CURE: Digestive Diseases Research Center, Veteran's Affairs Greater Los Angeles Healthcare System, Department of Medicine, Division of Digestive Diseases and Brain Research Institute, University of California Los Angeles, Los Angeles, California 90073
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ABSTRACT |
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The influence of intravenous peptide YY
(PYY) on the gastric injury induced by 45% ethanol was investigated in
urethane-anesthetized rats. PYY (25, 75, 125, and 250 pmol · kg1 · h
1)
significantly reduced gastric lesions by 36, 59, 40, and 38%, respectively. Antibody against ratPYY (2 mg/rat) injected intravenously completely prevented the gastroprotective effect of intravenous PYY (75 pmol · kg
1 · h
1),
whereas injected intracisternally (460 µg/20 µl), it significantly prevented intracisternal PYY (24 pmol/rat)-induced 58% reduction of ethanol lesions but not that induced by intravenous PYY. Vagotomy did not influence the gastroprotective effect of intravenous PYY. The
Y1/"PYY-preferring" receptor agonist
[Pro34]PYY (75 pmol · kg
1 ·h
1
iv) significantly decreased ethanol-induced gastric lesions by 82%,
whereas [Leu31, Pro34]NPY, a
Y1/Y3 agonist, and
PYY-(3-36), a Y2 agonist, had no effect. These data indicate that PYY-infused intravenously at doses reported to
mimic postprandial peak blood levels prevents ethanol-induced gastric
injury through vagal independent pathways and PYY-preferring receptors.
neuropeptide Y-receptor subtype; peptide YY antibody; vagotomy; ethanol; gastric lesions
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INTRODUCTION |
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PEPTIDE YY (PYY), neuropeptide Y (NPY), and pancreatic peptide (PP) belong to a family of structurally related 36-amino acid peptides. PYY, which was isolated from porcine duodenum (35), is widely distributed in the gastrointestinal tract, predominantly in the endocrine cells of intestine and pancreas (24, 26) and in neuronal elements of the gastrointestinal tract (7).
Postprandial release of PYY into the circulation has been established
in all species studied so far (36). Doses of PYY infused intravenously, reproducing the circulating postprandial peak levels, are in the range of 50-120
pmol · kg1 · h
1
in rats (19, 34). Intravenous infusion of PYY at doses
within this range inhibits stimulated gastric acid secretion (1,
16, 28, 30) and gastric emptying (3, 29) in humans
and dogs and exocrine pancreatic secretion in rats and dogs (19,
31, 37) and interrupts intestinal propagation in rats
(2). PYY is assumed to act as a physiological inhibitor of
upper gastrointestinal functions when nutrients reach the distal small
intestine (36).
PYY is a gut peptide that also acts in the brain to alter gastric secretory and motor functions through vagal pathways. Autoradiographic studies have demonstrated dense concentrations of PYY binding sites in the rat dorsal medulla (25). Saturable PYY binding has been observed in the region of the brain stem containing the dorsal vagal complex (DVC) after the intravenous injection of 125I-labeled PYY at doses reproducing postprandial blood concentrations in rats (18). We previously reported that intravenous PYY-induced inhibition of gastric acid secretion was prevented by intracisternal injection of PYY antibody, providing evidence for a central action of peripheral PYY (42). In addition, microinjection of PYY or NPY into the DVC at low doses inhibits vagally stimulated gastric contractions, whereas higher doses induce a vagal-dependent stimulation of gastric acid and hepatic bile secretion as well as gastric motor function in urethane-anesthetized rats (8, 40, 43-45). Our recent work also revealed that PYY injected intracisternally confers gastric protection against intragastric ethanol-induced gastric mucosal injury through vagal cholinergic-dependent pathways recruiting peripheral CGRP and nitric oxide (NO) mechanisms (20, 41). However, whether circulating PYY exerts a gastroprotective action is still unknown.
It is widely accepted that NPY/PYY/PP binds to and activates at least six Y-receptor subtypes, the cloned Y1-Y5 receptors and a "PYY-preferring" receptor, which is yet to be cloned (5). Pharmacological characterization of Y receptors established that [Pro34]PYY has preferential affinity for PYY-preferring/Y1 receptors, PYY-(3-36) for Y2, and [Leu31, Pro34]NPY for Y1-/Y3-/Y5-receptor subtypes (5). Studies using these prototypic peptide NPY-receptor agonists indicate that the central stimulatory effect of PYY on gastric motility and acid secretion and the central gastroprotective effect are mediated through the activation of Y1/PYY-preferring receptor (8, 20, 43). On the other hand, PYY injected intracisternally or microinjected into the DVC at low doses induced inhibition of vagally stimulated gastric secretion and motility involves Y2 receptors (8, 42). The inhibition of vagally stimulated gastric acid secretion by intravenous PYY infusion appears also to be mediated by central Y2 receptor (42).
