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ABSTRACT
IDENTIFICATION OF CONSTITUENTS OF CHYME

RESPONSIBLE FOR POSTPRANDIAL
INTESTINAL HYPEREMIA

BY

Siu Po Sit

Blood flow to the splanchnic viscera increases after a
meal. The purpose of the present study was: 1) to identify
which constituents of chyme are responsible for the hyperemia
and 2) to determine whether addition of amino acids to a
glucose solution will increase the hyperemic effect of the
solution when placed in the lumen of the jejunum. Two series
of experiments were performed. In the first series, the
vascular effects of luminal placement of the following solu-
tions were compared: 1) undigested homogenized dog food
diluted with 2 parts distilled water to 1 part food, 2) pan—
creatic enzyme preparation (ViokaseR) suspended in normal
saline (187.5 mg/lOO cc), 3) digested food, digested by the
pancreatic enzyme preparation and diluted with 2 parts dis-
tilled water to 1 part food, 4) supernatant of the digested
food, 5) precipitate of the digested food, 6) gallbladder
bile diluted with 2 parts normal saline to 1 part bile,

7) equal parts of undiluted digested food, distilled water

Siu Po Sit

and undiluted gallbladder bile, and 8) normal saline. These
solutions were paired into the following six combinations:

1) digested food and undigested food, 2) supernatant and
precipitate, 3) supernatant and digested food, 4) supernatant
and enzyme, 5) gallbladder bile and normal saline, and

6) digested food plus bile and digested food. Venous outflow
from two adjacent in situ canine jejunal segments were simul—
taneously measured; one segment contained one of the paired
solutions and the adjacent segment contained the other such
that the vasoactivity of the paired substances could be com-
pared. As a control, normal saline was placed in both seg-
ments before and after the comparisons.

Luminal placement of digested food, its supernatant and
the digested food plus bile solution significantly increased
blood flow. Undigested food, precipitate, the pancreatic
enzyme preparation, gallbladder bile (1:2 dilution) and
normal saline, however, did not have any vascular effect.

The hyperemic effect of digested food and its supernatant
was quantitatively the same. Their vascular effects were
significantly different from those of undigested food, pre-
cipitate and pancreatic enzyme, which did not increase blood
flow. The addition of gallbladder bile to the digested food
markedly augmented the hyperemic effect of the food. These
studies indicate that the hyperemia induced by the presence

of food in the lumen of the intestine requires the pancreatic

Siu Po Sit

enzymes and that the hyperemia is enhanced by the addition
of gallbladder bile. The substances responsible for post-
prandial hyperemia are in the supernatant of the digested
food and are likely to be the digestive products of food.

In the second series of experiments, the vascular ef-
fects of luminal placement of an isotonic glucose solution
and a mixture of glucose and amino acids were determined and
compared. The experiments were performed on two groups of
dogs utilizing the double segment preparation. The glucose
solution or the glucose-amino acids mixture was placed in
one segment while normal saline was placed in the other as
control. In the first group of dogs, the vascular effect of
the isotonic glucose solution was studied. Venous outflow
was obtained and vascular resistance calculated. These para-
meters were then compared with those obtained from the
second group of animals in which the vascular effects of
luminally placed isotonic glucose—amino acids mixture was
tested.

Luminal placement of both the glucose and the glucose-
amino acids mixture significantly increased blood flow and
decreased vascular resistance. The glucose-amino acids mix-
ture, however, had greater hyperemic effects than did the
glucose solution alone. The study suggests that amino acids

in the lumen enhance the hyperemic effect of glucose.

IDENTIFICATION OF CONSTITUENTS OF CHYME
RESPONSIBLE FOR POSTPRANDIAL

INTESTINAL HYPEREMIA

BY
Siu Po Sit
A THESIS

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

MASTER OF SCIENCE

Department of Physiology

1976

To my parents

ii

ACKNOWLEDGMENTS

I wish to express my sincere gratitude and admiration
to Dr. C. C. Chou for his invaluable guidance, encouragement,
and support throughout the course of this study. My appreci-
ation is also extended to Dr. J. M. Dabney and Dr. J. B.
Scott for their services on the examination committee. I am
especially indebted to Dr. Dabney for providing me the oppor-
tunity to get started when it all began.

Special thanks to Dr. J. A. Post, Mrs. Yanee Thoongsuwan
and Mr. P. Kvietys for their technical assistance and without
whose help this study would never have been possible. And

finally to Jean, for making everything worthwhile.

 

iii

TABLE OF CONTENTS

CHAPTER ‘ Page

LIST OF TABLES........0...’.............00.... V

 

I. INTRODUCTION....OOO...000......OOOIOOOOO0.0... 1
II. LITERATURE REVIEW..COOOOCOOOOO...0............ 3

Postprandial Hemodynamics.................. 3

Mechanisms of Postprandial Hemodynamics.... 12
Systemic and Local Nerves............... 12
Humoral Substances...................... 18

Initiation Factors in Postprandial Hemo-
dynamics................................ 27

III. METHODS...........0........................... 29
surgical Procedures. 0 I O O . . O . . O O . . I O . . . . . . . . 29
Preparation of the Solutions Studied....... 30
Experimental Procedures.................... 34

series 1......0..............00.0.0...I. 34

series 2................................ 35
Statistical Analysis of the Results........ 36

IV. RESULTS.......O...0........................... 37

series 100.......0..........0......OOOOOOOO 37
series 20......................O0......OOOO 43

v. DISCUSSIONCOCOOOOOCCOOOCCOOOOO......0.0.0.0... 47
VI. SUMMARY AND CONCLUSION........................ 54

REFERENCES.......0.0....0.0.0...0......OIOOOOOOOOOOOO 56

iv

LI ST OF TABLES

TABLE Page
1. Composition of the glucose-amino acids mixture... 33
2. Effects of placing various constituents of chyme

into the jejunal lumen on local blood flow (ml/
min/100 gm), vascular resistance (mm Hg/ml/min/
100 gm) and luminal pressure (mm Hg)............. 38

Percent change from precontrol values of venous

outflow and vascular resistance with paired solu-

tion in the lumen of the adjacent jejunal double
segments......................................... 41

Effects of luminal placement of the glucose solu-

tion and a mixture of glucose and amino acids on

blood flow (ml/min/lOO gm) and vascular resist-

ance (mm Hg/ml/min/lOO gm)....................... 44

CHAPTER I

INTRODUCTION

Many studies indicate that the cardiovascular system
responds to feeding in two distinctly different phases.
During presentation and ingestion of food, cardiac output,
heart rate, aortic pressure and vascular resistance in vari-
ous vascular beds are altered in a pattern which mimics an
increase in sympathetic neural activity. Within 5-30 minutes
following a meal, cardiac output, heart rate, aortic pressure
and blood flow to the heart and kidney return to control
levels while superior mesenteric arterial flow starts to rise
and reaches a maximum in 30-90 minutes. A recent study fur-
ther shows that this increase in mesenteric blood flow is
confined only to the mucosal layer of that intestinal region
which is exposed to food. The specific process triggering
the intestinal hyperemic response to food is not known. Nor
is it clear which of the constituents of intestinal contents
are responsible for the hyperemia. It has been postulated
that the digested products of food (i.e., fatty acids, amino
acids, glucose etc.) and their absorptive processes may be
involved in the local mesenteric hyperemia. Placement of

each of these substances in the lumen of the small intestine

has been shown to increase venous outflow and decrease vascu—
lar resistance. The cumulative effect of these nutrients on
mesenteric blood flow, however, has not yet been investigated.
The present study was undertaken to: 1) identify the

constituents of chyme that are responsible for the postpran—
dial hyperemia and 2) determine whether the intraluminal
placement of two elementary nutrients, i.e., glucose and
amino acids, as a mixture, have a cumulative effect on venous

outflow of the jejunum.

