellular peroxisomes and to a lesser extent the cytosol. Catalase is extremely effective in high level where the glutathione peroxidase/glutathione system is important in low level oxidative stress protecting cells from H2O2 produced in cells. Because catalase is effective in protecting cells from high level oxidative stress by redu cing H 2 O 2 it gains further importance in cellular pro tection when the presence of glutathione is inadequate or

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41 glutathione peroxidase activity is decreased. Insufficient antioxidant bioavailability supports oxidative stress and has been implicated in the oxidative damage linked to hypertension. 91 We expect an improvement in overall antioxida nt capacity following 8 weeks of resistance and endurance training and this will be measureable utilizing the Trolox equivalent antioxidant capacity (TEAC) assay which evaluates the p lasma levels of antioxidant capacity based on the scavenging of a radical by anitoxidants present in the sample. ADMA/DDAH/BH 4 /Homocysteine N G ,N G dimethylarginine (ADMA) is a methylated amino acid synthesized in various cell types, including vascular endothelial cells, which can competitively inhibit the binding of L arginine to eNOS reducing NO synthesis. O 2 is a known inhibito r of a key protein regulator of DDAH which controls the metabolism of ADMA Therefore inhibition of DDAH due to increased production of O 2 results in increased levels of ADMA. It is a metabolic by product of continual protein methylation in the cytopla sm on arginine residues of all human cells by protein arginine catalyzed by an enzyme set called S adenosylmethionine protein N methyltransferases (protein methylases I and II) and is closely related to the conditionally essential amino acid L arginine ADMA competitively in hibits the binding of L arginine to NOS s decreasing NO synthesis The methyl groups transferred to create ADMA are derived from the methyl group donor S adenosylmethionine, an intermediate in t he metabolism of homocysteine. Homocyst eine is a constituent of blood and is also a m arker of hypertension and cardiovascular disease. After synthesis ADMA can migrate into the extracellular space and blood plasma. ADMA concentrations are substantially elevated by native or oxidized LDL cholest erol. Thus a spiraling effect occurs with high endothelial LDL levels causing greater ADMA values, which in turn inhibit NO production needed to promote vasodilation. The elimination of ADMA

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42 occurs through urine excretion and metabolism T he major metab olic pathway for ADMA degradation is by the enzyme dimethylarginine dimethylaminohydrolase (DDAH) and is reported to be responsible for as much as 90% of all ADMA degradation Further, because ADMA is constantly produced during normal protein turnover it is the regulation of DDAH that is primarily responsible for ADMA level fluxuation. The role of homocysteine as a risk factor for cardiovascular disease is suggested to be mediated by homocysteine down regulating production of DDAH. There are two know iso forms of DDAH, DDAH 1 and DDAH 2. DDAH 2 is predominantly found in vascular tissues that express eNOS where DDAH 1 is found mainly in tissues which express neuronal NOS We speculate that plasma levels of ADMA will be reduced following 8 weeks or resista nce and endurance training in prehypertensives resulting in an improvement in the production of NO Inflammation Prehypertension is a proinflammatory condition and is associated with an increased risk of both heart disease and stroke. 5, 82 C Reactive protein, tumor necrosis factor a, and homocysteine levels are all elevated in prehypertensives without any clinical evidence of cardiovascular or other atherosclerotic disease. 12, 82 Increased vascular risk is associated with increased basal levels of cytokines such as IL reactants such as CRP, and fibrinogen. Both chronic and acute inflammation are individually associated with increased arterial stiffness in both hypertension and prehypertens ion 92 95 C Reactive Protein Creation of CRP has been highly correlated to other established risk factors for cardiovascular disease including smoking, hypercholesterolemia, and hypertension. 96 98 CRP promotes endothelial dysfunction by inhibiting endothelial dependent nitric oxide (NO) release the reby inhibiting autoregulated vasodilation. 99 Large cohort longitudinal studies have directly

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43 and independently linked CRP to increased incidence and as a future predictor of periphe ral arterial disease, myocardial infarction (MI), stroke, and sudden cardiac death independent of other Framingham Risk Factors. 97, 100 102 Recent research suggests that patients with elevated basal levels of CRP are at an increased risk of hypertension diabetes, and other cardiovascular disease. 103, 104 CRP is associated with lipid responses to low fat and high polyunsaturated fat diets. 105, 106 A study of over 700 nurses showed that those in the highest quartile of trans fat consumption had blood levels of CRP that were 73% higher than th ose in the lowest quartile. 106 Others have shown that CRP can exacerbate ischemic necrosis in a complement dependent fashion and that CRP inhibition can be a safe and effective therapy for myocardial and cerebral infarcts.(56) The JUPITER trial was conducted to determine if pat ients with elevated CRP levels but without hyperlipidemia might benefit from statin therapy. Statins were selected because they have been proven to reduce levels of CRP. The trial found that patients taking rosuvastatin with elevated CRP levels experienced a decrease in the incidence of major cardiovascular events. 107, 108 C reactive protein (CRP) has been shown to stimulate the production of inflammatory cytokines, gene expression and activity of metalloproteinase 9, and upregulation of endothelin 1. CRP down regulates and uncouples eNOS and decr eases pro s tacyclin release. Together, the effects of CRP can increase elastin breakdown and collagen formation in the medial vascular wall, increase vasoconstriction and reduce vasodilation. CRP is a group of proteins discovered during basic research of the human inflammatory response. It is directly linked to the immune system and growth is stimulated by infection and injury CRP is primarily synthesized in the liver hepatocytes in response to proinflammatory cytokines, especially IL 6, and then relea sed

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44 into the systemic circulation. 109, 110 It is also produced in vascular smooth muscle cells adipocytes and neurons, peripheral blood mononuclear cells, alveolar macrophages, and is a member of t he pentrax in family of proteins. CRP is an acute phase protein found in the blood the levels of which increase in response to inflammation. 111, 112 CRP levels previously thought to be a benign byproduct of the inflammation process are now recognized as a contributor during the proliferation of athrothrombosis. Recent evidence shows that CRP is involved in the adhesion and coagulation process and it is a good marker of the human inflammatory response to infection or injury. 97, 113 CRP has two binding sites for calcium ions and one for phospho ryl choline The latter of which is expressed on the surface of dead or dying cells cholesterol, and blood platelets, and the binding to CRP acti vate s the complement system protein (C1q) and Fc The resulting interaction with complement and model immunoglobulin G (IgG) immune complexes modulat es the platelet response 113 CRP inhibits tissue plasminogen activator (tPA) by generating the proinflammatory cytokines interleukin 1 beta (I L alpha (TNF 114 CRP has a plasma half life of roughly 19 hours and d ue to its relatively short half life in plasma and under normal conditions the production of CRP is the primary determinant of the existing levels in blood plasma. 115 T herefore measurement and the resulting values represent current levels of production. Interleukin 6 (IL 6) is a marker of immune system function, systemic precursor to CRP, and is linked to the development of arterial stiffness, hypertension, and cardiova scular disease. The levels of hsCRP and IL 6 are elevated in prehypertension. 2, 12 IL 6 induces lipolysis and fat oxidation. 116 Although exercise produces a short term increase in inflammatory markers associated with increased risk o f cardiovascular disease, cross sectional studies of longitudinal exercise training demonstrate a long term anti inflammatory effect. 117 Chronic resistance

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45 training decreases levels of hsCRP and other markers of inflammation 118 121 We expect similar results following 8 weeks of resistance and endurance training in prehypert ensives. RA A S The Renin Angiotensin Aldosterone System ( RA A S ) is activated in diseased vascular beds with the up regulation of the AT1R and AT2R. Elevations in plasma renin concentrations and activity have been described in prehypertension. 13, 122, 123 Excess activity of the renin angiotensin system promotes vascular hypertrophy both directly and through hemodynamic variations, increases vasoconstriction, and decreases vasodilation. Increased vasoconstriction and decreased vasodilation have been described in prehypertension consistent with these structural and functional findings. 124 Recent investigations determining the effects of altering the increased RA A S activity present in p rehypertensives have focused primarily on pharmacological intervention s administering angiotensin converting enzyme inhibition (ACE I) and angiotensin receptor blockade (ARB). These studies have decreased the development of hypertension in prehypertensive s by effectively reducing RA A S activity by diminishing the levels or blocking the effects of ANGII. 124, 125 Further, endothelial dysfunction is therapeutically reversible Therefore, physical exercise, as well as ACE Is, and ARBs can improve flow evoked endothelium dependent vasodilation in patients with hypertension 126 Based on previous evidence we do not expect any changes in plasma renin activity following 8 weeks of resistance and endurance trainin g in prehypertensives. ANGII ANG II is formed from the enzymatic cleavage of angiotensinogen to angiotensin I (ANG I) by the aspartyl protease renin secreted by the kidney. Increased secretion of renin from the granular cells of the juxtaglomerular apparatus of the kidney is stimulated by increased sympathetic outflow. The increased sympathetic nervous system activity can be a result of

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46 different states that alter baroreceptor function but primarily caused by a decrease in blood volume. Barorecept o r insensitivity and decreased sodium chloride levels cause increased 1 adrenergic receptors. ANG I is subsequently converted to ANG II by angiotensin converting enzyme (ACE). ACE2 is a carboxypeptidase which cleaves one amino a cid from either ANG I or ANG II thereby decreasing the levels of ANG II and increasing the metabolite Ang 1 7 which has vasodilator properties. Therefore the balance of ACE and ACE2 contribute to the control of ANG II in the circulation. Because ANG II i s a regulator of blood volume and a powerful vasoconstrictor it was thought that exercise induced reductions in blood pressure may be the result of reductions in plasma renin. 127 Although the available research is equivocal in response to this question it is i mportant to include the RAAS when discussing interventions and the management of prehypertensives. (37, 41, 50, 58, 62, 104) Research suggests that although plasma renin and ANG II levels are not altered in hypertensives they are reduced in normotensive su bjects following exercise treatment 128 133 Because research in hypertension has focused on the aged it remains to be determined if exercise will reduce plasma renin and ANG II in young prehypertensives. ANG II levels are elevated in prehypertensives when compared to age matched normotensive contro ls. 13, 134 We do not expect that circulating levels of ANGII will be reduced to levels similar to normotensive controls followin g 8 weeks of resistance and endurance training in prehypertensives. AT1 R eceptors Most known physiological effects of ANG II are mediated by the angiotensin type 1 receptors (AT1Rs). AT1Rs are broadly dispersed in all organs and the vasculature. AT1R s when bound by ANGII increases the generation of O 2 primarily through activation of membrane bound NAD(P)H oxidase. Increased AT1R mediated activity in the vascular beds is central to the development of in cr e ased arterial stiffness. Classically ANG II binds to the AT1R and

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47 activates a series of signaling cascades which regulate various physiological effects of ANG II. The pathways induced by ANG II are traditionally divided into two classifications; G protein and non G protein coupled signaling. AT1 R activates serine/threonine kinases such as PKC and MAPKs that are implicated in cell growth and hypertrophy. One of the major functions of ANG II is vasoconstriction which is mediated by the classic G protein dependent signaling pathways. AT1R couple t o G q/11 12/13 and G complexes which activate downstream effectors including phospholipase C, phospholipase A2, and phospholipase D resulting in increased calcium flux into the myocytes causing smooth muscle contraction through Ca+/calmodulin mediated reactions activation myosin light chain reactions. Acutely, increased levels of ANG II lead to an increased level of AT1R activation, however chronically elevated ANG II down regulates its receptor. In the vascular smooth muscle cells numerous growth fac tors and cytokines exert their effects on receptor expression. Agonists which upregulate expression are LDL, insulin, progesterone, and erythropoietin. Downregulation agonists include ANG II, NO, HMG CoA reductase inhibitors, estrogen, platelet derived g rowth factor to name a few. A T1R associated protein (ATRAP) modulates the expression of the AT1R. Downregulation of AT1R due to overexpression of ATRAP significantly decreases the number of AT1R on the surface of cardiomyocytes and ameliorates hypertroph y. 135 AT1R regulation can provide a mechanistic link between hypertension and hyperlipidemia AT2 R eceptors Although most of the vasoactive effects of ANG II occur through binding of AT1Rs, AT2Rs have been shown to exert important an ti proliferative and pro apopto tic changes in VSMCs. AT2R expression occurs mainly during fetal development and declines after birth but is induced again later on in adult life under pathological conditions. AT2Rs are expressed at low levels in the kidney, lung, and liver but their ex act role remains undetermined. AT2Rs