In the present study, we examined whether rat (r)/porcine (p) PYY infused intravenously modulates gastric mucosal injury induced by intragastric ethanol in urethane-anesthetized rats. To gain insight into the PYY site of action, the influence of antibody to r/pPYY (anti-PYY) injected peripherally or centrally on the gastroprotective action of intravenous PYY was investigated as well as the effect of vagotomy. Lastly, the Y-receptor subtype involved in the intravenous PYY-induced reduction of gastric injury to ethanol was assessed using prototypic PYY/NPY agonists with differential affinity for Y-receptor subtypes, namely [Pro34]PYY (PYY-preferring agonist/Y1), PYY-(3-36) (Y2 > PYY preferring), and [Leu31, Pro34]NPY (Y1/Y3/Y5) (5, 15, 23).
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MATERIALS AND METHODS |
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Animals
Animal care and experimental protocols were in accordance with approved protocols of the Veteran Administration Medical Center/West Los Angeles Research Service Animal Committee. Male Sprague-Dawley rats (Harlan Laboratory, San Diego, CA) weighing 250-320 g were maintained under conditions of controlled temperature (22-24°C) and illumination (12:12-h light-dark cycle starting at 6 AM) with ad libitum Purina Laboratory Chow (Ralston Purina, St. Louis, MO) and tap water. Animals were deprived of food for 16 h but had free access to water until 2 h before the beginning of the study. All experiments were performed in rats anesthetized with intraperitoneal injection of urethane (1.25 g/kg, Sigma, St. Louis, MO). The body temperature of rats was maintained at 37°C during the study with electrically heated pad.Substances and Treatments
r/pPYY, p[Leu31, Pro34] NPY (kindly provided by Dr. J. Rivier, Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, CA), and r/p [Pro34]PYY and r/pPYY-(3-36) (Peptides Synthesis Core Facility, CURE: Digestive Diseases Research Center, UCLA, Los Angeles, CA) were dissolved in 0.1% (BSA, Sigma), saline solution before intravenous infusion (1 ml/h) through the right femoral vein. For intracisternal injection, r/pPYY was dissolved in saline.The PYY antibody #9153 (CURE) was raised against the full-length r/pPYY
as previously described (22). The PYY antibody evaluated by radioimmunoassay has an ID50 of 30 fmol/ml for r/pPYY
and 120 fmol/ml for r/pPYY-(3-36) and no
cross-reactivity with rat or human PP or NPY (ID50 > 10,000 fmol/ml) as previously reported (6, 22). The PYY
antibody was purified using protein A-Sepharose column. Normal rabbit
(NR) IgG and anti-PYY IgG used for intracisternal injection were
concentrated using an S-43-70 Spectra/Pore stirred cell with 100 K
molecular weight cutoff type C ultrafiltration membranes (Spectrum
Medical Industries, Los Angeles, CA) and dialyzed against 20 mM
phosphate and 110 mM NaCl (pH 7.0). Concentrations of the IgG proteins
were estimated by measuring the optical density of the solution at
= 280.
For intracisternal injection, the head of the anesthetized rat was fixed with ear bars of stereotaxic equipment and the occipital membrane was punctured using a 50-µl Hamilton syringe (Hamilton, Reno, NV). The correctness of needle placement into the cisterna magna was insured by the presence of cerebrospinal fluid in the Hamilton syringe on aspiration before injection. The intracisternal injection of peptides and related vehicle was performed in 5 µl, and that of PYY antibody and NRIgG was performed in 20 µl.
Gastric Lesion Formation and Assessment
Gastric lesions were induced by intragastric administration of 45% ethanol (5 ml/kg, diluted in saline) using oral intubation with a stainless steel cannula in urethane-anesthetized rats. One hour after ethanol administration, rats were euthanatized by CO2 inhalation and the stomachs were removed. The areas of gastric mucosal lesions were measured by a computerized image-analyzer device using the National Institutes of Health image program. Lesions are expressed as percent coverage of the glandular stomach as in our previous studies (20, 41).Experimental Protocols
Effect of intravenous PYY on ethanol-induced gastric lesions.