CHAPTER II

LITERATURE REVIEW

Postprandial Hemodynamics

It is teleologically appealing to assume that blood
flow through the mesenteric vascular bed increases postpran-
dially because of an increase in digestive activities of the
gastrointestinal tract following a meal. Likewise, the
organs unrelated to digestion are expected to receive less
blood flow following food intake. Fronek and Stahlgren (22)
found that superior mesenteric blood flow increased after
food intake by as much as 133% while the brachiocephalic and
iliac arterial flows decreased to 86.5% and 74% of control,
respectively. The experiments were performed on conscious
dogs with implanted electromagnetic flow transducers around
the ascending aorta, brachio-cephalic, superior mesenteric
and iliac arteries. Blood flow and vascular resistance in
these vessels along with systemic arterial pressure was
recorded before a meal, during presentation and anticipation
(of food» during ingestion, and 1 hour and 3 hours following
food intake. During the anticipation and ingestion periods,

cardiac output was observed to increase by 142% with a

concomitant rise in both blood pressure and heart rate.

The changes in these parameters reached a maximum in the
first minute after the beginning of ingestion and gradually
declined back to control level 1 hour after feeding. Total
peripheral resistance tended to drop during anticipation of
food but increased modestly (5%) during ingestion. This
slight increase persisted even after the completion of food
intake. Brachiocephalic arterial flow increased during in-
gestion by 196% while the iliac arterial flow dropped to
75.4% of control level. Although there was a slight increase
in superior mesenteric blood flow at this time, mesenteric
regional resistance was found to increase by 28%. The
authors suggested that there was a general sympathetic
response to anticipation and actual ingestion of food. Dur-
ing digestion (l and 3 hours after ingestion), blood pres—
sure, cardiac output, heart rate and total peripheral resis-
tance were not significantly different from control levels.
However, there was a decrease in mesenteric regional re-
sistance as indicated by the increase of blood flow through
the superior mesenteric artery. There seemed to be a redis-
tribution of blood flow to the splanchnic bed since both
iliac and brachiocephalic arterial flows decreased signifi-
cantly. The ratio of flow in the superior mesenteric artery
to cardiac output was found to have increased from 9% at

control to 13% three hours after food intake.

This finding of postprandial blood flow redistribution
favoring the splanchnic bed, with cardiac output remaining
unchanged was inconsistent with earlier reports (14,23,31,
44). These earlier studies showed that there was a concomi-
tant rise in both cardiac output and splanchnic blood flow
after food intake. Blood pressure, heart rate and blood
flow to various other organs were also increased postprandi-
ally. The difference in the results between these early
studies and that of Fronek and Stahlgren (22) may be due to
differences in instrumentation, species, and methods used.
For example, in 1929 Grollman (28) studied the effect of
eating on cardiac output, pulse rate and blood pressure on
conscious human subjects, but did not measure splanchnic
blood flow. By employing the modified acetylene gas method
to measure the vascular responses indirectly, he found an
immediate increase in cardiac output after food ingestion
that may last as long as five hours. Pulse rate was observed
to increase transiently but systemic blood pressure was not
significantly altered. Herrick §E_§l, (31) utilized the
thermostrOmuhr method of Rein to measure blood flow in
trained dogs under local anesthesia (pantocaine). Blood flow
was found to increase in the femoral, carotid and superior
mesenteric arteries as well as the jugular vein following
ingestion. However, neither systemic arterial pressure nor

cardiac output were measured. Gladstone (23) measured the

effect of eating on cardiac output in conscious human sub—
jects by using the ethylene gas method and found it increased
by 25% of control. Dagenais gt El. (14) studied the hemo-
dynamic effects of carbohydrate and protein meals in man,
measuring the changes in cardiac output, heart rate and blood
pressure. Again mesenteric blood flow was not recorded.
Heart rate was monitored by electrocardiograph and blood
pressure by sphygmomanometer. A fine catheter was inserted
percutaneously through an antecubital vein to the superior
vena cava. Coomassie blue dye was injected through the
catheter to measure cardiac output. A protein rich meal
(filet mignon) brought a greater increment of cardiac output
(+46%) than did a carbohydrate rich diet (fruit juice, ice
cream, cake and syrup, 34%). There were comparable increases
in both heart rate and systolic blood pressure in both
instances. Maximal changes were reached in 1% hours after
the carbohydrate meal and much later (up to 3 hours) follow—
ing the protein meal. Brandt and associates (5), unlike
other investigators, estimated postprandial changes in
splanchnic blood flow by the bromsulfalein (BSP) method in
conscious human subjects. Protein feeding induced a 35%
increase in the estimated splanchnic blood flow in 20-50
minutes while glucose feeding did not elicit any change.
Cardiac output was not measured. Thus, the consensus among
these early investigators was that cardiac output and mesen—

teric blood flow increased concomitantly after a meal.

Since the introduction of the redistribution hypothesis
by Fronek and Stahlgren (22), many new studies have been
performed to investigate this phenomenon. Most of them have
made direct measurements on cardiac output, blood flow
through the mesenteric and various other vascular beds with
different types of flowmeters. Burns and Schenk (6) in
1969 measured cardiac output and blood flow through the
superior mesenteric artery on conscious dogs following meal
intake. Electromagnetic flowmeters were planted on the
ascending aorta and the superior mesenteric artery to moni-
tor blood flow. After consuming a standard meal of 15 oz.
of horsemeat, mesenteric blood flow began to rise within 5
minutes and reached a plateau approximately 50 minutes later.
The mean flow was still 50% above the control level 3 hours
after feeding. Although there were occasional changes in
cardiac output during ingestion, no detectable increment was
observed during digestion. By using various flowmeters,
Vatner gt 21. (57) found in conscious dogs that anticipation
and ingestion of a meal caused increases in cardiac output,
heart rate and aortic blood pressure. These increases re-
turned to the control level within 10-30 minutes after food
presentation and remained stable throughout the digestive
period. Although mesenteric bloOd flow decreased (10%)
transiently during anticipation, it began to increase during

actual ingestion and reached the maximal values (115—300% of

control) within an hour. This increase in blood flow to the
viscera may last up to 7 hours postprandially. The same
group of investigators (56) found later that in addition to
the above mentioned vascular changes, renal resistance in—
creased by 24%, iliac and coronary resistances decreased by
33% and 62% respectively during the anticipation and inges-
tion period. During digestion, the increase in mesenteric
flow was accompanied by a slight decrease (10%) in iliac
flow while cardiac output, heart rate, renal and coronary
vascular resistances returned to their control levels. This
suggested that there was vasoconstriction in the muscular
vascular bed to compensate for the increase in flow to the
mesenteric vascular bed during digestion.

In 1974, Vatner EE.2£: (58) studied the regional circu-
latory adjustments to eating and digestion in conscious
primates. Doppler ultrasonic flow probes were used to
measure blood flow changes in the mesenteric, renal, iliac
and coronary arteries. Arterial pressure was measured by
miniature gauges implanted in the thoracic aorta while heart
rate was monitored continuously by cardio-tachometer. A
total of eight baboons and one chimpanzee were used as
experimental subjects. During ingestion of a meal consist—
ing of different fruits, the baboons experienced an increase
in both heart rate (82%) and arterial pressure (25%). Like-

wise, iliac and coronary flows were observed to increase by

84% and 152% respectively. There was a transient but sig-
nificant decrease in both mesenteric (12%) and renal (4%)
blood flow during this time. During digestion, mesenteric
blood flow rose and reached a maximum in an hour. This
increase in flow may last up to 4 hours and was accompanied
by a significant decrease in iliac flow (31%). Heart rate,
arterial pressure, coronary and renal blood flow remained at
control levels throughout digestion. In the case of the
chimpanzee, the response to feeding was similar to that of
the baboons. However, mesenteric blood flow increased at

2 hours and reached a peak at 3 hours after eating, which
was much later than those occurring in the baboons.

These recent studies have, therefore, shown that
although cardiac output, heart rate and systemic pressure
increase during the anticipation and ingestion of food, the
changes are transient and decline to control levels during
digestion (6,22,56,57,58). Mesenteric blood flow began to
increase from 5 to 30 minutes after completion of food in-
take and the hyperemia may last up to 7 hours. This increase
in mesenteric blood flow during digestion is accompanied by
increased resistance in the brachiocephalic and iliac
arteries (22,56,58). There is a postprandial redistribution
of blood flow favoring the mesenteric vascular bed at the
expense of the muscle and skin. Indeed, the ratio of blood

flow in the superior mesenteric artery to cardiac output has

10

been observed to increase from 9% before meal to 13% during
digestion (22).

