CURE: Digestive Diseases Research Center, Veterans Affairs Greater Los Angeles Healthcare System, and Digestive Diseases Division, Department of Medicine and Brain Research Institute, School of Medicine, University of California, Los Angeles, California 90073
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ABSTRACT |
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The site of action of
peripheral peptide YY (PYY)-induced inhibition of vagally stimulated
gastric acid secretion was studied using immunoneutralization with PYY
antibody in urethan-anesthetized rats. Gastric acid secretion (59 ± 7 µmol/90 min) stimulated by intracisternal injection of the
stable thyrotropin-releasing hormone (TRH) analog RX-77368 (14 pmol/rat) was dose-dependently inhibited by 52%, 69%, and 83% by
intravenous infusion of 0.25, 0.5, and 1.0 nmol · kg1 · h
1 PYY,
respectively. PYY or PYY3-36 (2.4 pmol/rat) injected intracisternally also inhibited the acid response to intracisternal RX-77368 by 73% and 80%, respectively. Intravenous pretreatment with
PYY antibody (4.5 mg/rat), which shows a 35% cross-reaction with
PYY3-36 by RIA, completely prevented the inhibitory effect of intravenously infused PYY (1 nmol · kg
1 · h
1). When
injected intracisternally, the PYY antibody (280 µg/rat) reversed
intracisternal PYY (2.4 pmol)- and intravenous PYY (1 nmol · kg
1 · h
1)-induced
inhibition of acid response to intracisternal RX-77368 by 64% and
93.5%, respectively. These results provide supporting evidence that
peripheral PYY inhibits central vagal stimulation of gastric acid
secretion through an action in the brain.
immunoneutralization; vagus; dorsal vagal complex
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INTRODUCTION |
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PEPTIDE YY (PYY) is released by endocrine cells in the ileum in response to the presence of fatty acids in the intestinal lumen (30). PYY1-36 and PYY3-36 are the two molecular forms of PYY abundant in the blood (9). Peripheral administration of PYY produces a potent antisecretory effect that is selective for central vagally mediated stimulation of gastric acid and pancreatic exocrine secretions (24, 25), while having little, if any, effect on secretions elicited by peripherally acting exogenous secretagogues (24). Convergent studies indicate that the inhibition of gastric and pancreatic secretory and motor functions elicited by peripheral PYY involves a central vagal dependent mechanism. Circulating PYY may enter the brain through the area postrema and portions of the nucleus of the solitary tract (NTS), where the blood-brain barrier is incomplete and can be the portal of entry for circulating peptide hormones (10). PYY binding sites are presented in the area postrema and the dorsal vagal complex (DVC) (7, 18), which includes the NTS and the dorsal motor nucleus of the vagus (DMN) (16). The PYY derivatives [Leu31,Pro34]PYY (or Pro34 PYY) and PYY3-36 (or PYY13-36) show selective affinity to Y1 and Y2 receptors, respectively (1). Specific [125I][Leu31,Pro34]PYY (Y1) and [125I]PYY3-36 (Y2) binding sites have been detected in the NTS and the area postrema (7). PYY infused into peripheral circulation at physiological concentrations gains access to PYY binding sites located in specific portions of the DVC (12). In addition, peripheral injection of PYY activates neurons in the area postrema and dorsomedial NTS, as shown by Fos induction in these areas (4). Microinjection of PYY or PYY13-36 into the DVC inhibits gastric motility through Y2 receptors (6), whereas PYY or Pro34 PYY stimulates gastric motility and acid secretion through Y1/PYY-preferring receptors (6, 39). Both PYY and PYY13-36 administered in vivo, or in vitro to brain stem slice preparation, inhibit the activity of cholinergic vagal efferent neurons in the DMN, suggesting mediation through Y2 receptors (5). However, despite these convergent findings supporting a possible action of circulating PYY in the brain, direct evidence showing that the antisecretory effect of peripheral PYY is initiated at a central site is still lacking.