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48 antagonize AT1Rs by inhibiting its signaling pathways by activating tyrosine or serine/threonine phosphotases. In a mouse model of inflammation dependent vascular disease deletion of AT2Rs enhances neointimal formatio n and inflammation. Cholesterol Positive associations between prehypertension status and the prevalence of hypercholesterolemia have been reported by numerous studies. Triglycerides (TG) total cholesterol (TC) and LDL C are significantly elevated a nd HDL C is significantly decreased in prehypertensives when compared to normotensives. 13 The re is an inverse relationship between atherosclerosis and high density lipoprotein cholesterol ( HDL C ) levels. HDL C is important in the reverse cholesterol transpo rt system pathway. HDL C levels are closely correlated with coronary heart disease (CHD) Low blood levels of HDL C (<40 mg/dL) or h ypoalphalipoproteinemia (HA), is a strong risk factor for the development of essential hypertension and is believed to in crease the risk of a coronary event 2% for every 1% decrease in HDL C below optimal levels HDL C is the smallest and densest of the lipoproteins found in human physiology. The increased density is due to its high concentration of proteins with apolipo protein AI (apo AI) and AII (apo AII) being the most abundant. HDL C mobilizes cholesterol from peripheral tissues, such as fi broblasts and macrophages, returning them to the liver and other steroidogenic organs where it is esterified by lecithin choleste rol acyltransferase (LCAT). 136 Apo AI is a cofactor for LCAT. This cascade of events is called the reverse cholesterol transport process. This process occurs by the binding of apolipoprotein A I (apo A I), the major HDL apolipoprotein, to the high affinity HDL receptor scavenger receptor B type I (SR BI). 137 The cholesterol ester produced is t ransferred from the HDL C to apo lipoprotein B (apo B) containing lipoproteins, such as very low density lipoprotein (VLDL) intermediate density lipoprotein (IDL) and low

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49 density lipoprotein ( LDL ) by cholesteryl ester transport protein in the liver. 136 Triglyceri des, are major components of very low density lipoprotein (VLDL) and chylomicrons, and play an important role in metabolism as energy sources a nd transporters of dietary fat. The HDL C itself becomes enriched with triglycerides ( TG ) and subsequently becom es hydrolyzed by hepatic lipase. 136 By this mechanism, HDL C regains its original conformation and can further scavenge cholesterol. The protective effects of HDL C have been primarily attributed to its role in the reverse c holesterol transport process; h owever, evidence that HDL C has a number of additional cardioprotective actions is mounting. Further, many of these benefits entail direct modulation of endothelial cell phenotype. 138 HDL regulates eNOS subcellular distribution, prevents eNOS uncoupling by LDL, caus es membrane initiated signaling thereby stimulating eNOS activity, and regulates eNOS abundance. 138 HDL C stimulates eNOS via Akt and Map kinases mediated by SR BI signaling 138 In vivo, the intracellular site of NO synthesis has a major influence on the impact of the enzyme and in cultured endothelial cells the primary location of the eNOS is within the caveolae highly concentrated near the cellular membrane. 139 Oxidized LDL (OxLDL) causes the depletion of caveolae cholesterol in endothelial cells which leads to eNOS redistribution intracellularly reducing the capacity to activate the enzyme. 140, 141 Decreased levels of HDL C result in decreased cholesterol shuttling and increased levels of endothelium associated OxLDL. LDL has also been shown t o upregulate AT1R via posttranscriptional mRNA stabilization. AT1Rs are upregulated in platelets and ANG II induced vasoconstriction is enhanced in hypercholesterolemia. Based on the research which shows favorable alterations in lipid profile

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50 with exerci se we expect decreases in TC and LDL C and increases in HDL C with 8 weeks of resistance and endurance training in prehypertensives. Muscle Contraction and Exercise Contracting skeletal muscles produce free radicals and other reactive oxygen speci es (ROS). The balance of ROS and antioxidants in working muscles promotes optimal force production, fatigue resistance, and injury prevention. 142 Muscle contraction and exercise increase glucose uptake into skeletal and cardiac muscle, via a pathway independent to that stimulated by insulin. Skeletal muscle glucose upt ake is similar during exercise in insulin resistant individuals or patients with diabetes compared with healthy individuals. 143 Exercise induced acute increases in reactive oxygen species (ROS) are important cellular messengers in the signal transduction involved in activation of transcription factors such as at shock factor 1 (HSF1). 144 Skeletal muscle contraction d uring exercise causes increased ROS signaling which induce s adaptive responses including the maintenance of oxidant homeostasis and the prevention of oxidative damage. 144 146 crystallin, HSP27, HSP60, HSP70, and HSP90. 147 Increased HSP transcription occurs during exercise, immediately post exercise, and several hours following exercise. Time course studies using western blotting techniques typically demonstrate significant increases in protein content detectable within 1 2 days foll owing exercise stress. 148 151 Chronic exercise training resulting in a lifelong over expression its ability to adapt and re generate following acute stressors associated with aging. 152 Moreover, trained individuals exhibit an attenuated or abolished stress response to habitual exercise challenges, likely due to adaptations of base 153 156

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51 Endurance Aerobic Exercise The beneficial effects of aerobic exercise of moderate intensity in hypertension are well documented with regard to improvements in vascular function including changes in endothelial function (e. g. flow mediated dilation), carotid artery intima media thickness, and arterial distensability. 157 Aerobic endurance training results in improvements in metabolic control including glycemic control, weight loss and improvements in lipid profile. 157 Acute exercise stimulates macrophage function, utilizing NF ys, functioning as an important mediator of the immune response. 158 During exercise, IL 6 is thought to act in a hormone like manner to mobilize extracellular substrates and/or augment substrate delivery 116 IL 6 is significantly elevated with exercise, and precedes the appearance of other cytokines in the circulation. Longitudinal studies of the beneficial effects of regular exercise on lowering CRP suggested that physical activity may suppress systemic low grade inflammation. 159, 160 Follow up studies administering Escherichia inflammatory effects of exercise. 161, 162 In the human study, the two to three fold increase in TNF administered after 2.5 hours of a 3 hour cycle ergometer protocol. 162 This study suggests that the acute increase in IL 6 with exercise exerts an anti inflammato ry environment through the increases in IL 1ra and IL 10, known anti inflammatory cytokines. Resistance Exercise The benefits of habitual resistance training and their positive effects on muscle hypertrophy, muscular strength, basal metabolic rate, and quality of life have been well documented. 163 166 Habitual resistance training also favorably modifies traditional cardiovascular di sease risk factors by lowering blood pressure, fasting glucose, insulin levels, plasma

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52 triglycerides, an d percent body fat. 164, 167, 168 Muscular strength is als o inversely associated with multiple risk factors for coronary artery disease including hypertension, diabetes mellitus, arterial stiffness, and mortality and these associations are independent of cardiorespiratory fitness. 169, 170 Kiveloff and Huber reported in 1971 that chronic isometric handgrip training reduce s resting arterial blood pressure in a group which would today be categorized as prehypertensive. 171 This conclusion was echoed by Wiley et al. in a similar group of prehypertensive subjects. 172 Interestingly, both researchers reported greater decreases in diastol ic blood pressure when compared to the significant reductions in systolic blood pressure. 171, 172 One possible mechanism linking strength training to improved hypertensive status may be through the acute elevations in the arterial blood pressure and shear stress during bouts of weightlifting. It h as been suggested in previous research that 6 weeks of resistance training is sufficient to induce vascular adaptations. 50, 173 This increased stress may lead to long term protective changes in the smooth muscle content of the arterial wall and the load bearing properties of collagen and elastin leading to an overall decreased resting blood pre ssure. 174 During resistance exercise has been shown to result in peripheral blood pressures as high as 350 mm Hg and 200 mm Hg systolic and diastolic respectively. It has been previously reported that the acute increases in systolic blood pressure during resistan ce training may precipitate factors in the development of hypertension and be a risk factor for increased cardiac risk. 175 178 These repo rts and others similar may be the reason why the beneficial effects of resistance training in people with hypertension remain largely ignored. Incidence of developing hypertension among men with prehypertension decreases 54% with increased muscular stren gth. 23 This association of muscular strength and decreased risk of

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53 hypertension was independent of cardiorespiratory fitness, smoking, alcohol int ake, family history of HTN, and baseline systolic and diastolic blood pressure. Further, Maslow et al. reported an additive effect of muscular strength to reduced incidence of hypertension in prehypertensives with increased cardiorespiratory fitness. 23 The effects of resistance training are not only beneficial but very similar to the effects of endurance aerobic training on vessel function and blood pressure, and these effects are primarily mediated by the shear stimulus and improved endothelial function. The shear stimulus caused primarily due to the increased pressure and blood flow following contraction in response to an increased load. Summary To date and to our knowledge, only two prospective interventional studies have examined the effect of both endurance and resistance exercise on vascular function in prehypertension subjects The noninvasive techniques of vascular measurement utilized in our cardiovascular laboratory offer the unique ability to further characterize and determine the common mechanisms responsible for improved vascular function and the antihypertensive effects of resistance training. For the first time and to our knowledge, we will study the separate effects of 8 weeks of resistance exercise training and endurance aerobic exercise training on arterial function in a group of y oung healthy prehypertensives and compare these results to an age and gender m atched group of normote nsives. We expect that 8 weeks of whole body resistance and 8 weeks of endurance exercise training will decrease large artery stiffness increase r esting and peak limb blood flow, reduce both central and peripheral blood pressures, and will have beneficia l effects on the plasma levels of vasoactive agents, inflammatory factors, resting glucose, and lipid profile in prehypertensives Additionally, we expect that the antihypertensive benefits of resistance exercise training in young prehypertensives will be similar to those following endurance exercise

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54 training. It is our belief that the information gained from conducting this research will assist in the treatment of prehypertension.

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55 CHAPTER 3 MATERIALS AND METHOD S The study was conduct ed in the Center for Exercise Science, College of Health and Human Performance, at the University of Florida. This study is a single center, prospective, randomized, and controlled investigation of the effects of resistance and endurance exercise training on arterial stiffness and endothelial function in young prehypertensive but otherwise healthy subjects. Forty five (n=45) prehypertensive (SBP=120 139mmHg; DBP=80 89mmHg) but otherwise young healthy subjects (age 18 35yr) considered to be novice exerciser s, who had not participated in a structured endurance and/or resistance training program in the past 6 months, were recruited from the University of Florida and surrounding Gainesville, FL area. Fifteen (n=15) normotensive (SBP<120 mmHg; DBP<80 mmHg) young healthy subjects who had not participated in a structured endurance and/or resistance training program in the past 6 months, will also be recruited to serve as a normotensive healthy non exercising control group. Subjects were randomized to one of the fo llowing three groups; 1) resistance training (n=15), 2) endurance training (n=15), and 3) non exercising time control (n=15). All subjects were studied before training and after 8 weeks of the intervention or control period. Group Assignments At study ent ry, subjects were randomly assigned to either the group that performed resistance exercise training, endurance training or to the nonexercising control group. The resistance training group (n=15) and endurance training group performed exercise training 3 days per week. The resistance training regimen consisted of exercise on 7 variable resistance machines. The endurance training regimen consisted of treadmill walking. The control group was sedentary and refrained from initiating a structured exercise tr aining programs during the study. Duration of the exercise program was 8 weeks.

