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Gastric acid and pepsin secretion in the conscious young horse

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Title:
Gastric acid and pepsin secretion in the conscious young horse
Creator:
Campbell-Thompson, Martha L., 1954-
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English
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xi, 131 leaves : ill. ; 29 cm.

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Subjects / Keywords:
Bicarbonates ( jstor )
Dogs ( jstor )
Gastric juice ( jstor )
Gastroenterology ( jstor )
Histamines ( jstor )
Horses ( jstor )
Mucosa ( jstor )
pH ( jstor )
Physiology ( jstor )
Secretion ( jstor )
Dissertations, Academic -- Veterinary Medicine -- UF ( mesh )
Gastric Acid -- secretion ( mesh )
Horses -- physiology ( mesh )
Pepsin A -- secretion ( mesh )
Veterinary Medicine thesis Ph.D ( mesh )
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bibliography ( marcgt )
theses ( marcgt )
non-fiction ( marcgt )

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Thesis:
Thesis (Ph. D.)--University of Florida, 1988.
Bibliography:
Includes bibliographical references (leaves 118-130).
Additional Physical Form:
Also available online.
General Note:
Typescript.
General Note:
Vita.
Statement of Responsibility:
by Martha L. Campbell-Thompson.

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University of Florida
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University of Florida
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GASTRIC ACID AND PEPSIN SECRETION IN THE
CONSCIOUS YOUNG HORSE












By

MARTHA L. CAMPBELL-THOMPSON


A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY

UNIVERSITY OF FLORIDA


1988




GASTRIC ACID AND PEPSIN SECRETION IN THE
CONSCIOUS YOUNG HORSE
By
MARTHA L. CAMPBELL-THOMPSON
A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY
UNIVERSITY OF FLORIDA
1988


Martha
Copyright 1988
by
L. Caitipbell-Thompson


To Floyd and my parents


ACKNOWLEDGMENTS
I would like to acknowledge my entire committee for
creating a challenging graduate program, and specifically, my
mentor, Dr. A1 Merritt, who made the entire program possible
by accepting me as his graduate student. A1 guided me through
these last years, always encouraging self-taught discoveries.
I thoroughly enjoyed working with someone who was always
available for help or criticism, but was never over-powering
with his own opinions. I would also like to thank Dr. George
Gerencser who allowed me to write a paper for his course
which created the basis for my understanding the processes of
acid secretion and which continues to serve me to this day.
Dr. Stephen Russell was especially kind to remain active on
the committee despite moving to an endowed professorship at
the University of Kansas Medical Center. Finally, I am
indebted to Dr. James McGuigan who introduced me to his lab
and the incredible possibilities for research with the
gastric parietal cell. I learned to isolate viable canine
parietal cells and was thrilled to discover "life after
death".
I wish to acknowledge my husband, Floyd, for his never-
ending support, guidance and encouragement. I used his
computer (IBM XT compatible) software (WordPerfect,
iv


WordPerfect Corp.; Twin, Mosaic Software Inc.) and printer
(HP Laserjet Series II) to write this dissertation. I need to
thank Wesley Smith who introduced me to the IBM spreadsheet
and created the first template for my experiments. Drs. David
Williams and Colin Burrows were also kind to allow me to use
their computers and software. Susan Lowrey contributed
innumerable hours of technical assistance and various
students helped on this project through the years. Without
this assistance, I would not have been able to complete this
project in this amount of time.
I am privileged to be part of a family filled with
incredible loving people who always encouraged me in this
endeavor. I am thankful for the flexibility in this program
which allowed me to pursue several personal projects
including building a house and completing the American
College of Veterinary Surgery Boards. I would also like to
thank our friends, Will
and Donna
Wheeler-Harding,
who
have
shown me everything is
possible
if I'm willing
to
work
(train) for it.
v


TABLE OF CONTENTS
Page
ACKNOWLEDGMENTS iv
LIST OF TABLES viii
LIST OF FIGURES ix
ABSTRACT X
CHAPTERS
I INTRODUCTION 1
Methods for Studying Gastric
Acid Secretion 2
Gastric Mucosal Anatomy 8
Parietal Cell Function 12
Phases of Gastric Acid Secretion 20
Pepsinogen Secretion Rate 28
Gastric Fluid Composition 31
II REVIEW OF LITERATURE 35
Peptic Ulceration 35
Equine Gastric Secretory Physiology 44
III MATERIALS AND METHODS 4 6
Animals and Surgical Preparation 46
Methodology 49
Experimental Design 50
Statistical Analysis 55
IV RESULTS 57
Animal Preparation and Necropsy Findings 57
Gastric Secretory Studies 58
Control Studies 60
Pentagastrin Stimulation Studies 61
H2-receptor Antagonist Studies 66
vi


Page
V DISCUSSION AND CONCLUSIONS 81
Equine Gastric Fluid Secretion in
Comparison to Other Species 81
Future Directions 98
Summary 99
Conclusions 102
APPENDICES
A DATA TABLES 103
B ANOVA TABLES AND P VALUES 106
C CORRELATION MATRICES 117
REFERENCES 118
BIOGRAPHICAL SKETCH 131
vii


LIST OF TABLES
Table Page
3.1 Animal signalment 47
3.2 Treatment scheme for protocol IV 52
4.1 Phenol red recovery rates 59
4.2 Control gastric fluid variable averages 62
4.3 Maximal acid output during
step-dose pentagastrin infusion 64
4.5 Statistical analysis of replicate samples 80
5.1 Basal and stimulated gastric fluid secretion
in various species 90
5.2 Acid Output during basal and stimulated
conditions in various species 91
5.3Calculated parietal cell mass in the horse.... 93
viii


LIST OF FIGURES
Figure Page
4.1 Basal acid output in 13 horses 63
4.2 Acid output following pentagastrin infusion... 65
4.3 Hourly secretion rate for protocol IV 72
4.4 Hourly pH for protocol IV 73
4.5 Hourly acid concentration for protocol IV 74
4.6 Hourly acid output for protocol IV 75
4.7 Hourly pepsin concentration for protocol IV... 76
4.8 Hourly pepsin output for protocol IV 77
4.9 Hourly osmolality for protocol IV 78
ix


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
GASTRIC ACID AND PEPSIN SECRETION IN THE
CONSCIOUS YOUNG HORSE
by
Martha L. Campbell-Thompson
August 1988
Chairman: Alfred M. Merritt, DVM
Major Department: Veterinary Medicine
Gastric cannulation was performed in young horses to
determine the composition of parietal and nonparietal
components of gastric fluid during basal (fasting),
stimulated and inhibited conditions. Horses were fasted for
24 hours after which a 5-hour collection of gastric fluid was
made. Intravenous saline (200 ml/h) served as a control
treatment (29 experiments in 13 horses). Basal volume (290
77 ml/15-min) pH (2.0 0.5), and acid concentration (39
15 mEq/L) and output (56 30 /Eq/kg/15-min) were constantly
variable.
Stimulation of the parietal component of gastric fluid was
achieved with pentagastrin, a synthetic analog of the
hormone, gastrin. A dose-response curve showed that 6
Mg/kg/h, by intravenous infusion, stimulated maximal acid
output (5 experiments in 2 horses). Pentagastrin at 6
x


/g/kg/h IV for 4 hours produced maximal acid output during
the second and third hours by doubling flow rate to 610 260
ml/15-min and increasing acid concentration to 55 mEq/L.
Basal acid output (210 zEq/kg/h) was approximately 3 0% of the
maximal acid output (630 Eq/kg/h) .
The histamine H2-receptor antagonist, ranitidine (0.5
mg/kg intravenous bolus), minimally effected flow rate but
inhibited acid concentration and output (10 experiments in 5
horses, ANOVA, P<0.05). Ranitidine was also effective in
reducing pentagastrin-stimulated acid output to basal levels
by decreasing both flow rate and acid concentration.
Basal pepsin concentration was highly variable (110 34
ig/ml; 10 experiments in 5 horses) and first increased and
then decreased, during pentagastrin infusion, suggesting a
washout of stored pepsinogen with subsequent dilution as
gastric flow rate increased (P > 0.05). Ranitidine decreased
pepsin concentration for one hour, probably as a result of
decreased luminal acid (P > 0.05).
In comparison to other species, equine gastric fluid had a
low acid concentration and output during maximal stimulation,
despite a large flow rate and was constantly hypotonic.
These data suggest that there is a prominent nonparietal
component to equine gastric fluid secretion and this species
may be useful for studying the regulation of the nonparietal
component.
xi


CHAPTER I
INTRODUCTION
Gastric and duodenal ulceration has become a significant
disease in young and adult horses and its clinical and
pathological consequences have only recently been described
(30). While it appears that gastric ulceration is produced by
administration of nonsteroidal anti-inflammatory drugs, the
etiology of the spontaneously occurring gastroduodenal
ulceration seen only in suckling foals remains unknown. This
is not surprising since the etiology of duodenal ulceration
in people, although studied for decades, is also unknown
(103) The mechanisms regulating human gastric secretion, as
well as a variety of factors which appear important in the
development of human gastroduodenal ulceration, have been
studied extensively (103). Knowledge of equine gastric
physiology would provide an understanding of some of the
factors responsible for producing equine mucosal ulceration,
as well as a basis for its treatment (103).
Development of a technique to study equine gastric
secretion was necessary. This technique would not only
further our knowledge of gastric physiology in this species,
but would also serve as another animal model for studying
basic gastric physiology. Studies of basic gastric physiology
1


2
in different animal species have revealed variations in
mechanisms of regulating gastric secretion (40). Since the
young horse can develop spontaneous duodenal ulceration,
gastric physiology in this species is particularly
interesting as the young horse could provide an animal model
for duodenal ulceration.
This dissertation presents current knowledge concerning
the regulation and composition of eguine gastric fluid based
on studies performed in normal young horses using a new
gastric cannulation technigue.
Methods for Studying Gastric Secretion
Various methods are available for studying gastric
physiology (45) In the conscious person or animal,
nasogastric aspiration can be used with about an 80% recovery
rate of gastric contents (125). There can be contamination of
the fluid with saliva and duodenal contents, although people
can be instructed to not swallow their saliva and dental
suction can be employed. Even without these measures,
salivary contamination is estimated to be less than 10% of
the gastric contents.
The most common technigue of studying gastric secretion in
animals is the gastric fistula, where an adhesion is created
between the stomach and body wall and through which a
collection tube (Thomas cannula) is inserted. The fistula
technique leaves the stomach with intact innervation and
exposed to the normal flow of ingesta and secretions. With


3
correct attention for ventral placement and complete
collection of fluid, quantitative measurements of gastric
secretions can be made. However, gastric secretions may be
contaminated with swallowed saliva or regurgitated duodenal
contents and it is difficult to measure food-stimulated
secretions by this technique. Despite these limitations, the
gastric fistula remains the most common method employed for
chronic studies in laboratory animals.
The first important information about gastric physiology
in people was collected in 1825 by a military surgeon,
William Beaumont, who carefully studied a patient, Alexis St.
Martin, who had a chronic gastric fistula following an
abdominal gunshot wound (45). Beaumont made observations over
a 4 year period and produced the first accurate description
of gastric fluid secretion during different emotional states.
His observations were later confirmed by Pavlov and others in
different species.
Much of the knowledge concerning the control of acid
secretion has been derived from experimental surgical
preparations in dogs. These have allowed the study of neural,
humoral and endocrine factors that determine the rate of
secretion (68) To determine the effect of the central
nervous system on acid secretion, uncomplicated by the
effects of food in the stomach, acid output can be easily
measured using fundic pouches. Such preparations make it
possible to sample gastric juice without food contamination


4
while maintaining alimentary tract continuity. Pavlov is
credited with numerous basic observations concerning
gastrointestinal physiology and developed the innervated
fundic pouch (Pavlov pouch) as a means to study un
contaminated gastric secretions in response to food (45) .
Vagally innervated pouches permit extremely sensitive
assessments of changes in gastric secretion but usually
involve some degree of mucosal denervation as well as the
consequences of diverting the normal food stream from the
pouch mucosa. Heidenhain introduced the denervated fundic
pouch (Heidenhain pouch) as a means to study the intrinsic
control of gastric secretion (45) The sympathetic nervous
supply is intact as these nerves accompany the blood vessels.
These pouches usually have a low maximal secretory flow rate
which makes small but significant changes in secretion rate
difficult to measure. Antral pouches may also be prepared.
Total gastric pouches as developed by Dragstedt and Ellis
have a high flow rate but are generally not used due to
difficulties in maintaining the animals (45).
Pavlov also introduced the technique of permanent double
esophagostomies which allows sham-feeding in a dog with a
gastric fistula (45). The dog was fed through the distal
stoma between experiments. Komarov and Marks devised a 2-
stage esophagostomy where the esophagus is everted only
during the experimental period to divert food.