In vivo immunoneutralization has been extensively used to inhibit the biological actions of gastrointestinal peptides or neuropeptides and to assess their physiological relevance in the brain or periphery (32, 40, 41). Antibodies do not necessarily require access to intracellular compartments to inhibit peptide action and are extremely stable within biological tissues (36, 37). Antibodies administered into the lateral ventricles have been shown to diffuse through brain tissue (34, 35) and to become concentrated at sites expressing the immunogenic epitopes (31). In the present study, we first established that the specific PYY polyclonal antibody [Center for Ulcer Research and Education (CURE) no. 9153] injected intravenously or intracisternally prevents intravenous or intracisternal PYY-induced inhibition, respectively, of the acid response to central thyrotropin-releasing hormone (TRH) analog, and second, we administered the antibody intracisternally to assess whether peripherally infused PYY inhibits gastric acid secretion at a central site.
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MATERIALS AND METHODS |
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Animals. Male Sprague-Dawley rats (Harlan Laboratory, San Diego, CA) weighing 250-310 g were maintained under conditions of controlled temperature (22-24°C) and illumination (12:12-h light-dark cycle starting at 6 A.M.). Rats had ad libitum access to Purina laboratory chow (St. Louis, MO) and tap water. Animals were deprived of food for 24 h but had free access to water until 2 h before the beginning of the experiments. All studies were performed in rats anesthetized by intraperitoneal injection of urethan (1.5 g/kg, Sigma Chemical, St. Louis, MO).
Drugs and treatments.
Porcine/rat PYY (p/r PYY) (kindly provided by Dr. J. Rivier, Salk
Institute, La Jolla, CA) was dissolved in 0.1% BSA (Sigma Chemical)/saline before intravenous infusion. p/r PYY and p/r PYY3-36 (Peptides Synthesis Core Facility, University
of California, Los Angeles, CA) were dissolved in saline before
intracisternal injection. The stable TRH analog RX-77368
[pGlu-His-(3,3'-dimethyl)-Pro-NH2; Ferring
Pharmaceuticals, Feltham, UK] was diluted in saline before intracisternal injection from aliquots of a stock solution (30 µg/ml
in 0.1% BSA and saline, kept at 70°C). The control groups were
infused intravenously or injected intracisternally with the corresponding vehicles.
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Experimental protocols and measurement of gastric acid secretion.
In urethan-anesthetized rats, the jugular vein was cannulated with a
PE-50 catheter (Clay Adams) for intravenous infusion. The esophagus was
ligated at the cervical level, and a laparotomy was performed. The
pylorus was ligated, and a double-lumen gastric cannula was implanted
into the forestomach. After a 30-min stabilizing period, gastric acid
secretion was measured every 10 min by flushing the stomach through the
double-lumen cannula with two 5-ml boluses of saline at room
temperature and one 5-ml bolus of air at the end of each 10-min period.
Acid output was determined by titration of the flushed perfusate with
0.01 N NaOH using an autotitrator (TTT titrator, Radiometer,
Copenhagen, Denmark). The PYY infusion through the jugular vein (1.08 ml/h) was started 30 min before intracisternal injection of the stable
TRH analog RX-77368 (14 pmol/10 µl). Antibodies were administered
intravenously (1 ml/kg) or intracisternally (280 µg/20 µl) at 10 min before the start of intravenous PYY infusion (1 nmol · kg1 · h
1) or
intracisternal injection of PYY (2.4 pmol/5 µl) and RX-77368 (1.4 pmol/5 µl). Gastric acid secretions were measured from 20 min
before any treatment to 90 min after intracisternal injection of
RX-77368. In one experiment, PYY or PYY3-36 (2.4 pmol/5 µl) was injected intracisternally 10 min before intracisternal RX-77368 (14 pmol/5 µl). The net gastric acid output was calculated by subtracting the average basal value of acid output from each postinjection value. Reversal of the PYY intravenous or intracisternal inhibitory effect by PYY antibody was calculated by dividing the difference in acid output for PYY antibody and PYY vs. control antibody
and PYY by the difference in acid output for PYY vs. vehicle groups.
Statistical analysis. All results are expressed as means ± SE. Comparisons among multiple groups were performed by one-way ANOVA followed by Duncan's contrast. Comparisons between two groups were performed by Student t-test. P < 0.05 was considered statistically significant.
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RESULTS |
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Effect of intravenous PYY on gastric acid secretion stimulated by
intracisternal RX-77368.