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56 Prehypertensive Participant Eligibility Criteria Inclusion Criteria: Clinically healthy males and females with a systolic blood pressure between 120 and 139 mmHg or a diastoli c blood pressure between 80 89 mmHg Between 18 35 years of age Have not participated in a regular endurance exercise and/or resistance exercise program over the previous 6 months Eumenorrhea Exclusion Criteria: Currently smoke or have a history of smoking Have medical limitations that contraindicate exercise Take medications that would interfere with vascular function Resting blood pressure is below 120/80 Resting blood pressure is over 140/90 Norm otensive Control Participant Eligibility Criteria Inclusio n Criteria: Clinically healthy males and females with a systolic blood pressure below 120 mmHg and a diastolic blood pressure below 80 mmHg Between 18 35 years of age Have not participated in a regular endurance exercise and/or resistance exercise program over the previous 6 months Exclusion Criteria: Currently smoke or have a history of smoking Have medical limitations that contraindicate exercise Take medications that would interfere with vascular function Resting blood pressure is above 120/80

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57 Laboratory Measurements V isit #1 Screening An initial blood pressure screening will be required for all potential subjects. After consent is obtained, subjects will be asked to report to the Cardiovascular Laboratory in the Center for Exercise Science at the Univer sity of Florida. Resting blood pressure will be obtained in triplicate after 15 minutes of relaxation while subjects are in a supine position using an automated sphygmomanometer. Subjects will be allowed to continue in the study when a resting systolic b lood pressure is between 120 and 139 or a diastolic blood pressure is between 80 and 89. Arterial s tiffness t esting Pulse wave analysis (PWA) Vascular function measurements were performed at study entry and after 8 weeks of exercise training. Vascular function measurements were made in the Cardiovascular Laboratory in the Center for Exercise Science at the University of Florida. Subjects were asked to report to the laboratory in the morning after a 12 hr fast and refrained from alcohol and caffeine 12 hours prior to all testing. Subjects were also asked to refrain from exercise and to eat a low nitrate diet on the day prior to testing. Because vascular function if affected by changes associated throughout a normal menstrual cycle female participants w ill be measured during the same phase of their cycle. An average of three BP measurements were used for resting BP values. Following a 15 minute rest period in a supine position, brachial systolic, diastolic, and pulse blood pressure measurements were pe rformed in triplicate in the left arm using an automated noninvasive blood pressure (BP) cuff (VSM MedTech, Ltd.). Blood pressure was obtained in triplicate or until stable within 5 mmHg for systolic and diastolic. High fidelity pressure waveforms were r ecorded non invasively using a pencil type Millar

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58 Micro tip pressure transducer. Optimal recording of the pressure wave was obtained when the hold down force of the transducer on the artery was such that the resulting waveform had a stable baseline for at least 10 beats. The assessment of arterial wave reflection characteristics are performed noninvasively using the SphygmoCor system (AtCor Medical, Sydney, Australia). High fidelity radial artery pressure waveforms are recorded by applanation tonometry o mathematical transfer function the SphygmoCor system synthesizes a central aortic pressure waveform 179 181 This technique has been shown to be reproducible 182, 183 The reliability of aortic pressure waveform measurements in our laboratory was established by sequential measurements on 7 young healthy men on 3 separate days. The mean c oefficient of variation for these measurements was 6.5% 184 The central aortic pressure wave (Ps Pd) is composed of a forward traveling wave with amplitude (Pi Pd), generated by left ventricular ejection and a reflected wave with amplitude (Ps Pi) that is returning to the ascending aorta from the periphery (Figure 2 1) 60 The contribution or amplitude of the reflected wave to ascending aortic pulse pressure can be estimated by the aortic augmentation index ( AIx ). AIx is defined as reflected wave amplitude divided by pulse pressure and expressed as a percentage [ AIx = (Ps Pi)/(Ps Pd) x 100] 60, 185 Ps indicates peak systolic pressure, Pi is an inflection point tha t indicates the beginning upstroke of the reflected pressure wave, and Pd is the minimum diastolic pressure. The forward and reflected waves travel in opposite directions along the artery at the same velocity. The round trip travel time back is measured from the foot

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59 related to arterial pulse wave velocity and arterial stiffness, and directly related to the distance to the reflecting site 60 Arterial tonometry measurements took approximately 60 minutes per lab visit. Pulse wave velocity (PWV). With the subject supine, tonometry transi t distances from the supra sternal notch to the radial (SSN R), femoral (SSN F) and carotid (SSN C) and from the femoral to the dorsalis pedis (F DP) recording site were measured with a tape measure (Figure 2 2). Arterial applanation tonometry (SphygmoCor ) were then obtained from the carotid, radial, femoral, and dorsalis pedis arteries in that order in rapid succession. High fidelity pressure waveforms were recorded non to foot pulse wave velocity to each peripheral site (dorsalis pedis, radial and femoral) were calculated by determining the delay between the appearance of the pressure waveform foot in the carotid and peripheral sites 186 The distance between recording sites was adjusted for parallel tr ansmission in the aorta and carotid by subtracting SSN C from SSN R and SSN F. The corrected distances will be divided by the respective foot to foot transmission delays (Carotid radial, Carotid femoral) to give pulse wave velocity. Central pulse wave ve locity (in the mostly elastic aorta) was evaluated using the carotid femoral (C F) data and peripheral pulse wave velocity (in the more muscular conduits) using the femoral dorsalis pedis (F DP) and carotid radial (C R) data. Pulse wave velocity between t he various measuring sites were used as an indirect measure of regional arterial stiffness. The reliability of pulse wave velocity between the different regions was established by sequential measurements on 7 young men on 3 separate days. The mean coeffi cient of variation for C R, C F, and F DP were 4.5%, 2.1%, and 5.3%, respectively 184 Venous o cclusion p l ethysmography Forearm and calf blood flow. Forearm blood flow (FBF) and calf blood flow (CBF) was determined independently by venous occlusion plethysmography (EC 6, D.E. Hokanson, Inc.)

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60 using calibrated mercury strain gauges. 174 Strain gauges were applied to the widest part of the non dominant forearm or calf. Patients rested supine for 20 minutes with arms or legs elevated above the right atrium to achieve stable baseline measurements of FBF. To measure FBF or CBF, upper arm or thigh cuff was inflated to 40 mmH g for 7 seconds every 15 seconds using a rapid cuff inflator to prevent venous outflow. 52, 187 One minute before each measurement, a wrist or ankle cuff was inflated to constant pressure 50 mmHg above systolic pressure to occlude hand or ankle circulation during FBF or CBF measurements. The FBF or CBF output signal was transmitted to NIVP3 software program loaded on a laptop PC computer expressed as milliliters (mL) per minute per 100 ml of forearm tissue (mL/min per 100 mL tissue). FBF or CBF for one minute is the ave rage of one plethysmographic measurement every 15 seconds for one minute. 52, 187 Forearm and calf vascular resistance was calculated as the ratio of mean arterial pressure divided by FBF or CBF, respectively expressed as mmHgmL/min per 100 mL tissue. Blood pressure an d ECG was continuously monitored. Forearm flow during reactive hyperemia. Endothelium dependent FBF was measured following 5 minutes of upper arm arterial occlusion during reactive hyperemia of the forearm. 52, 187 Endothelium dependent vasodilation (EDV) during reactiv e hyperemia in the forearm has been shown to correlate highly with acetylcholine induced EDV in patients with essential hypertension 50 therefore, reactive hyperemia is a good non invasive measurement of EDV of resistance vasculature. A blood pressure cuff was placed on the upper arm 5 cm above the anticubital fossa, but below the venous occlusion cuff. After baseline FBF was confirmed to be stable for 2 m inutes and recorded, the cuff was rapidly inflated to 200 mmHg for 5 minutes and then released. FBF was measured every 15 sec for 4 minutes. Peak FBF was recorded as the highest FBF observed immediately following release of the cuff, and total FBF was re corded as

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61 the area under the time curve after baseline FBF was subtracted. 52, 188, 189 FBF in the contralateral arm was measured simultaneously as an internal control to exclude any systemic effects due to reactive hyperemia. Calf flow during reactive hyperemia. Endothel ium dependent CBF during reactive hyperemia of the calf was measured following 5 minutes of upper leg arterial occlusion. A blood pressure cuff was inflated on the upper thigh above the knee, but below the venous occlusion cuff. After baseline CBF was co nfirmed to be stable for 2 minutes, the cuff was rapidly inflated to 200 mmHg for 5 minutes and then released. Peak CBF was recorded as the highest CBF observed immediately following release of the cuff, and total CBF recorded as the area under the time c urve after baseline CBF was subtracted. 188, 189 CBF in the contralateral leg was measured simultaneously as an internal control to exclu de any systemic effects of CBF due to reactive hyperemia. Brachial a rtery flow m ediated d ilation Brachial artery reactivity testing was performed using a high resolution ultrasound (HDI 3000, ATL, Inc). Brachial artery reactivity measurements were made wi th the subjects in a supine position following a fast of at least 4 hours and abstaining from caffeine and alcohol for at least 12 hours prior to the measurements. After lying quietly for 15 minutes, a 10.5 MHz linear phase array ultrasound transducer was used to image the right brachial artery longitudinally and was recorded digitally using Pinnacle Studio Plus software (Pinnacle Systems, Inc.). After obtaining resting baseline end diastolic diameters and blood flow velocity, a blood pressure cuff placed on the upper forearm, 1 2 cm below the elbow, was inflated to 200 mmHg for 5 minutes. The transducer was held in the same position for the duration of cuff inflation. Using a cuff position that is distal to the site of the ultrasound measurement has bee n shown to produce less variability than proximal placement of the cuff 190 and has been suggested to serve as a more

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62 accurate bio assay of endothelia l nitric oxide (NO) availability 191 Immediately following cuff release, brachial artery blood flow velocity was measured for 20 seconds. Brachial artery diameter was then imaged and recorded for an additional 2 minutes. Reacti ve hyperemia blood flow results in flow mediated dilation (FMD) of the brachial artery due to shear stress induced NO release from the endothelial wall. About 60 seconds after cuff deflation, peak brachial artery diameter has been reported to occur and is a valid measure of endothelial mediated artery reactivity 192 relative change (%) in brachial artery diameter in response to the forearm hyperemic stimulus. Because the main stimulus for FMD is an acute increase in vascular shear stress or blood flow, peak FMD valu es will be normalized for the magnitude of the hyperemic stimulus 193 Shear rate (velocity/diameter) is used to quantify the hyperemic stimulus 191 With the use of artery diameter and mean velocity (Vmean) Doppler measurement s the blood flow in the brachial artery was calculated using the equation : Blood flow (ml/min) diameter/2)2 x 60 Blood viscosity was not measured, so shear stress was calculated us ing the equation for shear rate. 194 Shear Rate (s 1) = 4 mean blood velocity (cm/s) diameter (cm) 1 Brachial ar tery diameters are determined during end diastole via Vascular Research Tools % (Medical Imaging Applications LLC, Iowa) by measuring the distance between the near and far wall of the intima using the automated edge detection software for video analysis. B lood s ampling Blood samples were collected from all subjects before all vascular measurements. Venous blood was collected from a vein of the left or right forearm, using a butterfly catheter. Blood was collected in tubes containing EDTA and immediately underwent centrifugation at 3,000 rpm for approximately 15 minutes. All plasma tubes were stored at 80C and analyzed as a single batch at completion of the study. Blood samples were used to determine plasma levels of

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63 glucose, cholesterol, angiotensin II, arginine vasopressin, endothelin, hsCRP, tumor necrosis activity. Visit #2: Skeletal m uscle s trength t esting All resistance training subjects reported to the Center for Exercise Science at the University of Florida and performed tests designed to measure skeletal muscle strength at study entry and following 8 weeks of exercise training. Dynamic muscular strength was measured to assess the upper and lower body using two resistance exercises which included: chest press and leg extension. For each dynamic exercise, a one repetition maximum (1 RM) was determined. Prior to the measurement of the 1 RM, participants were positioned on the machine and performed a dyn amic warm up using a light weight. During the 1 RM test subjects started with a light weight and slowly extended their arms or legs through the full range of motion, followed by a slow return to the starting position for a total of one repetition. Diffic ulty was measured by having the participant rate his/her exertion level using the RPE scale. Weight was gradually added until a subject could not complete one repetition. Two to three minutes rest were given between trials to prevent premature fatigue. The last weight successfully lifted through the full range of motion with proper form was considered the 1 RM. This was usually determined in 5 to 6 trials. Aerobic c apacity t esting All endurance training subjects reported to the Center for Exercise Sc ience at the University of Florida and performed a test designed to measure aerobic capacity at study entry and following 8 weeks of exercise training. Subjects randomly assigned to the endurance training group were oriented to the Quinton endurance exer cise treadmill and underwent a

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64 symptom limited graded exercise test (GXT) to determine peak oxygen consumption (VO2peak) before and after 8 weeks of exercise training or the control period. Subjects randomized to the aerobic arm of the study completed a p eak oxygen consumption (VO2 Peak) protocol on a treadmill. Subjects began walking on a treadmill at 1.7 mph and a flat grade for 3 minutes. After this warm up stage the incline of the treadmill was increased to 10% while the speed remained at 1.7 mph for 3 minutes. Following this first stage of the Bruce protocol the grade was increased by 2% and the speed was increased by 0.8 mph every 3 minutes until the subject reached volitional fatigue or the subject stopped the test. During the test expired gases were collected through a low resistance on way valve (Hans Rudolph) and breath by breath analysis of the expired gases was performed continuously throughout the test using a metabolic cart (PARVO Medics, TrueMax 2400, Salt Lake City, Utah). The oxygen and carbon dioxide analyzers were calibrated before each test using a known gas mixture of 16% O2 and 4% CO2. Ventilatory responses (tidal volume and frequency of breathing) were measured with a pneumotachograph. Volume calibration was performed before each test using a 3 liter calibration syringe. Twelve lead electrocardiograms (ECG) were recorded throughout the test using standard lead placement with a Quinton Q4500 (Quinton Instruments, Seattle, WA). Blood pressure measurements were taken every other mi nute using a standard sphygmomanometer and RPE was obtained at the end of each minute throughout the test using 20 point scale. Resistance e xercise t raining Subjects randomly assigned to the resistance training group were oriente d to the MedX variable resistance exercise machines. Subjects performed a regimen of variable resistance exercises, 3 days per week, on the following MedX equipment: Leg Extension, Leg Curl, Leg Press, Lat Pull Down, Chest Press, Overhead Press, and Bicep s Curl. These machines are