Intravenous infusion of PYY (25, 75, 125, or 250 pmol · kg1 · h
1)
or vehicle (0.1% BSA/saline) was started 30 min before and ended 60 min after the intragastric administration of 45% ethanol (5 ml/kg).
Then rats were euthanized, and the stomachs were removed for the
measurement of gastric lesions. The regimen of PYY administration was
based on a previous dose-response study in fasted,
urethane-anesthetized rats showing that PYY infusion in doses ranging
from 24 to 240 pmol · k
1 · h
1
increased dose dependently plasma PYY and that postprandial levels are
reached 30 min after the infusion of ~120
pmol · kg
1 · h
1
(34).
Effect of intravenous anti-PYY on intravenous or intracisternal
PYY-induced gastric protection against ethanol.
PYY antibody or NRIgG was injected intravenously (2 mg/rat) 10 min
before the start of intravenous PYY (75 pmol · kg1 · h
1)
or vehicle (0.1 BSA/saline) infusion (1 ml/h) or intracisternal PYY (24 pmol/rat) or saline injection (5 µl). Ethanol (45%, 5 ml/kg) was
administered intragastrically 30 min after the start of intravenous PYY
infusion or intracisternal PYY injection. Rats were euthanized 60 min
later to monitor gastric lesions. The dose of PYY antibody was adjusted
based on our previous studies showing that intravenous infusion of PYY
at 1 nmol · kg
1 · h
1-induced
inhibition of the acid response to vagal stimulation was prevented by
the intravenous injection of PYY antibody at 4.5 mg/rat
(42).
Effect of intracisternal anti-PYY on intravenous or
intracisternal PYY-induced gastric protection against ethanol.
Anti-PYY or NRIgG (460 µg/rat) was injected intracisternally in
20 µl 10 min before the intravenous infusion of PYY (75 pmol · kg1 · h
1)
or vehicle (0.1% BSA/saline) or the intracisternal injection of PYY
(24 pmol/rat) or saline. Ethanol (45%, 5 ml/kg) was administered intragastrically 30 min after the start of intravenous PYY infusion or
intracisternal PYY injection. Rats were euthanized 60 min later to
monitor gastric lesions. The amount of PYY antibody injected intracisternally corresponds to the maximal concentration that could be
achieved in 20 µl.
Effect of vagotomy on intravenous PYY-induced gastric protection
against ethanol.
Bilateral cervical vagotomy or sham operation was performed in
urethane-anesthetized rats 2 h before the intravenous infusion of
PYY (75 pmol · kg1 · h
1)
or vehicle (1% BSA/saline). Ethanol (45%, 5 ml/kg) was administered intragastrically 30 min after the start of PYY infusion, and rats were
euthanized 60 min later to monitor gastric lesions.
Effects of intravenous NPY/PYY analogs on ethanol-induced gastric
lesions.
r/p[Pro34]PYY, p[Leu31,
Pro34]NPY, r/pPYY-(3-36) (75 pmol · kg1 · h
1),
or vehicle (0.1% BSA/saline) was infused intravenously from 30 min
before to 60 min after intragastric administration of ethanol (45%, 5 ml/kg). Rats were euthanized 60 min later, and the gastric lesions were monitored.
Statistical analysis. All results are expressed as means ± SE. Multiple-group comparisons were performed by ANOVA followed by Fisher's protected least-significant differences. A P value <0.05 was considered statistically significant.
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RESULTS |
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Effect of intravenous PYY on ethanol-induced gastric lesions.
Intragastric administration of 45% ethanol by oral intubation (5 ml/kg) produced macroscopic gastric lesions within 60 min visualized as
long dark-red vertical lines covering 18.8 ± 2.6% of the corpus
mucosa in urethane-anesthetized rats infused intravenously with
vehicle. PYY infused intravenously at 25 and 75 pmol · kg1 · h
1
from 30 min before to 60 min after the ethanol administration dose
dependently decreased 45% ethanol-induced gastric lesions to 12.0 ± 3.6 (P < 0.05) and 7.8 ± 2.2%
(P < 0.05), respectively. PYY infused intravenously at
125 and 250 pmol · kg
1 · h
1
reduced significantly gastric erosions induced by ethanol by a similar
magnitude as 25 pmol · kg
1 · h
1
(11.3 ± 1.4 and 11.7 ± 1.3%, respectively,
P < 0.05; Fig. 1). In
further studies, PYY was infused at 75 pmol · kg
1 · h
1,
which results in the maximal protective effect.
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Effect of intravenous anti-PYY on intravenous or intracisternal
PYY-induced gastric protection against ethanol.
