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This is to certify that the

thesis entitled
Effects of Distention and Neostigmine on EJunal

Vascular Resistance, Oxygen Uptake, and
lntraluminal Pressure Changes in Ponies

presented by

Andrew H . Parks

has been accepted towards fulfillment
of the requirements for

M.S. degreein Large Animal
Clinical Sciences

gym a. .9114me

Major professor

Date 8/4/89

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MSU Is An Affirmative ActlorVEqual Opportunity Institution

EFFECTS OF DISTENTION AND NEOSTIGMINE ON JEJUNAL
VASCULAR RESISTANCE, OXYGEN UPTAKE, AND

INTRALUMINAL PRESSURE CHANGES IN PONIES

BY

Andrew Hugh Parks

A THESIS
Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of

MASTER OF SCIENCE

Department of Large Animal Clinical Sciences

1989

(00410353

ABSTRACT

EFFECTS OF DISTENSION AND NEOSTIGMINE ON JEJUNAL VASCULAR
RESISTANCE, OXYGEN UPTAKE, AND INTRALUMINAL PRESSURE CHANGES
IN PONIES

BY
Andrew Hugh Parks

Postoperative ileus is associated with intestinal
hypomotility and distension; neostigmine methylsulphate is
the drug most commonly employed clinically in the treatment
of ileus in the horse. The influence of distension (high
baseline intraluminal pressure) and neostigmine
methylsulphate on intestinal vascular resistance, oxygen
uptake, and intraluminal pressure changes (rhythmic
contractions) was studied in terminal jejunal segments,
which were perfused at a constant blood flow, in 16
anesthetized ponies. When baseline intraluminal pressure
was increased from 0 to 10 mm Hg, the intestinal vascular
resistance and amplitude of rhythmic contractions were
increased. Neostigmine induced cyclic increases in
amplitude of rythmic contractions whether intraluminal
pressure was 0 or 10 mm Hg. Neostigmine also increased
intestinal oxygen uptake at intraluminal pressures of 0 mm
Hg but not at 10 mm Hg, and vascular resistance was not
altered at either intraluminal pressure. The results

indicate that intestinal hemodynamics are adversely affected

by distension. Further, neostigmine did not adversely
effect intestinal hemodynamics while increasing rhythmic
contractions, suggesting that neostigmine may be useful in

the treatment of ileus in equids.

This thesis is dedicated to the memory
of my father Alan Guyatt Parks for
imparting his love of scholarly pursuits
and to my mother Caroline Jean Parks for
extolling the virtue of common sense.

ii

ACKNOWLEDGEMENTS

I am indebted to my supervisor John A. Stick for his support
and encouragement. I am grateful to Dr. F.J. Derksen and
Dr. N.E. Robinson for participating on my committee.

Lastly, many thanks are due to Drs. Edward Scott, Frank
Nickels and Gayle Trotter for their much appreciated
interest and assistance in the development of my career.

iii

TABLE OF CONTENTS

Page

LISTOFTABI‘ES O0.00000....OOOOOOOOOOOOOOOOOOOOOO v

LISTOF FIGURES 0.0.0.0....OOOOOOOOOOOOOOOOOOOOOO Vii

INTRODUCTION OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO 1

LITERATURE REVIEW ............................... 2
Intestinal motility ........................ 5
Intestinal blood flow ...................... 9
Postoperative ileus ........................ 13

Intestinal distension ........ ...... ........ 18

MATERIAIS ANDMETHODS .0.000000000000000000000000 24

Experimental Design ........................ 32

RESULTS O...OO0.00...O...OOOOOOOOOOOOOOOOOOOOOOOO 34

DISCUSSION .......... 0.0000000000000000000000000. 50

CONCLUSIONS 0......O...OOOOOOOOOOOOOOOOOOOOO0.... 56

APPENDIX OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO... 57

LISTOFREFERENCES 0.0.00....00.00.000.0000000000 65

iv

LIST OF TABLES

Page
Table 1. Effects of Distension. ....................... 36

To determine the effects of distension, data from
resting controls and resting neostigmine treated
ponies (groups 1 and 3), and distended controls
and distended neostigmine treated ponies (groups 2
and 4) were combined to form 2 groups of 8 and
variables were compared 10 minutes after the
study period began. Data is shown as mean i SEM.
Data followed by similar superscripts are
significantly different at P < 0.05. RC = Rhythmic
contractions.

Table 2. Group 1. Resting Controls. ..... .......... .... 58

In resting control ponies the baseline
intraluminal pressure was 0 mm Hg. All variables
were monitored for 1 hour, the data was recorded
every 15 minutes and reported as mean 1 SEM. Data
followed by asterisks are significantly different
from baseline values at P < 0.05. RC = Rhythmic
contractions.

Table 3. Group 2. Distended Controls. ........... ...... 60

In the distended control ponies the baseline
intraluminal pressure was 10 mm Hg. All variables
were monitored for 1 hour, the data was recorded
every 15 minutes and reported as mean i SEM. Data
followed by asterisks are significantly different
from baseline values at P < 0.05. RC = rhythmic
contractions

Table 4. Group 3. Effects of neostigmine on
resting intestine. OOOOOOOOOOOOOOOOOOOCO 0000000000 62

Neostigmine (0.022 mg/kg intravenously) induced
cyclic fluctuations in intestinal intraluminal
pressure changes, with periods of increased

V

Page

activity (active periods = A) alternating with
periods of normal activity (quiescent periods =
Q). Therefore data were recorded 5 minutes before
neostigmine administration for baseline and at
each subsequent active and quiescent period. All
data is shown as mean i SEM. Data followed by
asterisks are significantly different baseline
values at P < 0.05. RC = Rhythmic contractions.

Table 5 Group 4. Effects of neostigmine on
distended intestine. ........................ ..... 64

Neostigmine (0.022 mg/kg intravenously) induced
cyclic fluctuations in intestinal intraluminal
pressure changes, with periods of increased
activity (active periods = A) alternating with
periods of normal activity (quiescent periods =
Q). Therefore data were recorded 5 minutes before
neostigmine administration for baseline and at
each subsequent active and quiescent period. All
data is shown as mean 1 SEM. Data followed by
asterisks are significantly different form
baseline values at P < 0.05.

vi

LIST OF FIGURES

Page
Figure 1. Extracorporeal circuit. .................... 27

Femoral arterial blood was used to perfuse the
intestinal segment with a peristaltic pump, venous
blood from the intestinal vein was drained into a
reservoir. Blood from the reservoir was returned
to the pony via the jugular vein using a non-
peristaltic pump. Portions of arterial and
venous blood were diverted from the main
extracorporeal circuit and pumped through the
arteriovenous oxygen content analyzer with a
second non-peristaltic pump. Solid lines signify
arterial blood, long dashes signify venous blood
and short dashes signify mixed arteriovenous
blood.

Figure 2. Isolated segment preparation. .............. 29

The segment was perfused by a single artery and
vein. Arterial perfusion pressure was determined
by means of a 20 gauge needle inserted into the
perfusion tubing close to the segment and
connected to a blood pressure transducer. A latex
balloon was inserted into the lumen of the segment
and tied at each end. After saline infusion into
the balloon, intraluminal pressure changes were
recorded by means of a pressure transducer
connected to the balloon by a 3-way stopcock.

Figure 3. Motility changes with neostigmine
treatment in pony 8 (group 3). .................. 38

Neostigmine (0.022 mg/kg intravenously) induced
cyclic fluctuations in intestinal intraluminal
pressure changes, with periods of increased
activity (active periods = A) alternating with
periods of normal activity (quiescent periods =
Q). In pony 8 the increase in amplitude of
rhythmic contractions was not accompanied by an
increase in intraluminal baseline pressure.
v11

Figure 4. Motility changes with neostigmine
treatment in pony 9 (group 3). ............ ......

Neostigmine (0.022 mg/kg intravenously) induced
cyclic fluctuations in intestinal intraluminal
pressure changes, with periods of increased
activity (active periods = A) alternating with
periods of normal activity (quiescent periods =
Q). In pony 9 the increase in amplitude of
rhythmic contractions was accompanied by an
increase in intraluminal baseline pressure.