5
The first attempt to depart from standard procedures using
a fistula or pouch involved exteriorization of the entire
stomach with the circulation intact (dog flap or vascularly
perfused mouse stomach) (45). This technique then allowed the
additional measurements of oxygen and glucose uptake, C02
production and blood flow and volume changes in gastric
circulation to be made. The Shay rat preparation involved
ligation of the pylorus under general anesthesia (45). The
rat was allowed to recover and, usually 4 hours later, was
re-anesthetized and the entire gastric contents removed.
Mucosal function has been studied extensively in isolated
preparations by mounting a mucosal segment (usually devoid of
the muscularis) in an Ussing chamber, where the serosal
(nutritive) and mucosal (secretory) chamber solutions can be
modified independently (45,119,138). Electrophysiological
studies could then be performed directly on the mounted
segment to determine tissue resistances or potential
differences. Consistent relationships between variables, such
as tissue secretory capacity, ionic composition of bathing
solutions, ion fluxes and electrical phenomena have been
established. Microelectrodes are also available to study
individual cells and intracellular ion and pH changes (137).
Difficulties in determining specific parietal cell
function in the intact mucosa have led investigators to
develop techniques for gland and cell separation (18,138).
For the gastric epithelium, enzymatic digestion using


6
collagenase or pronase produces primarily gastric glands.
Addition of calcium chelating agents such as EDTA to disrupt
tight junctions will isolate gastric cells. Advantages of
isolated glands include a more intact system with tight
junctions, normal shape and polarization and cell-cell
communications, the ability to follow pH changes and an
enrichment of parietal cells from 20% in the intact mucosa to
50% by volume. Advantages of isolated cells include similar
responses as the gland preparation with the ability to
further enrich specific cell types. Cell viability is
generally greater than 90% and the cells can also be
maintained in tissue culture.
Isolated cell preparations have allowed the determination
of parietal cell physiology previously clouded by the
presence of the numerous other cell types in the gastric
mucosa (137) For studies of amino acid uptake, ion fluxes or
membrane receptors, isolated parietal cells have been
necessary. Three techniques are used to enrich parietal cell
content: 1) the production of gastric glands automatically
enriches the parietal cell content as stated earlier; 2)
density gradient purification can be used with either rat or
canine parietal cells and yields a high purity of viable
cells; 3) cells can be separated by an elutriator rotor which
fixes the cells by centrifugal forces and by concurrent
solvent flow, elutes the cells based on their density (138).
Parietal cells are the largest cells in the gastric mucosa.


7
Indices of parietal cell responses to stimulation include
oxygen consumption, morphological transformation (coalescence
of cytoplasmic tubulovesicles into secretory canaliculus) and
aminopyrine uptake (18). Weak bases, such as aminopyrine,
partition between the gastric circulation and lumen as a
function of their pKa; at cytoplasmic pH, the bases are
unionized and can diffuse through lipid membranes such as
tubulovesicles and secretory canaliculi. Protonated bases are
trapped in the acid spaces and thus their uptake by the
parietal cell can be used as an index of parietal cell
responsiveness to stimulation. Aminopyrine accumulation
provides a quantitative index of the parietal cell
responsiveness to stimulation which is reflected in the
quantity of sequestered acid but not actual secretion rates
(138). Isolated cell preparations offer advantages such as
standardized experimental conditions and straight-forward
stimulus-response detection. On the other hand, all in vitro
models involve certain steps in their preparation that may
influence, or even damage, the receptors on the cell surface.
Many of the recent breakthroughs in parietal cell
physiology can be attributed to the characterization of
enzymatic activities associated with membrane fractions,
specifically the membrane vesicles from which the H+-K+-
ATPase was isolated (55,127). The highly glandular nature of
the gastric epithelium as well as the invagination of the
parietal cell apical surface makes the gastric mucosa


8
abundant in membrane material. Morphometric data yield values
of 400-500 cm2 of parietal apical membrane for each cm2 of
mucosa (138).
This discussion is intended to be a brief overview of 160
years of methods involved in the study of gastric secretion.
New information is available monthly on cellular- and
membrane-associated phenomena. Increasingly simplified models
facilitate the ability to explain the phenomena but on the
other hand, subtle regulatory processes present in the intact
animal may be lost and one may be misled as to the prominence
of a process in the simplified model. It is essential to
refer back to the intact animal or at least intact tissue
data to see whether or not information obtained in isolated
cells is consistent at all levels (138) .
Gastric Mucosal Anatomy
The gastric mucosa is arranged in folds, or rugae, with
the surface covered by a simple columnar epithelium of
surface mucous cells (86). The glandular mucosa is divided
into 3 regions, cardiac, fundic and pyloric, based on
histologic features. The cardiac region is located adjacent
to the esophageal region at the transition between squamous
and columnar epithelium and there is marked species variation
in its proportion of the total glandular surface (73). The
cardiac glands contain mucus and undifferentiated endocrine
cells. The fundic gland region contains mucous, chief,
parietal and endocrine cells and comprises the majority of


9
the glandular epithelium in the human and dog (~80%) (73).
The fundic gland is divided into the following 3 regions: 1)
isthmus surface mucous cells; 2) neck parietal and mucous
cells; 3) base chief and parietal cells. Pyloric glands are
located in the antrum and contain primarily mucous cells and
a few endocrine cells, such as gastrin cells which produce
gastrin. One or more simple or branched tubular gland opens
into a gastric pit which is also lined by mucous cells.
Pyloric and fundic glands also have enterochromaffin cells,
which secrete serotonin, and several types of endocrine
cells, which contain somatostatin and vasoactive intestinal
peptide (86) Some of these peptides may be released into the
tissue (paracrine secretion) rather than into the
circulation. One study has shown that the equine glandular
mucosa has gastrin and somatostatin positive cells in the
antrum and proximal duodenum (91). Other cells of the mucosa
include mast cells and plasma cells (for IgA synthesis)
within the lamina propria. The muscularis mucosa is generally
2-3 cell layers followed by a stratum compactum in some
animals.
The equine gastric mucosa is composed of approximately 1/3
stratified squamous and 2/3 glandular epithelium (135). This
composition is similar to that of rodents, but distinct from
that of most other species, where the gastric mucosa is
composed entirely of glandular epithelium (73). The mucosa of
the esophageal region is demarcated from the cardiac zone by


10
a fold known as the margo plicatus. The portion proximal to
the margo plicatus forms a large sac known as the saccus
cecus and is lined by stratified squamous epithelium. The
squamous mucosa is devoid of glands, but has a thick layer of
keratinized epithelium which is probably the main barrier to
acid and pepsin.
Normally, the gastric epithelial cells and inter-cellular
tight junctions provide an almost completely impermeable
barrier to the back-diffusion of H+ (101,128). The geometry
of the glands makes them relatively inaccessible and
contributes to the low permeability of the luminal surface to
cations (120). The "gastric mucosal barrier" is a descriptive
term which refers to the ability of the gastric mucosal
epithelium to maintain a large lumen to mucosal H+ gradient
under physiological conditions (39). Components which have
been used to describe the functional integrity of the
barrier, in addition to very low H+ diffusion from the lumen
to the mucosa, include a low diffusion of Na+ and K+ from
mucosa to lumen and the maintenance of a lumen-negative
transmucosal potential difference. Although no anatomical
barrier has been described, it has been suggested that the
mucous gel and epithelial phospholipids are constituents
(69,101).
The parietal cell is responsible for acid and intrinsic
factor secretion and is oval to pyramidal in shape (86). The
most conspicuous features of the cell are intracellular


11
canalculo., abundant smooth endoplasmic membranes called
tubulovesicles and abundant, large mitochondria. The
intracellular canaliculi are a structural specialization
which are open to the lumen but may become internalized in
nonsecretory states. Parietal cells have long and numerous
microvilli on their luminal surfaces and canalicular walls
which serve to increase surface area greatly. During
secretion at high rates, the microvillar surface increases
while the tubulovesicular membrane decreases. A detailed
study of these ultrastructural changes has led Forte and
coworkers to propose a mechanism of membrane formation based
on the fusion and recycling of tubulovesicles to and from the
apical membrane (56) In addition to membranes, the
morphological transformations seem to involve actin
microfilaments which have been suggested as the means by
which the microvillar membrane is withdrawn from the surface
and reconstituted into the tubulovesicular membrane (127).
The chief cell is responsible for pepsinogen secretion and
is located at the bases of glands (86) Pepsinogen is also
secreted by mucous neck cells of cardiac, fundic and pyloric
glands (72) Chief cells store pepsinogen in encapsulated
zymogen granules which are released by exocytosis (72,74).
Zymogen granules are synthesized and encapsulated in the
Golgi body. When first formed, the granules are argyrophilic
and stain poorly, but as they mature and migrate toward the
apex, they are argyrophobic and take a crystal violet stain.


12
As granules accumulate in the cell, a negative feedback
mechanism slows down new synthesis. When the cell is full of
granules, synthesis ceases except for a small steady resting
secretion rate which is approximately one fifth the maximal
stimulated rate. During maximal stimulation, the proenzyme is
secreted without going through the granule stage. This may
occur before an increase in water secretion is observed
resulting in an initially high concentration of pepsinogen in
gastric juice of low volume. There appears to be a delicate
balance between synthesis, storage and secretion so that the
chief cell is capable of both immediate and prolonged
continuous secretion.
Parietal Cell Function
The parietal cells, which constitute about one tenth of
the mucosal volume, increase the concentration of hydrogen
ions (H+) one million-fold in the fluid extracted from plasma
('4 x 108 M, pH 7.4) and secreted as gastric juice ('0.15 M)
(18,115,137). A large amount of energy is required to
transport H+ against this large concentration gradient and
the parietal cell's high mitochondrial content indicates the
important contribution of oxidative metabolism to the energy
economy of the cell.
Davenport developed a hypothesis for acid secretion which
still holds today (39). It is believed that water is
hydrolyzed to provide a H+ for secretion coupled to potassium
(K+) exchange and chloride (Cl-) secretion. The hydrolysis of


13
carbonic acid, which is formed by the hydration of carbon
dioxide through the action of carbonic anhydrase, neutralizes
the resultant hydroxyl ion and produces a bicarbonate ion,
which is removed by the venous blood (alkaline tide)
(39,138). Administration of pentagastrin, histamine or cyclic
AMP enhances the activity of carbonic anhydrase. Experiments
in vitro have demonstrated that the gastric carbonic
anhydrase can be separated into two isoenzymes and the
phosphorylation of one by a cAMP-dependent protein kinase
sharply increases its activity (138).
In parietal cells, two primary active ion transport pumps
have been demonstrated from isolated membrane studies (18) .
The classic Na+-K+-ATPase is localized to the basolateral
membrane while the H+-K+-ATPase is unique to the microvilli
of the secretory canaliculi. In isolated cells or mucosal
segments, sodium, potassium and chloride play essential roles
in the process of acid secretion.
Biochemical studies have led to the establishment of the
H+-K+-ATPase as the gastric proton pump (57,119). This enzyme
was first identified by Forte and coworkers in the form of K+
phosphatase activity in rabbit and frog mucosa (55) The
causal relationship between the K+-ATPase and H+ was provided
in studies which demonstrated that a K+-ATPase-rich
microsomal fraction from canine mucosa would extract protons
from the medium, implying that the microsomes were inside-out
sacs of the membrane generating HC1 in the intact cell (57).


14
Finally, Sachs et al. demonstrated that H+ accumulation was
the result of an ATP-driven electroneutral exchange of
intramicrosomal K+ by H+ (127) The precise number of H+
transported per ATP consumed is still controversial, with a
number of laboratories claiming measured H+-to-ATP ratios of
one or two. Substituted benzimidazoles, such as omeprazole,
have been identified as specific H+-K+-ATPase inhibitors
(50) .
The well-known enzyme associated with Na+ transport, the
Na+-K+-ATPase, has been identified in the parietal cell
fraction from several species (119). The enzyme shows a
positive correlation with basal acid output, is stimulated by
cholinergic agents, and is inhibited by atropine, epinephrine
and cAMP (138) .
The parietal cell is stimulated to secrete acid by
interactions between 3 chemical messengers, acetylcholine,
gastrin and histamine (115). Each agent utilizes different
modes of delivery to affect the parietal cell (18) Each
agent binds to a specific receptor on the parietal cell and
this union triggers a series of biochemical steps within the
parietal cell (137). A final common pathway involves the
activation of the H+-K+-ATPase with the resultant HC1
secretion (137). Gastric fluid stimulated by acetylcholine is
rich in all its components (water, acid, pepsin, mucus, ions)
(119). In contrast, gastrin and histamine stimulate mostly
water and acid, but much less pepsin and mucus (119).