These studies, however, have not determined the speci-
fic localization of the hyperemia within the mesenteric
circulation. Fara et 31. (18) observed that intraduodenal
instillation of corn oil in cats caused increases of blood
flow through the superior mesenteric, pancreatic and jejunal
arteries while flow through the stomach and colon were not
altered. Chou gt 2l° (12) found in anesthetized dogs that
the hyperemia through the various organs within the gastro-
intestinal tract seemed to follow the pattern of chyme move-
ment. The flow through the celiac artery was observed to
increase when food was introduced into the stomach but did
not change when instilled into the duodenum. Superior mesen-
teric blood flow on the other hand, fell transiently but not
significantly during intragastric placement of food; started
to rise 30 minutes after the placement and remained increased
for 3 hours. This is significant since the celiac artery
supplies the stomach; whereas, the superior mesenteric artery
supplies the small intestine. What this seemed to indicate
then, was that blood flow may increase only in that region
exposed to food and not indiscriminantly throughout the
gastrointestinal tract.

This possibility was furthhr explored by these investi-

gators when they infused food intraduodenally. In addition

11

to monitoring the superior mesenteric arterial flow, they
measured venous outflow from an isolated in gitu jejunal seg—
ment. As before, superior mesenteric blood flow was found
to increase during the intraduodenal food infusion but
venous outflow from the isolated jejunal segment which had
no contact with food was not altered. When the same food
was placed only into the isolated jejunal segment, the blood
flow through the segment increased but that through the su-
perior mesenteric artery did not. Subsequently venous out-
flows from two isolated adjacent in_§itu jejunal segments
were measured simultaneously; one segment contained 10 ml of
food and the other, the same amount of saline. The segment
with food increased its flow while no change was observed in
the control segment with saline. These findings suggested
that the intestinal hyperemia that occurs during digestion
is a local phenomenon. Radioactive microspheres were also
used by these authors (12) to study the compartmental blood
flow in the jejunum. Three isolated in gitg jejunal seg-
ments were used, one was left empty and the other two con-
tained either 10 m1 of non—absorbable polyethylene glycol
solution or the same amount of food. It was found that only
the segment containing food significantly increased its
total blood flow. The increase in the total wall flow re-
sulted from an increase in mucosal flow; flow to the sub~
mucosa and the muscularis remain unchanged. Yu gt_31. (61)

in a similar study using radioactive microspheres observed

12

that placement of 50% glucose solution in an isolated jejunal
segment in dogs induced greater blood flow to the mucosa but
not to the other two layers of the gut wall. Thus, the in-
crease in the superior mesenteric blood flow during digestion
may well be due to an increased flow in that portion of the
intestine that is in contact with food. Furthermore, the
increased flow is localized in the mucosal layer of the

intestinal wall (12,61).

Mechanisms of Postprandial Hemodynamics

Although some information has surfaced in recent years
concerning the mechanisms involving the cardiovascular re-
sponses to food intake, the overall picture is not entirely
clear. Opinions are not always unanimous as to what mediates
the local intestinal hyperemia during digestion. Nor is
there a concensus as to what initiates the increase in flow
to that part of the intestine that is in contact with food.
Nonetheless, investigations have been done to elucidate the
mechanisms of the postprandial responses. Among the medi-
ators that have been implicated are: 1) the systemic and
local neural pathways and 2) various humoral substances that

are released into the blood stream during digestion.

Systemic and Local Nerves

The efferent parasympathetic system to the gastroin-

testinal tract originates in the pre-optic and supraoptic

13

nuclei of the hypothalamus. It synapses with the dorsal
vagal nuclei and with cells in the second, third and fourth
sacral segments (52). The vagal preganglionic fibers are
connected directly and without interruption to the postgang-
lionic neurons in the intrinsic plexus of the visceral organs,
such as the liver, bile ducts, gallbladder, pancreas,

stomach, small intestine and the proximal colon (46). The
preganglionic neurons originate from the second, third and
fourth sacral segments innervating the distal colon through
the pelvic nerves (52).

The efferent sympathetic preganglionic fibers originate
from the hypothalamic region, relay in the lower seventh or
eighth thoracic segments (T5 to T12) and the upper lumbar
segments (L1 to L3). The axons run via the splanchnic nerves
to reach the postganglionic neurons in the celiac, superior,
inferior mesenteric and the inferior hypogastric plexuses.
The postganglionic fibers innervate the visceral blood ves-
sels and the secretory glands. Stimulation of the sympa-
thetic system causes vasoconstriction and inhibition of
motility (46,52).

Autonomic preganglionic fibers and most parasympathetic
postganglionic fibers to the gastrointestinal tract are
cholinergic; in contrast, the sympathetic postganglionic
fibers are known to be predominantly adrenergic (46).

There are two major intrinsic nerve plexuses within the

gastrointestinal tract. the submucosal plexus of Meissner

14

and the myenteric plexus of Auerbach. The former plexus con-
sists of unipolar and bipolar cells. It is situated between
the muscularis mucosa and the circular muscles of the intes-
tinal wall. The latter plexus is located between the longi-
tudinal and circular muscle coats and its cells are mostly
multipolar. The sensory endings of the visceral afferent
fibers are dendrites from the submucosal plexus that may be
situated in the mucosal epithelium, in the muscle layers or
in the plexuses. They are chemical and mechanical receptors
that respond to changes in the intestinal contents (peptides,
amino acids, fats, pH and osmolality) and stretch or disten-
sion (15). The afferent impulses may be conducted centrally
via the vagal and sympathetic fibers or be transmitted local—
1y via the submucosal plexus to the myenteric plexus (15,46,
52).

Zamiatina (62) found that presence of food or its di—
gestive products in the lumen of the gut can stimulate the
receptors in the intestinal wall. Cats anesthetized with
urethane were used in the study. Nerve branches of the
afferent innervations from the small and large intestine
were isolated and their impulses recorded by a cathode ray
oscillograph. During digestion in animals that were fed
with meat, high neural activity was seen from the afferent
nerves of the jejunum, mesentery and pancreas but not of the

colon. This was also true with glucose and amino acid

15

solutions infused into the gut. Glucose (4-10%) solution
had a stimulating effect on the upper part of the jejunum;
whereas, amino acid mixtures intensified the neural activi-
ties in the jejunum, mesentery and pancreas. In a similar
experiment, Sharma and Nasset (48) have also been able to
demonstrate that when glucose and amino acid solutions were
perfused through the lumen of the small intestine, the fre-
quency of firing from mesenteric nerves increased by as much
as 400% from control.

Fronek and Stahlgren (22) characterized the increases
in heart rate, blood pressure and cardiac output during
anticipation and ingestion of food as a generalized sympa—
thomimetic response. They cited as evidence the findings
of Ehrlich gt 31. (16) that there was no increase in mean
arterial blood pressure during ingestion in catecholamine-
depleted dogs.

The roles played by the autonomic nervous system during
anticipation, ingestion and digestion of food was examined
in detail by Vatner gE_al. (57). The effects of food pre-
sentation, actual ingestion and digestion on cardiac output,
heart rate, aortic pressure and mesenteric blood flow before
and after adrenergic and cholinergic blockade in conscious
dogs were investigated. Alpha and beta adrenergic blockade
by phenoxybenzamine (15 mg/kg) and propranolol hydrochloride

(3 mg/kg) respectively attenuated the increases in heart

16

rate, blood pressure and mesenteric resistance during the
anticipation and ingestion periods. No effect was observed
on the hyperemia in the mesenteric vasculature during diges—
tion period. Cholinergic blockade by atropine (0.1-0.2
mg/kg) prevented the mesenteric vasodilation during diges-
tion but bilateral thoracic vagotomy had no effect on the
response. Fara g£_al. (17) also observed in cats that
atropine (0.06—0.5 mg/kg, i.v.) blocked the increase in
superior mesenteric blood flow seen after the intraduodenal
instillation of milk, corn oil (fat), L-phenylalanine or
hydrochloric acid. Bilateral splanchnicectomy or combined
alpha and beta adrenergic blockades have no effect on the
vasodilation. The important role played by the cholinergic
fibers in the mesenteric hyperemia during digestion has also
been demonstrated by Vatner et_al. (58) in primates. They
have shown that the mesenteric vasodilation in the baboon
could be attenuated by prior cholinergic blockade with
atropine (0.6 mg/kg). Again the blockade has no effect on
the vascular responses seen in the early ingestion phase of
a meal.