Figure 5. Effect of neostigmine on oxygen
uptake in resting intestine. ....................

Neostigmine (0.022 mg/kg intravenously) induced
cyclic fluctuations in intestinal intraluminal
pressure changes, with periods of increased
activity (active periods = A) alternating with
periods of normal activity (quiescent periods =
Q). Therefore data were recorded 5 minutes before
neostigmine administration for baseline and at
each subsequent active and quiescent period.
Values are reported as the mean : standard error
of the mean. Asterisks indicate values
significantly different from baseline at P < 0.05.

Figure 6. Effect of neostigmine on amplitude of
rhythmic contractions in resting intestine. .....

Neostigmine (0.022 mg/kg intravenously) induced
cyclic fluctuations in intestinal intraluminal
pressure changes, with periods of increased
activity (active periods = A) alternating with
periods of normal activity (quiescent periods =
Q). Therefore data were recorded 5 minutes before
neostigmine administration for baseline and at
each subsequent active and quiescent period.
Values are reported as the mean i standard error
of the mean. Asterisks indicate values
significantly different from baseline at P < 0.05.

Figure 7. Effect of neostigmine on baseline
intraluminal pressure in resting intestine. .....

Neostigmine (0.022 mg/kg intravenously) induced
cyclic fluctuations in intestinal intraluminal
pressure changes, with periods of increased
activity (active periods = A) alternating with

viii

Page

43

45

Page

periods of normal activity (quiescent periods =
Q). Therefore data were recorded 5 minutes before
neostigmine administration for baseline and at
each subsequent active and quiescent period.
Values are reported as the mean 1 standard error
of the mean. Asterisks indicate values
significantly different from baseline at P < 0.05.

Figure 8. Effect of neostigmine on amplitude of
rhythmic contractions in distended intestine. ... 49

Neostigmine (0.022 mg/kg intravenously) induced
cyclic fluctuations in intestinal intraluminal
pressure changes, with periods of increased
activity (active periods = A) alternating with
periods of normal activity (quiescent periods =
Q). Therefore data were recorded 5 minutes before
neostigmine administration for baseline and at
each subsequent active and quiescent period.
Values are reported as the mean i standard error
of the mean. Asterisks indicate values
significantly different from baseline at P < 0.05.

ix

INTRODUCTION

The incidence of ileus after surgery in the horse with

colic is high; in one survey, 43.9% of postoperative deaths

1

were attributed to this complication. Ileus is associated

with intestinal distension2

pressures,3 which further inhibit intestinal motility via

and high intraluminal

the intestino-intestinal reflex.4 High intraluminal
pressures have been shown to reduce intestinal blood flow in
dogss'6 and have been implicated as a contributing factor to
mucosal injury in rabbits.7 Additionally, small intestinal
intraluminal pressures measured during colic surgery are
considerably higher in horses that die than in those that

3 Cholinesterase inhibitors have been advocated for

survive.
the treatment of postoperative ileus in horses.8'9
Neostigmine methylsulphate is the most commonly used drug of
this group.9 However, experimentally, neostigmine delays
gastric emptying and prolongs the small intestinal migrating

myoelectric complex in ponies,10.11

The purpose of the
study reported here was to evaluate the effects of
distension (higher than normal intraluminal baseline
pressure) and neostigmine on intestinal vascular resistance,

oxygen uptake, and intraluminal pressure changes (rhythmic

contractions) in the jejunum of ponies.

LITERATURE REVIEW

Colic is a major cause of economic loss to the equine
industry. The term colic means abdominal pain but is
commonly used to collectively describe the multitude of
conditions that cause abdominal pain. This pain, usually
associated with the gastrointestinal tract, originates from
tension on the mesentery, intestinal ischemia and intestinal

distension.12'13

Diseases causing colic have been grouped
by pathogenesis: simple obstruction, strangulating
obstruction, non-strangulating infarction, and inflammatory
disease.14
Common causes of small intestinal simple obstruction
include ileal impaction, ascarid impaction, and adhesions
associated with either previous surgery or abdominal
abscesses.14'15 Strangulating obstruction of the small
intestine commonly occurs following volvulus, incarceration
through a mesenteric rent, a hernia, or by pedunculated
tumors.14'15 Non strangulating ischemia of the small
intestine is uncommon but is probably associated with
parasitic larval migration through the intestinal
vasculature.14'15 Proximal duodenitis/jejunitis, an
inflammatory condition of the small intestine is associated

with functional obstruction of the small intestine.16 These

2

3

conditions cause either a mechanical or functional
intestinal obstruction that inhibits aboral movement of
ingesta, fluid, and gas within the small intestine.
Accumulation of ingested fluid, gas and ingesta, salivary
and alimentary secretions and gas from bacterial
fermentation proximal to the obstruction distends the
intestine.17 The intestine proximal to the obstruction
initially responds with periods of vigorous activity
interspersed among quiescent periods, while intestinal
motility distal to the obstruction is diminished or
unaffected.18'20 Later, motility is decreased throughout

the gastrointestinal tract.17

As the intraluminal pressure
increases, net absorption of the accumulated fluid changes
to net secretion of water exacerbating the distension.21
Concurrently, decreased fluid intake, insensible fluid loss
and sequestration of fluid within the intestine make the
horse hypovolemic. Progression of the disease may cause
either gastric rupture or cardiovascular failure or
both.15'17

Strangulating obstructions may cause mesenteric
vascular occlusion of either veins or both veins and
arteries in addition to the changes seen with simple
intestinal obstruction.17 Venous obstruction without
attending arterial occlusion initially results in the
intestine becoming edematous, whereas accompanying arterial
occlusion will arrest mesenteric blood flow with resulting

22

ischemia. Initially epithelial cells from the villus tip

4

loosen from the basement membrane and later slough.23
Prolonged ischemia leads to complete mucosal necrosis.
Reperfusion of the damaged intestine can exacerbate the
mucosal injury, further damaging the mucosal barrier.24
Damage to the mucosa allows rapid luminal to vascular
transport, and transperitoneal absorption of bacterial
toxins which may result in endotoxemia and shock.15'17

The clinical signs of horses with small intestinal
obstruction include pain, abdominal distension,
gastrointestinal reflux, and distended stomach and small
intestine.15 The time course of events is dependent on the
site and nature of the obstruction; proximal obstructions
are more acute than distal, and strangulating obstructions
more acute than simple.15 The patient's systemic parameters
reflect pain or compromized cardiovascular function or both.
The variables most likely to predict the prognosis ranked in
descending order of accuracy are: systolic blood pressure,
blood lactate concentration, oral mucous membrane capillary
refill time, diastolic pressure and arterial pulse
amplitude.25 These variables are those that best assess the
integrity of cardiovascular function.25 Even though the
surgical treatment of small intestinal obstructions has
become routine, survival is still limited by accessiblitiy
of the obstruction, amount of bowel involved, severity of
the intestinal lesions and the cardiovascular function of

the animal. Postoperative complications, including

5

persistent endotoxemia, peritonitis, adhesions, laminitis
and ileus, add to the morbidity and mortality rate.9
Distension and hypomotility are two of the hallmarks of
ileus and form the subject of the present study. The
following sections of the literature review discuss the
physiologic regulation of intestinal motility and blood
flow, and the pathophysiologic findings in postoperative

ileus and intestinal distension.

t a mo i

The complex control and integration of intestinal
motility is regulated by neural, humoral and myogenic
responses. The principle patterns of motility seen in
intermittent feeders, i.e. carnivores and omnivores are
postprandial segmental contractions and peristaltic
contractions with temporally interposed interdigestive
complexes called the migrating myoelectric complex.26'27
Horses feed almost continuously and the predominant motility
pattern is the migrating myoelectric complex.11'28

The segmental contractions and peristaltic activity
observed are caused by the regulated contraction of
intestinal smooth muscle. The intestinal muscle coat is
made of two layers, an inner circular layer and an outer
longitudinal layer.29 The smooth muscle cells within each
layer act as a syncytium, but there is no direct
communication between the muscle cells of the respective

layers.30 The smooth muscle cells of the longitudinal

6

muscle layer generate an intrinsic myogenic rhythmic
depolarization called the slow wave, basic electric rhythm
or electrical control activity.3°'31 The slow wave is
propogated by the smooth muscle syncytium in an aboral
direction, and is electrically connected to the circular
muscle layer.32 The frequency of the slow wave is greatest
in the duodenum and lowest in the ileum.30 Slow waves do
not initiate smooth muscle contractions.