15
Acetylcholine is released by vagal stimulation and
activates muscarinic cholinergic receptors on the parietal
cell after crossing a short synaptic gap from the
postganglionic fiber (66). In rabbit parietal cells, the
response to the cholinergic agent, carbachol, was less than
to histamine (40) In contrast, in canine cells carbachol
produced a sustained increased response which was greater
than that produced by histamine.
Acetylcholine stimulates parietal cell acid secretion by
increasing intracellular calcium (115,128,137). A calmodulin-
regulated, ATP-dependent calcium pump that could maintain
active calcium extrusion was found in the basolateral
membrane of parietal cells (128). Calmodulin regulates the
activity of several enzymes such as adenylate cyclase,
phosphodiesterase, phospholipase A2 and protein kinase and
membrane phosphorylation, and could thus regulate both
synthesis and breakdown of cAMP and synthesis of a protein
kinase or prostaglandin.
Gastrin is present in cytoplasmic secretory granules in
gastrin cells, which are interspersed singly or in small
clusters among the other epithelial cells in the antrum
(103). The major tissue form is the heptadecapeptide (G-17)
(103). Gastrin release appears to be controlled by a number
of factors, including direct action of luminal agents on the
gastrin cell and both stimulatory and inhibitory cholinergic
effects (40,65,66). Gastrin produces a small but definite


16
increase in parietal cell response in canine cells which is
markedly potentiated by histamine; however, gastrin is
relatively ineffective in the rabbit (32,138). Gastrin has
been linked to enhanced calcium influx or intracellular
mobilization but solid data is lacking.
Gastrin release is inhibited by acid bathing the antral
mucosa, probably by direct action on the G-cell, with marked
suppression at pH 2 and complete inhibition at pH 1 (36,66).
Gastric acid inhibition by antral acidification may also be
mediated by prostaglandins and somatostatin, both acting as
paracrine regulators of gastrin release (16,57,133). There is
also evidence that vagal fibers may inhibit gastrin release
(103) .
Histamine, whose release mechanism is unknown, is stored
by mast cells in the human and canine mucosa and by an
enterochromaffin-like endocrine cell in the rat mucosa
(86,126). Histamine-containing mast cells are in close
proximity to the parietal cells, usually in a ratio of 1 mast
cell to every 2-3 parietal cells (119) In the rat, but not
the dog, gastrin increases the mucosal concentration of
histidine decarboxylase, an enzyme that forms histamine
(138) The parietal cell has been shown to be the cell
responsible for histamine uptake and inactivation in the
gastric mucosa (138).
In canine cells, the action of histamine is relatively
weak but is markedly enhanced by the phosphodiesterase


17
inhibitor, isobutymethylxanthine (138). Species comparisons
have shown that in rabbit cells, concurrent histamine
stimulation is needed before gastrin stimulation will occur,
while in the canine cell and gland, there is a pure gastrin
response coupled to an important histamine component (138).
Histamine is less effective in vivo in stimulating acid
secretion in the rat than in the human, dog and cat (40,107).
Histamine stimulation of acid secretion is mediated by
cAMP and the regulatory subunits of protein phosphokinase
(128,138). Binding of histamine to the H2-receptor on the
parietal cell produces stimulation of adenylate cyclase which
results in cAMP production. This has been confirmed in
studies where H2-receptor antagonists were found to inhibit
production of cAMP during histamine stimulation of canine,
rat and guinea pig parietal cells and rabbit glands. Cyclic
AMP may stimulate a protein kinase which could result in
phosphorylation of protein components involved in HC1
transport, located either in membranes or in the cytoplasm of
parietal cells, such as carbonic anhydrase and the H+-K+-
ATPase. Adenylate cyclase is composed of regulatory subunits
such as the inhibitory guanine nucleotide-binding protein
(138). Prostaglandins have been shown to inhibit production
of cAMP by histamine in canine cells by interaction with the
inhibitory guanine nucleotide-binding protein (128,138). At
one time, histamine was considered the final common mediator
of acid secretion by the parietal cell (33). This theory was


18
renewed with the development of H2-receptor antagonists which
inhibited gastric acid secretion that had not only been
stimulated histamine, but also by gastrin and acetylcholine
(39,68). There have been 2 types of experiments which tend to
disprove this theory. First, gastric acid secretion was
studied in neonatal rats and occurred only after 2 weeks in
response to only acetylcholine and gastrin (1). An additional
2-3 weeks are needed before a histamine response was
observed. Second, identification of all 3 receptors on the
canine parietal cell also disposes of this once widely held
belief that histamine is the sole final common chemical
mediator for all stimulants (115,138).
Studies in dogs with denervated gastric pouches revealed
that combinations of stimulants produced potentiation,
defined as the simultaneous response to 2 stimulants that is
greater than the sum of the individual responses (40,68).
Potentiation implies that there is convergence on a common
stimulatory pathway after separate receptor binding. In
isolated canine parietal cells, only pairs of stimulants
using histamine or all 3 secretogues together have produced
potentiated responses (138). Potentiation using histamine may
occur because of the central role of cAMP production which
leads to stimulus-secretion coupling (40,138). Cyclic AMP is
responsible for protein phosphorylation which is necessary
for tubulovesicular membrane processes and is required for
ATP production for several ion pumps, namely the Na+- and H+-


19
K+- ATPases. Neither acetylcholine nor gastrin contributes to
the formation of cAMP nor influences its production by
histamine (138). This absolute component for HC1 secretion
supplied only by histamine may help explain the apparent non
specific action of H2-receptor antagonists in inhibiting HC1
secretion.
Non-specific action of H2-receptor antagonists or the
anticholinergic agent, atropine, results in inhibition of
stimulation by any of the 3 secretogues in vivo (40) This
finding suggests that during basal or fasting conditions, the
parietal cells are exposed to a constant background of
histamine and acetylcholine (and possibly gastrin) which
sensitizes the cells to additional amounts of these agents.
If histamine and acetylcholine are present as a potentiating
background, addition of H2-receptor antagonists or atropine
would (and does) interfere with all physiological modes of
acid stimulation (40). This interference does not indicate
whether the antagonist has acted against the basal background
concentration or against additional amounts which might have
been released by the secretogue. For example, H2-receptor
antagonists markedly inhibit acid secretion stimulated by
feeding (33) This suggests that histamine is involved in the
response to feeding but does not indicate whether the
component blocked is only the amount present in the basal
condition or whether feeding has released additional
histamine. In the case of gastrin, which can be measured by


20
radioimmunoassay, it can be determined whether a certain
mechanism involves additional release of gastrin (104,105).
Currently, methods are not available for determining how much
histamine or acetylcholine within the mucosa is being
released or presented to the parietal cell at a given moment
(40,118). Thus, it is not known how much more of these stores
have been released and are available to stimulate the
parietal cell after any given mode of stimulation.
Phases of Gastric Acid Secretion
Acid secretion has been divided into basal, cephalic,
gastric and intestinal phases although this probably
represents an oversimplification of several interacting
factors (39,68).
Basal Secretion
Basal acid secretion indicates an absence of all
intestinal stimulation and is usually studied after a fast of
several hours to ensure that the intestinal phase of gastric
secretion is over (39). Gastric emptying of a meal is usually
complete by 6 h in a person and by 24 h in a dog (40).
The stimulus for basal secretion is unknown, since it is
decreased but not abolished by vagotomy and antrectomy
(44,66). Histamine may play a role as indicated by the
finding in the rat that depletion of mast cells was followed
by decreased basal secretion but no reduction in response to
vagal and gastrin stimulation (40). Basal secretion in people
displays a circadian rhythm that is low in the morning and


21
high in the evening (40) This circadian rhythm is not
related to changes in plasma gastrin levels (110).
Concurrent gastric and duodenal motor activity during
basal acid and pepsin secretion has been studied in people
and dogs (64). Vantrappen found in people that phase III
activity of the migrating motor complex in the duodenum was
preceded by an increase in gastric acid and pepsin outputs
(148). In dogs with gastric fistulas, the rate of basal acid
secretion was 2 times higher during phase III activity than
at other times (still only 0.2% of maximal acid secretion)
(139). Thus, concurrent motor activity and gastric secretion
are integrated for digestion.
Cephalic Phase
The cephalic phase of gastric acid secretion is initiated
by stimulation of sensory vagal afferents through the
thought, smell or taste of food (25,141). Uvnas introduced
the theory that vagal impulses could stimulate acid secretion
by 2 mechanisms- acetylcholine released from postganglionic
parasympathetic neurons directly on the parietal cell and
another by stimulation of the G-cell to release gastrin (40).
This theory was confirmed when studies in dogs showed release
of gastrin following sham feeding (66). The maximal acid
secretion rate following sham feeding is 40-100% of the
maximal response to gastrin stimulation (40).


22
Gastric Phase
The entrance of food into the stomach initiates the second
phase of gastric secretion (39) The gastric phase of acid
secretion was recognized in 1879 by Heidenhain, but the
explanation for this humorally mediated secretion has been
found only recently (40). The gastric phase is initiated by
distension and activation of mucosal sensory afferents.
Distension-mediated acid secretion is thought to involve
stretch receptors which activate both long (vagovagal) and
short (intramural) reflexes involving direct stimulation of
the parietal cells by acetylcholine released from
postganglionic parasympathetic neurons (40,68).
Contact of food with the gastric mucosa also stimulates
acid secretion (39). Chemical agents such as caffeine,
alcohol, calcium ions (human but not dog) and the digestion
products of proteins stimulate chemoreceptors to release
acetylcholine which, in turn, stimulates the release of
gastrin from G-cells in the antrum (39) The digestion of
protein by pepsin preferentially releases tryptophan and
phenylalanine and these 2 amino acids are potent stimulants
of gastrin release (40). The strong correlation between the
increment of serum gastrin concentration and acid secretion
within subjects ingesting peptone meals suggests that gastrin
may be the main mechanism by which amino acids stimulate
gastric acid secretion during the gastric phase (40).
Stimulation of chemoreceptors by protein digestion products


23
and stretch receptors by distension leads to acid secretion
through acetylcholine-mediated gastrin release and direct
stimulation of the parietal cells by activation of long and
short reflexes.
Intestinal phase
Finally, the entrance of chyme into the small intestine
stimulates the third phase of gastric secretion (39). The
known mediators of the intestinal phase are distension and
protein digestion (39). A humoral mechanism has been proposed
as the response still occurs when all extrinsic nerves have
been cut. Intravenous amino acids stimulate acid secretion so
that part of the mechanism may due to amino acids absorbed by
the small intestine independent of gastrin release (human,
40) .
Stimulation of Acid Secretion
The greatest ability of the stomach to secrete acid is
measured by collecting gastric fluid in successive 15-min
periods after the subject has been given a sufficiently
strong stimulus (39). Acid secretion data is generally
expressed in millimoles per unit time and is often expressed
as a fraction of the maximal secretory rate of the stomach
(60,96,125). The maximal acid output (MAO) is the hourly
summation of acid output following a maximally effective dose
of histamine or pentagastrin and is linearly related to
parietal cell mass in people, dogs and pigs (31,100). Maximal
acid output in people has been found to be influenced by sex


24
(men > women), body weight (larger people have more parietal
cells) and lean body mass (leaner secrete more acid) (39).
A variety of substances have been used to produce maximal
stimulation of gastric acid secretion. Two-deoxy glucose acts
as a competitive antagonist of glucose receptors in the
brain, which stimulates vagal-induced acid secretion in
several species (25,38). In early studies using 2 horses
prepared with gastric cannulas, 2-deoxy glucose (100 mg/kg
IV) inhibited acid secretion while increasing volume
secretion rate and was associated with the side effects of
sweating and bradycardia.
Histamine was used initially to induce maximal acid
secretion in people and animals but required prior treatment
with an antihistamine (H^receptor antagonist) to inhibit
systemic side-effects (60,103). The minimal effective dose of
histamine that produced acid secretion in people was 10 times
less than that required for the dog (106). The rat is
insensitive to histamine when compared to the dog, cat, pig,
monkey, or rabbit (40).
Gastrin was used as a stimulant before pentagastrin was
available (60). Pentagastrin (Peptavlon' Ayerst Labs)
contains the biologically active carboxyl terminal
tetrapeptide of the gastrin molecule and is currently the
preferred agent to study maximal secretory rates (103). The
usual dose of 6 ^g/kg can be given parenterally (usually
subcutaneously) When acid output is expressed in /imoles/kg


25
body weight to normalize for large differences in size,
pentagastrin and histamine caused similar responses in the
human, while histamine was more effective in the dog and
rabbit (40).
Cholinomimetics are relatively weak stimulants of acid
secretion when compared to histamine and pentagastrin (40) .
One possible reason could be that cholinergic agents may
stimulate both inhibitory and stimulatory pathways. Recently,
Feldman and Schiller suggested that the weak stimulatory
effect may be explained by a concomitant stimulation of
nonparietal (bicarbonate) secretion by the surface epithelium
(47,48).
Inhibition of Acid Secretion
Inhibition of acid secretion may be caused either by
direct action on the parietal cell or indirectly by the
release of other inhibitory agents or by changes in blood
flow (119). Gastric acid secretion can be decreased by
inhibition of the H+K+-ATPase, receptor blockage, or
inhibition of intracellular messengers (115). Atropine and
H2-receptor antagonists are potent inhibitors of both
pentagastrin and histamine stimulated acid secretion in the
human, dog and rat (40).
As mentioned earlier, gastrin release can be inhibited by
acidification of the antrum, by release of somatostatin and
by vagal fibers (103). There is evidence that somatostatin is
important in the inhibition of gastrin release by H+ in the


26
lumen (40,103). Somatostatin cells possess cytoplasmic
processes that extend to neighboring gastrin cells and
parietal cells in the fundus. Both the inhibition of gastrin
release and parietal cell secretion are by paracrine and
endocrine effects.
Acid secretion is also inhibited in the intestinal phase
by humoral agents released from the small intestine in
response to duodenal acidification or hyperosmolarity or
increasing lipid content (39,40). A variety of hormones
(gastric inhibitory peptide, enteroglucagon, vasoactive
intestinal peptide and cholecystokinin) are capable of
inhibiting parietal cell response, but their physiological
significance is not established (40). Duodenal acidification
causes the release of secretin from the duodenal mucosa which
stimulates pancreatic bicarbonate secretion and inhibits
gastric acid secretion. Lipids cause the release of
cholecystokinin from the mucosa which stimulates gall bladder
contraction. Cholecystokinin is structurally related to
gastrin in its carboxyl terminus and is a weak agonist of
acid secretion in the cat (40).
Histamine has long been recognized as one of the most
potent stimulants of acid secretion, however, its gastric
secretogue effect is not blocked by conventional
antihistaminic drugs, which inhibit the effects of histamine
on smooth muscle of the intestinal tract and bronchi (33) .
This led to the postulation that there were two separate