Thus, these findings seem to suggest that although the
sympathetic nervous system may be involved in the anticipa—
tion and ingestion responses to food, it is the parasympa—
thetic system that plays a major role in the mesenteric vaso-

dilation during digestion. The fact that bilateral thoracic

l7

vagotomy has no effect on the postprandial vascular response
indicates that cholinergic influence may be at the local
level; most likely involving the intramural nerve plexus.

Chen gt a1. (9) have demonstrated that dibucaine can
attenuate the vascular effects of intraluminally placed
hypertonic salt solutions. Before applying the local anes-
thetic, 1500 mOsm of NaCl, KCl, MgCl2 or CaCl2 salt solu-
tions all increased blood flow in an in_§itu jejunal loop.
However, after the mucosa of the segment had been exposed to
0.4% dibucaine, only MgCl2 increased blood flow. Other solu-
tions either lowered blood flow or had no effect on the
jejunal vasculature. Chou gt a1. (10) showed that dibucaine
can also attenuate the increase in blood flow evoked by
hypertonic glucose solution in the lumen of the gut. Yu
gt_al. (61) observed that the inhibitory effect of the local
anesthetic on the vasodilation is limited to the mucosal
layer of the luminal wall. Prior exposure to dibucaine
attenuated the mucosal hyperemic response to hypertonic glu-
cose solution in the lumen. Blood flow to the other two
layers was not affected by the anesthetic.

As discussed above, the cardiovascular responses seen
during the anticipation and ingestion of food may, in part,
be mediated by the sympathetic fibers. The parasympathetic
system, on the other hand, is likely to be involved in the

postprandial hemodynamics. Local cholinergic plexuses have

18

been suggested to play a role in mediating the mesenteric
hyperemia due to food. Precisely what are the neural mechan-
isms that lead to the vascular adjustments during digestion
is not clear. It is likely that receptors in the gut wall
continuously monitor the content of the chyme and provide
vital information for the local reflex arc during the pres-
ence of food in the lumen. In turn, the intraluminal cholin-
ergic plexus may either act on the blood vessels or release
local vasoactive agents to produce the vascular responses to

food intake.

Humoral Substances

 

Gastrointestinal hormones: The specific actions of the
three gastrointestinal hormones, i.e., gastrin, secretin and
cholecystokinin (CCK) on secretion, absorption, motility and
metabolism of the gastrointestinal tract have long been
under intense scrutiny. It was not until recently that at-
tention has been given to their possible vascular effects.
All three of these hormones are released from the upper
gastrointestinal tract during digestion. They have been
shown to have specific vascular effects on different organs.

Gastrin was first proven to exist by Grossman and
colleagues (29) in a transplanted fundic pouch with a dis-
tended antrum. In 1964, Gregory and Tracy (27) succeeded
in isolating the hormone which later was identified as a 17

amino acid peptide amide with a molecular weight of 2,114.

l9

Species variation have been known to exist and the differ-
ences occur between residues 5 and 10 with the rest of the
molecules being identical. Interestingly, all the physio-
logical actions of the hormone can be reproduced by the
C—terminal tetrapeptide amide of the molecule (15,34,52).

A synthetic acyl derivative of the tetrapeptide called penta-
gastrin has long been available commercially for scientific
research in both humans and animals. The antrum of the
stomach is the main source of gastrin. The release of the
hormone from the antrum may be stimulated by vagal stimula-
tion, gastric distention or various chemicals (e.g., meat
extracts, amino acids, histamine and alcohol) in the stomach.
Inhibition of the release of the hormone occurs when the
antral pH drops below 3.5 (34).

Chou gt_al. (11) observed in dogs that infusions of
gastrin extracted from porcine antrum (0.2 mg/ml at 0.19-
7.75 ml/min) into the superior mesenteric artery decrease
the resistance of the vessel by 10 to 12%. They attributed
the phenomenon to the hormone's vasodilating effect on the
small vessels in the intestine. Laureta gt a1. (38) found
local intra-arterial infusion of the same dose of the hor-
mone at a slower rate to have similar effect on the canine
stomach. It was concluded that gastrin may very well be
vasoactive in both the gastric and mesenteric vascular beds.

Swan and Jacobson (51) on the other hand, found that gastrin

20

had no effect on the total blood flow to a gastric pouch but
did increase its mucosal blood flow. The effects of subcu-
taneous injection of gastrin extracted from porcine antrum
were demonstrated by Burns and Schenk in dogs (6). Injec—
tion of 2 units/kg of the extract subcutaneously increased
mesenteric blood flow within 5 minutes, flow reached a peak
(45% above control) in 1 to 2 hours and remained elevated
for up to 3 hours. In addition to its effects on the gastric
and mesenteric vasculature, gastrin has also been shown to
increase pancreatic secretion and blood flow (24) as well as
decrease hepatic vascular resistance (42). Whether these
vascular effects of the hormone resulted from a direct influ-
ence on the visceral blood vessels or indirectly through

the release of intermediary agents is still not clear.

Fasth gt_al. (19) observed in cat small intestine that atro-
pine (1 mg/kg, i.v.) can attenuate the increase in intes-
tinal motility but not the increase in blood flow induced by
the intra-arterial infusion of the hormone (3 ug/kg/min).
Bowen g£_al. (4) recently found that cholinergic blockade by
atropine (0.5 mg/kg) abolished the vasodilating effect of
pentagastrin (0.5 ug/kg/min, i.a.) in the canine distal
ileum. Thus, depending on the species, the hormone's ac-
tions on both motility and blood flow may well be mediated

through cholinergic receptors.

21

Secretin was first isolated by Mutt and Jorpes (40) and
synthesized by Bodanszky gt_al, (3). The hormone is a poly—
peptide containing 27 amino acid residues in which all are
required for activity. It has a molecular weight of 3,056.
It is believed that secretin is produced by villus epithelial
cells in the duodenum (15,34). Hydrogen ions in the duodenum
are the most effective stimulant for the release of the hor—
mone. Intraduodenal instillation of fatty acids and amino
acids have also been shown to cause the release of the pep-
tide (34). Secretin is most effective in stimulating the
secretion of bicarbonate and fluid in the pancreas and pepsin
in the stomach (15,34,45).

The vascular effects of secretin in the gastrointestinal
vasculature have been studied in cats (17,45), dogs (4,11,
24,38) as well as in humans (54). Chou gt_§1. (11) and
Laureta gt_§l. (38) did not observe any change in vascular
resistance when they infused the hormone intra-arterially
into the canine superior mesenteric artery (1 ug/ml) and the
stomach (0.133 ug/ml) at various rates (0.19-7.75 ml/min).
Goodhead 32 31. (24) used radioactive rubidium (85Rb) to
measure cardiac output and blood flow to various organs in
the canine gastrointestinal tract. Secretin infusion
(5 units/kg, i.v.) only caused increases in pancreatic and
duodenal blood flow and not in other organs. Recently Bowen

25.21; (4) observed in dogs that high doses of synthetic

22

secretin (0.03 ug/kg/min and 0.3 ug/kg/min for 10 minutes)
administered intra-arterially into a loop of distal ileum
did not elicit any response. Burns and Schenk (6) on the
other hand, found in dogs that intravenous injection of 1.5
units/kg of an impure extract of secretin increased mesen—
teric blood flow within 5 minutes. This increment reached
a maximum (38% above control) in 2 hours. Ross (45)
examined the effects of a natural secretin extract on
arterial pressure as well as on blood flows through the
femoral, hepatic and superior mesenteric arteries in cats.
Rapid injection (1-10 units, i.a.) decreased resistance in
the superior mesenteric and femoral arteries but not the
hepatic artery. These changes were accompanied by a pro-
longed increase in blood pressure. Fara gt_gl. (l7) ob-
served that intravenous administration (0.4-10.3 units) of
a pure, natural secretin into cats increased the superior
mesenteric, pancreatic and jejunal arterial blood flow.
Uden (54) observed in humans that secretin injection in-
creased the radius of the portal vein but not the hepatic
artery. Thus, substantial disagreement exists as to the
vascular effects of secretin in the stomach and the small
intestine. This may stem from the fact that most studies
were conducted with purified secretin rather than the syn—
thetic one. Naturally obtained extracts of the hormone are

known to contain various other vasoactive substances such as

23

CCK or plasma kinin. These contaminants may have contributed
to many of the vasodilating effects of secretin. Only Bowen
and associates (4) have used synthetic secretin in their
studies. Unfortunately, they did not examine the vascular
effects of the hormone in the entire gastrointestinal tract.