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65 designed to work all major muscle groups. The initial resistance for each subject on each RM. Subjects completed two sets of 8 to 12 repetitions performed to volitional fatigue per machin e. When 12 repetitions are achieved on the second set, the training weight was increased 5% at the next training session. Recovery time between exercises was 1 specialist mon itored each participant during all exercise training sessions. Aerobic e xercise t raining Subjects randomly assigned to the endurance training group were oriented to the Quinton endurance exercise treadmill and underwent a symptom limited graded exercise t est (GXT) to determine peak oxygen consumption (VO2peak) before and after 8 weeks of exercise training or the control period. Subjects performed a 5 minute warm up at low speed and incline, then 45 minutes of continuous aerobic exercise, followed by 5 min utes of cool down, 3 days per week. The endurance training intensity level was set at 60% of their previously determined VO2 Peak. 20 Borg scale of self reported rating of perceived exertion (RPE training. When the subject was able to complete the entire 45 minutes of treadmill exercise with an RPE of less than 13=Somewhat Hard the intensity level was increased by 5%. An exercise s pecialist monitored each participant during all exercise training sessions. Criteria for t ermination of e xercise t ests : Fatigue Failure of monitoring equipment Light headedness, confusion, ataxia, cyanosis, dyspnea, or nausea Circulatory insufficiency Onse t of angina with exercise

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66 Symptomatic Supraventricular tachycardia 3 mm horizontal or downsloping ST depression Exercise induced left bundle branch block Onset of second or third degree A B block R on T PVC Excessive hypotension (greater than 20mm Hg drop in systolic BP) Excessive hypertension (systolic FP >220 mm Hg; diastolic BP > 110 mm Hg) Inappropriate bradycardia (HR drops > 10 bts/min) Possible d iscomf orts and r isks Strength and Endurance Testing/Training. The source of discomfort to the subject was from residual muscle soreness. This may have occurred 24 48 hours after testing or training and usually resolved spontaneously. However, by administering a familiarization session to accommodate the subject to the training process, the risk associated with training was reduced. Further, resistance training intensity was increased by only 5% when patients were able to complete more than 12 repetitions. En durance training intensity was increased by only 5% when patients were able to complete the entire training session below their pretrained rating of perceived exertion (RPE). Lastly, the Living Well training facilities were equipped with exercise machines and experienced training personnel that optimized safety. Vascular m easurements The tonometry measurements of large vessel function have been performed in over 10,000 patients without a single complication, as would be expected for this totally non invasi ve study.

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67 For the brachial artery occlusion, not a single permanent adverse event has been associated with this procedure in over 40,000 examinations reported in the medical literature. Subjects may have experienced some temporary discomfort when the blo od pressure cuff was inflated to 200 mmHg for 5 minute occlusion period. The discomfort lasted only as long as the cuff remained inflated. Blood d raw Veno us blood samples for serum were collected in tubes containing no additive, allowed to clot at room temperature for 15 minutes, and immediately centrifuged at 3,000 rpm for 15 minutes at 4 ethylenediaminetetraacetic acid (EDTA), placed on ice for 15 minutes, and centrifuged immediately using the same protocol as the serum tubes. Plasma that was used for measurement of l ipid peroxidation was stored with diethylenetriamine pentaacetic acid (DTPA) and butylated hydroxytoluene (BHT) for a final concentration of 0.01 mM to prevent autooxidation during freezing and thawing. All serum and plasma samples were aliquoted into 1.5 ml eppendorf tubes and immediately stored at precautions mandated by the CDC and OSHA were used in the handling of human blood. Biochemical Analyses Vasodilator P roduction Because NO is rapid ly converted to nitrate and nitrite (NOx) in plasma, NOx was used to estimate NO production. Since plasma NOx levels can be influenced by dietary nitrate, subjects were asked to follow the National Institutes of Health low nitrate diet guidelines 36 48 ho urs prior to each blood draw. 195 Plasma NOx was measured using commercially available kit (Cayman Chemical, Inc.), which converts all nitrate to nitrite using nitrate reductase. Spectrophotometric analysis of total nitrite was performed using Greiss reagent and the

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68 absorbance measured at 540 nm. The major metabolite of the vasodilator prostacyclin, 6 keto prostaglandin F1 keto Vasoconstrictor M easurement Plasma levels of the vasoconstrictor endothelin 1 (ET 1) were measured using an ELISA kit (R & D systems, Inc.) Plasma levels of the vasoconstrictor angiote nsin II (ANG II) were measured using an ELISA kit (Cayman Chemical, Inc.). A specific monoclonal anti Angiotensin II is immobilized on a well plate. The immunological reaction with ANG II the traps the molecule and is covalently linked to the plate by gl utaraldehyde via amino groups. After washing and a denaturing treatment ANG II reacts again with the acetylcholinesterase labelled monoclonal antibody used as a tracer. The plate is read at 405 nm on a spectrophotometer and the absorbance is proportional to the amount of tracer bound to the well and is proportional to the amount of ANG II. Lipid Peroxidation Isoprostanes are important products of lipid peroxidation, and their measurement is currently the best assay to determine lipid peroxidation in biological samples. Limited amounts of isoprostanes can be absorbed and diet has a limited effect on plasma levels of these compounds. 196 Therefore, oxidative stress induced lipid peroxidation was assessed by measuring plasma levels of 8 iso iso competes for binding with 8 isoprostane covalently attached to alkaline phosphatase. The assay plate is then incubated with p nitrophenyl phosphate and the reaction stopped with the addition of an acid. The plate is read at 405 nm on a spectrophotometer and the absorbance is inversely proport ional to 8 iso PGF

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69 Antioxidant C apacity Plasma levels of antioxidant capacity were measured using the Trolox equivalent antioxidant capacity (TEAC) assay (Random Laboratories, Ltd.). The TEAC assay is based on the scavenging of a radical by anitoxi dants present in the sample. During the assay plasma is added to a free radical generating system and is based on the suppression of the absorbance of azinobis (3 ethylbenzothiazolone 6 sulfonate) (ABTS) by antioxidants present in the sample. 197 Inhibition of the free radical reactio n is proportional to the antioxidant capacity of the plasma. Inflammatory M arkers High sensitivity C reactive protein (hsCRP) was determined by a commercially available ELISA (BioQuant). The hsCRP assay is a solid phase direct sandwich method. The samp les and anti CRP antibodies conjugated wit h horseradish peroxidase (HRP) are added to wells coated with monoclonal antibodies (MAb) to CRP. CRP in the serum binds to the anit CRP MAb and the second antibody then binds to CRP. The unbound protein and HRP conjugate are removed by the wash buffer. After addition of the substrate the plate is read at 450 nm on a spectrophotometer and the absorbance is proportional to the concentration of CRP in the samples. Similarly, interleukin 6 (IL 6) was measured using a sandwich ELISA (Cayman Chemical) where the second antibody was conjugated with acetylcholinesterase and its product was read at 405 using a spectrophotometer. Plasma Renin Activity Plasma renin activity was measured using a luminescent immunoassay (LIA ) designed for quantifying the angiotensin I (ANG I) generated by renin activity in plasma. Before the immunoassay protease inhibitors to prevent degradation of ANG I in the pl asma sample. ANG I I generation phase. During the immunoassay

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70 incubation another set of protease inhibitors is involve to stop the generation of new ANG I and to stop the degradation of existing ANG I to smal ler peptides. The relative luminescence units (RLUs) are measured Statistical Considerations Statistical Analysis. All statistical analyses were performed using SPSS version 18.0 for Windows (SPSS, Chicago, Illinois). Continuous variable data are prese nted as mean SD. All data were tested for normal distribution with the Shapiro Wilk test for normality. An alpha level of p < 0.05 was required for statistical significance. Repeated measures analysis of variance (ANOVA) was used to evaluate the conti nuous primary dependent variables, peripheral and central blood pressure, brachial FMD, pulse wave analysis, pulse wave velocity and venous occlusion plethysmography; and the secondary dependent variables, NOx, ET 1; the plasma biomarkers, patient characte ristics, and all other data. When a statistically significant main effect between treatment variable to analyze the timepoint mean differences from baseline for each g roup and to determine within group timepoint significance. Further, Tukey post hoc analysis was performed utilizing the within subject timepoint effect mean square error and test of between subject effect mean square error derived from the primary repeate d measures ANOVA. When significant differences between timepoints were observed for the each group, and there were no other significant differences between groups at baseline or between timepoints within the control groups, the significant p values for th e absolute mean changes are reported within group by timepoint to simplify the presentation of the exercise treatment effect. Statistically significant absolute values are represented in the figures as percent changes from gnificance between group between timepoint are reported.

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71 Repeated measures ANOVA between exercise treatment and time control was used to analyze the descriptive patient characteristics, metabolic profile, cardiac intervention history, drug regimens, and g raded exercise test results. These data are reported as mean SD. Sample Size Calculation. A power analysis was performed to estimate the statistical power related to testing the following hypotheses in 45 patients: 1) Whole body resistance and enduranc e training will improve endothelial function in peripheral muscular conduit arteries measured via flow mediated dilation of the brachial artery. 2) Whole body resistance and endurance training will elicit commensurate changes in endothelial derived vasoac tive agent NOx. Based on the data of Edwards et al, 198 for Hypothesis 1 the post treat ment means are anticipated to be 11.2 % and 8.4 % for exercise treatment and time control respectively. The anticipated standard deviation was about 3.3 % for the exercise treatment group and 2. 3 % for the time control group. A study of 30 evaluable prehyper tensive subjects (n=15 resistance and n=15 endurance) and 30 evaluable controls (n=15 prehypertensive and n=15 normotensive) will have 99% power, based on the Satterthwaite corrected t test to have a P value below 5% two sided. Based on the data of Edward s et al. 198 for Hypothesis 2 the post treatment means are anticipated to be 34.7 and 3 0.16 mol/L for exercise treatment and time control respectively The anticipated standard deviation was about 8.67 mol/L for the exercise treatment group and 5.64 mol/L for the time control group A study of 30 evaluable prehypertensive subjects (n=15 resistance and n=15 endurance) and 30 evaluable controls (n=15 prehypertensive and n=15 normotensive) will have 99% power, based on the Satterthwaite corrected t test to have a P value below 5% two sided.

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72 Figure 3 1. Ascending aortic pressure wave form.

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73 Figure 3 2. Hemodynamic parameters derived from pulse wave analysis

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74 Figure 3 3 Determination of the pulse wave transit distances from body surface measurements.

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75 CHAPTER 4 RESULTS A total of forty three (n=43) prehypertensive subje cts were recruited and randomly assigned to participate in either an 8 week resistance training program, an 8 week endurance training program, or an 8 week non exercising control group. Additionally fifteen (n=15) normotensive participants were recruited to participate in an 8 week non exercising control group. Subject Characteristics before and after Exercise T raining or T ime C ontrol The baseline characteristics for the exercise training and time control participants are presented in Table 4 1. The pr ehypertensive and the normotensive groups did not differ at baseline with respect to age, height, weight, body mass index, or resting heart rate. Additionally after assignment to the 3 study groups the prehypertensive groups did not differ a t baseline wi th respect to resting systolic blood pressure or resting diastolic blood pressure. However, at study entry the prehypertensive resistance training (P H RES) group, endurance training (PHEND) group, and control (PHCON) group had significantly higher baseline systolic blood pressure and diastolic blood pressure compared to normotensive (NORMCON) controls Brachial Artery Endothelial Function after Exercise Training Brachial artery flow mediated dilation ( FMD ) results are presented in Table 4 2 and Figure 4 1. The prehypertensive and normotensive groups did not differ at baseline or after 8 weeks with respect to resting brachial diameters. All 3 prehypertensive groups exhibited significantly lower brachial artery FMD, absolute change in diameter, and FMD no rmalized to shear rate compared to normotensives at baseline. As shown in Figure 4 1 there was a significant increase in brachial artery FMD, absolute change in diameter, and FMD normalized to shear rate in the PHRES and PHEND groups following 8 weeks of training. There was no significant change in