Anti-PYY injected intravenously (2 mg/rat) did not significantly alter
the formation of gastric lesions induced by 45% ethanol in rats
infused intravenously or injected intracisternally with respective
vehicles (15.1 ± 2.0 and 19.7 ± 2.3%, respectively). PYY
infused intravenously (75 pmol · kg1 · h
1)
or injected intracisternally (24 pmol/rat) significantly reduced gastric lesions to 5.2 ± 0.8 and 7.0 ± 0.6%, respectively,
in rats injected intravenously with NRIgG (2 mg/rat). PYY antibody injected intravenously (2 mg/rat) abolished the gastroprotective effect
of intravenous PYY (16.7 ± 3.4%, P < 0.05 vs. intravenous NRIgG) but did not influence the reduction of gastric lesions induced
by intracisternal PYY (6.5 ± 1.1%; Fig.
2).
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Effect of intracisternal anti-PYY on intravenous or intracisternal
PYY-induced gastric protection against ethanol.
PYY antibody injected intracisternally (460 µg/rat) did not alter the
formation of gastric lesions induced by 45% ethanol in rats infused
intravenously or injected intracisternally with vehicle (17.9 ± 2.1 and 17.3 ± 2.6%, respectively). PYY infused intravenously
(75 pmol · kg1 · h
1)
or injected intracisternally (24 pmol/rat) reduced ethanol-induced gastric lesions to 6.6 ± 2.3 and 7.2 ± 3.1%, respectively,
in rats pretreated intracisternally with NRIgG (460 µg/rat). The protective effect of intracisternal PYY was significantly attenuated by
PYY antibody injected intracisternally (12.0 ± 1.2%;
P < 0.05 vs. intracisternal NRIgG), whereas that of
intravenous PYY was not influenced (5.7 ± 2.8%;
P > 0.05; Fig. 3).
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Effect of vagotomy on intravenous PYY-induced gastric protection
against ethanol.
There was no significant difference between sham-operated and
vagotomized groups in the formation of gastric lesions induced by
intragastric ethanol in intravenous vehicle-infused rats. Bilateral cervical vagotomy did not influence intravenous PYY (75 pmol · kg1 · h
1)-induced
gastric protection against 45% ethanol (Table
1).
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Effects of intravenous NPY/PYY analogs on ethanol-induced gastric
lesions.
r/p[Pro34]PYY (75 pmol · kg1 · h
1
iv) significantly decreased 45% ethanol-induced gastric lesions to
3.5 ± 1.0% (P < 0.01) compared with 18.6 ± 3.3% in
the intravenous vehicle group. In contrast, p[Leu31,
Pro34] NPY and r/pPYY-(3-36) infused at
the same dose had no effect on gastric lesions (15.9 ± 3.9 and
22.5 ± 4.3%, respectively; Fig.
4).
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DISCUSSION |
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The present study showed 1) that r/pPYY infused intravenously and injected intracisternally exerts a gastroprotective effect against intragastric administration of 45% ethanol-induced mucosal lesions in urethane-anesthetized rats; 2) PYY antibody injected intravenously prevented the gastric protective effect of intravenous but not intracisternal administration of PYY; 3) the gastroprotective action of intravenous PYY is independent of the vagal pathway; and 4) r/p[Pro34]PYY decreased the formation of gastric lesions induced by intragastric administration of 45% ethanol, whereas p[Leu31, Pro34]NPY and r/pPYY-(3-36) infused at the same dose had no effect.
It is well established that PYY is released from the distal ileum after
a meal in various species and in humans (36). In conscious
rats, PYY postprandial plasma values rise to peak levels of 75-160
pmol/l at 30-60 min, then decline to basal levels within 2-3
h depending on the meal composition and the mode of administration (intraduodenal or intragastric) (4, 11, 19). Doses of
exogenous PYY reproducing postprandial levels have been reported to be
50 pmol · kg1 · h
1
in conscious rats and 120 pmol · kg
1 · h
1
in urethane-anesthetized rats (19, 34). In the present
study, PYY infused intravenously at 25 and 75 pmol · kg
1 · h
1
significantly reduced gastric injury by 36 and 59%, respectively, in
urethane-anesthetized rats. Although circulating levels of PYY were not
measured, the doses of intravenous PYY inducing gastroprotection were
within the range reported to reproduce postprandial circulating levels
of PYY (4, 11, 19, 34). Immunoneutralization with specific
PYY antibody has been used to establish the physiological actions of
PYY on gut function (6, 22). We showed that the intracisternal or intravenous injection of antibody against r/pPYY in
fasted, urethane-anesthetized rats did not influence gastric lesions in
response to intragastric administration of 45% ethanol. This suggests
that endogenous PYY did not modulate the resistance of the gastric
mucosa to injury induced by ethanol under these conditions. These data
may be related to the low levels of circulating PYY reported to be
around 7 pmol/l in fasted urethane-anesthetized rats (4,
34).