Ivy and Oldberg's cholecystokinin (33) and Harper and
Raper's pancreozymin (30) have been proven to be one single
hormone (36) whose structure was discovered by Mutt and
Jorpes recently (39). It is a polypeptide consisting of 33
amino acids. Its C-terminal pentapeptide is identical to the
minimal active fragment of gastrin and thus, the action of
the two hormones are quite similar (34,39). There are,
however, quantitative differences between the two agents.
Unlike gastrin, CCK is a strong stimulant of gall bladder
contraction and a weak stimulant of gastric secretion. In
fact, CCK has been shown to antagonize the action of gastrin
on gastric acid secretion. The mechanism is thought to be
through competitive inhibition (34). Although amino acids,
fatty acids and hydrogen ions in the duodenum all stimulate
the release of CCK from the upper small intestine, vagal
stimulation has little or no effect on the release of the
hormone (34).

Fara et a1, (18) was able to mimic the vascular effects
of intraduodenal fat by intravenous infusion of CCK.

In cats, infusion of 4.7 units/kg/hour of the partially

24

purified hormone increased both superior mesenteric blood
flow and duodenal motility. It was postulated that CCK may
be the mediator of fat-induced vasodilation in the duodenum.
Fasth 32 21. (19) found that local intra-arterial infusion
of the hormone (4.3 units/kg/min.) into the cat's small
intestine caused an immediate but short lasting increase of
blood flow through the superior mesenteric artery. Both the
vascular and metabolic effects of CCK were examined by Fara
gg_al. (17) in cats. Between the dosage of 1.1-4.3 units/
kg/hour, i.v., at constant infusion, CCK increased blood
flow and O2 consumption in the jejunum and pancreas. These
effects were not blocked by atropine (0.5 mg/kg, i.v.) or
vagotomy. Bowen et_gl. (4), however, observed in canine
ileum that the increases in superior mesenteric blood flow
and O2 consumption after infusion of CCK (0.1 ug/kg/min for
10 minutes) can be blocked by atropine (0.5 mg/kg, i.v.).
Route of infusion and dosage of the hormone as well as
species difference may account for the contrasting results.
Fara gt 21. (17) suggested that the mesenteric vasodi-
lation caused by CCK may have been the consequence of the
release of local vasoactive agents triggered by the hormone.
Their in yitrg studies have shown that CCK could not modify
the active vascular tension on a strip of the superior
mesenteric artery. Thus, it is unlikely that the hormone has

any direct vascular effect on the mesenteric vasculature.

25

Biber gt El. (2) observed in cats that blocking the vascular
effects of 5-hydroxytryptamine (5-HT), a vasodilator, by an
a-receptor antagonist (dihydroergotamine) can abolish the
intestinal vascular responses to CCK infusion. It was sug—
gested that S-HT, may be the intermediary vasoactive agent
for the mesenteric vasodilation elicited by CCK. Hilton and
Jones (32) perfused the cat's pancreas with CCK and found
increases in both pancreatic blood flow and secretion. In
addition, they found that the activity of the active kinin-
forming enzyme 'kallikrein' in the perfusate had increased
about fourfold. This led them to speculate that plasma kinin
may play a prominant role in the functional vasodilation of
the pancreas during CCK infusion.

In summary, all three hormones have been shown to be
vasoactive in the gastrointestinal vasculature. Infusion
(both i.a. and i.v.) of gastrin in dogs and cats produced
vasodilation in the superior mesenteric, pancreatic and
hepatic arterial blood flows (6,11,24,38,42). Whether this
hormone acts directly or through other vasoactive agents is
not known. Findings concerning the vascular effects of
secretin are controversial. .There is conflicting evidence
as to whether or not the hormone is vasoactive in the small
intestine (4,6,11,17,38,45). Its vasodilating effect on the
pancreas, however, has been well-established (20,24,41,S4).

CCK is known to decrease vascular resistance in the small

26

intestine (2,4,11,17,18,53), stomach (38), pancreas (24,32,
41) as well as in the portal vein (42,53). It was suggested
that the hormone's action may be mediated by 5-hydroxytrypt-
amine (2) and kallikrein (32).

It must be emphasized that much of the vascular effects
of the hormones cited in this review were obtained from
pharmacological doses. Thus, any extrapolation from these
data must be treated with caution. Chou* recently found
that of the 3 hormones, only CCK is able to exert its vascu-
lar effects at physiological doses (2-8 p units/ml). This
is compatible with the observation of Fara 22 a1. (17) in
cats that infusion of low doses of CCK mimicked the vascular
response induced by intraduodenal fat. Furthermore, atropine,
which prevents the release of CCK (59), has been shown to
prevent postprandial mesenteric vasodilation (17,56,58).
What these findings seem to suggest then, is that the mesen-
teric vasodilation could be a consequence of the release of
CCK. It is unlikely, however, that CCK is the sole vaso-
active agent involved since mesenteric blood flow has been
shown to increase by as much as 300% of control postprandial—
1y (56,58). The average increase of flow in the superior
mesenteric artery after CCK infusion (even at pharmacologi-

cal doses) is less than 100% (2,4,17).

 

*
Personal communication with Dr. C. C. Chou.

27

Other vasoactive substances: Many other substances

 

have been shown to be vasoactive in the mesenteric vascula-
ture. Unfortunately, their exact role in postprandial
hyperemia have not been determined. Both S-hydroxytryptamine
(2) and kallikrein (32) have been suggested as possible
mediators for the vascular effects of CCK in the small in-
testine and the pancreas (2,32). Intra-arterial infusion

of high carbon dioxide tension blood, ATP, ADP, AMP, brady-
kinin, prostaglandins, acetylcholine or histamine in the dog
causes intestinal vasodilation (15,25,52). What role these
substances play in postprandial hemodynamics, however, has
not been elucidated. Thus, besides the three gastrointes—
tinal hormones, little is known concerning the possible role
of other endogenous humoral substances in eliciting the

local increase of mesenteric blood flow.

Initiation Factors in Postprandial Hemodynamics

If the role played by various endogenous vasoactive
substances during postprandial hyperemia is poorly under-
stood, much less is known about the food constituents that
are responsible for the vasodilation. Very little informa-
tion is available concerning the initiating process of the
vascular responses after eating. It has been observed by
Dagenais et_gl. (14) that the time of maximal change of the

vascular response to food was comparable to the time of

28

maximal absorption of carbohydrates and proteins. The site
for transmembrane transport of water, electrolytes and other
nutrients is located in the mucosal layer (15). That the
hyperemia is confined only to this layer of the intestine
would certainly lead one to speculate that the digestive pro—
ducts of food and their absorptive processes may be involved
in the initiation of postprandial hyperemia (12). Whether
digestion of food is necessary for the increase in mesenteric
blood flow, however, has not been determined. Although
various digestive products have been shown to be capable of
increasing blood flow when placed in the lumen of the intes—
tine (10,l7,55,61), their role in the initiation process has
yet to be elucidated.

The purpose of this present study was twofold: l) to
identify the constituents of chyme that are responsible for
the postprandial intestinal hyperemia and 2) to determine
whether the intraluminal placement of two elementary
nutrients, i.e., glucose and amino acids, as a mixture, have

a cumulative effect on venous outflow of the jejunum.