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76 brachial artery FMD, absolute change in diameter, and FMD normalized to shear rate in the PHCON or NORMCON groups after 8 weeks Further, there were no significant differences in brachial artery FMD, absolute change in diameter, and FMD normalized to shear rate between PHRES and PHEND, and normotensive controls after 8 weeks of resistance or endurance exercise training Blood Pressure and Pulse Wave Analysis after Exercise Training Blood pressure componen ts and pulse wave analysis (PWA) results are presented in Table 4 3 and Figures 4 2 4 3, and 4 4 There were no significant differences between the prehypertensive groups at baseline with respect to heart rate, resting systolic blood pressure, resting di astolic blood pressure and mean blood pressure. The prehypertensive groups exhibited significantly elevated resting systolic, resting diastolic, and mean blood pressure s at baseline when compa red to the normotensive group. There was no significant change with respect to resting systolic, resting diastolic, or mean blood pressures in the PHCON or NORMCON groups after 8 weeks. As shown in Table 4 3 there were significant reductions in resting systolic, resting diastolic, and mean blood pressures in the PHR ES and PHEND groups following 8 weeks of training. Further, there were no significant differences in resting systolic, resting diastolic, and mean blood pressures between PHRES and PHEND groups and normotensive controls after 8 weeks of resistance or end urance exercise training. Pulse wave analysis demonstrated significant elevations in augmentation index (AIx), augmentation index normalized for heart rate @75bpm (AIx@75), and left ventricular wasted energy (LVEW) in the prehypertensive groups when compar ed to the normotensive group at baseline. There were no significant differences in AIx, AIx@75, and LVEW between the 3 prehypertensive groups at baseline. There was no significant change with respect to AIx, AIx@75, and LVEW in the PHCON and NORMCON grou ps after 8 weeks. As shown in

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77 Figures 4 2, 4 3, and 4 4 there were significant reductions in AIx, AIx@75, and LVEW in the PHRES and PHEND groups following 8 weeks of training. Central and Peripheral Artery Stiffness after Exercise Training Centra l and peripheral pulse wave velocity (PWV) results are presented in Table 4 4 and Figure 4 5, 4 6, and 4 7 There were no significant differences in carotid to femoral artery (CF), carotid to radial artery (CR), and femoral to dorsalis pedis artery (FD) PWV in the prehypertensive groups at baseline. Pulse wave transit time analysis demonstrated significant elevations in CF, CR, and FD PWV in the prehypertensive groups when compared to the normotensive group. There was no significant change with respect to CF, CR, FD PWV in the PHCON or NORMCON groups after 8 weeks. Both CR and FD PWV peripheral indices of arterial stiffness, were reduced in the PHRES and PHEND groups after 8 weeks of training. There were no significant decreases in C F PWV central ind ex of aortic stiffness, in PHRES and PHEND groups after training. Forearm and Calf Resistance Artery Blood Flow after Exercise Training Forearm and calf resistance artery blood flow results at rest and during reactive hyperemia are presented in Figures 4 8, 4 9, 4 10, 4 11, 4 12, and 4 13 There were no significant differences in resting, peak, or total area under the curve (total AUC ) calf blood flow measurements in the prehypertensive groups at baseline. Venous occlusion plethysmography demonstrated s ignificant reductions in calf resting, peak, and total AUC blood flow in the prehypertensive groups when compared to normotensive controls. There w as no significant change with respect to resting, peak, or totalAUC calf blood flow in the PHCON or NORMCON g roups after 8 weeks. As shown in Figures 4 8, 4 9, and 4 10 there were significant increases in resting, peak, and total AUC calf blood flow in the PHRES and PHEND groups after training.

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78 There were no significant differences in resting, peak, or totalAUC forearm blood flow measurements in the prehypertensive groups at baseline. Venous occlusion plethysmography demonstrated significant reductions in calf resting, peak, and total AUC blood flow in the prehypertensive groups when compared to normotensive cont rols. There was no significant change with respect to resting, peak, or totalAUC forearm blood flow in the PHCON or NORMCON groups after 8 weeks. As shown in Figures 4 11, 4 12, and 4 13 there were significant increases in resting, peak and totalAUC fore arm blood flow in the PHRES group after training. There were significant increases in peak and totalAUC forearm blood flow in the PHEND group after training. However, there was no significant change in resting forearm blood flow in the PHEND group after training. Vasoacti ve Balance Plasma levels of nitrate /nitrite (NOx), endothelin (ET 1), and NOx/ET 1 ratio are presented in Figure 4 14. NOx was significantly lower at baseline in the prehypertensive groups when compared to the normotensive control group (18.863.48, 18.843.34, 18.164.60, and 23.49 11.17 mol/L in PHRES, PHEND, PHCO N, and NORMCON, respectively; p< 0.05). There were no differences in plasma NOx levels between the prehypertensive groups at baseline. Plasma NOx levels were significantly i ncreased to the same magnitude after 8 weeks of either resistance or endurance training (18.863. 48 to 22.43 1.61 and 18.843.34 to 24.562.08 mol/L in PHRES and PHEND, respectively; p< 0.05). There were no differences in plasma ET 1 levels between the p rehypertensive groups at baseline. There were no significant changes in NOx in either control group. ET 1 was significantly higher at baseline in the prehypertensive groups when compared to the normotensive control group (1 .216 0.233 1 .244 0.272 1 .288 0.248 and 0.976 0.176 pg/ml in PHRES, PHEND, PHCO N, and NORMCON, respectively; p< 0.05). ET 1 was significantly decreased to the same magnitude after 8 weeks of

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79 either resistance or endurance train ing (1 .216 0.233 to 1 .023 0.205 and 1 .244 0.272 to 0.94 0 0.159 pg/ml in PHRES and PHEND, respectively; p<0.05). There were no significant changes in ET 1 in either control group. The ratio of NOx and ET 1 was significantly lower at baseline in the prehypertensive groups when compared to th e normotensive cont rol group (1 6 .32 6 .07, 1 5 .85 5 .97, 1 4 .54 4 .70, and 2 6 .761 4 48 in PHRES, PHEND, PHCON, and NORMCON, respectively; p<0.05). NOx/ET 1 was significantly increased after 8 weeks of both resistance and endu rance training (1 6 .32 6 .07 to 2 2 .581 0 .03 and 1 5 .85 5 97 to 2 7 .361 0 45 in PHRES and PHEND, respectively; p<0.05) Oxidative and Reductive Stress Balance Plasma levels of 8 iso Equivalent Antioxidant Capacity (TEAC) are presented in Figures 4 15 and 4 16. Plasma levels of 8 iso significantly lower in the prehypertensive groups when compared to the normotensive control group at baseline ( 410.06 73.46 394.62 136.40 411.38 127.11 and 701.50 452.10 pg/ml in PHRES, PHEND, PHCON, and NORMCON, respectively; p < 0.0 5). There were no differences in plasma 8 iso There were no significant changes in either PHRES or PHEND groups after training when compared to baseline (410.06 73.46 to 490.31155.42 and 394.6 2 136.40 to 475.80146.65, respectively; p>0.05). Plasma levels of TEAC were significantly lower in the prehypertensive groups when compared to the normotensive control group at baseline (122.4419.98, 121.6120.47, 119.4821.59, and 142.477.17 mMol Tro lox equiv/L in PHRES, PHEND, PHCON, and NORMCON, respectively; p > 0.05). There were no differences in plasma TEAC levels between the prehypertensive groups at baseline. There were no significant changes in TEAC in either control group. Plasma TEAC levels were significa ntly increased after 8 weeks of either resistance or

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80 endurance training ( 122.4419.98 to 141.91 10.55 and 121.6120.47 to 142.14 10.91 mMol Trolox equiv/L in PHRES and PHEND, respectively; p<0.05). Vaso dilation and Vaso constriction Factors P lasma levels of 6 keto PGF1 and ANG II are presented in Figures 4 17 and 4 18. Plasma levels of 6 keto compared to the normotensiv e control group at baseline (22 3 .25 6 .7, 23 5 .38 0 .3, 21 7 .85 4 .8, and 32 9 .212 8 5 pg/m L in PHRES, PHEND, PHCON, and NORMCON, respectively; p<0.05). Levels of 6 keto ance and endurance training (22 3 .25 6 .7 to 27 6 .47 9 .6 and 23 5 .38 0 .3 to 28 7 .79 6 4 pg/mL in PHRES and PHEND, resp ectively; p<0.05). There were no differences in plasma 6 keto between the prehypertensive groups at baseline. There were no significant changes in levels of 6 keto y different in the prehypertensive groups when compared to the normotensive group at baseline or following 8 weeks of exercise training or control time period (15.806.40 to 15.898.92, 16.486.80 to 16.248.54, 16.696.96 to 16.526.48, and 16.966.62 to 16.897.49 pg/mL in PHRES, PHEND, PHCON, N ORMCON, respectively; p>0.05).

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81 Table 4 1. Baseline subject characteristics before and after exercise training and time contro l PHRES PHEND PHCON NORMCON (N=15) (N=13) (N=15) (N=15) Before After Before After Before After Before Afte r Age, y 21.12.5 21.22.5 20.11.1 20.31.1 21.62.9 21.72.9 21.62.7 21.82.7 Height, cm 174.89.4 175.19.5 177.0 7.8 178.67.1 180.110.5 180.110.5 173.39.4 173.39.4 Weight, kg 84.218.4 85.018.9 86.714.1 84.112.7 87.816.8 88.517.8 80.913.1 81.713.1 BMI, kg/m 2 27.45.1 27.5 85.2 28.75.5 28.35.9 27.04.3 2 7.24.6 24.53.4 25.62.9 Resting HR, bpm 6313.8 6110.7 6417.9 566.2 607.5 587.5 578.8 587.2 Resting SBP, mmHg 130.43.1* 122.06.4 131.5 4.5 121.810.1 128.03.7* 130.17.1* 110.56.0 112.26. 3 Resting DBP, mmHg 80.35.8* 74.16.4 81.26.2* 75.13.2 80.67.6* 80.78.2* 67.03.7 67.76.2 Values are meanSD. BMI indicates body mass index; HR, heart rate; SBP, systolic blood pressure; DBP, diastolic blood pressu re. There were no significant differences between prehypertensive groups at baseline (P>0.05). Signific ance values are reported from between group and between timepoint repeated measures ANOVA and Tukey post hoc analysis. *P<0.05 versus normotensive control values at same timepoint. Table 4 2. Brachial artery flow mediated dilation before and after exerc ise training and time control PHRES PHEND PHCON NORMCON (N=15) (N=13) (N=15) (N=15) Before After Before After Before After Before After Baseline diameter (mm) 4.180.15 4.290.16 3.910.17 4.010.18 3.990.14 4.050.15 4.240.15 4.400.16 Absolute dilatio n (mm) 0.260.03 0.340.04 0.220.03 0.340.03 0.240.03 0.180.03 0.350.03 0.360.04 FMD (%) 6.170.89 8.301.15 5.920.97 9.641.25 6.200.83 8* 5.851.07 8.230.89 8.301.15 Normalized FMD (s 1 ) 0.210.03 0.250.03 0.160.02 0.280.03 0.190.04 0.190.03 0.290.02 0.290.04 Values are meanSEM. FMD indicates flow mediated dilation. Significance values are reported from between gro up and between timepoint repeated measures ANOVA and Tukey post hoc analysis. *P<0.05 baseline versus normotensive versus pretreatment values.

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82 Table 4 3. Pulse wave analysis before and after exercise training and time control PH RES PHEND PHCON NORMCON (N=15) (N=13) (N=15) (N=15) Before After Before After Before After Before Af ter R est ing HR, bpm 60.93.37 58.12.44 66.53.94 59.92.85 64.43.26 60.32.37 57.03.49 57.82.53 PSBP, mmHg 130.51.02 120.91.52 130.81.14 119.61.70 130.6 0.96* 128.51.43* 110.01.06 110.91.57 PDBP, mmHg 79.51.37 72.31.51 80.31.53 74.01.69 79.81.28 78.61.42 67.31.42 67.11.57 PMAP, mmHg 94.12.02 85.41.91 94.12.26 86.32.13 94.81.90 94.31.79 8 79.12.09 81.01.97 PPP, mmHg 54.43.10 48.53.23 50.53.47 45.63.61 50.8 2.69 49.9 2.80 42.73.21 43.83.35 ASBP, mmHg 113.71.48 103.51.75 113.81.66 103.21.96 113.61.39 110.51.64 93.51.53 94.11.81 ADBP, mmHg 80.31.50 72.81.61 81.41.67 74.41.80 80.81.41 78.21.51 67.81.55 67.71.66 AMAP, mmHg 95.01.54 86.41.84 96.61.67 88.11.99 95.71.44 92.61.72 79.11.54 79.81.84 APP, mmHg 33.51 .14 30.71.23 32.41.27 28.81.37 32.81.07 32.41.15 25.71.18 26.41.27 AgBP, mmHg 3.871.06 0.730.93 3.671.19 1.171.04 3.651.00 3.530.88 0.07 1.10 0.070.97 AIx, % 10.732.90 3.202.81 11.173.24 3.083.14 9.562.65 8.392.57 2.293.00 1.212.91 AIx@75, % 3.733.29 5.733.27 6.273.84 3.003.82 4.633.19 3.003.17 10.153.54 9.463.51 p, ms ec 156.68.01 173.08.76 159.58.29* 172.69.07 157.97.53 160.18.23 196.88.29 194.49.07 r, ms ec 176.17.52 163.98.60 172.47.78 165.78.90 173.6 7.06 172.38.08 144.27.78 145.28.90 ED, ms ec 3325.31 3374.78 3325.49 3384.95 3324.99 3324.49 3415.49 3404.95 LVE W dynes 620168 47154 681174 109160 600153 544141 8174 25160 ASTTI 213589 188977 228699 192886 218683 210073 1 68992 169280 DPTI 358675 334067 351684 332375 348771 345263 307178 309269 SEVR % 165.98.76 180.18.80 159.89.79 175.49.84 162.18.23 164.28.27 184.69.07 186.49.11 Values are meanSEM. HR indicates heart rate; PSBP, peripheral systolic blood pressure; PDBP, peripheral diastolic blood pressure; PMAP, peripheral mean arterial pressure; PPP, peri pheral pulse pressure; ASBP, aortic systolic blood pressure; ADBP, aortic diastolic blood pressure; AMAP, aortic mean arterial pressure; APP, aortic pulse pressure; AgBP, augmented blood pressure; AIx, augmentation index; AIx@75, augmentation index normali zed for heart rate; p, round trip travel time of reflected pressure wave from ascending aorta to peripheral reflecting sites and back; r, systolic duration of reflected wave; ED, ejection duration; LVE W left ventricular wasted energy; ASTTI, aortic systolic tension time index; DPTI, diastolic pressure tension index; SEVR, sub endocardial viability ratio Significance values are reported from between group and between timepoint repeated measures ANOVA and Tukey post hoc analysis. *P<0.05 baseline versus normotensive contr