We previously reported that intracisternal PYY-induced gastroprotection
against intragastric administration of 45% ethanol is mediated by
vagal cholinergic pathways and peripheral CGRP and NO mechanisms
(41). There is evidence that 125I-labeled PYY
infused intravenously at doses mimicking plasma concentrations measured
after a meal results in a dense representation of
125I-labeled PYY binding sites in the medullary area,
solely in brain nuclei regulating gastric functions through the vagus
nerve, such as the area postrema and the DVC (18, 25). In
addition, we reported that the inhibition of central vagally stimulated
gastric acid secretion induced by intravenous infusion of PYY is
mediated by a peptide action at medullary sites (42).
These findings suggest that the gastric protection induced by
intravenous infusion of PYY may be mediated through central
vagal-dependent pathways. However, the present findings do not support
such a contention. Bilateral cervical vagotomy did not influence the
gastric protection induced by intravenous PYY, providing evidence that
vagal afferent and efferent signaling pathways are not involved in the
gastroprotective effect. This contrasts with the gastroprotection
induced by intracisternal PYY that is mediated by muscarinic-dependent
mechanisms (41). In addition, intracisternal injection of
PYY antibody (460 µg/rat) did not influence intravenous PYY (75 pmol · kg1 · h
1)
induced-gastric protection. The lack of effect of the PYY antibody injected intracisternally is unlikely to be related to the inadequate access of the PYY antibody to the area postrema and portion of the
nucleus of the solitary tract with fenestrated capillaries reached by
circulating PYY (14, 18). In previous studies, the same
PYY antibody (#9153) injected intracisternally at a lower dose (280 µg/rat) than used in the present study abolished the gastric
antisecretory effect of PYY infused intravenously at a supraphysiological dose (1 nmol · kg
1 · h
1)
(42). Moreover, the intracisternal injection of the
PYY antibody (460 µg/rat) blunted intracisternal PYY-induced
reduction of ethanol injury, whereas intracisternal injection of NRIgG
had no effect. The partial prevention (52%) of the gastroprotective
effect of intracisternal PYY by intracisternal PYY antibody may be
related to the insufficient immunoneutralization due to the limitation to IgG concentration within the small volume used for intracisternal injection. The present data also showed that intravenous injection of
PYY antibody did not modify the intracisternal PYY induced-gastric protection while blocking the gastric protective effect of intravenous PYY. These data indicate that intracisternal PYY-induced reduction of
gastric lesions is not exerted peripherally as a result of peptide
leakage from the cerebrospinal fluid into the systemic circulation
(38), supporting that intracisternal PYY acts centrally to
reduce gastric erosions (20, 41). Together, previous and present findings support distinct mechanisms for intravenous and intracisternal PYY-induced gastroprotection against ethanol injury.
It is now widely accepted that NPY/PYY/PP binds to and activates at
least six Y-receptor subtypes (5). Insight to the
Y-receptor subtype(s) mediating a specific NPY/PYY/PP action can be
obtained by the use of prototypic NPY/PYY agonists with differential
binding affinities for the Y-receptor subtypes. PYY has a strong
affinity for Y1, Y2, and PYY-preferring
receptor subtypes (5). [Pro34]PYY is a
preferential agonist at Y1 and PYY-preferring receptors, whereas [Leu31, Pro34]NPY is an agonist at
Y1/Y3/Y5 and
PYY-(3-36) is an agonist at Y2-receptor
subtypes (15, 23). In the present study,
r/p[Pro34]PYY infused intravenously (75 pmol · kg1 · h
1)
induced similar gastric protective action as that induced by the
maximal effective dose of PYY. By contrast, intravenous infusion of
p[Leu31, Pro34]NPY or
r/pPYY-(3-36) had no effect. These findings suggest
that intravenous PYY-induced gastroprotection against intragastric ethanol is preferentially mediated via the activation of PYY-preferring receptors. Dose-response studies with PYY infused intravenously showed a linear dose-related response resulting in a 36 and
59% reduction of gastric lesions at 25 and 75 pmol · kg
1 · h
1,
respectively, whereas at 125 or 250 pmol · kg
1 · h
1,
PYY tends to be less efficient (40 and 38% reduction, respectively) than at 75 pmol · kg
1 · h
1.