CHAPTER III

METHODS

Surgical Procedures

 

Mongrel dogs (15-25 kg) of either sex were fasted for
twenty-four hours, anesthetized with sodium pentobarbital
(30 mg/kg, i.v.) and ventilated with a positive pressure
Harvard respiration pump (Model #607, Dover, Mass.) to
achieve normal arterial pH. Systemic arterial pressure
(mm Hg) was monitored by a Statham pressure transducer
(Model #P23Gb, Hato Ray, Puerto Rico) via a cannula (PE 280)
inserted into the femoral artery, and continuously recorded
on a four channel Sanborn oscillograph (7700 series, waltham,
Mass.).

The abdominal cavity was exposed through a midline in-
cision and a loop of the jejunum about 30 cm distal to the
ligament of Treitz was exteriorized and divided into two
segments of equal length. The vein draining each segment
was cannulated with a polyethlene tubing (PE 240) after an
intravenous administration of sodium heparin (6 mg/kg).

The venous outflow was collected in a reservoir initially

containing 200 m1 of 6% dextran in normal saline.

29

30

The venous blood was returned to the animal continuously
with a Holter pump (Model RE 161, Extracorporeal Medical
Specialties, Inc., King of Prussia, Pa.) via a femoral vein
at rates equal to the rates of the total venous outflow.

A rubber tube (i.d. = 0.3 cm; o.d. = 0.5 cm) was introduced
into the lumen of each segment for the placement of the
test substances. The tubes were connected to a Statham
pressure transducer (P23Gb) for the measurement of the
intestine luminal pressure when the solutions were in the
lumen. Both ends of each segment were tied and the mesentery
cut to exclude collateral flow. The two segment were then
covered with a plastic sheet and kept at 37°C with a heat

lamp.

Preparation of the Solutions Studied

The solutions studied were: 1) undigested food,
2) digested food, 3) the supernatant of the digested food,
4) the precipitate of the digested food, 5) the pancreatic
enzyme preparation (ViokaseR, Viobin Co., Monticello, Ill.)
used in the preparation of the digested food, 6) gallbladder
bile, 7) digested food plus bile, 8) normal saline, 9) iso—
tonic (5.4%) glucose solution, and 10) a mixture of glucose

and 16 amino acids.

31

The food solutions were made from commercially avail-
able dog food (protein 12%, fat 7%, fiber 1.5%, ash 3%,
linoleic acid 0.4%, moisture 78%) (Alpo Beef, Allen Products
Co., Allentown, Pa.). A can of this dog food was homogenized
in an electric blender, then the pH of the homogenate was
adjusted to 7.0 by adding sodium bicarbonate. A part of
the homogenate was retained to be used in the experiments
as undigested food. To the other part of the homogenate a
pancreatic enzyme preparation (187.5 mg/100 cc; Viokase,
Viobin Co., Monticello, Ill) was added and the whole was
gently mixed with a magnetic stirrer at room temperature for
5 hours to permit digestion. The digested food was then
made near isotonic by adding 2 parts of distilled water to
1 part of the digested food. A part of this diluted digested
food was retained to be used in the experiment as digested
food while the other part was centrifuged (19,250 G) and
divided into supernatant and precipitate. The mean : S.E.M.
osmolality of the supernatants of digested food made from
six cans of dog food was 278 :_29 mOsm/kg. The undigested
food mixtures were also diluted 1:2 with distilled water and
the whole was stirred for one hour with a magnetic stirrer
at room temperature before the experiment. The osmolality
of the supernatant of the diluted undigested food was
178 :_12 mOsm/kg (mean :_S.E.M., N = 6). The higher osmol-

ality of the digested food indicated that digestive products,

32

about 100 mOsm/kg, are produced after digestion by the pan—
creatic enzyme preparation in_yitrg. The pancreatic enzyme
preparation was dissolved in normal saline (187.5 mg/100 cc)
and its osmolality was 317 :_17 mOsm/kg (mean :_S.E.M., N==6).

Prior to each experiment bile was withdrawn from the
animal's gallbladder with a needle and syringe. The volume
of the bile obtained from each dog varied from 15 to 30 ml.
The digested food plus bile solution was prepared by adding
equal parts of undiluted digested food, distilled water and
the gallbladder bile together. The whole was then mixed
gently with an electric stirrer for about 15 minutes. The
pH and osmolality of this solution was 6.3 :_0.13 and 356 i
30 mOsm/kg (mean i_S.E.M., N = 6) respectively. The bile
to be placed in the lumen was diluted with 2 parts normal
saline to 1 part bile. The diluted gallbladder bile had a
pH of 7.0 :_0.37 and an osmolality of 284 :_2.4 mOsm/kg (mean
-_l-_ S.E.M., N = 6).

The composition of the isotonic glucose-amino acids
mixture is shown in Table l. The mixture was prepared by
first dissolving tyrosine and cystine in 1.2 cc of 3 M NaOH
solution. This was necessary because these two amino acids
do not dissolve in distilled water readily. The remaining
14 amino acids along with the glucose solution and an appro-
priate amount of distilled water were added to the solution

to make a final mixture (Table 1). To ensure adequate

33

 

 

 

Table 1. Composition of the glucose-amino acids mixture.

Essential L - Amino Acids Mixture: (mM)
1. Isoleucine 14.05
2. Leucine 21.14
3. Methionine 6.47
4. Phenylalanine 8.33
5. Threonine 13.19
6. Tryptophan 1.74
7. Valine 15.91
8. Lysine 13.34

Nonessential L - Amino Acids Mixture:

1.
2.
3.
4.
5.
6.
7.
8.

Glucose

Arginine 7.00
Aspartic acid 13.40
Cystine 1.07
Glutamic acid 18.93
Glycine 14.27
Histidine 3.13
Proline 11.50
Tyrosine 3.13

100.00

 

34

mixing, this mixture was sonified (Ultrasonic Inc., Plainview,
Long Island, N.Y.) and the pH was adjusted to approximately
7.0 with 3 M NaOH. The osmolality of the mixture was 303 i

3 mOsm/kg (mean : S.E.M., N = 6).

Experimental Procedures

Two series of experiments were performed. The protocol
for the experiments of both series consisted of three 15-
minute periods: pre-control, test and post-control. In the
pre- and post-control periods, both segments contained 10 m1
normal saline. The luminal contents in the test period,
however, varied with each experiment (see below). During
each 15-minute period, venous outflows from the two jejunal
segments were simultaneously collected in three 3-minute
samples followed by two l-minute ones in graduated cylinders.
There were one minute intervals between these collections.
After each lS-minute period, the test solution or the normal
saline were withdrawn and the lumens of the segments were
washed gently with warm normal saline. The temperature of

all solutions placed into the lumen was 37°C.

Series 1
In the first series of experiments the vascular effects
of luminal placement of undigested food (1:2 dilution),

digested food (1:2 dilution), supernatant and precipitate of

35

the digested food, the pancreatic enzyme preparation, gall—
bladder bile (l:2 dilution), the digested food plus bile
solution and normal saline were studied. The purpose was to
identify the constituents of chyme that are responsible for
the postprandial hyperemia. Thus, the solutions were paired
into the following six combinations: 1) digested food and
undigested food (N = 11), 2) supernatant and precipitate

(N = 6), 3) digested food and supernatant (N = 6), 4) super-
natant and the pancreatic enzyme (N = 6), 5) bile and normal
saline (N = 6), 6) digested food plus bile and digested

food (N = 9). During the test period, 10 ml of one of the
paired solutions was placed into one segment and the same
amount of the other solution was introduced into the adjacent
segment. Since both segments were subjected to the same
systemic influences at any given time, any difference in the
vascular effects of the paired test solutions can reasonably
be attributed to the variations in their vasoactive pr0per-

ties.

Series 2

In the second series of experiments, the vascular
effects of luminal placements of the glucose—amino acids
mixture and the isotonic glucose solution (300 mM glucose)
were determined and compared. The purpose was to determine

whether the digestive products glucose and amino acids, as

36

a mixture, have a cumulative hyperemic effect. A total of
12 dogs were used in this series and they were divided into
two groups. In the first group (6 dogs), the vascular
effects of the glucose solution was studied. During the
test period, one segment contained 10 ml of the glucose
solution and the other segment 10 ml of normal saline so that
the vascular effects of this solution could be studied using
saline as a control substance. In the second group (N = 6),
the vascular effects of luminal placement of the glucose-
amino acids mixture was studied and the mixture was placed
in one segment while normal saline in the other segment dur-

ing the test period.