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83 Table 4 4. Pulse wave velocity before and after exercise training and time control PHRES PHEND PHCON NORMCON (N=15) (N=13) (N=15) (N=15) Before After Before After Before After Before After Carotid Femoral msec 6.94 0.18 6.81 0.18 6.92 0.20 6.86 0.20 7.02 0.17 7.04 0.17 6.55 0 .18 6.59 0.18 Carotid Radial, msec 8.810.30 7.810.30 8.630.36 7.710.35 8.780.28 8.750.27 7.920.31 7.900.31 Femoral Dista l, msec 10.41 0.25* 9.39 0.27* 8.93 0.23 10.19 0.33* 8.60 0.25 8.62 0.36 Values are meanSEM. Significance values are reported from between group and between timepoint repeated measures ANOVA and retreatment values. Table 4 5. Forearm and calf v enous occlusion plethysmography before and after exercise training or time control PHRES PHEND PHCON NORMCON (N=15) (N=13) (N=15) (N=15) Before After Before After Before After Before After Resting FBF 1.67 0.14 1.92 0.14 1.72 0.17 1.61 0.16 1.65 0.12 1.69 0.12 2.02 0.17 2.12 0.17 Peak FBF 13.7 1.19 16.7 1.03 15.2 1.39 18.5 1.20 1 4.5 1.03 14.2 0.89* 16.3 1.03 16.2 1.03 Total FBF AUC 3min 5.04 0.53 6.09 0.85 5.14 0.62* 5. 92 1.00 4.78 0.46 4.83 0.74 6.19 0.85 6.13 0.85 Resting CBF 1.70 0.14 2.29 0.18 1.80 0.17 2.08 0.23 1.76 0.12 1.76 0.16 2.30 0.18 2.29 0.18 Peak CBF 14.3 1.16 19.9 1.36 16.5 1.42* 24.5 1.66 15.1 1.00 14.8 1.17* 20.9 1.36 21.0 1.36 Total CBF AUC 3min 3.870.45 5.330.72 3.140.56 6.270.89 3.820.39 3.850.63 4.870.45 4.93 0.72 Values are meanSEM. FBF indicates forearm blood flow; AUC, area under the curve; CBF, calf blood flow. Significance values are reported from between group and between timepoint repeated measures ANOVA and Tukey post hoc analysis. *P<0.05 baseline

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84 Figure 4 1. Brachial artery flow mediated dilation (FMD) at baseline and after exercise training or time control. Data are expressed as meanSEM; *P<0.05. Figure 4 2. Aortic Augmentation index (AIx) at baseline and after exercise training or time control. Data are expressed as meanSEM. P*<0.05.

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85 Figure 4 3. Aortic augmentation index normalized for heart rate at 75 bpm at baseline and after exercise training or time control. Data are expressed as meanSEM. P*<0.05. Figure 4 4. Wasted le ft ventricular energy (LVEW) at baseline and after exercise training or time control. Data are expressed as meanSEM. P*<0.05.

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86 Figure 4 5. Carotid femoral pulse wave velocity (PWV) at baseline and after exercise training or time control. Data are expressed as meanSEM. P*<0.05. Figure 4 6. Carotid radial pulse wave velocity (PWV) at baseline and after exercise training or time control. Data are expressed as meanSEM. P*<0. 05.

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87 Figure 4 7. Carotid radial pulse wave velocity (PWV) at baseline and after exercise training or time control. Data are expressed as meanSEM. P*<0.05. Figure 4 8. Resting calf blood flow at baseline and after exercise training or time control. Data are expressed as meanSEM. P*<0.05.

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88 Figure 4 9. Peak calf blood flow at baseline and after exercise training or time control. Data are expressed as meanSEM. P*<0.05. Figure 4 10. Total calf blood flow at baseline and after exercise training or time control. Data are expressed as meanSEM. P*<0.05.

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89 Figure 4 11. Resting forearm blood flow at baseline and after exercise training or time control. Data are expressed as meanSEM. P*<0.05. Figure 4 12. Peak f orearm blood flow at baseline and a fter exercise training or time control. Data are expressed as meanSEM. P*<0.05.

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90 Figure 4 13. Total forearm blood flow at baseline and after exercise training or time control. Data are expressed as meanSEM. P*<0.05.

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91 Figure 4 1 4 NOx, ET 1, and N Ox/ET 1 at baseline and after exercise training or time control. Data are expressed as meanSEM. P*<0.05.

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92 Figure 4 1 5 8 Isoprostane PGF2 at baseline and after exercise training or time control. Data are expressed as meanSEM. P*<0.05. Figure 4 1 6 Trolox Equivalent Antioxidant Capacity (TEAC) at baseline and after exercise training or time control. Data are expressed as meanSEM. P*< 0.05.

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93 Figure 4 1 7 6 at baseline and after exercise training or time control. Data are expressed as meanSEM. P*<0.05. Figure 4 1 8 Angiotensin (ANG II) at baseline and after exercise training or time control. Data are expressed as mean SEM. P*<0.05.

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94 CHAPTER 5 DISCUSSION Main Findings To date and to our knowledge, this is the first randomized normotensive controlled study to evaluate the independent effects of 8 weeks of resistance and endurance exercise training on endothelial functio n, arterial stiffness, and blood flow in young prehypertensives. The major findings of the present study are that 8 weeks of resistance or endurance exe rcise training similarly reduce peripheral and central blood pressures, improve endothelial function an d blood flow, and reduce arterial stiffness in young prehypertensives. Peripheral Resting Systolic and Diastolic Blood Pressure The present study demonstrated that 8 weeks of resistance or endurance training in previously sedentary unmedicated prehypertens ives leads to significant reductions in resting systolic and diastolic blood pressure. Fif ty minutes of whole body progressive resistance training consisting of 2 sets of 8 12 repetitions with incrementally increased weights that elicit volitional fatigu e 3 times per week for 8 weeks resulted in reductions in resting systolic and diastolic blood pressure by 8mmHg and 6mmHg, respectively (Table 4 1) Additionally, fifty minutes of treadmill endurance interval training with incremental workrate increases 3 times per week for 8 weeks resulted in reductions in resting systolic and diastolic blood pressure by 10mmHg and 6mmHg, respectively ( Table 4 1) The results of the present study are in agreement with those of Bavikati et al. in a large cohort study of p rehypertensives (n=2478) who participated in community based programs implementing therapeutic lifestyle changes. 49 These co mmunity programs targeted changes in nutrition, weight management, stress management, smoking cessation, and exercise training interventions. Resting blood pressures were reduced in both resting systolic and diastolic blood pressure by an average of 7 an d 6 mmHg respectively. 49

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95 The findings of the present study are also in agreement with previous studies in normotensives. Ca rter et al. found that 8 weeks of resistance exercise training in previously untrained young (210.3, meanSEM) normotensives resulted in decreases in both systolic and diastolic blood pressure by 9 and 8 mmHg respectively. 24 These peripheral blood pressure reductions were not accompanied by changes in muscle sympathetic nerve activity (MSNA). 24 Sinoway et al. reported an attenuated sympathetic response and decreased arterial pressure during dynamic handgrip exercise after forearm resistance training. 63 These reports are contrary to the idea that chronic resistance training results in increased basal levels of sympathetic outflow and humoral concentrations of epinephrine an d norepinephrine In young prehypertensives Collier et al. found that after only 4 weeks of endurance training systolic and diastolic blood pressure was reduced by 5mmHg and 3mmHg, respectively. 44 Further they found that resistance training result ed in similar decreases in both systolic and diastolic blood pressure by 4mmHg and 4mmHg, respectively. A continuous and consistent relationship exists between blood pressure and risk of cardiovascular disease events which is independent of other risk fa ctors. 4 Simply, t he higher the blood pressure the greater the chance of myocardial infarction heart failure, stroke, and kidney disease. Our results are clinically significant based on the findings of Whelton et al. which show ed a 5 mmHg reduction in systolic blood pressure results in a 14, 9, and 7 percent decrease risk in stroke, coronary heart disease, and overall mortality, respectively. Blood pressure reduction is the primary goal of hypertension therapy. 4 Brachia l Artery Endothelial Function and Exercise Training The present study further demonstrates that prehypertensives exhibit reduced conduit artery endothelial function and NOx bioavailability when compared to young normotensives as assessed by brach ial artery FMD. T his study also demonstrated that 8 weeks of resistance or

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96 endurance exercise training improves brachial artery endothelial function and the improvements may be due, in part, to increase s in NOx bioavailability ( 19% and 23%, respectively ) reduction s in the vasoconstrictor ET 1 ( 16 and 24%, respectively) and subsequently improved NOx/ET 1 ratio (Figure 4 14) Previous studies of the effects of resistance training on endothelial function are equivocal. This may be due in part to the inclusion of young normotensive participants who exhibit normal endothelial function prior to study inclusion. Recently, Gian n otti and colleagues evaluated endothelial function and repair capacity of early endothelial progenitor cells (EPCs) in older normotensive, pre hypertensive, and hypertensive men and women. 199 They reported a decrease in radial artery endothelial function in prehypertensives when compared to matched normotensives. Our study confirms these results in young prehypertensives. The present study demonstrated that young sedentary prehypertensives exhibit reduced endothelial dependent vasodilation, as measured by brachial artery flow mediated dilation, by 31%, 26%, and 36% for absolute dilation in millimeters, percent dilation, and percent dilation normalized to shear rate, respectively (Table 4 2) Giannotti et a l. also reported that i n vivo endothelial repair capacity of early EPCs was also reduced in prehypertensives and this reduction was positively correlated with FMD which suggests that impaired early EPC mediated repair capacity in prehypertensives is relate d to the reduced endothelial dependent vasodilation. 199 Moreove r, nitric oxide production was decreased providing an additional possible mechanism for the observed reduction in endothelial function. 199 MacEneaney et al. reported impairment in EPC colony formation in prehypertensive adults with systolic blood pressures greater than 130 mmHg, similar to the pressures exhibited in o ur study. 200 EPC colony forming capacity is related to flow mediated brachial artery vasodilation. 201 It was reported by Rehman et al. that exercise acutely

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97 increases EPCs and cultured/circulating angiogenic cells in previously sedentary older subjects (5410 years). 202 However, it is unknown at this time if exercise can alter the EPC phenotype described by Giannotti and colleagues. 199 The results of the present study show that 8 weeks of endurance training improved change in brachial FMD abs olute diameter, percent dilation, and normalized percent dilation by 54%, 63%, and 75% (Table 4 2) Additionally, we found that 8 weeks of resistance training improved but to a lesser magnitude brachial artery FMD change in absolute diameter, percent di lation, and normalized percent dilation by 30%, 34%, and 19%, respectively (Table 4 2) These significant improvements in the exercise trained prehypertensive groups resulted in flow mediated dilation values that were not significantly different from thos e exhibited by our se dentary normotensive controls. Previously we found no change in brachial artery FMD following 12 weeks of resistance training in young normotensives 203 Th ose results likely differ due to the presumably normal endothelial function of the normotensive subjects resulting in no changes in function after training. Indeed, t he bene fits of exerci se on endothelial function in a symptomatic subjects are less consistent than in subjects who exhibit decreased endothelial function before exercise treatment. 204 Ho wever, Ray et al. demonstrated that isometric handgrip training improved endothelial function and decreased resting arterial blood pressure without altering sympathetic nerve activity or resting heart rate pathetic outflow. 53 Additionally Tinken et al. reported improvement s in brachial artery FMD in normotensive subjects following 6 weeks of forearm resistance exercise The authors concluded that exercise induced increases in shear stress are responsible for th e improved endothelial function and vascular remodeling. 65 Further, Okamoto et al. demonstrated that whole body low intensity resistanc e training for 10 weeks in young normotensives resulted in improved brachial

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98 artery flow mediated dilation with no change in baseline artery diameter 205 In a study of unila teral strength training in previously sedentary subjects, Zoeller and colleagues used magnetic resonance imaging to determine brachial artery diameter and cross sectional area of the biceps brachii before and after training. Artery diameter was increased an average of 5.5% in the trained arm with no change in the untrained arm. 51 The increase in resting diameter suggests a unique adaptation caused by resistance trai ning that may be mediated by persistent chemical stimuli that affect arterial tone (NO, ET 1, ANGII). 51, 52 in prehypertensives as well as in the present study of prehypertensives baseline artery diameters and blood flow were not significantly differen t between trained and unt rained control groups. 199 In summary, both resistance and endu rance training independently improve endothelial function in previously sedentary young prehypertensives. The mechanism for the improvement in FMD response following exercise training is likely due to improvement in NO bioavailability. In the present stu dy we observed increased resting levels of NOx after 8 weeks of exercise training (~25 %) which suggests an increase in NO production (Figure 4 14) At study entry, the prehypertensive groups exhibited significantly lower levels of NOx when compared to n ormotensive controls. To our knowledge this is a novel finding that has not been previously reported in young prehypertensives. Both the resistance and endurance trained groups showed post exercise intervention improvements in plasma NOx levels of 19% a nd 30%, respectively (Figure 4 14) This improvement in endothelial function may have been due to the upregulation of eNOS and the subsequent increase in the production and release of endothelial derived NO 18, 204 This is important in prehypertension because arterial stiffness and decreased endothelial function are mechanisms responsible for increased blood p ressure in this group.