Basal gastric acid secretion was low (0-0.4 µmol/10 min) in
urethan-anesthetized rats. In rats intravenously infused with vehicle,
the stable TRH analog RX-77368 (14 pmol/rat) injected intracisternally
induced a net acid secretion of 58.8 ± 6.7 µmol/90 min. The
acid response began at 10 min and reached its peak 20-40 min after
intracisternal injection of the TRH analog. PYY (0.25, 0.5, or 1 nmol · kg1 · h
1) infused
intravenously starting at 30 min before intracisternal RX-77368 (14 pmol) dose- dependently inhibited the acid response to intracisternal
RX-77368 by 52%, 69%, and 83%, respectively, compared with
vehicle-infused control, whereas PYY at 0.125 nmol · kg
1 · h
1 had no
significant inhibitory effect (61.7 ± 13.9 µmol/90 min) (Fig.
2). Intravenous PYY infusion (0.125, 0.25, 0.5, or 1 nmol · kg
1 · h
1 for 30 min)
did not influence basal gastric acid secretion in urethan-anesthetized
rats (data not shown).
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Effect of intravenous PYY antibody on intravenous PYY antisecretory
action.
The PYY antibody injected intravenously (2.25 or 4.5 mg/rat, 10 min)
dose-dependently blocked peripheral PYY (1 nmol · kg
1 · h
1 iv)-induced
inhibition of the acid response to intracisternal RX-77368 (14 pmol) in
urethan-anesthetized rats. PYY antibody at 2.25 or 4.5 mg/rat returned
gastric acid output values to 29.5 ± 16.3 and 79.3 ± 5.4 µmol/90 min, respectively (3- and 8-fold increases, respectively,
compared with 10.1 ± 5.2 µmol/90 min in rats without antibody
pretreatment). PYY antibody at a lower dose (1 mg/rat iv) did not
influence the PYY (1 nmol · kg
1 · h
1 iv)
inhibitory effect on intracisternal RX-77368-induced gastric acid
secretion (14.7 ± 2.0 µmol/90min) (Figs. 2 and
3). PYY antibody alone injected
intravenously at 4.5 mg/rat did not influence basal acid secretion in
urethan-anesthetized rats (net acid output, 2.7 ± 5.8 µmol/90
min; n = 4).
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Effect of intracisternal PYY and PYY3-36 on
gastric acid secretion-induced by intracisternal RX-77368.
In the saline-pretreated group (5 µl saline ic, administered at 10
min), the acid response to RX-77368 (14 pmol/5 µl) was 112 ± 28 µmol/90 min (Fig. 4).
Pretreatment with intracisternal PYY (2.4 pmol/5 µl) or
PYY3-36 (2.4 pmol/5 µl) significantly inhibited
the acid response to intracisternal RX-77368 by 80% and 73%,
respectively, compared with the intracisternal saline-pretreated group
(Fig. 4). PYY (2.4 pmol) injected intracisternally did not influence
basal gastric acid secretion (see Fig. 7).
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Effect of intracisternal PYY antibody on intracisternal PYY
antisecretory action.
The control antibody (280 µg/20 µl ic) injected 10 min before
intracisternal injection of a mixture of PYY (2.4 pmol) and RX-77368
(1.4 pmol) in a volume of 5 µl did not influence the inhibitory
effect of intracisternal PYY on RX-77368-induced acid secretion. The
net acid output (25.5 ± 15.4 µmol/90min, Fig.
5) was similar to that obtained when the
two peptides were injected intracisternally separately (Fig. 4). In
contrast, intracisternal PYY antibody pretreatment (280 µg/20 µl,
10 min) reversed the PYY inhibitory effect by 64%, and the net acid
output returned to 77.0 ± 13.2 µmol/90min (Fig. 5).
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Effect of intracisternal PYY antibody on intravenous PYY
antisecretory action.
The PYY antibody (280 µg/20 µl) injected intracisternally 10 min
before the intravenous infusion of PYY (1 nmol · kg1 · h
1) reversed
the intravenous PYY-induced inhibition of gastric acid secretion
stimulated by intracisternal RX-77368 (14 pmol) (Fig. 6). The net acid responses to
intracisternal RX-77368 in intracisternal control and PYY
antibody-pretreated rats infused intravenously with PYY (1 nmol · kg
1 · h
1) were
4.5 ± 3.5 and 55.3 ± 10.0 µmol/90 min, respectively. This represents a 93.5% reversal of the inhibitory effect of intravenous PYY on the acid response to intracisternal RX-77368 (Fig. 6). PYY
antibody (280 µg) or the control antibody (280 µg) injected intracisternally did not significantly influence either the basal gastric acid secretion or the acid response to intracisternal RX-77368
(14 pmol) in urethan-anesthetized rats (Fig.