Statistical Analysis of the Results

The Student's t-test modified for paired comparison was
used for all analyses. In addition, the Student's group
t-test for equal variance with unpaired but equal numbers of
observation was used to compare the vascular effects of the
isotonic glucose solution and the glucose-amino acids mix-
ture. The statistical significance was set at p values

less than 0.05.

CHAPTER IV

RESULTS

The mean : S.E.M. systemic arterial pressure was 130 i
2.0 mm Hg (N = 38) and was not significantly (p<:0.05)
altered by the placement of various test and control solu-
tions. The weights of the ifl.§l£2 jejunal segments ranged
from 15 to 28 gm with an average of 20.2 i 2.0 gm (mean :_

S.E.M., N = 38).

Series 1

The effects of luminal placement of undigested food,
digested food, supernatant and precipitate of the digested
food, pancreatic enzyme preparation, gallbladder bile, di-
gested food plus bile and normal saline on venous outflow,
vascular resistance and luminal pressure are shown in Table
2. The flow values are collected during the last (14th to
15th minute) collection of blood flow in the 15 minute
period. These values were chosen for presentation because
venous outflow reached a steady state 10 to 15 minutes after
placement of the test solutions. The flow Obtained during

the 8th to 11th minute collection period were not

37

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40

statistically different from those obtained during the 14th
and 15th minute period. As shown in Table 2, none of the
solutions tested altered lumen pressure when placed into the
lumen. The percent changes from precontrol of both flow and
resistance produced by the paired test solutions are shown
in Table 3. It also shows the difference (D = A-B) between
the changes produced by the paired test solutions.

As shown in Table 2, luminal placement of digested food,
its supernatant and digested food plus bile significantly
increased blood flow as compared to precontrol. Undigested
food, precipitate of the digested food, the pancreatic
enzyme preparation and gallbladder bile, however, did not
significantly alter venous outflow as compared to precontrol.
When the vascular effects of digested food and supernatant
were compared, digested food increased venous outflow by
13.4% and decreased vascular resistance by 11.7% (Table 3).
Similar values, i.e., 11.3% increase in flow and 10% decrease
in resistance, were obtained in the adjacent segment con-
taining the supernatant of this digested food. There was no
significant difference between the hyperemic effects of the
two solutions. Addition of bile to digested food enhanced
the hyperemic effects of the food (Table 2). While luminal
placement of digested food plus bile solution increased
blood flow by 54.8% and decreased vascular resistance by

32.4%, that of digested food alone increased flow by only

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42

17.8% and decreased resistance by 13.9% (Table 3). The dif-
ferences in blood flow (37%) and vascular resistance (18.5%)
between the digested food plus bile solution and the digested
food were statistically significant (Table 3). However, bile
itself in the same concentration (1:2 dilution) in the lumen
did not produce any significant vascular effect in the
jejunal segment, i.e., +l.l% on blood flow and -l.3% in
resistance (Table 3).

When the vascular effect of digested food was compared
with undigested food, digested food again significantly in-
creased blood flow (+11.5%) and decreased vascular resistance
(-8.6%) (Tables 2 and 3). Undigested food, however, did not
significantly alter jejunal blood flow or vascular resist-
ance. The difference in changes produced by these two solu-
tions was 9.4% in blood flow and 9.0% in vascular resistance
(first row, Table 3) which was significant at p<<0.05. When
the hyperemic effects of supernatant and precipitate (both
from the same digested food) were compared, the former again
raised venous outflow but the latter did not (Tables 2 and
3). Supernatant increased blood flow 11.3% and decreased
resistance by 9.0% while precipitate had no effect. The dif-
ference in their vascular effects was 12.7% for blood flow
and 12.0% for vascular resistance. The pancreatic enzyme
preparation did not have any significant effect on the

jejunal vasculature (Table 2).

43

The following conclusion can be drawn from this series
of experiments: 1) Digested food increased blood flow but
undigested food did not. 2) Of the two constituents of
digested food, only the supernatant raised blood flow and
decreased vascular resistance; the precipitate did not have
any vascular effect. 3) Intraluminal placement of digested
food and its supernatant have similar effects on jejunal
blood flow and resistance. Their vascular effects, however,
were significantly different from those of the precipitate
and undigested food. 4) The action of digested food and its
supernatant was not likely due to the pancreatic enzyme
preparation contained in these two solutions since the enzyme
itself did not alter blood flow. 5) The addition of bile
in the digested food potentiated the hyperemic effect of
the food. Intraluminal placement of bile itself, however,

did not have any effect on the jejunal segment.

Series 2

The vascular effects of the isotonic glucose solution
and a mixture of glucose and amino acids were determined in
this series of experiments. In each case the test solutions
were placed in one segment while normal saline was placed in
the other as a control. Table 4 shows mean :_S.E.M. venous
outflow and vascular resistance during the control and

experimental periods in the double segments and the percent

44

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45

change from precontrol of flow and resistance produced by
the glucose and glucose-amino acids solutions. The flow
values were collected during the last (14th to 15th minute)
collection of blood flow in the 15 minute period. The table
also contains the comparison of changes (from precontrol)
that occurred in the experimental and control segments dur-
ing placement of the test solutions (D = E—C, Table 4).
Luminal placement of both solutions significantly in—
creased blood flow and decreased vascular resistance. When
glucose was in the lumen, blood flow increased by 6.4% and
resistance decreased by 6.0%. Venous outflow increased from
a precontrol value of 72.9 i 8.0 to 77.5 i 8.2 ml/min/100 gm
while resistance decreased from 1.83 :_0.2 to 1.72 i 0.2 mm
Hg/ml/min/lOO gm (Table 4). These values returned to con-
trol level during the postcontrol period after the glucose
solution was withdrawn and normal saline was placed inside
the lumen. The difference between the changes.(from pre-
control) that occurred in the experimental and control seg—
ments was 8.2% for blood flow and 6.7% for resistance.
These values were significant at p<<0.05. Intraluminal-
placement of the glucose-amino acids mixture significantly
increased blood flow from 57 :_5.0 to 66 :_5.0 ml/min/100
gm. This represents a 16.7% increase from precontrol.
Vascular resistance on the other hand, decreased signifi-

cantly from 2.60 i_3.0 to 2.15 :_0.16 mm Hg/ml/min/lOO gm;

46

a 15.6% drop from precontrol. During the postcontrol period,
blood flow returned to 55.0 i 7.0 ml/min/lOO gm while
resistance was 2.67 i 0.29 mm Hg/ml/min/lOO gm; these values
were not significantly different from the precontrol period
(Table 4). The difference between the changes in the experi-
mental and control segments (D = E—C, Table 4) was 17.4% for
blood flow and 15.1% for resistance.

Although the glucose solution and the glucose-amino
acids mixture both increased venous outflow and decreased
vascular resistance when placed inside the lumen, the mag-
nitude of these changes was found to be different (Student's
group t-test, p<=0.05). Intraluminal placement of the
glucose-amino acids mixture produced a greater hyperemic
effect (+16.7%) on the jejunal vasculature than did the
glucose solution (+6.4%). The presence of the amino acids
mixture in the lumen thus seemed to have an additive effect

on the hyperemia induced by the isotonic glucose solution.

CHAPTER V

DISCUSSION

Many studies indicate that blood flow through the
splanchnic viscera increases during digestion (12,21,22,56,
57,58). Unfortunately, little is known concerning the con-
stituents of intestinal chyme that are responsible for this
postprandial mesenteric hyperemia. One of the objectives
of the present study was to identify which of the constitu—
ents of chyme are responsible for the hyperemia. Thus,
digested food, its supernatant and precipitate, undigested
food, pancreatic enzyme preparation, gallbladder bile,
digested food plus bile as well as normal saline were placed
intraluminally into the in gitu jejunal segments and their
vascular effects determined and compared. These solutions
were paired into the following combinations: digested food
and undigested food; supernatant and precipitate; super-
natant and digested food; supernatant and enzyme; gallbladder
bile and normal saline; digested food plus bile and digested
food alone. The two food solutions compared were individual—
ly placed in the two adjacent jejunal segments simultaneous-

ly. The testing of the vasoactivities of different food

47

48

solutions under the same systemic conditions allowed a fair
comparison of their capacity to influence the intestinal
vasculature.