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99 To our knowledge and to date, there appears to be few animal studies that have examined the effects of resistance training on endothelial dysfunction Available studies appear to confirm results of the present study and demonstrate endothelial function improvement after resistance training. 206, 207 Figard et al. reported improvement in endotheliu m dependent relaxant response to acetylcholine in the thoracic artery of ovariectomized rats following resistance training They concluded that the increased endothelial function was mediated by improvements in cyclooxygenase products, Ca 2+ pathways, and endothelium derived hyperpolarizing factor (EDHF), contributing to NOS activation. 206 The training induced improvement in endothelial function was accompanied by a significant reduction in resting systolic blood pressure. These results were confirmed by Harris et al. who reported improved femoral artery endothelial function in young and old resistance trained male Fisher 344 rats. 207 In this study, it was further determined that the improvement in endothelial function was not due to an increase in eNOS protein expression or phosphorylation but rather may be the result of increased Hsp90 expression thereby upregulating eNOS activity 207 The major functions of Hsp90 are folding newly synthesized proteins and translocation of proteins in the cytosol, nucleus, and endoplasmic reticulum The improve ment in endothelial function and NO bioavailability after exercise training may be a result of alterations in early EPC phenotype, repair capacity, and colony forming capacity as well as endothelial cell function through the shear stress mediate d mechanotr ansduction pathway. Shear Stress and Mechanical Transduction Improvement in endothelial dysfunction with exercise is not mediated by changes in cardiovascular risk factors but rather by an independent adaptation to exercise and shear stress. 66 The hyperemic blood flow and intermittent increase in pressure during exercise tra ining results in an increase in shear stress along the intimal wall of the arteries. Based on the current body of

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100 evidence shear stress appears to be the mechanism and key signal to the improvements in vascular function induced by exercise. The cytoskele ton has a c entral role in the transmission of tension changes mediated by shear stress, throughout the cell in the decentralized model of endothelial mechanotransduction 69 Direct sign aling can occur through deformation of the luminal surfac e. L ocalized activation of potassium, sodium and calcium ion channels, phospholipase activity leading to calcium signaling, G protein activation and caveolar signaling all work in concert 69 Mechanotransduction is also mediated through junctional signaling Junctional signaling is the transmission of forces to intercellular junction protein complexes by way of the cortical and/or filamentous cytoskeleton. Vascular endothelial growth factor ( VEGFR2 ) located at the luminal surface or near the junction can associate with VE catenin, and phosphatidylinositol 3 kinase to phosphorylate Akt and the primary transmembrane protein at this location Cytoskeletal forces are also transmitted to adhesion sites. Transmembrane integrins bound to the extracellular matrix serve as a focus for deformation. This deformation results in autophosphorylation of FAK, which binds the SH2 domain of c Src, a kinase family that phosphorylates paxillin and p130cas and leads to integrin dependent activation of MAP kinases via Ras GTPase. 81 A second parallel integrin mediated pathway involves the activation of Shc, which binds Src family kinases through SH2 domains. Shc phosphorylation leads to Ras MAP kinase activity. 81 Ras relea ses the trans s cytosolic inhibitor, and thus enables its translocation to the nucleus where it binds to the promoters of multiple target genes. 81 A third integrin mediated pathway involves rhoA activation, wh ich prof oundly influences actin assembly and, therefore, transmission of mechanical stimuli. 69 Nuclear deformation is also likely to result in mechanically induced signaling

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101 V ascular adaptatio n, even in vascular beds distant from active muscle, may occur due to the exercise increases in pulse pressure and blood flow. The effects of resistance training on vascular improvement seem to be similar to those of endurance training. 208 In fact, Tinken and Green concluded in a recent publication that resistance exercise induced alterations in shear stress are responsible for the improved endothelial function and vascular remodeling associat ed with and in response to resistance exercise in human subjects. 65 Arterial Stiffness, Pulse Wave Characteristics, and Central Blood Pr essure The present study demonstrates that young prehypertensives exhibit increased peripheral arterial stiffness and central aortic blood pressures when compared to age matched normotensives as assessed by pulse wave analysis. However, central aortic st iffness was not evident. The present study also demonstrated that 8 weeks of resistance or endurance exercise training reduces peripheral arterial stiffness and central blood pressures. Peripheral arterial stiffness, as measured by pulse wave velocity, wa s increased in prehypertensives for carotid to radial and femoral to dorsalis pedis artery by 10% and 21%, respectively (Table 4 4) Zhu et al. reported in a large cohort study of American youth that prehypertensives exhibit increased radial and foot puls e wave velocity but central aortic PWV was normal 8 This finding is comparable to what is reported in older prehypertensives 8, 209 In a study conducted in middle aged Korean adults with prehypertension, Kim et al. found increases in brachial ankle pulse wave velocity. 210 In their study central artery velocity is incorporated in the brachial to ankle index. In the present study we observed no significant differences in carotid to femoral artery (cen tral) pulse wave velocity when compared to normotensives. Based the observations of the present study and the findings of Zhu, any increase in aortic PWV seems to be passively caused by the increases in the peripheral artery velocities 8 Alternatively, these differ ences could be the result of the increased central stiffness associated with advancing age or

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102 persistent and unaltered prehypertension in the middle aged Korean subjects Increased arterial stiffness is a hallmark of alterations in the common carotid inti ma media layer in aging, where the elastin is infiltrated with collagen and fibrin decreasing the elastic properties of the vessel. Kim and colleagues also report a significant increase in left ventricular mass and carotid artery medial thickening in the middle aged adults (526 years) with pre hypertension but this has yet to be reported in young prehypertensives. 210 The comparison of the effects of resistance and endurance training on PWV in prehypertensives is understudied. In one of the few repo rts, Collier et al. found that after 4 weeks of endurance training in pre and stage 1 hypertensives decreased pulse wave velocities in carotid to femoral and femoral to dorsalis pedis, whereas 4 weeks of resistance training resulted in significant increas es in PWV in both measures. 44 The authors concluded that resistance training increases arterial stiffness in pre and stage 1 hypertensives 44 This may be due to an acute but transient vascular altera tion to resistance training. For instance when comp aring chronic resistance trained subjects to age, gender, and blood pressur e matched non resistance trained subjects an acute bout of resistance exercise impair s the endothelial function in the unconditioned subjects, whereas, endothelial funct ion in the chronic resistance trained subjects remained unchanged. 62 More importantly, the same authors reported no significant differences in flow mediated dilation response between chronic resistance trained subjects compared to non resistance trained subjects. 62 These data suggest th at chronic resistance training may protect against transient vascular dys function and that resistance training protects against the adverse affects of a resistance load in hypertensives. 62 This may explain the transient arterial stiffness reported, by a few investigators, when measurements are made in previously sedentary subjects, especially after beginning a high intensity resistance training program and having measurements

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103 of arterial stiffness after a short period following baseline. Further research in this area needs to be performed. Celik et al. reports stiffness index of the carotid artery in middle aged prehypertensives when compared to age matched (346 years) normotensives. 10 But in young prehypertensives (204 years) Zhu and colleagues reported no significant differences in left ventricular wall thick ness in prehypertensives when compared to matched normotensive controls. 8 Additionally, the present study demonstrated that 8 weeks of resistance or endurance exercise training improves peripheral arterial stiffness, as measured by arterial pulse wave velocity Res istance training reduced carotid to radial and femoral to dorsalis pedis artery pulse wave velocity by 11%, and 10%, respectively (Table 4 4) Similarly, endurance training reduced carotid to radial and femoral to dorsalis pedis artery pulse wave velocity by 10% and 13%, respectively (Table 4 4) Moreover, these improvements in peripheral pulse wave velocity resulted in PWV values which were not significantly different from matched sedentary normotensives. The increases in central pulse wave velocity, le ft ventricular mass, and carotid artery stiffness observed in prehypertensives over the age of 35 years may be a consequence of the elevated central pressures persisting over a decade or more T hese cardiovascular structur al abnormalities remain undetecte d in the young prehypertensives Hypertension, as determined from standard brachial artery sphygmomanometry is a well established cardiovascular risk factor. However, peripheral blood pressure measurements, obtained by standard brachial artery ( cuff) techniques, are not always a reliable measure of ascending aorta pressure. 60 In fact, data from The Strong Heart Study have shown that non invasively obtained central arterial pressure is more strongly related to cardiovascular outcomes and central pressure is a stronger stimulus to left ventricular hypertrophy than brachial

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104 pressu re 61, 211 The present study confirmed that young sedentary prehypertensives exhibit increased aortic pulse, mean arterial, and augmented pressure when compared to matched normotensives. More importantly, the present study demonstrated that 8 weeks of resistance or endu rance exercise training improves central pulse, mean arterial, and augmented pressure. The findings of the present study agree with those reported by Heffernan et al. in a study of the effects of 6 weeks of resistance training in normotensive men. 26 In the present study aortic m e a n arterial pressure was reduced in the resistance and endurance trained groups by 8 .6 and 8.5 mmHg, respectively (Table 4 3) However aortic pulse pressure was significantly reduced in just the endurance training group by 3.6 mmHg (Table 4 3) In the r esistance training group the average 2.8 mmHg reduction in aortic pulse pressure did not reach significance and resulted in only a trend (p=0.10). Augmented pressure due to early reflection of the pulse pressure wave form was significantly reduced by re sistance and endurance training by 81% and 68%, respectively (Table 4 3) Moreover, these improvements in central pressures resulted in aortic pulse, mean arterial, and augmented pressure values which were not significantly different after exercise traini ng from matched sedentary normotensives A ortic pulse pressure in the resistance training group remained significantly different from normotensives The timing and amplitude of the reflected wave to ascending aortic pulse pressure can be estimated by the aortic augmentation index (AI x ). The findings of the present study de monstrate that young prehypertensives have an elevated AIx AIx normalized to heart rate (AIx@75) and left ventricular wasted energy (LVE W ) when compared to normotensives. AIx and AIx@ 75 across all groups of prehypertensives averaged 10.52.9% and 4.93.4% compared to 2.33.0% and 10.23.54% in normotensives, respectively (Table 4 3) These data in young prehypertensives are in agreement with findings in older prehypertensives. Gedl iki et al.