7).
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DISCUSSION |
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TRH is an endogenous neurotransmitter in the medulla that plays an
important physiological role in the vagal regulation of gastric
functions (28). Medullary TRH-synthesizing neurons are mainly located in the caudal raphe nuclei and project to innervate the
DMN (17, 19, 27). TRH microinjected into the DMN
stimulates gastric acid secretion through activating the vagus
(13, 21). The intracisternal injection of the stable TRH
analog RX-77368 is a well established and widely used tool to induce
central vagally mediated stimulation of gastric acid secretion and
motility in conscious or anesthetized rats (28). In the
present study, PYY infused intravenously dose-dependently inhibited
gastric acid secretion induced by intracisternal RX-77368 in
urethan-anesthetized rats. This finding provides additional evidence
that peripheral PYY is a potent inhibitor of central vagally stimulated
gastric acid secretion, as previously reported in other models, such as acid responses to sham feeding (24) and 2-deoxy-glucose
(25). The minimal effective dose at which intravenous PYY
exerts an antisecretory effect (250 pmol · kg1 · h
1) is in the
range similar to that previously reported (14) to induce
physiological concentrations in the circulation. The acid response to
intracisternal RX-77368 (14 pmol) mimics the levels of acid secretion
stimulated by cold stress (42), which has been shown to be
mediated through medullary TRH (11, 42). Based on the
well-established demonstration that medullary TRH stimulates vagal
efferent activity (22) and plays a physiological role in
the cephalic phase of acid secretion (2, 29), whereas PYY
is one of the enterogastrones (30), the present findings suggest a possible physiological relevance of the interaction between
peripheral PYY and central TRH to regulate gastric acid secretion
during digestion.
Although the physiological significance of endogenous PYY and its
interactions with other gastrointestinal peptides to regulate gastric
secretion after a meal is important to investigate, the present study
was focused on the mechanism of peripheral PYY inhibitory action.
Growing evidence (8, 26) has revealed the central vagal
components that respond to a meal. In particular, Fos immunoreactivity was induced in neurons of the NTS and area postrema after feeding and
intraduodenal loading (8, 26, 38). Peripheral injection of
PYY has a similar effect (4). Several lines of
morphological and functional evidence (7, 12, 18,
23-25) also support the view that the medulla is the action
site for peripheral PYY to inhibit gastric and pancreatic functions. To
be consistent with the hypothesis that intravenously administered PYY
inhibits central TRH-induced gastric acid secretion by acting in the
medulla, PYY injected directly into the cisterna magna at lower doses
should mimic the inhibitory effect of peripherally infused PYY. Indeed, PYY or PYY3-36 injected intracisternally at 2.4 pmol
inhibits intracisternal RX-77368-stimulated acid secretion similarly to intravenous infusion of PYY at 0.5-1
nmol · kg1 · h
1.
PYY1-36 and PYY3-36 are the two
molecular forms that are abundant in the blood (9). Both
PYY and PYY3-36 (or PYY13-36)
exhibit similar affinity to the Y2 receptors (1), and when applied to the DMN in femtomole levels,
inhibited DMN neuronal activity (5), as well as
TRH-stimulated gastric motility (6). These findings,
together with present results showing that PYY and
PYY3-36 injected intracisternally are equipotent to
inhibit vagally stimulated acid secretion by intracisternal TRH analog,
support the view that the medulla is an action site for a low dose of
PYY to inhibit vagally stimulated gastric functions through
Y2 receptors.