27
histamine receptors. Black and co-workers discovered that a
histamine analog inhibited histamine stimulated acid
secretion, identified the receptor on which it acted and
named it the histamine H2 receptor (21).
Since then, numerous H2 antagonists have undergone
clinical trial as potent inhibitors of acid secretion (142).
The first antagonists were developed by lengthening the side
chain and adding a thiourea group to the imidazole ring of
histamine. Cimetidine (Tagamet, Smith, Kline & French)
contains an imidazole ring and, except for the side chain,
has a structure similar to histamine. Raniditine (Zantac,
Glaxo, Inc.) contains a furan ring and has been found to be
5-10 times more active on a molar basis than cimetidine in
inhibiting basal and stimulated gastric acid secretion in
humans and dogs (121). Side effects attributed to the
imidazole ring of cimetidine have not been observed for
ranitidine, namely: 1) antiandrogenic effect characterized by
impotence and gynecomastia in men; 2) mental confusion; 3)
interaction with other drugs attributed to inhibition of
hepatic cytochrome P-450 oxidase enzymes; and 4) bone marrow
depression (20,102).
Like cimetidine, ranitidine has been shown to promote
significant healing in human peptic ulceration in several
double-blind clinical studies (142). It is well absorbed from
the human small intestine and has a plasma half-life similar
to that of cimetidine (approximately 90 minutes)


28
(37,78,92,121). It is excreted in the urine either unchanged
(70%) or as N-oxide and S-oxide metabolites. Ranitidine given
at breakfast to people suppresses acid secretion at lunch and
dinner, thus having a long duration of action. Because of the
increased potency and long duration of effect, ranitidine is
prescribed twice daily and studies are underway to determine
the effectiveness of once per day treatment at night when
acid secretion is highest (142). A possible cytoprotective
effect of ranitidine has been described in people and rats
which may be related to its ability to induce production of
endogenous prostaglandins (151).
Pepsinogen Secretion Rate
The term, pepsin, was introduced in 1836 by Schwann for
the protease in gastric juice (39,74). In 1930, almost one
hundred years later, Northrup crystallized pepsin from
porcine gastric mucosa. Pepsinogen initiates the process of
protein digestion which leads to the formation of peptides
that serve as signals for the release of various hormones,
including gastrin and cholecystokinin (72). In turn, these
hormones serve as major regulators of protein digestion.
Pepsinogen is most active on collagen, which is found in
greater quantity in meat than vegetable protein, implying
that carnivores should have higher secretion rates (72) .
Pepsinogen secretion is also thought to be important in those
species where mastication of food is minimal (dog) (72).


29
Pepsinogens are secreted as a heterogenous group of
inactive proenzymes and are converted into active,
proteolytic enzymes by acid (62,74). Seven distinct mammalian
pepsinogens have been characterized on the basis of
electrophoretic mobility, pH optima and immunologic
reactivity. The five fastest migrating pepsinogens (PI) can
be distinguished from pepsinogens 6 and 7 (P2). Group 1
pepsinogens are found in the chief cells and mucous neck
cells of the fundic glands, whereas group 2 pepsinogens are
found in fundic, pyloric and duodenal glands.
There is a small continuous basal secretion of pepsinogen
in humans (72) Additional pepsinogen secretion is stimulated
by primarily muscarinic cholinergics, but is also stimulated
by pentagastrin and histamine in the human and several other
species (74) In the human or dog, maximal pepsinogen
secretion is 3-4 fold greater than basal rates (72). The rate
of pepsinogen secretion in vivo during histamine
administration in dogs and cats was the subject of
controversy until dose-response curves showed reduced
secretion rates at high doses of histamine (75). Initial
increases, then decreases, in pepsinogen secretion may be due
to release of stored pro-enzyme (wash-out theory) (74).
Pepsinogen secretion activated by luminal acid has also been
demonstrated and probably occurs via local cholinergic
reflexes (72). Differences in species and the combined


30
possibilities of wash-out and acid activation make evaluation
of pepsinogen secretory data difficult.
After secretion into the gastric lumen, pepsinogen is
irreversibly converted by acid to the active enzyme, pepsin
(Mol. wt. 34,500), by loss of a variable amino terminus
(pepsin inhibitor fragment) (74). Following this loss, the
protein undergoes a conformational change, apparently to
expose a binding cleft that will accommodate a peptide of
about 8 amino acids. The active site contains 2 aspartyl
residues, which is similar to 2 other carboxyl proteases,
cathepsin and rennin. The catalytic site appears similar in
all species, including the horse (62). Once activated, pepsin
can be denatured by pH > 7.2 or temperatures above 65C.
Pepsin is an endopeptidase with a pH optimum of 1-3
depending on the substrate, and is most active against
peptide bonds adjacent to aromatic peptides (phenylalanine
and tyrosine) or dicarboxylic L-amino acids (39,74). Some
free amino acids and polypeptides are produced. The extent of
digestion is determined by the physical state of the ingested
protein, the length of time it stays in the stomach and the
activity of the pepsin. Gastric protein digestion is not
essential in humans, since those with achlorhydria have no
impairment of protein digestion and absorption (39).
The most traditional technique used to determine the
concentration of pepsin in gastric fluid is by the digestion
of hemoglobin substrate at pH 1.7 as first described by Anson


31
and Mirsky (10). Pepsin splits off products from hemoglobin
which are soluble in trichloroacetic acid. With this
technique, 1 peptic unit (PU) represents the activity of
pepsin which releases 0.1 /M tyrosine from 5 ml of 2%
hemoglobin at pH 1.7 in 10 minutes at 37C (10).
Gastric Fluid Composition
The composition of gastric fluid is determined by the
different secretory systems existing side-by-side in the
gastric mucosa: 1) the parietal cell secretes electrolytes
and acid (HC1); 2) the chief cell synthesizes pepsinogen
which is stored for rapid release but may also be made and
secreted continuously; and 3) the mucous epithelial cell
which constantly secretes water, mucus and bicarbonate (39).
Each secretory product has a specific role in protein
digestion (acid and pepsin) or mucosal protection (mucus and
bicarbonate).
While pure parietal or nonparietal fluid has not been
measured directly, several theories have been put forth to
explain the composition of gastric fluid in relation to
different mixtures of parietal and nonparietal components.
The ionic composition has been determined for human and
animal species on the basis of positive (or negative)
correlation with the rate of H+ secretion according to the
two-component theory (82,99). This theory assumes that the
parietal component has a constant composition, independent of
the rate of secretion, which is pure, isotonic HC1, and the


32
nonparietal component is also assumed to have a constant
composition which is an isotonic ultrafiltrate of plasma
containing primarily Na+, bicarbonate, mucus and enzymes
(99) Each component may be secreted at different rates. At
maximal rate of acid secretion, gastric fluid is an isotonic
mixture of almost pure HC1 mixed with K+ (estimated ionic
composition: 149 mM H+, 166 mM Cl-, 17 mM K+) (84,98). The
composition of the nonparietal component has been estimated
to be 140 mM Na+, 5 mM K+, 120 mM Cl, 25 mM HC03. To
maintain the striking gradients between H+ and Na+ between
plasma and gastric fluid, the gastric mucosa is practically
impermeable to the passive diffusion of these ions and
maintains a transepithelial potential gradient of 40 mV
(mucosa negative) (39) Sodium is apparently not essential
for Cl- entry into the cell and has a constant output with an
inverse relationship to H+ concentration (84,98).
In addition to active H+ secretion, chloride has been
shown to be actively secreted by the gastric mucosa against
both a concentration and electrical gradient (95,119). This
active secretion results in a negative potential difference
(mucosa negative). The existence of the potential is not
dependent on the acid secretory rate of the mucosa, as the
stomach secretes Cl- even when there is no H+ secretion, but
is produced by active Cl- secretion in excess of the H+
secretion (95,119). This so-called non-acidic Cl- secretion
manifests itself as the lumen-directed negative short circuit


33
current and PD. Measurement of Cl- fluxes in amphibian or
piglet mucosa clearly shows that upon stimulation of acid
secretion the Cl~ transport from blood to mucosa increases
with a value corresponding to the H+ secretion. Passive and
facilitated Cl~ transport systems have been identified and
consist of the following systems: 1) an anion-coupled
antiport C1/HC03- exchange at the basolateral surface; 2)
Na+ facilitated Cl- transport at the basolateral surface
(uncertainty if NaCl co-transport or Na+/H+ and C1-/HC03-
exchange) ; 3) a KCl co-transport at the apical surface; and
4) Cl- conductance pathways at the apical and basolateral
membranes (95).
Gastric secretion of bicarbonate ion was postulated by
Schierbeck in 1892, and Hollander proposed that secretion of
a bicarbonate-containing fluid was the main mechanism for
regulating gastric acidity (52,82). Gastric bicarbonate has
only recently been found to be an active process which can be
stimulated and inhibited in the fundic, pyloric and duodenal
mucosa (52,46). The amount of bicarbonate transported by the
mucosa might be sufficient to account for the well known
constant loss of H+ from acid contents in accordance with the
two-component theory. The amount of Na+ co-transport or
reaction with H+ would decrease luminal osmolality and excess
water would move into the mucosa (51). However, bicarbonate
secretion may also appear as a surface neutralization of H+
rather than as a secretion with a defined volume (53). Direct


34
measurements of pH at the mucosal surface strongly suggest
that neutralization of H+ diffusing from the lumen by
bicarbonate from the epithelial surface occurs in a narrow
zone within the surface mucous gel layer and not in the
luminal bulk solution (52) The exact mechanism by which
gastric bicarbonate is secreted is unknown. The fact that
there is virtually no change in gastric electrical potential
difference during stimulation of bicarbonate secretion
suggests that bicarbonate transport may take place via an
electroneutral ion exchange mechanism (such as with Cl~) at
the luminal or basolateral membrane (95).


CHAPTER II
REVIEW OF LITERATURE
Peptic Ulceration
Gastric Ulceration
Although gastric ulcers in foals have been reported since
1964, information is still lacking on the prevalence of
squamous versus glandular lesions (15,30,124). Erosions and
ulcers are found usually at the margo plicatus in the
squamous mucosa and have been reported as incidental findings
in 2-25% of foals presented for necropsy. Fifty percent of
perforated ulcers in one study were in the squamous mucosa.
These lesions have also been recently reported in adult
horses without a history of previous medication. Diet and
physical stress have been proposed as etiological factors.
Ulcers in the squamous mucosa near the cardia (junction of
esophageal and gastric mucosa) are common in swine fed high
protein or pelleted diets. Surveys of farms with equine
gastroduodenal ulceration have not shown any effect of diet
but additional studies are needed concerning feeding
practices on these farms.
The squamous mucosal ulcers in foals may be similar to
"stress erosions" seen in seriously ill people following
major surgery or trauma (103). Stress erosions in people,
35


36
however, occur in the glandular mucosa. The pathogenesis of
gastric ulceration in people, in general, is less associated
with excess acid and pepsin secretion and more associated
with decreased mucosal resistance normally produced by
secretion of mucus and bicarbonate. With restoration of
normal defense mechanisms, stress ulcers heal rapidly within
several days. Experimental evidence in laboratory animals
also suggests that stress ulceration results from a temporary
failure of gastric mucosal defense mechanisms, rather than
from excessive secretion of acid and pepsin, however, mucosal
lesions can not be produced without luminal acid (103). Since
the eguine sguamous epithelium does not appear on histologic
sections to be covered by mucus to as great an extent as the
glandular epithelium, it may be more easily damaged than the
glandular epithelium when there is failure of gastric mucosal
defense mechanisms.
Equine gastric ulcers of the glandular epithelium are seen
less frequently than those of the squamous mucosa and have
been reported in ill neonates (30) Glandular gastric ulcers
have also been experimentally produced with nonsteroidal
anti-inflammatory drugs (NSAID),in foals and ponies (145).
Ulceration following NSAID administration probably results
partly from inhibition of endogenous prostaglandin synthesis.
Prostaglandins have been shown to inhibit acid and pepsin
secretion, stimulate mucus and bicarbonate secretion and
maintain mucosal blood flow (122,123,151). Additionally,


37
prostaglandins promote rapid restitution of damaged
epithelium in doses which do not inhibit acid secretion
(103,122).
Duodenal Ulceration
The eguine cranial duodenum is sigmoid-shaped with an
initial ampulla separated by a slight constriction from the
second ampulla into which the hepaticopancreatic duct enters
(135). Duodenal ulcers in the horse are generally located on
the anti-mesenteric surface as solitary or multiple lesions
in the proximal duodenum or can diffusely involve the entire
duodenum (15,28). The hepatic duct may be secondarily
obstructed due to duodenitis or stricture formation distal to
its opening into the duodenum.
Duodenal ulcers are more commonly seen in 2-6 month old
foals and can occur as a herd outbreak (30). Diarrhea
frequently precedes other clinical signs which include teeth
grinding, excessive salivation, depression, anorexia and
colic. Delayed gastric emptying usually results in squamous
gastritis and esophagitis. In foals with gastric outlet
obstruction from duodenal ulcer disease, gastrojejunostomy
has resulted in rapid healing of gastritis and esophagitis
without recurrence of duodenal ulceration (28).
Unfortunately, duodenal ulcers in foals may perforate and
result in rapid life-threatening deterioration within 48
hours of the first clinical signs of ulcer disease.