Smooth muscle contraction occurs in response to action
or spike potentials.30 The stimulus for action potential
formation is depolarization of the cell membrane, mostly
caused by the release of acetylcholine by postganglionic
neurons, but there are also noncholinergic stimulatory
neurons.33'34 Hyperpolarization of the cell membrane,
probably mediated by purine nucleotide transmitters,
inhibits action potential formation.3o Therefore action
potential formation is more likely to occur when the cell
membrane is already less polarized, i.e. at the peak of the
slow wave. Action potentials in smooth muscle are not an
'all or none’ phenomenon as they are in skeletal muscle.30
The force of smooth muscle contraction is related to the
number, frequency and magnitude of action potentials.3°'32
Slow waves therefore act as a pacemaker by directing the
direction and rhythm of intestinal smooth muscle action
potential activity.

Neural regulation of intestinal smooth muscle activity

occurs at three levels, 1) the enteric nervous system which

7

includes the myenteric and submucosal plexuses, 2) the
prevertebral ganglia and 3) the parasympathetic and
sympathetic divisions of the autonomic nervous system and
higher centers.35 Ten percent of the nerve cells in the
submucosal and myenteric plexuses are afferent and efferent
neurons to and from the mucosa, muscularis and serosa, the

12 In the absence of external

rest are integrative neurons.
influences, the enteric nervous system provides the basic
neural circuitry that governs the different patterns of
intestinal activity seen in the intact animal.36
The parasympathetic and sympathetic nervous systems
provide extrinsic control of intestinal motility.
Parasympathetic preganglionic neurons reach the enteric
plexuses through the vagus nerve and are of 2 types, those
that terminate on excitatory cholinergic neurons and those
that terminate on inhibitory, nonadrenergic, noncholinergic
neurons.37 The postganglionic neurons are cholinergic and
terminate at the neuromuscular junction where they are
excitatory; they form the final common pathway for short and

34

long enteric reflexes. In most species, vagal stimulation

causes excitation.37
Sympathetic preganglionic neurons leave the spinal cord
through the ventral roots, and reach the prevertebral

ganglia via the splanchnic nerves.37

In the prevertebral
ganglia the preganglionic neurons synapse with the
postganglionic neurons. The postganglionic neurons are

adrenergic and inhibitory, most terminate on cholinergic

8

neurons in the enteric plexuses and the rest end in the
smooth muscle.37 Sympathetic inhibitory activity is
modulated by visceral and somatic input, and by higher
central influences such as stress.12 The long enteric
reflexes are inhibitory and sympathetically mediated at
three levels, within the mural plexuses, through the
prevertebral ganglia, and via the spinal cord.12 The best
understood of these reflexes is the intestino-intestinal
reflex. This reflex causes inhibition of motility
throughout the intestinal tract in response to a regional
stimulus such as distension or surgical manipulation.37 In
summary, the sympathetic nervous system normally exerts a
tonic inhibitory influence on intestinal motility but can
suppress motility further when subject to other influences.
Humoral factors may affect gastrointestinal motility
via the systemic circulation, paracrine action or through a
neural pathway.38 Inhibitory influences on the stomach and
small intestine are exerted by glucagon, serotonin, gastrin
and cholecystokinin, while somostatin and motilin increase
motility.38 The search for the role of gastrointestinal
hormones in the regulation of itestinal motility patterns

has been inconclusive.27

Peak plasma motilin concentrations
have been shown to coordinate with the cyclic activity of

the migrating myoelectric complex in the dog, but in humans
this correlation is not as convincing because some complexes

are not accompanied by increases in motilin concentration.27

9

Therefore, the exact role of gastrointestinal hormones in

regulating the various patterns of motility is uncertain.

W

The small intestinal blood supply comes from the
cranial mesenteric artery which divides into anastomosing
arcuate vessels within the mesentery.39'40 The vasa recti
branch from the arcuate vessels, enter the serosa, and
arborize into several branches. Some branches form the
subserosal trunks and course towards the antimesenteric
border. Other branches pierce the muscular layers to form
the submucosal plexus. The blood supply to the muscular
layers is derived from the serosal and submucosal vascular
plexuses. From the submucosal plexus, arteries traverse
towards the mucosa and some arborize around the crypts while
others reach the villi.39 The microvascular structure
within the villus is complex and variable between species,
however, most patterns have a principle villus arteriole
that extends to the tip of the villus with or without prior
branching.41 The arteriole arborizes into a dense capillary
latticework directly beneath the mucosa. One or two venules
drain the villus and merge with the submucosal vessels. The
efferent vasculature parallels the arterial supply,
eventually to exit the mesentery via the portal vein.41 The
presence of specialized arteriovenous anastomoses within the
subserosal plexus is controversial,41'42 but microvascular

casting studies at elevated intraluminal pressures

10

identified vascular junctions highly suggestive of
arteriovenous anastomoses.43

Blood flow to the gastrointestinal tract has been
measured under resting conditions in several species and
ranges from 30-70 ml/100 g in humans, cats and rabbits;
higher flows, up to 150 ml/min/100g, occur in the rat and
dog.39 The majority of the intestinal blood flow,
approximately 60-90% is directed to the submucosa and
mucosa, presumably reflecting the higher metabolic demands
of these tissues.39 Within the submucosa/mucosa 5-37%, 24-
37% and 21-27% is delivered to the submucosa, villi and
crypts respectively.39 Both pharmacologic and physiologic
interventions may alter total blood flow and the mural
distribution of blood flow to the intestine.

Intestinal blood flow is regulated through intrinsic
factors, extrinsic neural input and vasoactive agents.39'44
Moment to moment control of the intestinal circulation is
performed mainly by local regulatory mechanisms which
function independently of neural control. 0f the intrinsic
mechanisms proposed to control the intestinal circulation,
the myogenic and metabolic factors are the most important.
The metabolic theory dictates that the local blood flow is
regulated so that delivered nutrients meet local metabolic
demand.39'44'45 If oxygen delivery does not equal demand
there is a local accumlation of metabolites, many of which
have been shown to possess local vasodilatatory properties,

for example H+, K+, adenosine and adenosine nucleotides.39

11

In this way reduced oxygen availability is compensated by
vasodilation, causing an increase in blood flow in order to
restore the balance between oxygen delivery and demand. The
myogenic theory of local blood flow control postulates that
the vascular resistance is directly proportional to
arteriolar transmural pressure due to the effect of stretch

39'44'46 In other

on vascular smooth muscle activity.
words, in response to an increase in arterial pressure,
which would increase blood flow if the vessel diameter
remained constant, the myogenic response causes a decrease
in lumen diameter, an increase in vascular resistance and
subsequently a modulation of blood flow. From a homeostatic
point of view, the myogenic mechanism maintains capillary
pressure and transcapillary fluid exchange constant, while
the metabolic mechanism ensures that oxygen delivery matches
the tissue requirements.39
Autoregulation is the intrinsic phenomenom that

maintains organ blood flow constant despite fluctuations in

44 Intestinal autoregulation is weak

arterial pressure.
compared to other organs and is dependant on the physiologic
state of the intestine, the fasted state and distension both

47'48 In the small intestine

reduce autoregulatory capacity.
blood flow is maintained over an arterial pressure range of
40 - 125 mm Hg.47 Intestinal oxygen uptake, the amount of
oxygen removed from the blood per unit time and weight of

tissue, is also maintained constant at blood flows greater

than 30 ml/min/lOOg and arterial pressures greater than 30

12

mm Hg.39'49 As blood flow decreases oxygen extraction, the
amount of oxygen removed per unit of blood, increases to
keep oxygen uptake constant.