The comparison between digested food and undigested
food revealed that only the former was capable of increasing
blood flow. The different responses from the two solutions
were not due to changes in either aortic or luminal pressure
since neither of these parameters were altered. Nor was it
due to their different osmolalities--which for digested food
was 278 :.29 mOsm/kg and undigested food, 178 :_12 mOsm/kg.
Kvietys e£_al. (37) have recently shown that lumen osmolality
within a range of 180 to 1,000 mOsm/kg is not a contributing
factor in the increase in mesenteric blood flow when food is
in the intestine. In their study, the digested food having
an osmolality of 183 i 5.8 mOsm/kg produced similar hyperemia
as the one having an osmolality of 291 i 5.3 mOsm/kg did.

The hyperemic effect of digested food was also not due
to the pancreatic enzymes present in the food since their
placement in the lumen of the intestine did not alter blood
flow (Tables 2 and 3). The hyperemic effect of digested
food, therefore, appears to be due to the digested products
of food. This conclusion is further supported by the find-
ing that supernatant of digested food has a hyperemic effect
similar to digested food while the precipitate has no vas-

cular effect (Tables 2 and 3).

49

This conclusion is also supported by the findings that
the onset of the intestinal hyperemia occurs earlier with
digested food than undigested food. Fara gt 31. (17) found
in anesthetized cats that intraduodenal instillation of milk
and corn oil did not increase superior mesenteric arterial
flow until 7 to 20 minutes after placement. On the other
hand, the onset of hyperemia after amino acids placement was
much shorter (1 to 5 minutes). Chou e£_al. (12) also found
that blood flow through the superior mesenteric artery did
not increase until 30 minutes after intragastric placement
of undigested food. However, mesenteric blood flow increased
within 5 minutes after the intraduodenal instillation of
digested food. These studies indicate that the time of the
onset of the hyperemia occurs more rapidly with digested
food than undigested food. This present study shows that
the digestion of food plays a vital role in postprandial
hyperemia and provides an explanation for the delay of the
onset of intestinal hyperemia following a meal.

This present study also shows that addition of bile
into the digested food markedly increases the hyperemic
effect of the food (Tables 2 and 3). The increase is not
due to the vascular effect of bile since bile itself in the
lumen of the intestine does not alter local blood flow
(Tables 2 and 3). The potentiation of the hyperemia appears

to be due to the digestive actions of bile on the food.

50

Gallbladder bile contains bile salts which facilitate diges-
tion of lipids (8,15,49,50). Kvietys et a1. (37) have shown
that the greater the concentration of the digestive products
of food in the gut lumen, the greater was the increase in
venous outflow of the intestine. Therefore, one effect of
bile in increasing the hyperemic effect of digested food
appears to result from an increase in the concentration of
digestive products of fat. Another effect of bile may be
due to its effect in facilitating the absorption of fatty
acids (8,15,49,50), proteins and sugars (l).

The magnitude of hyperemia induced by the intraluminal
placement of digested food in the present study was lower
than previously reported (12). After the addition of bile,
however, digested food increased blood flow by 107 to 230%
of control, which was comparable to those values observed
previously in both conscious and anesthetized dogs (6,12,22,
56,57,58). The digestive actions of bile, therefore, play
an important role in the postprandial intestinal hyperemia.

The second objective of the present study was to
examine whether intraluminal placement of the digestive
products, glucose and amino acids, as a mixture, have a
cumulative effect on blood flow in the small intestine.

The vascular effects of the isotonic glucose solution and
the glucose-amino acids mixture were determined and com-

pared. Intraluminal placement of the glucose-amino acids

51

mixture produced a greater hyperemic effect than did the
placement of the glucose solution. While the isotonic glu-
cose solution increased blood flow by only 6.4%, the glucose-
amino acids mixture raised it by 16.7% above control (Table
4).

The magnitude of the hyperemia produced by the isotonic
glucose solution was comparable to that observed in previous
studies (10,55). The effects of luminal placement of the
16 amino acids used in this study have been examined recently
in our laboratory (unpublished observation). Placement of
the 16 amino acids in the jejunal lumen produced an increase
of 12.0% above the precontrol flow values. Therefore, the
hyperemic effect of the glucose-amino acids mixture appears
to be the sum of the vascular effects of glucose and amino
acids in combination.

A recent study from our laboratory also showed that a
fatty acid and bile salt solution of oleic acid (40 mM),
monoolein (20 mM) and taurocholate (10 mM) increased venous
outflow when placed into the lumen of the jejunum. Since
the critical micellar concentration for taurocholate is 2.5
mM (49), the fatty acids used were in micellar form and,
therefore, were well digested. Thus, various digestive
products of carbohydrates, proteins and fat are able to
increase jejunal blood flow when placed into the lumen of

the intestine. The magnitude Of the hyperemia, however,

52

appears to depend not only on the concentration of the diges—
tive products (37) but also on the type of food ingested.
It has been suggested that different hyperemic effects may
be expected from carbohydrates, protein or fat feedings (43).
Many investigators have also shown that protein-rich meals
increased splanchnic blood flow (5,18,31) as well as oxygen
consumption (5,14,28) more than carbohydrate-rich meals.
This present study shows that the constituents of chyme
responsible for postprandial hyperemia are suspended in the
supernatant of the digested food and are likely to be the
digestive products of food. This study as well as recent
studies in our laboratory further show that glucose, amino
acids, fatty acids and monoglycerides are vasodilators when
placed into the lumen of the upper small intestine. Post-
prandial intestinal hyperemia, therefore, appears to be
triggered by the exposure of these elementary digestive
products to the intestinal mucosa. It has been shown that
the increase in intestinal blood flow is confined only to
the mucosal layer of the intestine which is exposed to food
(12). The mucosal layer is the major site for transmembrane
transport of water, electrolytes and nutrients in the in—
testine (13,15,49,50). Thus, it is quite possible that the
hyperemia is related to the mucosal absorption of these
elementary digestive products. However, mucosal neural

reflexes and vasodilating hormones released from the

53

intestinal tissue may also participste in the hyperemia.
These elementary digestive products have been shown to be
capable of releasing local hormones (34) and stimulate local
mucosal nerves (48,62). Finally, it is possible that during
the process of food digestion vasoactive-compounds are
formed that act directly on the intestinal vasculature to

cause vasodilation.

CHAPTER VI

SUMMARY AND CONCLUSION

In order to identify the constituents of chyme that are

responsible for the postprandial hyperemia in the intestine,

the vascular effects of luminal placement of various food

solutions were compared. An in_situ double jejunal segment

preparation was used and the venous outflow from the seg-

ments was measured before, during and after luminal place-

ment of these solutions. The results indicate that:

1)

2)

3)

4)

5)

Luminal placement of digested food, its supernatant
and the digested food plus bile solution increased

local blood flow and decreased vascular resistance.

Undigested food, precipitate of the digested food,
the pancreatic enzyme preparation and gallbladder

bile did not have any vascular effect.

The hyperemic effect of digested food and its super-

natant was quantitatively similar.

The addition of gallbladder bile to the digested

food markedly enhanced the hyperemic effect of food.

Intraluminal placement of either the glucose or the

glucose-amino acids mixture increased venous outflow

54

55

and decreased vascular resistance. However, the
glucose-amino acids mixture had greater hyperemic

effect than did glucose alone.

6) None of the solutions studied had any effect on
either luminal or aortic pressure upon luminal

placement.

It is concluded that the pancreatic enzyme preparation
and gallbladder bile in 1:2 dilution are not vasoactive when
placed in the lumen of the jejunum. Postprandial hyperemia
in the intestine, however, requires the digestive action of
the pancreatic enzyme and is markedly increased by gall—
bladder bile. The substances responsible for the hyperemia
are suspended in the supernatant of the digested food and
likely to be the digestive products of food. The digestive
products of carbohydrates and proteins, i.e., glucose and
amino acids, both contribute to the hyperemia and their

effects are additive.

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