38
Human duodenal ulceration represents the classic condition
brought about by the proteolytic action of acid and pepsin
(103) Excess acid may result from many factors such as an
increased basal or nocturnal secretion rate, increased
parietal cell number, increased vagal inputs in response to
food, increased sensitivity to or release of gastrin and
heredity. Breakdown of mucosal resistance is also important
in duodenal ulceration and a decreased bicarbonate secretion
rate has been reported (49).
Pathophysiology
The mechanisms by which the gastric and duodenal mucosa
normally resists the onslaught of food and secreted acid and
pepsin are not completely understood (39) It is generally
thought that mucosal damage is induced by acid, pepsin and
bile after the integrity of the gastroduodenal mucosa has
been damaged. Research into the etiology of human duodenal
ulceration has tended to concentrate on factors that control
acid and pepsin secretion, while factors that determine
mucosal resistance have been investigated in gastric
ulceration (103). It is generally agreed that the presence of
sufficient luminal acid and pepsin are required for both
gastric and duodenal ulceration to develop. Gastric acid is
considered the primary damaging agent which also activates
the proteolytic enzyme pepsin from secreted pepsinogen.
Mucosal ischemia appears to compromise the ability of the
gastric mucosa to dispose of intracellular acid which may


39
have diffused into the mucosa (39). Although gastric acid and
pepsin seem essential for the formation of ulcers, gastric
ulcer patients frequently secrete acid at rates
indistinguishable from normal patients (103).
In contrast, nearly half of the duodenal ulcer patients
have increased basal and maximal acid secretion rates (103).
The mechanisms for these augmented secretory rates have been
attributed to increased responsiveness of the gastric
parietal cell to stimulation by neural and hormonal (gastrin)
agents, increased parietal cell mass, hypergastrinemia and
impaired duodenal mucosal bicarbonate secretion. The
pathophysiological processes underlying duodenal ulceration
are not fully understood but there are indications that one
of them may be an inadequate neutralization of an excessive
gastric juice entering the duodenal bulb. The rate of acid
and pepsin delivered to the duodenum by factors regulating
gastroduodenal motility are also being investigated with
regard to development of peptic ulceration.
In circumstances of normal secretory rates, acid probably
plays primarily a permissive role and attention has focused
on factors that may protect the mucosa from acid and pepsin.
The components of the mucosal barrier include a surface layer
of mucus, surface epithelial bicarbonate secretion, mucosal
blood flow, epidermal growth factor concentration (inhibits
acid secretion and epithelial repair and regenerative
processes (30,39,114). Agents known to "break" the barrier


40
are acids (HC1, salicylic), detergents that attack the lipid
portion of the plasma membrane (bile acids), hyperosmolar
solutions and ethanol (39).
Mucus is secreted as an insoluble gel adherent to the
mucosa and as a soluble form mixed in the lumen with gastric
contents (149). It functions as a barrier for hydrogen ions
with neutralization by bicarbonate secreted from the surface
epithelium, as a diffusion barrier for pepsin and as a
lubricant to prevent mechanical damage (14,69,152). Finally,
the surface epithelium is capable of rapid restitution after
acute superficial damage by migration of the surface
epithelium.
Secretion of bicarbonate by both gastric and duodenal
surface epithelium beneath the mucous layer maintains the
surface pH near neutrality in spite of a luminal pH as low as
1 (52). Bicarbonate secretion is stimulated by luminal acid
and this response is mediated by endogenous prostaglandins,
humoral factors and, probably, neural inputs (47).
Abnormalities of gastroduodenal motility have been
investigated in people with peptic ulceration (30,103). In
both gastric and duodenal ulceration, increased
duodenogastric reflux has been reported. Delayed gastric
emptying can produce gastric ulcers by increasing the
duration of mucosal contact with acid and pepsin. Delayed
gastric emptying can result from gastric stasis due to
gastroenteritis or can be secondary to duodenal ulceration.


41
In people with gastric ulceration, antral hypomotility, and
hence decreased emptying of solid foods, has been reported.
In duodenal ulceration, gastric accommodation to distension
is not altered nor are there changes in the rhythm or
freguency of gastric peristalsis. There are reports of
increased gastric emptying rates and the rapid entrance of
acidified chyme into the duodenum could contribute to the
inability of the duodenum to neutralize the acid, leading to
ulceration. An abnormality in local motility of the duodenum
might contribute to the formation of ulcers at specific
sites, such as the duodenal bulb, as the proximal duodenum
helps to regulate emptying of acid from the stomach. Delayed
gastric emptying has been reported in foals with duodenal
ulceration and it has usually been a result of stricture
formation from healed ulcers. Information is not available
concerning changes in gastric secretion or motility in these
foals, which could provide clues to the pathogenesis of this
disease in horses.
Inhibition of endogenous prostaglandin synthesis by NSAID
seems likely to be the cause of mucosal damage that can be
produced by these agents (123,151). Some NSAID's also
increase gastric acid secretion. Prostaglandins inhibit the
stimulation of cAMP production from ATP by inhibition of
adenylate cyclase (138). This enzyme is stimulated in the
gastric parietal cell following binding of histamine as
mentioned earlier. Several experimental studies in foals and


42
ponies have shown ulcerogenic properties of phenylbutazone
(30,144). Oral lesions were observed more frequently
following oral administration than parenteral. Administration
of an oral prostaglandin E2 prevented phenylbutazone-induced
ulceration in ponies, although it is not known if the dose
used also decreased acid secretion.
An infectious or toxic etiology has been proposed to
explain the occurrence of diarrhea and clustering of affected
foals on certain farms (15,30). Such an agent could directly
damage the gastroduodenal mucosa or possibly affect
gastroduodenal motility, resulting in ulceration. An organism
or toxin has not been isolated (2) Currently there is much
excitement concerning the possible role of Campylobacter
pyloridis in the pathogenesis of human gastric ulceration
(26) Campylobacter sp. are urease-positive and lie beneath
the antral mucosa. The bacteria might damage the mucosa by
trapping ammonium thereby exposing the mucosa to excessive
hydrogen ions.
Bile salts have been implicated in causing gastric mucosal
damage and have also been found to inhibit mucus and
bicarbonate secretion in people (30). With recent techniques,
bile reflux has been found in normal fasting humans, dogs and
pigs, and has been observed during endoscopy and
experimentation in normal horses. Bile reflux may be
important if the gastric mucosa is already damaged. In foals
treated for gastric outlet
obstruction
with


43
gastrojejunostomy, clinical signs of ulceration did not
worsen after total diversion of proximal duodenal contents
including bile into the stomach. Bile reflux may not be a
major factor in the development of gastric ulceration in the
foal.
There has been interest in pepsinogen as a contributor to
the formation of peptic ulceration (149). Pepsin constantly
digests the mucous layer covering the mucosa. Several studies
have shown that the instillation of acid alone was
insufficient to produce ulceration; pepsin had to be present
as well. In duodenal ulcer patients, both basal and
stimulated pepsin secretion, like acid secretion, are usually
higher than in normal subjects. Both pepsinogens 1 and 2 can
be detected in serum and Samloff et al. found a greater
proportion of PI in duodenal ulcer patients than normal
subjects (129). Pepsinogen 1 has a mucolytic activity over a
wider range of pH including that seen in the duodenal bulb.
However, there is considerable overlap in serum pepsinogen
concentrations between normal subjects and patients with
duodenal ulcer disease and thus serum levels are not
considered diagnostic. The lack of interest in antipepsin
therapy is due in part to the success of antacid therapy,
since acid secretory inhibitors suppress pepsinogen secretion
and lead to a higher luminal pH which reduces pepsinogen
activation.


44
Equine Gastric Secretory Physiology
Until recently, equine gastric physiology has received
little interest primarily due to a paucity of gastric
diseases and difficulties in creating a gastric fistula model
in this species. Little information is therefore available on
the composition and control of gastric secretion in the
horse. Russian investigators described experiments in fasted
young horses (1.5-2 years old) with a gastric fistula and
found a continuously variable gastric fluid output that could
not be further stimulated by offered food (73,145). Atropine
caused regurgitation of duodenal contents and markedly
decreased the volume of secretion. The pH of equine gastric
contents has been reported to range from 1.13-6.8 and 1.6-6
(necropsy specimens).
Volatile fatty acids and lactic acid were measured in
gastric contents of the fed horse (8,13). Equine fundic and
pyloric mucosa were found to absorb volatile fatty acids but
only the pyloric mucosa transported significant amounts to
the serosal surface (13). The stratified epithelium did not
absorb the fatty acids and had a low tissue conductance
indicating it was relatively impermeable to passive ion
transport. The nonglandular and glandular regions had similar
pH recordings and the lowest values obtained after feeding
had a mean value greater than pH 2 (13) Electrolytes have
also been measured in the gastric contents of fed ponies, and


45
had mean values of 62 12 mEq/L Na+, 28 5 mEq/L K+, 78
15 mEq/L Cl and 8.6 2 for total C02 (5,11).
Gastric empyting is rapid in the horse as judged from
radiographic studies and from studies using liquid and
particulate markers (7,12,27). Gastric emptying rate in foals
was studied by contrast radiology and has been reported to be
slower in the nursing foal than in the weaned foal in one
study (7). However, another study did not find any difference
in gastric emptying rate due to age (27) In the adult, 75%
of a liquid marker had emptied by 30 minutes; however
nondigestible particulate markers were retained for a length
of time directly proportional to their size (12). Gastric
capacity is estimated to be only 10% of the total
gastrointestinal tract (135).
A technique for gastric cannulation has only recently been
reported and was developed by the authors for these studies
(29) Equine gastric fluid was secreted continuously during
basal conditions and acid output was inhibited by ranitidine
given at 0.5 mg/kg IV. Although several other investigators
have adapted the use of this cannula technique, results of
their studies have not yet been published.


CHAPTER III
MATERIALS AND METHODS
Animals and Surgical Preparation
Thirteen horses of various breeds and sexes, ranging from
4-12 months of age, were selected since the problem of
gastroduodenal disease is seen primarily in 2-6 month-old
horses (Table 3.1). The horses were free of clinical signs of
gastrointestinal disease and were dewormed (Eqvalan, Merck &
Co., Inc.) and vaccinated for encephalitis and tetanus
(Cephalvac, VEWT, Cooper Animal Health Inc.) before surgery.
The gastric cannula was constructed entirely of medical
grade silicone rubber tubing (1.6-cm, ID; 2.2-cm, OD;
Silastic, Dow Corning Corp, Midland, Mich). Three flanges
were made from the silastic tubing and two were permanently
fixed to the tube with silicone glue, one at the inner
gastric end and the other at the inner ventral body wall
position. The middle flange (outer gastric flange) was freely
movable to allow positioning after placement of the tube with
the inner flange within the gastric lumen. The cannula was
also supplied with an inner tube plugged at the gastric end
to occlude the cannula between experiments. The inner tube
and an outer body wall flange made of soft rubber were held
in place with a hose clamp.
46


47
Table 3
1. Animal
signalment.
Horse
#
Age
Sex
Breed
Weight
(m)
(kg)
Dustin
1
6
M
Quarter Horse
173-182
Brownie
2
10
M
Quarter Horse
245-258
Marvin
3
6
M
Thoroughbred
187-230
Benny
4
12
M
Thoroughbred
186-232
Linus
5
12
M
Thoroughbred
265-282
Charro
6
5
F
Thoroughbred
200-215
Herb
7
4
M
Thoroughbred
160-170
Ramar
8
12
M
Arabian
235-264
Boo
9
4
M
Quarter Horse
211-220
Tara
10
6
F
Thoroughbred
227-247
Scout
11
5
M
Quarter Horse
132-166
Silver
12
6
F
Quarter Horse
154-175
Pokey
13
6
M
Quarter Horse
170-190


48
The horse was anesthetized with halothane and a ventral
midline incision made to gain access to the cranial abdomen.
The stomach was isolated with moistened towels to prevent
contamination of the abdomen with spilled gastric contents.
Two stay sutures were placed about 20 cm apart on the ventral
surface of the stomach between the lesser and greater
curvatures and were used to elevate the stomach to the
incision. Three purse-string sutures were placed around the
intended gastrotomy using #2 polyglactin 910 (Vicryl, Ethicon
Inc.). A stab incision was made in the center of the purse
string suture pattern and the cannula was inserted into the
gastric lumen. The sutures were tied allowing the serosa to
invert around the tube before securing the outer gastric
flange to the serosa with #2 polyglactin 910. The cannula was
brought through a stab incision in the left ventral abdomen
and the abdominal incision was closed with 3 layers of suture
in a routine manner.
Horses were allowed to drink only water during the first
24 hours after surgery and then were gradually fed alfalfa
hay. Each horse was given gentamicin (2 mg/kg IM TID) and
procaine penicillin (10,000 U/kg IM BID) perioperatively and
a nonsteroidal anti-inflammatory drug (flunixin meglumine,
Banamine@, Schering Corp.) was administered if any signs of
pain were observed.
The horses were given 2 weeks to recover from surgery and
were trained to accept gentle restraint by cross-tying in a


49
stocks. Body weights were determined biweekly. They were
maintained on a diet of grain and free choice coastal hay and
salt block. After several weeks, they could be turned out in
a large pasture to exercise.
Endoscopy was performed via the cannula to evaluate the
condition of the gastric and duodenal mucosa in horses 5-13
(Video-Endoscope@, Welch-Allyn). Each horse was euthanitized
after completion of the studies and a full necropsy was
performed. Histologic sections were examined from the gastric
sguamous and glandular mucosa, margo plicatus and duodenal
mucosa using hematoxylin-eosin and PAS stains.
Methodology
Experiments were designed to address the following
guestions:
1) Protocol I: What is the basal acid secretion rate in
the horse?
2) Protocols II and III: Can the equine stomach be
stimulated to secrete acid by intravenous pentagastrin
infusion and what is the dose which will produce maximal acid
output?
3) Protocol IV: What are the effects of a H2-receptor
antagonist (ranitidine) on equine gastric acid and pepsin
secretion under basal and pentagastrin stimulated conditions?
Secretory Experiments
The horse was fasted for 24 hours with access to water and
then placed in a room isolated from other horses and food.