Extrinsic regulation of intestinal blood flow is both
neural and humoral. The intestinal vasculature is richly
supplied with sympathetic neurons but is devoid of
parasympathetic neural input.39 Stimulation of the
splanchnic nerves initially causes intestinal
vasoconstriction, but continued stimulation causes partial
or complete restoration of blood flow, a phenomenon known as

autoregulatory escape.39

Following restoration of blood
flow a transient active hyperemia can occur. Stimulation of
the vagus causes little or no alteration in intestinal blood
flow.39 Neural control on intestinal blood flow, therefore,
is modulated by variation in sympathetic tone.

Vasoactive agents including catecholamines, serotonin,
vasoactive peptides and gastrointestinal peptides, may
increase or decrease intestinal blood flow.39'50 The
intestinal effects of those agents which have a systemic
action must be interpreted in the light of these actions,
i.e. drugs that cause a decrease in systemic blood pressure
may reduce intestinal blood flow despite a decrease in
intestinal vasculature resistance. Naturally occuring
catecholamines, norepinephrine and epinephrine, cause
vasoconstriction of the splanchnic vasculature.39 This is

related to the effects of these agents on alpha and beta

receptors and the numerical predominance of the different

13

receptors. Acetylcholine decreases intestinal vascular
resistance, however, it also decreases systemic blood
pressure and increases intestinal smooth muscle activity
thereby potentially compressing the mural vasculature.51'53
The interrelationship between intestinal motility and
blood flow have been extensively studied and reviewed.5'54’
56 Mild rhythmic contractions may increase intestinal blood
flow related to an increase in metabolic demand.5 When this
occurs, the increase in blood flow is confined to the

muscularis.57

Local vascular compression may overcome the
vasodilator response. Studies concerning the effect of
altered blood flow on intestinal motility show no change
with increases in blood flow and variable changes with
ischemia.56 Generally, severe ischemia causes an initial
phase of hypermotility followed by hypomotility for the

duration of the ischemia.56

Postoperative ileus

The original meaning of the word ileus is abdominal
pain due to intestinal obstruction but has come to be

synonymous with intestinal obstruction.58

It may be
subcategorized into mechanical ileus caused by a physical
obstruction, and functional ileus caused by a functional
intestinal obstruction and by common usage has often come to
imply the latter. There are many causes of functional

ileus, of which intestinal postoperative ileus is only one,

but most are thought to have a common pathogenesis.2'59

14

In 1890 Pal noted the absence of intestinal mechanical
activity after opening an animals abdomen.2 In 1899 Bayliss
and Starling showed that the inhibition of intestinal
motility induced by opening an animals abdomen could be
abolished by splanchnicectomy, thereby implicating the
sympathetic nervous system in the pathogenesis of
postoperative ileus.60 This is supported by other studies
in which spinal cord ablation, spinal anesthesia and
chemical sympathectomy all alleviate the inhibition of
intestinal motility secondary to ileus inducing
stimuli.2'59'61 Vagotomy, on the other hand, does not alter
the course of ileus.2

Electromechanical studies of postoperative ileus show
that the basic electrical rhythm is unaltered but the
spiking activity associated with the migrating myoelectrical
complex is disrupted or absent.28 Mechanical activity is
depressed in association with the decreased electrical
activity28 but the intestinal musculature is not paralysed
and is still responsive to electrical and chemical stimuli.2
It is thought, therefore, that functional ileus is caused by
sympathetic hyperactivity and parasympathetic
hypoactivity.28

From our current understanding of the innervation of
the gastrointestinal tract and the pathogenesis of ileus,
several potential avenues of treatment for postoperative

ileus are apparent, increase cholinergic activity, decrease

15

ganglionic inhibition by sympathetic innervation, and
decrease dopaminergic inhibition.

Increased cholinergic activity within the intramural
plexuses and at the neuromuscular junction can be achieved
by increasing the release of acetylcholine by the nerve
terminals, delaying the degradation of acetylcholine at the
receptor site with anticholinesterases and direct
stimulation of the muscarinic and nicotinic receptors with
pharmacologic agonists. The latter two options have
received the most attention. Experimentally, neostigmine,
an anticholinesterase, has been shown to restore gastric
emptying and colonic transit, and improve small intestinal
transport in rats with ileus, however, clinically the
results of treatment with anticholinesterases has been

dissapointing.61'62

Bethanacol and carbacol, direct
cholinergic agonists, both partially restored small
intestinal transit in postoperative ileus.61'63 Cisapride,
which enhances release of acetylcholine from nerve
terminals, has been recently shown to enhance small
intestinal motility in phase III of the migrating
myoelectric complex and decreases the duration of
postoperative ileus in human clinical patients.64
Adrenergic antagonists have been used both
experimentally and clinically to alleviate postoperative
ileus. Both alpha and beta receptors have been shown to be

important in the pathogenesis of postoperative ileus,

however, as with anticholinesterases, the results achieved

16

with antagonists have been mixed.65'66 Synergism between
adrenergic antagonists and anticholinesterases in restoring
intestinal motility has been demonstrated clinically.67
Guanethidine and bethanidine inhibit norepinephrine release
by adrenergic nerve terminals.68 Guanethidine increased
gastric emptying and colonic transit in postoperative ileus
in rats but did not increase small intestinal transit.61 No
response was seen with bethanidine in a human clinical
double blind study.69

Metoclopramide has several mechanisms of action which
include an antidopaminergic and a direct cholinergic
effect.71'73 Metoclopramide increases small intestinal
contractile activity during phase three but does not
increase the duration of the migrating myoelectric complex
in the normal dog.73 In a model of postoperative ileus,
metoclopramide reversed inhibition of phase three of the
migrating myoelectric complex at the antrum and pylorus of
the stomach and partially reversed the inhibition at the

74

duodenum and jejunum. Clinical trials in human patients

have not shown a consistent decrease in the duration of
postoperative ileus.62'74'75
Small intestinal motility patterns in fasted horses
resemble those seen in the dog.11'28 Motility changes seen
following adrenergic agonists, direct parasympathomimetics
and metoclopramide are comparable to those seen in other

72,77

species. Studies on gastric and small intestinal

electromechanical activity in horses with postoperative

17

ileus show prolonged periods without gastric action
potentials, disruption of the normal migrating myoelectric
complex, and uncoupling of the normal synchrony between
gastric and jejunal cycles of activity.28 Return of the
latter is thought to be the most significant event in the
resolution of postoperative ileus.28 Although neostigmine
decreases gastric emptying and prolongs the migrating

myoelectric complex in normal horses,1°I11

suggesting that
in normal horses neostigmine may decrease intestinal
motility,1°'11 it has been shown to hasten the return of
normal motility after a an experimental strangulating

obstruction.78

In another study of postoperative ileus,
propranolol, yohimbine, yohimbine plus bethanacol, and
metoclopramide all caused an earlier return of motility
compared to controls, however, metoclopramide was the most
effective in restoring the synchrony of gastric and jejunal
cyclic activity.28 Domperidone, a peripheral dopamine
antagonist, decreases the duration of experimentally induced
postoperative ileus, thus confirming the importance of
dompamine inhibition in the pathogenesis of postoperative

ileus.79

In the same study cisapride also decreased the
duration of postoperative ileus.79 More recently, working
on a different approach to the problem, Coatney has shown
that motilin, an intestinal polypeptide, increases
postoperative intestinal motility.80 Various therapies have

been outlined and several have shown promise in

experimentally induced equine postoperative ileus but

18

controlled trials are needed to determine their clinical

applicability.