The lack of linear dose response at the highest doses may be related to
the activation of other Y receptors having opposite actions on gastric
mucosa injured by ethanol. It is of note that the Y2
preferential agonist PYY-(3-36) infused intravenously
at 75 pmol · kg
1 · h
1
shows a tendency to increase ethanol-induced gastric lesions. Previous
studies indicate that Y1/PYY-preferring and Y2
receptors can exert opposite effects on gastric function (8,
40).
The peripheral mechanisms through which intravenous PYY induces
gastroprotection via vagal independent pathways are still to be
elucidated. It is unlikely to be secondary to intravenous PYY-induced
changes in gastric acid secretion. First, we previously showed that the
dose-related inhibition of vagally stimulated gastric acid secretion
induced by intravenous infusion of PYY in urethane-anesthetized
rats occurred at higher doses (0.25-1 nmol · kg1 · h
1)
(42) than those reducing ethanol-induced gastric lesions
(25-75 pmol · kg
1 · h
1)
in the present study. Second, vagotomy that inhibits gastric acid
secretion did not influence the gastroprotective action of intravenous
PYY. Third, several reports indicate that gastric lesions induced by
ethanol are not influenced by antisecretory treatments (33,
46). The intravenous infusion of PYY-induced gastroprotection
against intragastric ethanol is also unlikely to be secondary to
alterations of gastric emptying of ethanol administered
intragastrically. Studies (32) in conscious rats showed
that there is no change in gastric emptying after intraperitoneal injection of PYY at a dose 17-fold higher than that used in the present
study and at 4 nmol/kg, PYY reduced gastric emptying of a liquid by
52%. Moreover, pylorus ligation, which prevents gastric emptying, did
not influence the percentage of gastric erosions induced by
intragastric ethanol administration (46). Existing evidence also does not suggest a mediation of the intravenous PYY
gastroprotective action through the release of gut peptides known to
influence ethanol-induced gastric lesions (9, 21). In
dogs, PYY infused at a dose that strongly inhibited the cephalic phase
of gastric acid secretion did not influence the release of gut
peptides, including gastrin, somatostatin, secretin, gastric inhibitory
polypeptide, PP, and neurotensin (12, 17, 39). In
isolated, vascularly perfused rat stomach, PYY perfused at concentrations of 10 pM to 100 nM did not change somatostatin secretion
(10, 13). Further investigations as to whether PYY influences gastric CGRP and NO pathways may provide valuable
information on the peripheral mechanisms of PYY gastroprotective
functions. There is evidence for the presence of a 65-kDa cell surface
receptor that binds to PYY on the epithelial cells of the stomach,
duodenum, and intestine (27). The possible action through
these receptors needs to be investigated.
In summary, PYY infused intravenously at doses reproducing reported postprandial plasma levels induces a gastroprotective effect against ethanol lesions that is independent of the vagus nerve and not altered by central injection of PYY antibody. The intracisternal injection of PYY also induced gastric protection, which is blunted by PYY antibody injected intracisternally, whereas intravenous PYY antibody selectively blocked intravenous but not intracisternal PYY-induced gastroprotection. The use of prototypic PYY/NPY agonists at Y receptors indicates that the action of intravenous PYY is mediated by PYY-preferring receptors. These results suggest that PYY released after a meal may exert a physiological role to increase the resistance of the gastric mucosa to injury.
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ACKNOWLEDGEMENTS |
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We thank Dr. J. Rivier (Clayton Foundation Laboratories for Peptide Biology, Salk Institute, La Jolla, CA) for the supply of r/pPYY, Dr. J. R. Reeve Jr. (Peptides Synthesis Core Facility, UCLA, Los Angeles, CA) for supply of r/p[Pro34]PYY, r/pPYY3-36, and P. Kirsh for assistance in preparing the manuscript.
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FOOTNOTES |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-30110 (to Y. Taché) and DK-41301 (to CURE/DDRC Animal Core, Antibody Core and Peptide Core).
Address for reprint requests and other correspondence: Y. Taché, CURE: DDRC, VA GLAHS, Bldg. 115, Rm. 203, 11301 Wilshire Blvd., Los Angeles, CA 90073 (E-mail: ytache{at}ucla.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
August 7, 2002;10.1152/ajpgi.00154.2002
Received 26 April 2002; accepted in final form 25 July 2002.
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