50
The experiments began between 7:30 and 9:00 am to control for
possible diurnal variation in acid secretion as has been
described for people, but were not addressed in this study
(48) They were conducted once per week to control for
possible residual drug effects and to maintain animal health.
Isotonic saline was administered at 200 ml/h for 5 hours
through a jugular catheter to replace electrolytes lost
during the experiments and the catheter was used as the route
of administration for test drugs. A plasma sample was taken
at catheter placement for determination of plasma osmolality
(all horses). The gastric cannula was opened for 30 minutes
to allow gravity drainage of any residual chyme before
beginning the 5 hour collection.
Experimental Design
Protocol I
Gastric fluid was collected every 15 minutes for 5 hours
in 13 horses to determine basal rates of secretion.
Intravenous 0.9% saline was administered at 200 ml/h.
Protocol II
Gastric fluid was collected as for protocol I. Two horses
were given step-wise increasing doses of pentagastrin
(Peptavlon, Ayerst Labs) at 1.5, 3, 6 and 12 /ng/kg/h by
intravenous infusion (Harvard infusion pump, Harvard
Instruments). The pentagastrin was dissolved in water by
increasing the pH to 9 with 0.1 N NH4OH, and NaCl was added
to achieve isotonicity before a final pH adjustment to 7.4. A


51
one hour baseline collection was made and the pentagastrin
infusion started at the beginning of the second hour. These
doses of pentagastrin were selected based on studies in other
species.
Protocol III
Gastric fluid was collected as for protocol I. At the
beginning of the second hour, 8 horses received pentagastrin
at 6/xg/kg/h by intravenous infusion.
Protocol IV
Gastric fluid was collected as for protocol I. At the
beginning of the second hour, 4 treatments were given (Table
3.2). A randomized block design was used where five horses
received 4 treatments in random sequence and in duplicate (8
experiments per horse). The treatments were randomized to
minimize effects due to the gastric cannulation (fatigue) and
adaptation by the animal to the secretory studies (learning).
As each horse served as its own control, individual variation
could be evaluated and since duplicates of each treatment
were performed, any missing data was accounted for by using
an average of the two treatments. The use of repeated
measures also increased the confidence in the results given
the small number of animals.
Measured parameters
The fluid was collected in a Erlenmeyer flask, and every
15 minutes the flask was emptied into a graduated cylinder.
The volume was measured to the nearest 2 ml and the sample


52
Table 3.2 Treatment scheme for protocol IV.
Hour
1
2
3
4 5
Treatment
1. Saline3-
z diinu
Ranitidine13
3 Ocli. J.
Pentagastrin0-
4 Dai. JL1C
rcnLayasurin-"
Ranitidine
3 NaCl 0.9%, 200ml/h.
b Ranitidine IV bolus, 0.5 mg/kg.
c Pentagastrin infusion, 6 /Lig/kg/h.


53
was decanted to remove a top layer of foam (usually 5-20 ml).
The sample was filtered through glass wool to remove any
particulate material and an aliquot saved.
Each aliquot was analyzed the same day for pH, H+
concentration and osmolality. The pH was measured immediately
using a glass electrode with the pH meter (PHM 61,
Radiometer) calibrated at 20C using commercial buffer
solutions of pH 2 and 7 (pH Standard, Fischer Scientific
Co.). Hydrogen ion concentration (H+ mEq/L) was determined in
duplicate by titrating a 1 ml sample diluted 1:10 with
deionized water with 0.1 M NaOH to pH 7.4. The number of
milliliters of titrant was equal to the molarity*10_1 of HC1
in the gastric juice (ex. 2 ml of 0.1 M NaOH = 1 ml of 0.2 M
HC1) .
Gastric fluid and plasma osmolality were measured in 200
uL samples by freezing point depression (Advanced Digimatic
Osmometer, model 3DII, Advanced Instruments, Inc.) and
expressed as mosmoles per kilogram.
An aliquot from alternate time periods (ie. every 30
minutes) was stored at 4C for pepsin determination which was
performed within 1 week, using a modification of the Anson
and Mirsky method (19). All reagents were equilibrated to
25.5C (method 1) or 37C (method 2). Bovine hemoglobin
substrate (3 ml of a 2% solution in 0.06 M HC1; Fischer
Scientific) was incubated with a 0.5 ml sample of gastric
juice diluted 2.5-10 times with 0.01 M HC1 for 10 minutes and


54
the digestion stopped by addition of 5 ml of 5%
trichloracetic acid. The digestion mixture was agitated and
filtered through #2 or #50 Whatman paper. Peptic activity was
estimated in the resulting filtrate by measuring the density
of color produced by liberated tyrosine and tryptophane
(phenol reagent method, method 1) or by their absorbance at
280nm (UV method, method 2). The phenol method determines the
content of split products in the resulting filtrate by
addition of 0.5 M NaOH and phenol reagent and reading
absorbance
at 578
nm.
Pepsin
concentration
(Mg/ml)
was
determined
from a
standard curve based on
5-40 /xg
of
crystalline
pepsinogen
(Cooper
Biomedical).
A blank
was
prepared for each sample by precipitation of the hemoglobin
substrate with trichloroacetic acid before addition of the
sample. The 2 methods were compared on 3 occasions by
preparation of standard curves from the same pepsin
standards. Coefficients of correlation between the 2 methods
were determined as well as the mean, standard deviation and
coefficient of variation for replicates of standards.
Calculated parameters
Acid (H+ xEg/kg) or pepsin (pepsin ug/kg) output was the
product of the respective concentration and volume. Output
values were divided by the animal's body weight to normalize
the data between animals and to allow comparison with other
species of various sizes. Basal acid output (BAO, g/kg/h)
was the sum of the first four 15-minute periods during which


55
no treatment other than intravenous saline had been given and
was calculated for each experiment. Maximal acid output (MAO,
/xg/kg/h) was the sum of the four consecutive 15-minute
periods with the highest total after pentagastrin infusion.
Maximal acid concentration (MAC) was the highest hydrogen ion
concentration achieved during pentagastrin infusion.
Statistical Analysis
Means and standard deviations (STD) were calculated for
all variables (volume, pH, hydrogen ion concentration, acid
output, pepsin concentration and output, osmolality) with n
equal to the number of animals. Correlation coefficients were
calculated for overall and hour 1 control gastric fluid
variables and between the 2 methods for pepsin analysis.
Coefficients of variation (CV, STD/Mean*100) were calculated
within- (n=10, average of replicate experiments coefficients
of variations) and between-animals (n=13) during control
experiments. Within-assay coefficients of variation were
calculated for replicates of hydrogen ion concentration,
osmolality and pepsin concentration.
The hourly average for each variable was analyzed by
repeated measures ANOVA with 2 within-subject factors,
treatment (4 levels) and time (5 levels). If the treatment
time interaction term was significant, a multiple comparison
test was used to determine significant differences between
means. Both within-treatment (ie. treatment 1, hours 1-5) and
within-time (ie. hour 1, treatments 1-4) were tested. The


56
Scheff test is considered a conservative multiple comparison
procedure and was used for all variables except for pH, where
a t-test with pooled variances was used. The t-test is a more
liberal multiple comparison test and was used because of the
large standard deviation in control pH and small differences
between treatment means. Significance was determined at P <
0.05 for both tests.
Phenol Red Recovery
The efficiency of gastric fluid collection was tested by
instilling a phenol red solution (phenolsulfonphthalein,
Sigma Chemical Co.; 50 mg/L in 0.16M HC1) over a 1-minute
period into the stomach of each fasted horse (Trial 1). Five
to ten weeks later, the test was repeated (Trial 2). Gastric
contents were collected at 1, 5, 15 and 3 0 minutes and
volumes were recorded. Colorimetric estimation of phenol red
concentration was determined in each gastric fluid sample
after a 1:5 dilution and alkalinization with 1M NaOH.
Absorbencies were measured spectrophotometrically at 520, 560
and 600nm and a 3-wave length correction applied, correcting
for background absorbencies in this region of the spectrum
(130).
[Phenol Red] = 560 0.5 (520+600)
Phenol red recovery rate (%) was determined by summation of
each sample's phenol red content divided by the total amount
given.


CHAPTER IV
RESULTS
Animal Preparation and Necropsy Findings
All horses recovered from surgery without major
complications. In several animals, fever developed 3-8 days
post-operatively which was attributed to focal inflammation.
Abdominal pain occurred in most animals, but was infrequent
and readily managed with xylazine (Rompun; Haver-Lockhart)
or flunixin meglumine.
One horse was euthanitized after experiencing several mild
bouts of colic 10 weeks after surgery, and necropsy findings
revealed massive abdominal adhesions from generalized
peritonitis. Another horse developed a fistula between the
left dorsal colon and stomach along the cannula. In the other
horses, the only remarkable findings on necropsy were fibrous
adhesions around the cannula with adhesion of the large colon
to the ventral body wall. Few adhesions were found in the
cranial abdomen indicating peritonitis was not a major
complication of this procedure. In animals cannulated for
over 2 months, the cannula became incorporated into the wall
(2) or lumen (5) of the large colon at the diaphragmatic or
sternal flexure. This incorporation occurred without apparent
abdominal pain or abscessation.
57


58
The gastric mucosa was in good condition in all horses on
gross inspection. In one horse, a glandular gastric ulcer,
discovered by endoscopy 12 weeks prior to necropsy, was
completely healed. It was located opposite the cannula on the
lesser curvature and may have resulted from using a long
inner-tube for the cannula. Six horses had 1-3 small sguamous
mucosal erosions at the margo plicatus. These lesions
appeared histologically as a mild superficial gastritis with
primarily a neutrophilic infiltrate. Two horses had 1-2
linear mucosal creases at the gastrotomy which were
associated with the inner-most suture line. The duodenum
appeared normal in all animals.
Phenol Red Recovery Rates
The results of phenol red recovery are shown in Table 4.1
and demonstrated that most horses had greater than 80% of the
instilled solution recovered through the gastric cannula. The
majority of the solution was recovered by 1.5 minutes. A
greater recovery rate was achieved by administration of the
larger dose in horses 3-13. There was generally good
agreement between duplicate trials in horses, and also
between recovery rates at the beginning and end of an
experiment. The corrected standard curve was linear.
Gastric Secretory Studies
Results from the gastric secretory studies are described
for each variable during control (saline) and stimulated
(pentagastrin) treatments. For example, all control


59
Table 4.1. Phenol red
recovery rates (%).
Horse3
Trial 1
Trial 2
AVG.
1
45
51
48
2
89
64/79b
84
3
100
92
96
4
92
ND
92
5
95
97
96
6
91
81
86
7
87
ND
87
8
86
100/83b
92
9
76
ND
76
10
98/106b
ND
102
11
82
91
87
12
82
ND
82
13
75
ND
75
a Solution administered at 500 ml
except horses 1 and 2 (200 ml).
b Before and after an experiment.
experiments whether performed for protocol I or IV, will be
presented together. This has been done to allow the most
accurate estimate of each variable with the greatest sample
size. Finally, for protocol IV, the results are analyzed by
variable for each treatment (control, stimulated, inhibited,
stimulated then inhibited) and time (hours 1-5) (Analysis of
variance, 2 within-subject factors). Data are reported as the
mean standard deviation (STD, n= number of horses), except
in the figures where the standard error of the mean (SEM) is
shown. A P value of less than 0.05 was considered
significant. This statistical analysis allowed each variable


60
to be analyzed with regard to the great amount of individual
horse variation in basal secretory rates.
Control Studies
Collection of gastric contents for 5 hours did not result
in dehydration or substantial electrolyte loss for any of the
horses as packed cell volume and total protein and plasma
sodium, potassium and osmolality did not change. After a fast
of 24 hours, the gastric contents contained chyme (100-500
ml) which was removed during the initial 30 minute drainage
period before the 5-hour study began. Gastric fluid was clear
and watery in samples with a low pH and was dark green to
yellow and viscous in samples with a high pH. Periodic
duodenal reflux, indicated by a high pH and visible bile
discoloration, occurred intermittently in most horses. After
the fluid was measured in a graduated cylinder, a white
frothy layer floated to the top (5-30 ml) in most collections
and was presumed to be saliva as the pH was greater than 8.
Basal gastric fluid secretion was determined in 29
experiments in 13 horses (Table 4.4, Figure 4.2, Appendix A).
Gastric volume (flow rate), pH, H+ concentration (H+ mEq/L)
and acid output (AO, H+ Eq/kg) were continuously variable
between 15-minute collections. Gastric flow rate ranged from
50 to 710 ml/15-min with a mean of 290 80 ml/15-min (STD).
Gastric pH was highly variable and ranged from 1.3 to 6.4
with a mean of 1.98 0.51.