Intestinal Distension

Surgeons have long been peturbed by intestinal
distension because the prognosis in patients with intestinal
obstruction was worse in those patients with extensive small

81-83

intestinal distension. These changes were thought to

be the result of distension induced ischemia and

gangrene.82'83

Basal intraluminal pressures in resting
bowel have been determined in man, cat and dog to be 2-4 mm
Hg.43'84'85 After simple obstruction, sustained basal
intraluminal pressure increases to 5-10 mm Hg in the cat

and dog.8‘1'86

In ponies intraluminal pressures in resting
intestine and in intestine after 12 hours simple obstruction
are 8-20 and 8-24 mm Hg respectively.20 lntraluminal
pressures ranged from 4.5 - 21 cm of water in horses with
naturally occuring intestinal obstruction.3 There is little
evidence, however, to confirm that distension, at
intraluminal pressures observed in clinical patients, causes
morphologic changes in the intestine.85 One study reported
villus necrosis in rabbit small intestine associated with
distension to 30 cm water,7 but distension at 18 cm water
for 4 hours failed to show any changes other than
interstitial edema in the horse.87

The first attempts to quantify the effect of distension

on blood flow were made by timed collection of venous return

19

from isolated segments of intestine and showed decreased
venous outflow with increased intraluminal pressure.81'83
Previous qualitative experiments had examined distended
intestine microscopically by direct or transmural
illumination. There is now a general agreement that an
increase in intraluminal pressure decreases small intestinal
blood flow when the intraluminal pressure is greater than 20
mm Hg.88'91 Above this threshold stepwise increases in
intraluminal pressure cause further reductions in blood flow
until a minimum plateau is reached.88'90 Because pressure
equals the product of flow and resistance, the decrease in
blood flow with distension indicates an increase in vascular
resistance. Vascular resistance also increased in distended
intestine perfused at a constant blood flow.92 In intestine
perfused at constant arterial pressure, blood flow may
return to near control with time at lower distension
pressures.48 This has been attributed to stress relaxation;
encasing the bowel in plaster of Paris to prevent stress
relaxation after distension of the intestine by a constant
volume, prevented the return of blood flow to control

levels.93

Following release of intestinal distension there
is an overshoot in blood flow before returning to control
flows.48 This may be attributed to a reactive hyperemia.
Investigations into the distribution of blood flow
within the intestinal wall during distension show that the

increase in blood flow sometimes seen at 20 mm Hg

intraluminal pressure is confined to the muscularis.57 At

20

higher intraluminal pressures injection studies have shown
there a relative reduction in blood flow to the mucosa and
muscularis compared with the serosa and submucosa, but
microsphere studies indicate a greater decrease in blood
flow to the mucosa than to the muscularis.9°'91'94 At these
higher distending pressures it is thought that arteriovenous
fistulae allow diversion of blood away from the capillary
beds. The evidence for the existence of arteriovenous
fistulae is fourfold. Firstly, regardless of the distension
pressure there is always a residual mural blood flow
suggesting that some blood manages to bypass the collapsed
capillary beds.90 Secondly, at distension pressures of at
least 30 mm Hg arteriovenous oxygen differences decrease
indicating that blood is bypassing the capillary
beds.9°'95'96 Thirdly, a decrease in capillary filtration
coefficient occurs exceeding that which would be expected to
accompany the decrease in blood flow observed.88 Lastly,
arteriovenous fistulae have been shown in casts of the
intestinal vasculature made when the intestine was
distended.43

Oxygen uptake either increases97

or is unaffected by
intestinal distension pressures of 20 mm Hg.43'89'92 When
the intraluminal pressure is elevated more that 20 mm Hg
oxygen uptake decreases. This decrease in oxygen uptake

occurs partly because oxygen availability is decreased with

decreased blood flow, but also because oxygen extraction

21

decreases, thought to be caused by arteriovenous
shunting.9°'95'96

Artificial distension, produced by rapid increases in
intraluminal pressure, does not resemble the dilation of
intestine found after prolonged obstruction for 2 reasons;
artificial distension causes an increase in rhythmic
contractions while prolonged obstruction decreases
intestinal motility,57'89 and obstructed small intestine is
much more compliant.98 Therefore several studies have
compared the hemodynamics of obstructed intestine to both
resting intestine and artificially distended intestine. An
initial study showed that feline intestine obstructed for 72
hours and then decompressed has similar hemodynamics and
oxygen consumption to non-obstructed intestine.99 Other
studies have shown that blood flow to obstructed intestine
may actually increase.1°°'101 Therefore it is unlikely that
distension per_§g compromizes intestinal viablility.

The combined effects of distension and obstruction have
been examined, again in feline intestine after 72 hours of
obstruction. The obstructed intestine was decompressed and
then artificially distended by 20 mm Hg increments in
intraluminal pressure, the controls were non-obstructed
intestine subject to the same distension protocol. At 20 mm
Hg, the capillary filtration coefficient and oxygen

102 The capillary filtration

consumption were decreased.
coefficient is a measure of hydraulic conductance which is

proportional to capillary permeability and the surface area

22

of perfused capillaries. In this experiment a decrease in
the capillary filtration coefficient represents
compression of the microvascular beds because it is unlikely
that capillary permeability decreases. To evaluate these
findings, these investigators compared artificial distension
at 20 mm Hg in intestine after uninterrupted obstruction to
controls in which the obstruction was decompressed.
Artificial distension caused the capillary coefficient to
decrease in both groups but to a much greater extent in the
uninterrupted distension group.98 It would seem then, that
obstruction predisposes the intestine to the effects of
repeated distension and ischemia. This effect is partially
reduce by intestinal decompression.

In summary, artificial distension deleteriously effects
intestinal hemodynamics and oxygen consumption. But at
intraluminal pressures that are present in naturally
occuring disease, the balance of evidence suggests that
distension does not compromize intestinal viability.

Natural and experimental obstruction in the horse causes
higher intestinal intraluminal pressures compared to other
species, however, the effect of distension on the equine
intestinal vasculature has not been examined. Ileus is the
result of an imbalance between the sympathetic and
parasympathetic stimulus to the intestine. Therapies, of
which neostigmine has received the most clinical attention

in the horse, aimed at decreasing sympathetic stimulation or

23

increasing parasympathetic stimulation have been tried with
mixed results.

The present study was designed to investigate the
following hypotheses. Firstly, distension adversely effects
equine intestinal hemodynamics and oxyxgen consumption.
Secondly, neostigmine increases motility in both non-

distended and distended equine intestine.

MATERIALS AND METHODS

Sixteen healthy adult ponies (118 to 219 kg) were
vaccinated against equine influenza, encephalomyelitis, and
tetanus, treated with an anthelminthic (pyrantel pamoate,a
6mg/kg of body weight, PO), and fed a diet of mixed hay and
oats for 1 month before entering the study. Results of
physical examination verified that each pony was healthy
before being studied. Food, but not water, was withheld for
12 hours before each experiment.

All experiments were performed under general anesthesia
and were terminal. Preanesthetic medication was not used.

A 14-gauge, 13-cm catheter was inserted into the left
jugular vein. Anesthesia was induced with a bolus of
thiamylal sodium administered IV to effect (6.6 mg/kg of
body weight); following endotracheal intubation, anesthesia
was maintained with 2% halothane and oxygen in a semi-closed
anesthetic system. Manual ventilation with a rebreathing
bag and hourly blood gas analyses were used to ensure normal
arterial blood pH, PaCOZ, and hemoglobin saturation with
oxygen. Lactated Ringers solution was given through the

jugular catheter at 11 ml/kg of body weight/h.

 

a Strongid paste, Pfizer Inc, New York, NY.
24

25

The ponies were positioned in dorsal recumbency. The

b which was

facial artery was cannulated with PE-240 tubing,
connected to a pressure transducer.C Through a midline
celiotomy, a 12 to 15 cm segment of terminal jejunum,
approximately 1 m from the ileocecal valve, was
exteriorized.

An extracorporeal circuit was established between the
femoral artery and the single perfusing artery of the
jejunum (Figure 1). Heparin sodium (500 U/kg of body
weight) was administered IV (jugular vein) hourly 3 times.
The femoral artery was cannulated with PE 320 tubing and the
perfusion artery of the jejunum with a 14 gauge needle. The
intestine was perfused with arterial blood by a pulsatile
pumpd interposed inbetween the femoral and jejunal arteries.
The perfusing artery pressure was measured via a 20 gauge
needle connected to the perfusion tubing between the pump
and the perfusing artery attached to a pressure transducer
(Figure 2). The single vein draining the segment was
cannulated with a 14 gauge catheter attached to PE 320
tubing and the venous outflow directed into a reservoir.

Blood was returned to the pony from the reservoir by a

second pumpe through the jugular catheter. The ends of the

 

b Intramedic polyethylene tubing, Clay Adams Inc,
Parsippany, NJ.

c Model P-23 Db, Statham Instruments Inc, Cleveland, Ohio.
d Model T8SH, Sigmamotor Inc, Middleport, NY.

e Model 7535-00, Masterflex, Cole-Palmer Instrument Co,
Chicago, Illinois.