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105 reported, in a recent study of older (306) prehypertensives, significantly increased AIx in prehypertensives compared to age matched normotensive controls. 209 In the present study, the increases in aortic pressure wave char a cteristics led to an increased LVE W in prehypertensives (633165 dynes s/cm 2 ) when compared to normotensives ( 8174 dynes s/cm 2 ) (Table 4 3) LVE W is an index of ex tra myocardial oxygen requirement that is due to early systolic wave reflection and depends on the amplitude of central aortic pressure augmentation and systolic duration of the pressure wave 212 Increased LVE W resulting from enhanced wave reflection contributes to the development of left ventricular hypertrophy. 212 Prehypertensives not only exhibit increased left ventricular mass and wall abnormalities but have a significantly greater age related increase in left ventricular wall thickness and increased incidence of lef t ventricular remodeling compared with normotensive individuals. 213, 214 The increased LVE W observed in the present study may contribute to the increased left ventricular mass reported in older but not in younger prehypertensives. The findings of the present study demonstrat e that 8 weeks of resistance or endurance exercise reduces AIx and LVE W in prehypertensives. Resistance training reduced AIx, AIx@75, and LVE W by 7.5%, 9.5%, 573 dynes s/cm 2 respectively (Table 4 3) Endurance training was similarly efficacious in reduc ing AIx, AIx@75, and LVE W by 8%, 9.3%, and 572 dynes s/cm 2 respectively (Table 4 3) In the present study the reductions in LVE W were primarily due to reductions in augmented pressure. In the present study we observed no significant reductions in the sy stolic duration of the reflected pressure wave. Based on the findings of the present study we reason that the reductions in peripheral arterial stiffness may be explained by the improvements in endothelial function and vasoactive balance. Whereas the redu ctions in augmentation index and central pressures are secondary to decreases in arterial stiffness.

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106 Peripheral Resistance Artery Endothelial Function and Exercise Training T o date and to our knowledge t he present study is the first to report that young prehypertensives exhibit reduced resistance artery endothelial function when compared to young normotensives as assessed by forearm and calf venous occlusion plethysmography (VOP) Additionally, this study demonstrated that 8 weeks of resistance or endur ance exercise training improves resistance artery endothelial function as assessed by forearm and calf VOP. T he present study demonstrates that young prehypertensives exhibit reduced resting, peak, and total blood flow (total AUC ) in both the calf and forea rm when compared to age matched normotensives. Forearm resting, peak, and total AUC were ~ 17%, 11%, and 13% lower in prehypertensives, respectively (Table 4 5) Calf resting, peak, and total AUC were ~ 23%, 26%, and 26% lower in prehypertensives, respectiv ely (Table 4 5) In the present study microvascular blood flow increased in both the forearm and the calf following 8 weeks of resistance or endurance training. Forearm resting blood flow was increased by 15% after resistance training whereas in the endu rance trained group there was no significant change from baseline. However, after 8 weeks of endurance training, peak and total AUC blood flow in the forearm was increased by 22% and 15%, respectively (Table 4 5) Resistance training similarly increased f orearm peak and total AUC by 22% and 21%, respectively (Table 4 5) Calf resting, peak, and total AUC increased after resistance training by 34%, 39%, and 37%, respectively (Table 4 5) After endurance training resting and peak blood flows were increased b y 16% and 48%, whereas total AUC increased by almost 2 fold in these previously sedentary prehypertensives (Table 4 5) These findings are somewhat suppor ted in the current literature. Bank et al. reported increased peak forearm reactive hyperemic blo od flow and vasodilation in response to the NO agonist acetylcholine in healthy subjects following forearm resistance exercise. 215 The results of

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107 Bank et al. are bolstered by the work of Heffernan and colleagues who rep ort ed significant increases in forearm blood flow and reductions in forearm vascular resistance following 6 weeks of resistance training in young normotensives 26 Resistance training not only improved microvascular function and limb blood flow but the improvements were maintained after 4 weeks of detraining. 26 These data suggest that the beneficial effects after resistance training may not be transient. In a study of the effects of resistance and aerobic training in older (48.21.2 years) pre and stage 1 hypertensives Collier et al. reported significan t improvements in microvascular vasodilatory capacity as measured by venous occlusion plethysmography. 44 In that study, resting, peak, and total area under the curve forearm blood flow increased after 4 weeks of resistance or endurance training. 44 Increased post occlusion blood flow suggests increased capillary or arteriolar proliferation and enhanced resistanc e vessel endothelial function. There is evidence that resistance training can elicit vascular adaptations similar to changes that we re previously found primarily following chronic aerobic endurance training. Since these blood flow measurements are indicative of the vasodilatory capacity of the resistance vessels and are due to factors such as nitric oxide availability, it is possible that both resistance and endurance training may upregulate nitric oxide signaling similarly, leading to the increase in limb blood fl ow after training. Vasoactive Balance In addition to the evidence of arterial dysfunction, t he present study provides novel biochemical evidence of endothelial dysfunction. P re hypertensives exhibit reduced nitric oxide and prostacyclin bioavailability and increased levels of endothelin This study also demonstrated that 8 weeks of resistance or endurance exercise training im proves NO and PGI2 bioavailability and reduces the vasoconstrictor ET 1, and subsequently improve s NOx/ET 1 ratio.

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108 In the pr esent study we observed that N O x and 6 keto were significantly lower in prehypertensives ~20% and 31% than normotensive values, respectively (Figure 4 14) Sedentary prehypertensives exhibited higher plasma levels of ET 1 by ~28% when compared to matched norm otensives (Figure 4 14) S ubsequently, the NOx/ET 1 ratio was significantly lower by ~41% in prehypertensives when compared to normotensives (Figure 4 14) Exer cise training has generally been shown to be beneficial to the vasculat ure. This research has primari ly focused on th e improvements to the endothelial nitric oxide ( eNOS ) pathway. Our prehypertensive participants exhibited reduced endothelial function and plasma levels of NOx at study entry T herefore the improvements in FMD, VOP, and NOx after 8 weeks of resistance o r endurance training are not surprising. In the present study plasma levels of NOx improved by ~19% and 23% in the resistance and endurance trained groups, respectively (Figure 4 14) Endothelin is recognized as the most potent endothelium derived vasoc onstrictor. 216 It has been suggested in a small number of longitudinal training studies that exercise exerts a direct effect on this vasoconstrictor pathway in healthy older adults 217 219 To date and to our knowledge, this is the first study to evaluate the effects of exercise training on plasma levels of ET 1 and ar terial function in young prehypertensives. The results of the present study demonstrate that resistance and endurance training reduced the levels of ET 1 in young prehypertensives by ~16 and 24% (Figure 4 14) Prostaglandins are released from t he endothelium in response to both mechanical and humoral stimuli and can profoundly affect peripheral vascular resistance. Prostacyclin (PGI 2 ), a potent vasodilator is detected in plasma by measuring levels of the major metabolite of prostacyclin, 6 ket o PGF S imilar to nitric oxide shear stress is one of the major stimuli for

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109 PGI 2 release In the present study prehypertensives exhibited ~31% reduced plasma level of 6 keto PGF when compared to normotensives ( Figure 4 17) Resistance and enduranc e training increased levels of 6 keto PGF by 19% and 22%, respectively (Figure 4 17) The results of the present study demonstrate that resistance and endurance training increased levels of 6 keto PGF comparably in young prehypertensives (Figure 4 17) In the present study we utilized plasma measures of 8 isoprostane (8 iso PGF ) and Trolox equivalent antioxidan t capacity (TEAC) as an index of total oxidative stress and total antioxidant status, respectively. Surprisingly, plasma levels of 8 iso PGF in our groups of young sedentary prehypertensives were lower by ~42% when compared to our normotensive control group (Figure 4 16) This finding is contradictory to a previous report from Sathiyapriya et al. who compared slightly older prehypertensives a nd normotensives (369 and 398 years), respectively. 86 Those authors reported significant increases in oxidat ive stress when measur ing malondialdehyde (MDA) an end product of polyunsaturated fatty acid peroxidation and protein carbonyl a biomarker of protein oxidation in whole blood. 86 Their results suggest that oxidative stress is present in prehypertensives and free radical damage is reflected systemically. Further, they determined that reduced glutathione (GSH) and catalase were significantly elevated and glutathione peroxidase was significantly reduced, suggesting that the antioxidant defenses in prehypertensives are compromised. 86 They conclude that prehypertensives may exhibit an imbalance in the oxidant/antioxidant ratio. In the present study we observed significant reductions at study entry in antioxidant capacity in all groups of young prehypertensives by ~ 15% when compared to normotensive age matched, and activity matched controls (Figure 4 16) After both resistance and endurance training we report a significant increase in TEAC by ~16% and 17%, respectively (Figu re 4 16)

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110 Additionally, we observed a ~20% and 21% increase in plasma levels of 8 iso PGF in the resistance and endurance trained groups, respectively (Figure 4 16) Oxidant/Antioxidant balance in plasma is sensitive to a host of redox sensitive appara tus of both the cellular and extra cellular compartments. Due to the lack of direct enzymatic analysis, we can only conclude that there appears to be a disparity in redox balance in young prehypertensives. Angiotensin is a regulator of blood volume and a powerful vasoconstrictor I t is thought that exercise induced reductions in blood pressure may be the result of reductions in plasma renin. 127 Increases in renal angiotensin II content and tubular angiotensin II receptors were reported in a study of prehypert ensive spontaneously hypertensive rats. 134 In a study of vasoactive substances in older h umans (48.88.9 years), Wang et al. reported a stepwise increase in ANGII levels when comparing normotensive, prehypertensive, and hypertensives. 13 Although the plasma levels of ANG II were significantly higher in hypertensives when compared to normotensive s the smaller increases between prehypertensives and normotensives did not reach significance Although the available research is equivocal regarding the role of ANGII in prehypertension, it is important to include the renin an g iotensin aldosterone syste m (RAAS) when discussing interventions and the management of prehypertensives. 123, 124, 220 222 Research suggests that plasma renin and ANG II levels are not altered by exerc ise training in hypertensives but they are reduced in normotensive subjects following exercise treatment. 128 133 R esearch in hypertension has primarily focused on older populations and it remains to be determined if exercise will reduce plasma renin and ANG II in young prehypertensives. In the pres ent study we observed no differences in resting plasma levels of ANG II between any prehypertensive groups and the normotensive controls. Further, we detected no significant differences in ANG II levels after 8 weeks of resistance or endurance training (F igure

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111 4 18) Based on these results we conclude that differences in levels of ANG II were not responsible for the increased blood pressures and arterial stiffness in our cohort of young prehypertensives before or after exercise training. Conclusions Exercise is recommended by the JNC7 as the primary and first line intervention for prehypertension. To date, however, there have been few studies examining the efficacy of either endurance or resistance exercise in young prehypertensives. The present ran domized normotensive controlled study was designed to determine the independent effect s of 8 weeks of either resistance or endurance exercise on blood pressure and arterial function in young prehypertensives. Prehypertensives are at increased risk of deve loping hypertension cardiovascular disease and t ype II d iabetes. 48 Increased physical fitness reduces the likelihood of pre hypertensives developing essential hypertension. 23 A strong, inverse and graded association between exercise capacity and all cause mortality has been observed in prehypertensive individuals and the protective effects of increased fitness were more pronounced in younger than older individuals. 42 Levels of muscular strength and cardiorespiratory fitness have been examined in prehypertensives and the incidence of developing hypertension decrease s by 45% with increased muscular strength and cardiorespiratory fitness when compared to ind ividuals with low fitness levels 23 Further, muscular strength is inversely associated with the development of essential hyperten sion in prehypertensives regardless of cardiorespiratory fitness level. 23 A study of therapeutic lifestyle modification in prehypertensives suppor ts the JNC7 recommendations for lifestyle modification as the first line intervention to reduce blood pressure and the risk factors associated with prehypertension. 49 This study demonstrates that both resistance and endurance training independently reduce resting peripheral and central blood pressures, improve endothelial function, reduce

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112 augmentation index, improve blood flow, increase NO bioavailability, decrease ET 1, improve antioxidant/oxidant balance, and increase prostaglandin. Limitations and Future Directions Our interpretation of improvements in endothelial function may be limited due to the fact that endothelium in dependent testing was not performed in the current study The interpretation of the results of the present study may be limited by the small sample size. However, we believe that a larger sample size would support and possibly augment the significance of the present results. Future research should involve more direct measurements of arterial and endothelial function to determine the specific mechanisms underlying the improvements in endothelial function, blood flow, and pulse pressure wave characteristics responsible for the reductions in peripheral and central blood pressure reductions in prehypertensive after exercise training.

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132 BIOGRAPHICAL SKETCH Darren Thomas Beck is the son of Susan Thompson Beck and Bayard Rodney Beck, Sr He was born in Wilmington, Delaware and raised in Bear, Dela ware. He complet ed his undergraduate degree in e xercise s cience at the University of Delaware in 2002. Immediately following undergraduate school he began pursuing a Master of Science degree in e xercise p hysiology at the University of Delaware where he served as a G raduate R esearch A ssistant and taught the Physiology of Activity Laboratory course. Following graduate school at the University of Delaware he began his doctoral studies as a Graduate Research Assistant in Dr. r Laboratory in the Department of Applied Physiology and Kinesiology at the Univerisity of Florida where h e has been persuing his PhD in applied p hysiology. As a doctoral student he taught the undergraduate Clinical Exercise Physiology course in addition In August of 2008 he passed his qualifying examination for Doctor of Philosophy and was admit ted to candidacy August 8, 2008 H e received his degree on December 17, 2010