61
Hydrogen ion concentration and acid output varied markedly
between and within horses. Hydrogen ion concentration ranged
from 0 to 67 mEq/L with a mean of 39 15 mEq/L and acid
output ranged from 0 to 131 /iEq/kg/15-min with a mean of 56
30 /xEq/kg/15-min. Basal acid output (BAO) was determined by
summation of the first 4 15-minute periods and ranged from 0
to 541 /Eq/kg/h with a mean of 210 109 /Eq/kg/h.
The results are expressed both as an overall average of 20
15-minute collections and as the average of the first 4 15-
minute collections (hour 1) in Table 4.2. Average values of
the first hour were highly correlated to the overall average
(Appendix C).
Pentaqastrin Stimulation Studies
Protocol II
Pentagastrin, given by step-dose infusion (1.5, 3, 6 and
12 jug/kg/h) produced an augmentation in acid output by
increasing both hydrogen ion concentration and secretory rate
in 2 horses (5 experiments; Appendix A) Six micrograms per
kilogram was selected as the dose producing maximal
stimulation of acid output, as doubling the dose decreased
acid output (Table 4.3).
Protocol III
Pentagastrin, 6 jug/kg/h by intravenous infusion, produced
increases in hydrogen ion concentration and volume output
which reached a steady and maximal rate by the second hour in
14 experiments in 8 horses (Figure 4.2, Appendix A). Acid


62
Table 4.2 Control gastric fluid variable averages
(29 experiments in 13 horses).
Overall
Mean
(5 Hours)
Coefficient
STD Inter
Variation3
Intra
Volume (ml/15-min)
287
77
27
19
PH
1.98
0.51
26
24
H+ mEq/L
39
15
39
27
H+ /Eq/kg/15-minb
56
30
54
33
Hour 1
Volume (ml/15-min)
295
84
28
20
PH
2.03
0.58
28
26
H+ mEq/L
41
26
32
47
H+ iEq/kg/15-minb
52
27
53
39
a Inter-animal coefficients of variation for 13 animals
and intra-animal coefficients of variation based on
average coefficients of variation for replicate
experiments in 10 animals (see Appendix A for number of
experiments per horse).
b Acid output per period.


63
c
70 T
60-
E
i
m
50-
cn
40-
cr
Ld
s
30-
+
X
20-
10-
Figure 4.1. Basal acid output in 13 horses (29 experiments).
All horses received 0.9% NaCl, 200 ml/h IV, throughout the 5-
h experiment.


64
Table 4.3 Maximal acid output during step-dose
pentagastrin infusion for 5 experiments in 2
horses (mean STD).
Dose (g/kg/h)
Maximal Acid Output
per 15-minutes
(H+ /xEq/kg)
per hour
1.5
128 27
338 53
3.0
188 28
496 94
6.0
197 31
495 104
12.0
145 19
455 60


H+ /lE q / k g /1 5 min
65
Figure 4.2. Acid output following pentagastrin infusion (6
jug/kg/h) which began at hour 2 (14 experiments in 8
horses).


66
output was increased within 30 minutes. The maximal hydrogen
ion concentration (MAC) achieved was 97 mEq/L (pH 1.15),
while the average MAC was 65 18 mEq/L. Gastric fluid pH was
lowered to 1.3 0.15 and had less variation than during the
control experiments (coefficient of variation = 7%) .
The maximal acid output (MAO) during the second hour of
infusion ranged from 296 to 944 uEq/kg/h, with an overall
mean of 622 171 /iEq/kg/h. Analysis of variance indicated
that during the second and third hours of pentagastrin
infusion, acid output was maximal and greater than the first
and fourth hours (Appendix B). The coefficients of variation
for MAO were approximately 25% for each hour, which were much
less than that observed during the control hour (57%).
Pentagastrin administration produced excessive salivation
in one horse. Several horses started grinding their teeth,
but this was also observed during experiments without
pentagastrin. One horse developed mild gastric hemorrhage
during the last 30 minutes of pentagastrin infusion, and
diffuse glandular mucosal hyperemia and petechiation were
seen on endoscopy.
H2~Receptor Antagonist Studies
Protocol IV
Each response variable was analyzed by repeated measures
ANOVA within each treatment, followed by a within hour
analysis (Appendix B). This allowed each variable to be
evaluated both to its own daily control (HR1) and to the


67
other treatments at the same hour. Due to the small sample
size, only those P-values greater than 0.05 by Scheff's
multiple comparison procedure are reported, as well as
results following the Tukey HSD and t-test in Appendix B.
The basal period, or hour one (HR1), was analyzed for all
treatments to determine variation within animals between
treatment days in the rates of gastric fluid constituents.
Statistical analysis revealed no significant differences
between treatments, or within the entire control experiment
for volume, pH, hydrogen ion concentration, acid output or
osmolality. Pepsin concentration during hour 1 was not
significantly different between treatments. However, pepsin
concentration did vary markedly during the control
experiment.
Volume
Gastric secretory rate tended to be higher and more
variable during the first hour (372 120 ml/15-min) than the
entire control treatment (310 78 ml/15-min, Figure 4.3).
During ranitidine administration, secretory rate was
significantly decreased from its baseline period only during
the last hour (P<0.05). During pentagastrin infusion, the
secretory rate was nearly doubled to 610 260 ml/15-min and
remained elevated for the entire infusion, but was
significantly decreased to baseline levels when ranitidine
was administered.


68
m
Gastric fluid pH was variable during the first hour
between treatments and averaged 1.77 0.46 versus 2.14
0.70 for the entire control treatment (Figure 4.4). The
control treatment had the most variation, and because of
this, between treatment comparisons had to have marked
changes to show statistical significance. Following
ranitidine administration, variation increased between
animals, especially at hour 2, where the pH ranged from 2.09-
5.24 and averaged 3.49 1.41. Analysis using the t-test
revealed a significant increase in pH for 2 hours following
ranitidine administration. When compared within each hour to
the other treatments, ranitidine increased pH above the
levels obtained only with pentagastrin at hours 2 and 5. This
was mainly due to an immediate increase following ranitidine
administration and the relatively long time before gastric pH
was significantly effected by pentagastrin. Gastric pH was
decreased to a minimum of 1.15 following pentagastrin
infusion which was significantly different from its own
control hour during the last 3 hours of infusion. This
decrease in pH was returned to control levels by ranitidine
administration.
Hydrogen Ion Concentration
Hydrogen ion concentration remained stable during the
control treatment (34 8 mEq/L, Figure 4.5). Ranitidine
produced an immediate decrease in H+ concentration to 17 6


69
mEq/L which was maintained for 2 hours during control
conditions. Pentagastrin infusion increased H+ concentration
maximally during hours 4 and 5 to 55 10 mEq/L which was
significantly different than control. Ranitidine
administration during pentagastrin infusion lowered H+
concentration to control levels for 3 hours.
Acid Output
The overall acid output during control was 46 13
/iEq/kg/15-min, which was lower than hour 1 for all treatments
(62 22 jUEq/kg/15-min, Figure 4.6). Ranitidine produced an
inhibition of acid output during all 4 hours when compared to
its own baseline collection (50-64% inhibition of control).
Pentagastrin produced a significant increase in acid output
for the duration of the experiment, but this increase was
inhibited (50%) for 2 hours by ranitidine administration.
Pepsin Concentration
Pepsin concentration was highly variable (110 34 nq/ml)
and was the only variable where a significant difference was
demonstrated during the control treatment (HR2 < HR3, Figure
4.7). Ranitidine tended to decrease pepsin concentration for
one hour, but this was not a significant change from control.
Pentagastrin tended increase pepsin concentration for one
hour, but then decreased it during hours 3-5.
Pepsin Output
There was more variation in pepsin output than any other
variable (205 107 /xg/kg/15-min, Figure 4.8). Ranitidine


70
tended to decrease pepsin output for one hour, but because of
the great amount of variation, a significant difference was
not demonstrated. Pentagastrin increased pepsin output
significantly during the first hour of infusion (HR2), after
which, pepsin output returned to control levels. Ranitidine
administration during pentagastrin infusion did not alter the
trends in pepsin output from pentagastrin infusion alone.
Osmolality
Gastric fluid osmolality was relatively stable (255 6
mosm/kg) and was less than plasma osmolality in all horses
(276 8 mosm/kg, Figure 4.9). A significant difference could
not be demonstrated for any treatment, although there was a
trend for gastric fluid osmolality to decrease following
rantidine administration, with or without pentagastrin
infusion. Pentagastrin tended to increase osmolality when
compared within hours.
Precision of Methods
Hydrogen ion and pepsin concentration and osmolality were
determined in replicate samples (Table 4.5). The coefficient
of variations for H+ titration and osmolality determinations
were acceptable, and for the H+ titration, indicated an
average error rate of about 3% for a given sample. The
coefficient of variation for the phenol method of pepsin
concentration determination was generally higher than the UV
method. In replicate samples, the coefficient of variation of


Legend for Figures 4.3-4.9.
These results are based on duplicate sets of 4
experimental treatments in 5 horses (protocol IV, see page
52) The control treatment involved a 5-h collection of
gastric fluid, during which a 0.9% saline drip was
administered at 200 ml/h. The second treatment was similar to
the control treatment, except ranitidine (0.5 mg/kg IV bolus)
was given at the beginning of hour 2. In the third treatment,
a pentagastrin infusion (6 M9/kg/h) was started at the
beginning of hour 2. In the fourth treatment, a pentagastrin
infusion was started at hour 2, and then ranitidine (0.5
mg/kg IV) was given at the beginning of hour 3. Analysis of
variance was performed for two within-subject factors,
treatment (4 levels) and time (5 levels). Scheff's multiple
comparisons procedure was used to determine significant
differences between treatment means at each hour with a P <
0.05 considered significant except for pH data where the t-
test was determined (see page 55). In the figures, a
significant difference for a treatment hour from its own
control (hour 1) is indicated by "a", while a significant
difference from the control treatment at the same hour is
indicated by "b".


Volume (ml/15 min
72
I I Control
Ranitidine
LWN Pentagastrin
ll Pentagastrin
+ Ranitidine
MeanSEM (n = 5)
Time (Hour)
Figure 4.3. Hourly secretion rate for protocol IV (see legend
on page 71 for treatment scheme; a= significantly different
from own control (hour 1) and b= significantly different from
control at same hour; P < 0.05).


73
I I Control
Ranitidine
LWN Pentagastrin
Pentagastrin + Ranitidine
4.5 T
a
4.0-
3.5-
3.0
0 12 3 4 5
Time (Hour)
Figure 4.4. Hourly pH for protocol IV (see legend on page 71
for treatment scheme; a= significantly different from own
control (hour 1) and b= significantly different from control
at same hour; P < 0.05).
'ZZZZZZZZZ&


H+ mEq/L
74
1 I Control
Ranitidine
\\N Pentagastrin
0 12 3 4 5
Time (Hour)
Figure 4.5. Hourly acid concentration for protocol IV (see
legend on page 71 for treatment scheme; a= significantly
different from own control (hour 1) and b= significantly
different from control at same hour; P < 0.05).


75
I 1 Control
1 Ranitidine
LWN Pentagastrin
Pentagastrin + Ranitidine
180
1 60
0 12 3 4 5
Time (Hour)
Figure 4.6. Hourly acid output for protocol IV (see legend on
page 71 for treatment scheme; a= significantly different
from own control (hour 1) and b= significantly different from
control at same hour; P < 0.05).


76
CD
3
c
V)
CL
Q)
Q_
Control
Ranitidine
LWN Pentagastrin
I3S3 Pentagastrin + Ranitidine
1 60 -r
140-
120-
100-
80-
60-
40-
20-
0-
0
o
2 3
Time (Hour)
I
Figure 4.7. Hourly pepsin concentration for protocol IV
(see legend on page 71 for treatment scheme; a=
significantly different from own control (hour 1) and
b= significantly different from control at same hour; P
< 0.05).


Pepsin /.g/kg/1 5-min
77
I l Control
Ranitidine
LWN Pentagastrin
lW>l Pentagastrin + Ranitidine
400 t
350
0 12 3 4 5
Time (Hour)
Figure 4.8. Hourly pepsin output for protocol IV (see legend
on page 71 for treatment scheme; a= significantly different
from own control (hour 1) and b= significantly different from
control at same hour; P < 0.05).