26

Figure 1. Extracorporeal circuit. Femoral
arterial blood was used to perfuse the intestinal
segment with a peristaltic pump, venous blood from
the intestinal vein was drained into a reservoir.
Blood from the reservoir was returned to the pony
via the jugular vein using a non-peristaltic pump.
Portions of arterial and venous blood were
diverted from the main extracorporeal circuit and
pumped through the arteriovenous oxygen content
analyzer with a second non-peristaltic pump.

Solid lines signify arterial blood, long dashes
signify venous blood and short dashes signify
mixed arteriovenous blood.

27

 

O Intestine O

Peristaltic

 
     
    

3+

pump

____ _J Femoral
:- TL Artery
l ‘l
I I
l Nonperistaitic
: pump
l
l
I
I
I
l
L Juguiar

vein

- Nonperistaltic
pump

Reservoir

Figure 1. Extracorporeal Circuit

28

Figure 2. Isolated segment preparation. The
segment was perfused by a single artery and vein.
Arterial perfusion pressure was determined by
means of a 20 gauge needle inserted into the
perfusion tubing close to the segment and
connected to a blood pressure transducer. A latex
balloon was inserted into the lumen of the segment
and tied at each end. After saline infusion into
the balloon, intraluminal pressure changes were
recorded by means of a pressure transducer
connected to the balloon by a 3-way stopcock.

29

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segment were ligated and severed from adjacent bowel to
exclude collateral blood flow. Blood flow, was adjusted to
keep perfusion pressure equal to systemic arterial pressure
during isolation of the intestinal segment and then
maintained constant for the duration of the study. At the
end of the experiment, the intestinal blood flow was
measured with a graduated cylinder and stopwatch, and the
segment weighed. Vascular resistance (R) was calculated by
dividing perfusion pressure (P) by IBF and the weight of the

segment (K), using the following equation:

R (mm Hg/ml/min/loo g) = P
(IBF / K) x 100

A portion of both arterial and venous blood was
diverted from the afferent and efferent arcs of the
extracorporeal circuit to a spectrophotometric
arteriovenous oxygen content analyzer (AVOX).f'104
Arteriovenous oxygen difference.(AV02) was determined
continuously by perfusing the diverted blood through
separate cuvettes within the arteriovenous oxygen content
analyser with a nonperistaltic pump9 at 14 ml/min. The AVOX
was balanced at the beginning of the experiment by
simultaneoulsy perfusing both cuvettes with arterial blood

and and balancing was repeated every 20 minutes throughout

the experiment. Oxygen uptake (V02) was calculated as the

 

f Avox Systems Inc, San Antonio, Texas.

9 Minipuls 2, Gilson, Middleton, Wisconsin.

31

product of the AVOZ and the IBF divided by the segment

weight (K), using the following equation:

V02 (ml/min/lOO g) = IBF x AVQZ x 100
K—

A thin-walled rubber balloon connected to a latex tube
was placed into the lumen of the intestinal segment and the
balloon was tied in place to the each end of the segment.
The latex tube was connected to a pressure transducer by a
3-way stopcock. The intestinal segment was covered with a
plastic sheet to keep it moist and kept at 370 C by
suspending a heat lamp above it. Five to 10 ml of warm
physiologic saline (370 C) was introduced into the balloon
through the stopcock until the baseline intraluminal
pressure (BILP) was 0 mm Hg in groups 1 and 3 and the
segments allowed to recover from surgery for 45 minutes.

A single increase in intraluminal pressure caused by
increasing intraluminal volume is followed by a steady
decrease in intraluminal pressure, as a result of stress
relaxation in the bowel wall.104 Repeated small increases
in distending volume are required to maintain a given
intraluminal pressure.88 To avoid repeated additions of
saline solution to the balloon during the 1 hour measurement
period (which would falsely alter intraluminal pressure
changes of rhythmic contractions) yet maintain a stable BILP
of 10 mm Hg during distension, we raised and maintained BILP
between 12.5 and 15 mm Hg for 30 minutes by incremental

increases in balloon volume in groups 2 and 3. The balloon

32

volume was then decreased until BILP was 10 mm Hg, which is
within the range of intraluminal pressures found in equine
small intestinal obstruction. Then the segment was allowed
to recover from manipulation for an additional 15 minutes.
Rhythmic contractions were defined as regular oscillations
in intraluminal pressure and were analyzed by measuring the
frequency, amplitude, and baseline of the pressure
recording. For the purposes of this study, resting
intestine is defined as intestine with a BILP of 0 mm Hg,
while distended intestine is defined as intestine with a

BILP of 10 mm Hg.

W

The 16 ponies were allotted to 4 groups. In group 1
(n=3), baseline intraluminal pressure was set at 0 mm Hg and
control measurements were taken. In group 2 (n=3) BILP was
set at 10 mm Hg to study the effects of distension. The
influence of neostigmine on resting intestine (BILP = 0 mm
Hg) was determined in group 3 (n=5). The effect of
neostigmine on distended intestine (BILP = 10 mm Hg) was
studied in group 4 (n=5). Measurements were started 45
minutes after surgical manipulation was complete in groups 1
and 2 (t=0) and 45 minutes after the initiation of
distension in groups 3 and 4 (t=0) and continued for 1 hour
(t=60). Neostigmineh was administered as a bolus into the

jugular vein at 0.022 mg/kg of body weight at t=15 minutes.

 

h Stiglyn 1 = 500, Pitman-Moore Inc, Washington Crossing, NJ

33

Mean systemic arterial pressure, segment artery
perfusion pressure, arteriovenous oxygen difference and
intraluminal pressure were recorded continuously for 60
minutes using a 4 channel physiographi and a direct writing
oscilloscope. Control group data (groups 1 and 2) were
analysed every 15 minutes. Neostigmine induced cyclic
fluctuations in amplitude of rhythmic contractions, with
periods of increased rhythmic contractions, defined as
active periods, alternating with periods of normal rhythmic
contractions, defined as quiescent periods. Therefore, in
neostigmine treated groups data were recorded 5 minutes
before neostigmine administration for baseline and at each
subsequent active and quiescent period.

To determine the effects of distension, data from
groups 1 and 3, and groups 2 and 4 were combined to form
single groups of 8 and variables were compared 10 minutes
after the study period began (t = 10) (before neostigmine
was administered in groups 3 and 4), using the Students' t
test.

The effect of neostigmine on intestinal vascular
resistance, oxygen uptake and intraluminal pressure changes,
were analyzed, using a single factor repeated measures
analysis of variance. Differences between the control and
treatment means were evaluated, using the Student-Newman-
Keuls procedure. Significance level for all tests was set

at P _<_ 0.05.

 

i Model SP2000, Gould Inc, Cleveland, Ohio.

RESULTS

Mean systemic pressure remained unchanged throughout
the experimental period in all groups. Mean blood flows for
groups 1 through 4 were 63, 71, 58, and 66 ml/100g
respectively.

Intestinal distension resulted in a significant
increase in the amplitude of rhythmic contractions and in
intestinal vascular resistance (Table 1). However, the
frequency and baseline values of rhythmic contractions were
unchanged.

Control groups were stable throughout the experiment
except: in group 1 a decrease in frequency of rhythmic
contractions occured by 60 minutes and in group 2 vascular
resistance had decreased from baseline by 30 minutes
(Appendix, Tables 2 and 3).

Neostigmine induced cyclic changes in intestinal
intraluminal pressure changes, with active periods
alternating with quiescent periods (Figures 3 and 4).
Active periods were defined by an increase in amplitude of
rhythmic contractions. During quiescent periods, amplitude
of rhythmic contractions was not different from pretreatment
values. No difference was seen in the number of cycles
between resting (group 3) and distended intestine (group 4)

34

35

Table 1. Effects of Distension. To determine the
effects of distension, data from resting controls
and resting neostigmine treated ponies (groups 1
and 3), and distended controls and distended
neostigmine treated ponies (groups 2 and 4) were
combined to form 2 groups of 8 and variables were
compared 10 minutes after the study period began.
Data is shown as mean 1 SEM. Data followed by
similar superscripts are significantly different
at P < 0.05. RC = Rhythmic contractions.