In the absence of available specific Y2 receptor antagonists, to obtain direct evidence that peripheral PYY acts in the medulla to inhibit gastric acid secretion, we used the immunoneutralization method of approach. The PYY antibody CURE 9153 proved to be valuable in evaluating the role of circulatory PYY in intestinal nutrition-induced absorption (3) and inhibition of gastric acid secretion (43) in dogs. This antibody is selective for PYY and has ~35% cross-reactivity with PYY3-36 (present study) but does not cross-react with pancreatic polypeptide (3). The PYY antibody injected intravenously completely blocked intravenous PYY-induced inhibition of the acid response to intracisternal RX-77368, and when injected intracisternally, prevented the inhibitory effect of intracisternal PYY by 64%. This provides biological evidence of its immunoneutralizing potency in rats. The lower amount of PYY antibody that has no peripheral effect abolished the antisecretory effect of intravenously infused PYY by 93.5% when injected into the cisterna magna. To avoid the possibility of serendipitous phenomenon, the same experiment was repeated three times with similar reproducible significant results each time. These findings provide strong evidence that peripherally infused PYY does act in the brain to inhibit intracisternal TRH analog-induced stimulation of gastric secretion. It is most likely that the PYY antibody injected intracisternally neutralized PYY that entered from the circulation into the medulla via the area postrema and part of the NTS, where the blood-brain barrier is deficient (10). The present result is in line with the demonstration that intravenous infusion of PYY at physiological concentrations gains access to PYY binding sites located in portions of the DVC (12). The possibility that the intracisternal-injected PYY antibody reacts with intracisternal-injected RX-77368 to increase acid secretion can be excluded, because intracisternal injection of PYY antibody or control antibody did not influence basal and RX-77368-induced gastric acid secretion.
Intracerebroventricular or intracisternal passive immunization has been used extensively to inhibit central actions of peptide (20, 32). It has been proved by immunohistochemistry that antibody injected intracerebroventricularly penetrated into brain tissues (34) and specifically accumulated by neurons with the antigen protein (31). The vast majority of investigators using this technique made the assumption that the small quantities of antisera or purified antibodies administered into the ventricles inhibit the action of a neuropeptide specifically within the brain and do not gain access to peripheral tissues in substantial quantities. This assumption is based on an understanding of limited transport of large-molecular-weight proteins across the blood-brain barrier (15) and the unlikelihood that antibodies can reach the systemic circulation in significant amounts after intracisternal or intracerebroventricular administration. However, recent studies (33) revealed that small quantities of antisera injected intracerebroventricularly can neutralize peripheral peptides. All three tested antisera injected into the rat cerebroventricle were detected in the systemic circulation within 30 min after intracerebroventricular infusion of 5 µl antiserum (33). However, it is unlikely that similar mechanisms would contribute to the results obtained in the present study. Although 280 µg/rat of purified anti-PYY IgG injected intracisternally almost completely prevented the antisecretory action of intravenous PYY, a 10-fold larger amount (2.25 mg/rat) of the same antibody injected intravenously showed a much weaker effect. To obtain a potency similar to that observed after intracisternal PYY antibody injection, the required dose of intravenous PYY antibody was 4.5 mg, i.e., 16 times larger than the intracisternal effective dose.
Zhao et al. (43) recently reported that intravenous PYY antibody did not prevent intraduodenal fat-induced inhibition of acid secretion in dogs. The results of the present study are not incompatible with the findings of Zhao et al. (43). Our observations are consistent with other previous studies (24, 25) showing that PYY is more potent in inhibiting the cephalic phase of acid secretion, whereas in the study of Zhao et al.(43) there was no cephalic phase involved, as the acid was stimulated by intragastric peptone, which mimics a gastric phase of acid secretion.
In summary, PYY was more potent in inhibiting intracisternal TRH analog-induced stimulation of gastric acid secretion in urethan-anesthetized rats when administered intracisternally rather than intravenously. PYY antibody was more potent in reversing the antisecretory action of intravenously infused PYY when injected intracisternally rather than intravenously. In addition, intracisternal injection of PYY3-36 mimics the antisecretory effect of intracisternal PYY. These findings, together with previous observations (4, 5, 7, 12, 18, 23-25), strongly support the view that peripheral PYY-induced inhibition of vagally stimulated gastric functions involves a Y2-mediated central mechanism, possibly at a medullary site.
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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 supplying rat PYY, Dr. J. Reeve, Jr. (Peptides Synthesis Core Facility, University of California, Los Angeles, CA) for supplying porcine/rat PYY and porcine/rat PYY3-36, and Paul Kirsch for assistance in manuscript preparation.
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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 (Y. Taché), DK-50255 (H. Yang), and DK-41301 (Animal Core, Antibody Core, and Peptides Core).
Address for reprint requests and other correspondence: H. Yang, CURE: Digestive Diseases Research Center, Veterans Affairs Greater Los Angeles Healthcare System, Bldg 115, Rm. 203, 11301 Wilshire Blvd., Los Angeles, CA 90073 (E-mail: hoyang{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. §1734 solely to indicate this fact.
Received 2 February 2000; accepted in final form 10 April 2000.
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