Osmolality mosm/kg
78
I I Control
Ranitidine
LWN Pentagastrin
I3MI Pentagastrin + Ranitidine
270 t
260
250
240
230 4-
0
12 3 4 5
Time (Hour)
Figure 4.9. Hourly osmolality for protocol IV (see legend on
page 71 for treatment scheme; a= significantly different
from own control (hour 1) and b= significantly different from
control at same hour; P < 0.05).
V/////////////////////Ata


79
the lowest pepsin standard (5 /ig/ral) was 17% by the UV method
and 25% by the phenol method, indicating that both methods
had poor repeatability and precision at low pepsin
concentrations. The coefficient of variations of the other 3
standards ranged from 3.1 to 9.2 by either method.
Relationship Between the UV and Phenol Methods
The two methods were compared by two means. First, two
sets of 4 pepsin standards were measured in quadruplicate and
the regression lines for each method determined. The
coefficient of correlation between the 2 methods was 0.986
(P<0.000) The regression equations were:
(UV) = -0.052 + 1.087(PHENOL)
= 1.86 + 33.04* ABS
(PHENOL) = 0.060 + 0.895(UV)
= 0.375 + 35.45* ABS
where (UV, PHENOL) was the pepsin concentration in /xg/ml
estimated by either method. The slopes were close to 1
indicating good agreement between the 2 methods while the y-
intercepts were different.
Second, the regression lines from all standards of both
methods were:
(UV) = 3.04 + 33.86*ABS
(59 standards,replicated)
(PHENOL) = -1.74 + 53.55*ABS
(20 standards, replicated)


80
There is close agreement between the regression equations
from the UV method, using either 8 or 59 standards, while the
regression equation for the phenol method had a steeper slope
when more standards were analyzed.
Table 4.5. Statistical analysis of replicate
samples.
Hydrogen ion concentration
(n=5)
Sample 1 2
3 4
5
6
Mean(mEq/L) 25.3 42.9 62
.8 74.8
92.2 50
. 1
STD 1.02 1.92 1
.23 1.91
2.06 1
. 31
CV 3.98 4.48 1
.97 2.56
2.24 2
. 62
Osmolality (n=5)
Sample 1
2
3
4
Mean(mosm/kg) 274.4 274.8
273.0
270.3
STD 1.14
1.48
1.77
1.50
CV 0.42
0.54
0.65
0.56
Pepsin standard absorbance
Sample 5
10
20
40
UV Method (n=4)
Mean(jug/ml) 0.099
0.240
0.588
1.208
STD 0.017
0.019
0.015
0.038
CV 16.9
8.07
2.57
3.12
Phenol method (n=4)
Mean 0.113
0.285
0.638
1.264
STD 0.028
0.026
0.022
0.040
CV 25.0
9.22
3.50
7.57


CHAPTER V
DISCUSSION
Ecruine Gastric Fluid Secretion in Comparison to Other Species
A new procedure was developed to study gastric fluid
secretion in the young horse, a monogastric herbivore, and
revealed previously unknown parameters of equine gastric
physiology. The preparation was chosen to replicate normal in
vivo conditions and involved chronic, surgically prepared,
cannulated horses. Based upon the two-component hypothesis
for gastric fluid composition, the parietal component was
represented by acid output and the nonparietal component was
represented by pepsin output (99). Secretory rate and
composition were studied during basal (fasting) and
stimulated conditions. Stimulation of acid output was
achieved with a synthetic analog of gastrin rather than by
feeding, as the presence of food would have lowered the H+
concentration by dilution and neutralization 39) Histamine
has been shown to be important in the paracrine regulation of
parietal cell function so the effects of a H2-receptor
antagonist, ranitidine, were also studied in this model
(33,40,137,138). Vagal stimulation of acid secretion was not
studied, as previous attempts using 2-deoxyglucose were
unsuccessful in this preparation (see page 24) As well,
81


82
atropine was not selected as an antagonist of parietal cell
function due to the possibility of colonic impaction (12).
The following discussion will present these findings with
reference to gastric fluid secretion in other species,
especially the human and rat. These two species are relevant
for several reasons: 1) gastric and duodenal ulceration can
develop spontaneously in humans and gastric acid and pepsin
are the primary damaging agents (103), 2) the rat is commonly
used as a model for gastric and duodenal ulceration (140),
and 3) gastric mucosal anatomy in the rat is very similar to
the horse, being divided nearly equally into non-glandular
and glandular regions (135).
Since younger horses develop spontaneous duodenal
ulceration, animals between the age of 6 and 12 months were
studied. Age influences the rate of gastric fluid secretion
and it is therefore possible that there may be further
differences between 2-4 month old foals and these
experimental horses (1,3,87,70,107). These differences may
relate more to the amount of parietal or chief cell
responsiveness to stimulation or inhibition. It is therefore
expected that younger horses would also secrete acid and
pepsin during basal conditions, respond to pentagastrin by
increasing acid output, and respond to H^-receptor
antagonists by decreasing acid output.
External factors which could potentially stimulate basal
gastric acid secretion were minimized. Basal acid secretion


83
in humans displays a circadian rhythm with a peak in the
early morning (39). Each experiment was therefore started in
the morning between 7:30 and 9 am to control for any similar
rhythm in the horse. A fast of 24 hours was sufficient to
empty the stomach of all but a minimal amount of chyme. This
finding was in contrast to a report that some chyme remains
in the equine stomach after a 48-hour fast (73).
Contamination of gastric juice with swallowed saliva could
not be prevented in this model. It is assumed that salivation
was minimal since Alexander reported that parotid salivation
only occurs during mastication (6). The presence of a cannula
was clearly a deviation from the normal gastric condition but
this technique was the only one available to accurately
quantitate gastric secretion. Nasogastric aspiration of
gastric contents would not be successful, as the tube often
becomes occluded with chyme and its presence in the pharynx
stimulates salivary secretion (personal experience).
The position of the cannula in the left ventral abdomen
allowed collection of most gastric fluid by gravity. Phenol
red recovery rates indicated that some gastric fluid
continued to bathe the antrum and duodenum. Complete
diversion of gastric acid from the antrum and proximal
duodenum would remove inhibition of gastrin release resulting
in an artificial increase in basal acid output (40).
The phenol red recovery rate was lower in horse 1,
possibly because of the small volume of solution given (200ml


84
rather than 500ml) and lack of a 1-min sample. This may have
caused a false decrease in phenol red recovery because,
although phenol red is commonly used as a non-absorbable
intestinal marker, it may be adsorbed to surface epithelial
cells (130). A larger volume of administered fluid would
appear to have a better recovery rate because a smaller
proportion is lost due to surface adsorption. In subsequent
trials, the 1-min sample contained most of the phenol red
solution. A mean recovery rate of 83% for 12 horses with this
technique compares favorably with recovery rates from other
species with gastric cannulas.
The volume of gastric fluid collected displayed the least
intra-animal variation of all the fluid variables and was
constantly formed even during inhibition of acid secretion
with a H2-receptor antagonist. The increase in flow rate
observed during pentagastrin infusion was sustained and did
not suggest fatigue of parietal secretory mechanisms.
Rantidine decreased flow rate during pentagastrin stimulation
indicating that pentagastrin stimulated primarily the
parietal component.
Gastric fluid production in adult humans is nearly 3
liters/day, while pancreatic juice and biliary and salivary
secretions contribute another 4 liters/day to the upper
gastrointestinal tract (103). In contrast, combined parotid,
biliary and pancreatic secretions have been estimated to be
about 30 liters/day in a 100 kg pony (9) Argenzio reported


85
13.6 liters/day from salivary and gastric secretions and 18.2
liters/day from pancreatic, biliary and upper small
intestinal secretions in a 175 kg pony (11). During basal
conditions, the horses in the present study had an average
body weight of 200 kg and gastric flow rates of 1.4 liters/h
which could be stimulated to 2.5 liters/h. If these
stimulated rates could be extrapolated to feeding conditions,
these horses might secrete up to 30 liters of gastric fluid
per day. A combination of profuse salivary and constant
gastric, pancreatic and biliary secretions requires active
resorption of a large volume of fluid.
The purpose of such a large volume of secretion may be
related to the feeding habits of the horse. Gastric microbial
digestion of cellulose or other plant polymers allows
utilization of carbohydrates which are not hydrolyzed by
digestive enzymes (11,73). Under normal conditions, horses
are continual grazers and the gastric microbes would receive
a steady supply of substrate which saturated with
bicarbonate-rich saliva (4,9). Equine gastric microbial
fermentation of glucose yields pyruvate which is mainly
converted to lactic acid rather than volatile fatty acids as
in the pig and ruminants (11). Lactate concentrations peaked
in the stomach 4 hours after a meal in the stomach and
rapidly decreased aborad to the proximal small intestine to
very low levels in the cecum and large intestine (8,13).
Optimal conditions might thus be maintained for the


86
continuous production of lactic acid at a rate which may
contribute to the animal's nutrition.
In ruminants, the stratified epithelium of the rumen is a
site of volatile fatty acid, and Na+ and Cl" absorption (11).
The isolated stratified epithelium of the equine stomach
appears to be impermeable to ions and volatile fatty acids,
while the pyloric mucosa can absorb and transport volatile
fatty acids when the lumen pH is buffered to 7.4 (13). Such a
pH probably occurs during feeding as intragastric pH was
about 5.6 two hours after a meal (11,13).
Equine gastric fluid pH did not reach the minimal levels
reported for many other species during basal and maximal acid
stimulation conditions (Table 5.1) (12,40). This suggests a
large nonparietal component serving to dilute and neutralize
acids (HCl, lactic) and helping to protect the mucosa.
Periodic upward fluctuations in gastric pH, and hence
downward fluctuations in H+ concentration, were observed
during the control experiments and appeared unrelated to any
external factors. Such fluctuations have also been observed
by Russian investigators in the horse (145). Periodic
alkaline fluctuations in gastric pH have also been reported
in humans and occur mainly during the night or during non
meal periods (23,68). The episode frequency (10.6 in 24
hours) is similar to the rapid spiking activity frequency
(phase III) of the migrating myoelectrical complex of the
proximal duodenum reported in the human (90) The neuro-


87
hormonal interaction between gastric secretion and proximal
duodenal motility may be highly organized to allow
coordination of digestive processes. In dogs, pancreatic and
biliary secretion seems to be coordinated with the phase III
of the proximal duodenum (131). In humans, basal pancreatic
secretion also seems to vary with the phase of interdigestive
motility (phases II and III > I and IV) (24) Gastric acid
secretion may be increased during the gastric phase III
(148). In anesthetized cats, direct vagal stimulation
stimulates gastric bicarbonate secretion which precedes an
increase in gastric acid secretion (112). However, it is not
known whether fluctuations in equine pH reflect
duodenogastric reflux or decreased gastric acid secretion (or
enhanced gastric bicarbonate secretion) in phase with
myoelectrical activity.
Gastric acid concentration is determined by: 1) the rate
at which it is secreted (acid output), 2) neutralization and
dilution by non-parietal secretions, and 3) back-diffusion
into the mucosa (probably minimal)(39,68). Acid concentration
is determined by titration to pH 7.4 with a standard base
(NaOH). Hydrochloric acid is probably the only acid substance
present during fasting conditions since lactic acid is
produced by the action of microbes on food and carbonic acid
would be rapidly converted to C02 and water.
Gastric acid secretion has been studied primarily in the
human, dog, rat and rabbit (40,128,138). Significant species


88
differences exist in the rates of basal and stimulated acid
secretion (Table 5.1). Continuous basal secretion of both
gastric acid and pepsin, occurs in the human, monkey, pig,
chicken, rodent and herbivore (including the horse), but is
minimal in the dog and cat (72). Basal acid concentration in
the horse is similar to the human and pig (Table 5.1).
Basal acid output is high in the rat and rabbit (20 and
25% of maximal acid output, respectively) and very low in
the dog (1%) (40). Humans are intermediate in their basal
acid output, which is approximately 10% of maximal. Basal
acid output in the horse was 33% of the maximal induced by
pentagastrin stimulation. Basal acid output varies
considerably day-to-day in humans and from person to person
(coefficient of variation 80%) (48,150). Basal acid output in
the horse was also continuously variable between 15-minute
collections and between horses (coefficient of variation
60%) .
The main purpose of performing a stimulation test is to
provide an estimate of the functional capacity of the stomach
(60,96). The choice of stimulant is based on preference and
absence of side-effects. The only side-effect noted in these
8 horses was in one that developed profuse salivation. The
route of administration is also by preference, but
intravenous infusion allows prompt termination of the drug if
any side-effects occur.


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I certify that I have read this study and that in my
opinion it conforms to acceptable standards of scholarly
presentation and is fully adequate, in scope and quality, as a
dissertation for the degree of Doctor of Philosophy.
George A. Gerencser
of Physiology
I certify that I have read this study and that in my
opinion it conforms to acceptable standards of scholarly
presentation and is fully adequate, in scope and quality, as a
dissertation for the degree of Doctor of Philosophy.
Stephen W. Russell
Adjunct Professor of
Veterinary Medicine
This dissertation was submitted to the Graduate
Faculty of the College of Medicine and to the Graduate School
and was accepted as partial fulfillment of the requirements
for the degree of Doctor of Philosophy.
Dean, Graduate School
August, 1988