36

Table 1. Effects of distension.

 

Variable Resting Distended
Vascular Resistance 0.88 i 0.05a 1.41 i 0.08a
i SEM

(mm of Hg/ml/min/loo g)

Oxygen uptake 0.87 i 0.11 1.03 i 0.18
i SEM

(ml/min/100 g)
Frequency of RC 7.3 i 1.09 7.78 i 0.4
1 SEM (/min)

Amplitude of RC 1.25 : 0.23b 4.16 : 0.53b
i SEM (mm of Hg)

37

Figure 3. Motility changes with neostigmine
treatment in pony 8 (group 3). Neostigmine
(0.022 mg/kg intravenously) induced cyclic
fluctuations in intestinal intraluminal
pressure changes, with periods of increased
activity (active periods = A) alternating with
periods of normal activity (quiescent periods =
Q). In pony 8 the increase in amplitude of
rhythmic contractions was not accompanied by an
increase in intraluminal baseline pressure.

38

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39

Table 2. Group 1. Resting Controls. In resting
control ponies the baseline intraluminal
pressure was 0 mm Hg. All variables were
monitored for 1 hour, the data were recorded
every 15 minutes and reported as mean : SEM.
Data followed by asterisks are significantly
different from baseline values at P < 0.05. RC
= Rhythmic contractions.

40

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41

(5.4 i 0.6 and 5.6 i 0.51, respectively), with a range of 4
to 7 cycles in both groups. The mean periodicity of cycles
was 5.7 minutes in group 3 and 4.7 minutes in group 4.
Because the cyclic fluctuations in rhythmic contractions
showed no temporal consistency between ponies, data were
analysed during both active and quiescent periods for 4
cycles in each pony.

In resting intestine (group 3; Appendix, Table 4),
vascular resistance (0.96 i 0.06 mm Hg/ml/min/lOOg) and
frequency of rhythmic contractions (9.05 i 1.78 /min) did
not change after neostigmine administration. However,
neostigmine caused an increase in oxygen uptake during all 4
active and quiescent periods analysed (figure 5), amplitude
of rhythmic contractions was increased during active periods
(figure 6) and baseline values of rhythmic contractions were
increased during quiescent periods (figure 7). Vascular
resistance (1.47 i 0.12 mm Hg/ml/min/100g), oxygen uptake
(0.91 i 0.57 ml of Oz/min/loog), frequency of rhythmic
contractions (7.48 i 0.56 /min), and baseline values of
rhythmic contractions (10.15 i 0.23 mm Hg) were not
significantly altered by neostigmine administration in
distended intestine (group 4; Appendix, Table 5). However,
the amplitude of rhythmic contractions during the first
active period was significantly increased by neostigmine

(figure 8).

42

Figure 5. Effect of neostigmine on oxygen uptake
in resting intestine. Neostigmine (0.022 mg/kg
intravenously) induced cyclic fluctuations in
intestinal intraluminal pressure changes, with
periods of increased activity (active periods = A)
alternating with periods of normal activity
(quiescent periods = Q). Therefore data were
recorded 5 minutes before neostigmine
administration for baseline and at each subsequent
active and quiescent period. Values are reported
as the mean 1 standard error of the mean.
Asterisks indicate values significantly different

from baseline at P < 0.05.

43

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44

Figure 6. Effect of neostigmine on amplitude of
rhythmic contractions in resting intestine.
Neostigmine (0.022 mg/kg intravenously) induced
cyclic fluctuations in intestinal intraluminal
pressure changes, with periods of increased
activity (active periods = A) alternating with
periods of normal activity (quiescent periods =
Q). Therefore data were recorded 5 minutes before
neostigmine administration for baseline and at
each subsequent active and quiescent period.
Values are reported as the mean 1 standard error
of the mean. Asterisks indicate values
significantly different from baseline at P < 0.05.

45

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46

Figure 7. Effect of neostigmine on baseline
intraluminal pressure in resting intestine.
Neostigmine (0.022 mg/kg intravenously) induced
cyclic fluctuations in intestinal intraluminal
pressure changes, with periods of increased
activity (active periods = A) alternating with
periods of normal activity (quiescent periods =
Q). Therefore data were recorded 5 minutes before
neostigmine administration for baseline and at
each subsequent active and quiescent period.
Values are reported as the mean 1 standard error
of the mean. Asterisks indicate values
significantly different from baseline at P < 0.05.

47

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. mm
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. ( .I.
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48

Figure 8. Effect of neostigmine on amplitude of
rhythmic contractions in distended intestine.
Neostigmine (0.022 mg/kg intravenously) induced
cyclic fluctuations in intestinal intraluminal
pressure changes, with periods of increased
activity (active periods = A) alternating with
periods of normal activity (quiescent periods =
Q). Therefore data were recorded 5 minutes before
neostigmine administration for baseline and at
each subsequent active and quiescent period.
Values are reported as the mean : standard error
of the mean. Asterisks indicate values
significantly different from baseline at P < 0.05.

49

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DISCUSSION

Maintaining intestinal distension at an intraluminal
baseline pressure of 12.5 - 15 mm Hg for 30 minutes by
adding increments of saline to the balloon, followed by
reduction of baseline intraluminal pressure to 10 mm Hg,
resulted in a stable baseline intraluminal pressure for the
entire measurement period, without adding further increments
of saline to the balloon, in groups 2 and 4. This procedure
also eliminated changes in distensibility that occur as the

102 which is associated with a decreased

bowel relaxes,
capillary filtration coefficient and blood flow when the
intestine is distended.98'102

Groups 1 and 2 show that the preparation was remarkably
stable. A significant decrease in frequency of rhythmic
contractions was seen in group 1 by 60 minutes, the same
trend was seen in the other three groups but was not
significant. Slow wave frequency is remarkably resistant to
change after various stimuli, however it does slowly

32 and this is

decrease with decreases in body temperature
the most likely explanation for this finding. The decrease
in vascular resistance that occured in group 3 is probably

related to further slight stress relaxation and was not seen

in group 4, either because group 4 parameters were not

50

51

measured for so long or because the effects of neostigmine
obscured the stress relaxation.

Intestinal distension caused increases in amplitude of
rhythmic contractions (Table 1), as previously reported in
dogs.57 Vascular resistance was higher in distended
intestine than in resting intestine, but oxygen consumption
did not differ (Table 1). This suggests that although
equine intestinal hemodynamics are adversely affected by
distension, intestinal viability is not compromised because
oxygen uptake did not change. Studies in other species
indicate that, at intraluminal pressures of 20 mm Hg,
intestinal blood flow may either be increased,57 or
unaffected;43'88'94'loo but at higher intraluminal
pressures, blood flow is decreased.‘1'3'9°'91'94'100
Microsphere studies have indicated that redistribution of
blood flow within the bowel wall develops with increases in
intraluminal pressure, the mucosal/submucosal blood flow
decreases while the muscularis/serosal blood flow may
actually increase because of active hyperemia.57'94 The
reduction in mucosal/submucosal blood flow is attributed to
mechanical compression of vessels. The difference in
vascular resistance between distended and resting intestine
at 10 mm Hg intraluminal pressure suggests that equine
intestinal vascular resistance may be more easily increased
by distension than that of other species. However, because
no accompanying decrease in oxygen uptake developed, it is

unlikely that intestinal viability is compromised when BILP

52

is 10 mm Hg. The absence of histologic lesions after

prolonged artificial distension in another study in horses

supports this suggestion.80
At an intraluminal pressure of 20 mm Hg, oxygen uptake

96 or remain unchanged,43'88 but at

is reported to increase
higher distending pressures a stepwise reduction in oxygen
uptake occurs that is caused by a reduction in blood flow

due to increased vascular resistance,88

and decreased oxygen
extraction through opening of arteriovenous shunts.43
Therefore it is not supprising that no decrease in oxygen
uptake was seen at 10 mm Hg in ponies. However, as ileal
oxygen consumption in the dog shows a direct relationship to

motility,1°5

it is more supprising that no increase in
oxygen uptake was seen with the increase in motility
provoked by distension. This may be because of the wide
individual variation between animals and that each animal
did not act as its own control for the determination of
variables altered by distension. Alternatively, an increase
in oxygen uptake by the muscularis may be offset by a
decrease in mucosal oxygen consumption.

Neostigmine did not alter vascular resistance in either
group 3 or 4, which suggests that neostigmine is unlikely to
compromise intestinal viability in the horse with colic, but
redistribution of blood flow cannot be excluded. In
contrast, physostigmine increases vascular resistance,57

probably related to the large increase in baseline

intraluminal pressure observed.

53

Oxygen uptake increased after neostigmine
administration in both active and quiescent periods in group
3. This is most likely related to increased smooth muscle
activity. There is no apparent explanation why oxygen
uptake did not increase after neostigmine administration in
distended intestine.

Neostigmine induces a cyclic increase in motility in
resting and distended intestine. Amplitude of rhythmic
contractions was increased during active periods. Baseline
values of rhythmic contractions were increased during
quiescent periods in resting but not distended intestine.
Neostigmine prolongs the half-life of acetylcholine at the
synapse, thereby amplifying the action of cholinergic
synapses on receptor tissues.106 Thus, the persistence of
acetylcholine at the motor end plate of intestinal smooth
muscle would increase the tension in the bowel wall. The
cyclic fluctuation in amplitude of rhythmic contractions may
be caused by amplification of cyclic fluctuation in motility
that was already present but not apparent before neostigmine
administration. Cyclic fluctuations in the intestinal slow
wave would cause similar fluctuations in the number and size
of action potentials generated in response to constant
acetylcholine release, with corresponding variation in
smooth muscle tone. Cyclic fluctuations in amplitude of
slow wave depolarization (spindling) occur in the cat and
107

rabbit, but have not been investigated in the horse.

They are localized, and of shorter periodicity than seen in

54

our study, but they may form the basis of this phenonenom;
however, further study is needed to substantiate this
hypothesis. Alternatively, a cylic release of acetylcholine
at the motor end plate may either be caused or exaggerated
secondary to ganglionic effects of neostigmine.

In healthy conscious ponies, neostigmine is reported to
delay gastric emptying and prolong the migrating myoelectric

complex;1°'11

these findings are taken to indicate a
decrease in motility. However, in our study neostigmine
increased segmental motility and it caused an earlier return
of migrating myoelectric complexes in postoperative ileus in
another.78 Bethanacol, a direct cholinergic agonist, is
reported to reduce the duration of postoperative ileus when
used in combination with yohimbine.28 More recently
cisapride, which augments acetylcholine release, has also
been shown to be effctive in reducing the postoperaive
inhibition of intestinal motility.79 Although neostigmine
may deleteriosly effect the patterns of motility in normal
intestine, this experiment shows that neostigmine increases
segmental contractions. In ileus, the intestinal
musculature is still responsive to pharmacologic stimuli,2
therefore, the stimulation of segmental contractions with

neostigmine may initiate a return to normal myoelectrical

activity.

55

Baseline intraluminal pressure (P) is related to the
bowel wall tension (T) by the equation:
P = T/r

103 The tension in the bowel wall

where r is the radius.
that develops secondary to neostigmine administration is
dependent on the smooth muscle fiber length and the
thickness of the bowel wall.103 Because the radius, the
smooth muscle fiber length, and bowel wall thickness are
unknown, direct comparisons between the effects of
neostigmine on baseline intraluminal pressure and amplitude
of rhythmic contractions between groups 3 and 4 cannot be
made. The larger intestinal segment radius in group 4 could
explain why an increase in baseline intraluminal pressure
was seen in group 3 and not group 4.

These results indicate that, although intestinal
hemodynamics are adversely effected by distension at 10 mm
Hg baseline intraluminal pressure, this is unlikely to
compromise intestinal viability in normotensive animals
because oxygen uptake remains unchanged. Further,
neostigmine did not adversely effect intestinal hemodynamics
while increasing rhythmic contractions, suggesting that
neostigmine may be useful in the treatment of ileus in

equids.

CONCLUS IONS

1) Distension of equine small intestine to 10 mm Hg
increased intestinal vascular resistance but oxygen
consumption was not changed. This indicates that distension
to 10 mm Hg adversely affects intestinal hemodynamics but is

unlikely to compromise intestinal viability.

2) Neostigmine induced cyclic increases in rhythmic
contractions in both resting and distended intestine but did
not adversely affect intestinal hemodynamics suggesting that

neostigmine may be useful in the treatment of equine ileus.

56

APPENDIX

57

Table 2. Group 1. Resting Controls. In resting
control ponies the baseline intraluminal
pressure was 0 mm Hg. All variables were
monitored for 1 hour, the data were recorded
every 15 minutes and reported as mean i SEM.
Data followed by asterisks are significantly
different from baseline values at P < 0.05. RC
= Rhythmic contractions.

58

Table 2. Group 1, Resting Controls

 

Variable 0 Min 15 min 30 min 45 min 60 min
Systemic 65.8 64.2 61.8 65.0 63.5
Pressure 13.6 13.0 14.3 17.6 15.9
mm Hg

Vascular 0.8 0.76 0.74 0.72 0.74
Resistance 10.06 10.05 10.04 10.03 10.04
mm Hg/ml/min/100g

Oxygen 0.96 0.95 0.94 0.92 0.90
Consumption 10.07 1.04 10.04 10.03 10.10
ml/min/lOOg

Frequency 8.07 8.33 8.20 7.90 7.47*
OflRC 10.35 10.43 10.36 10.46 10.30
S'

Amplitude 2.42 2.00 2.00 1.83 1.83
of RC 10.92 11.00 11.00 11.09 11.09
mm Hg

Baseline 0.33 0.67 0.67 0.67 0.67
Of RC 10.17 10.33 10.33 10.33 10.33

mm Hg

59

Table 3. Group 2. Distended Controls. In the
distended control ponies the baseline
intraluminal pressure was 10 mm Hg. All
variables were monitored for 1 hour, the data
were recorded every 15 minutes and reported as
mean 1 SEM. Data followed by asterisks are
significantly different from baseline values at
P < 0.05. RC = rhythmic contractions

60

 

Table 3. Group 2, Distended Controls
Variable 0 Min 15 min 30 min 45 min 60 min
Systemic 82.5 82.5 75.8 76.7 77.5
Pressure 16.6 16.3 15.8 +13.6 +13.8
mm Hg
Vascular 1.33 1.29 1.22* 1.22* 1.20*
Resistance 10.10 10.09 10.08 10.08 10.09
mm Hg/ml/min/100g
Oxygen 1.22 1.25 1.22 1.21 1.17
Consumption 10.25 10.26 10.22 10.26 +0.25
ml/min/100g
Frequency 8.27 8.27 8.37 8.27 8.10
OflRC 10.59 10.68 10.73 10.77 +0.85
8'
Amplitude 7.75 7.42 7.33 7.25 7.17
Of RC 11.77 11.80 11.83 11.63 +1.42
mm Hg
Baseline 10.08 9.92 9.58 9.50 9.42
Of RC 10.30 10.51 10.79 10.87 +1.08

mm Hg

61

Table 4. Group 3. Effects of neostigmine on
resting intestine. Neostigmine (0.022 mg/kg
intravenously) induced cyclic fluctuations in
intestinal intraluminal pressure changes, with
periods of increased activity (active periods =
A) alternating with periods of normal activity
(quiescent periods = Q). Therefore data were
recorded 5 minutes before neostigmine
administration for baseline and at each
subsequent active and quiescent period. All
data is shown as mean 1 SEM. Data followed by
asterisks are significantly different baseline
values at P < 0.05. RC = Rhythmic contractions.

62

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63

Table 5 Group 4. Effects of neostigmine on
distended intestine. Neostigmine (0.022 mg/kg
intravenously) induced cyclic fluctuations in
intestinal intraluminal pressure changes, with
periods of increased activity (active periods =
A) alternating with periods of normal activity
(quiescent periods = Q). Therefore data were
recorded 5 minutes before neostigmine
administration for baseline and at each
subsequent active and quiescent period. All
data is shown as mean 1 SEM. Data followed by
asterisks are significantly different form
baseline values at P < 0.05.

64

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10

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