Supraphysiological effects of pancreatic polypeptide on gastric motor function and nutrient tolerance in humans.

Pancreatic polypeptide (PP) is known to affect food intake. In this exploratory study, we set out to investigate its supraphysiological effect on food tolerance, gastric accommodation, and emptying. In 12 healthy volunteers, 0, 3, or 10 pmol*kg-1 *min-1 PP was administered intravenously (PP0, PP3 or PP10). Thirty minutes thereafter, nutrient drink infusion (60 ml*min-1 ) through a nasogastric feeding tube was started until maximum satiation. Gastric accommodation was assessed by measuring the intragastric pressure (IGP; nasogastric manometry). In a separate test, the effect of PP0 or PP10 on gastric emptying was tested in 10 healthy volunteers and assessed using the 13 C breath test. Results are presented as mean ± SEM, and p < 0.05 was considered significant. For the IGP test, PP increased ingested nutrient volume: 886 ± 93, 1059 ± 124, and 1025 ± 125 ml for PP0, PP3, and PP10, respectively (p = 0.048). In all groups, Nadir IGP values were reached upon food intake (transformed values: 1.5 ± 0.2, 1.7 ± 0.3, and 1.6 ± 0.3 mmHg for PP0, PP3, and PP10, respectively; NS) to return to baseline thereafter. For the gastric emptying study, volunteers ingested a similar nutrient volume: 802 ± 119 and 1089 ± 128 ml (p = 0.016), and gastric half-emptying time was 281 ± 52 and 249 ± 37 min for PP0 and PP10, respectively (NS). No significant correlation between tolerated nutrient volume and IGP drop (R² < 0.01; p = 0.88 for PP0 vs. PP3 and R² =0.07; p = 0.40 for PP0 vs. PP10, respectively) or gastric half-emptying time (R² = 0.12; p = 0.32) was found. A supraphysiological PP dose enhances food tolerance; however, this effect is not mediated through gastric motility. CLINICAL TRIAL REGISTRY NUMBER: NCT03854708 is obtained from clinicaltrials.gov.

Prevention of Type 1 Diabetes with Acetalated Dextran Microparticles Containing Rapamycin and Pancreatic Peptide P31.

Type 1 diabetes (T1D) is a common autoimmune disease with no cure. T1D subjects are dependent on daily exogenous insulin administration, due to the loss of functional insulin-producing ß cells. Needed are immunotherapies that prevent and/or treat T1D. One approach of immunotherapy is to administer an autoantigen to selectively tolerize diabetogenic effector T cells without global immunosuppression. To date, however, strategies of antigen-specific immunotherapy are largely ineffective in the clinic. Using an antigen-specific approach, a biodegradable polymeric delivery vehicle, acetalated dextran microparticles (Ace-DEX MPs), is applied and T1D development is prevented through coadministration of the immunosuppressant rapamycin and the diabetogenic peptide P31 (Rapa/P31/MPs), via alterations of both innate and adaptive immunity. Ex vivo, adoptively transferred CD4+ T cells exhibit reduced proliferation and an increased ratio of FoxP3+ to IFNγ+ T cells. In vitro analysis indicates dendritic cells exhibit a less mature phenotype following coculture with Rapa/P31/MPs, which results in reduced CD4+ T cell proliferation and proinflammatory cytokine production (IFNγ and IL-2), but promotes PD-1 expression. Together these results demonstrate Ace-DEX MP-based antigen-specific therapy effectively tolerizes diabetogenic CD4+ T cells to prevent T1D, thereby demonstrating one of the first successful attempts of T1D prevention using a single-formulation particulate delivery platform.

Elucidating the roles of gut neuropeptides on channel catfish feed intake, glycemia, and hypothalamic NPY and POMC expression.

Both intrinsic and extrinsic factors modulate food intake and glycemia in vertebrates, in part through interactions with hypothalamic neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons. The objective of this project was to elucidate the effects of ghrelin (GHRL), gastrin-releasing peptide (GRP), cholecystokinin (CCK), glucagon-like peptide (GLP), pancreatic polypeptide (PP), and peptide YY (PYY) on appetite, glycemia, and hypothalamic expression of NPY and POMC in channel catfish. Catfish were injected intraperitoneally with a single peptide at concentrations of either 0 (control), 50, 100, or 200 ng/g body weight (BW), respectively. Fish were allowed to recover for 30 min, and then fed to satiation over 1 h. Feed intake was determined 1h post-feeding. Catfish injected with GHRL at 50 and 100 ng/g BW and GRP at 200 ng/g BW consumed significantly (P<0.05) less feed compared to controls. A tendency (P<0.1) to suppress feed intake was also observed in the 200 ng/g BW GHRL and PP treatments. PYY, CCK, and GLP had no effects on feed intake. Glycemia was not affected by GHRL, GRP, PP, and PYY treatments, but was suppressed by CCK. A tendency toward lower plasma glucose concentrations was observed in fish administered GLP at 50 ng/g BW. Hypothalamic NPY expression was highly variable and not significantly affected by treatment. POMC expression was also variable, but tended to be reduced by the highest concentration of CCK. These results provide new insight into the roles and regulation of gut neuropeptides in catfish appetite and glycemia.

Effect of pancreatic polypeptide on gastric accommodation and gastric emptying in conscious rats.

Pancreatic polypeptide (PP) is an anorexigenic hormone released from pancreatic F cells upon food intake. We aimed to determine the effect of PP on gastric accommodation and gastric emptying in conscious Wistar HAN rats to investigate whether effects on motor function could contribute to its anorexigenic effects. Intragastric pressure (IGP) was measured through a chronically implanted gastric fistula during the infusion of a nutrient meal (Nutridrink; 0.5 ml/min). Rats were treated with PP (0, 33 and 100 pmol·kg(-1)·min(-1)) in combination with N(G)-nitro-L-arginine methyl ester (L-NAME; 180 mg·kg(-1)·h(-1)), atropine (3 mg·kg(-1)·h(-1)), or vehicle. Furthermore, the effect of PP was tested after subdiaphragmal vagotomy of the stomach. Gastric emptying of a noncaloric and a caloric meal after treatment with 100 pmol·kg(-1)·min(-1) PP or vehicle was compared using X-rays. PP significantly increased IGP during nutrient infusion compared with vehicle (P < 0.01). L-NAME and atropine significantly increased IGP during nutrient infusion compared with vehicle treatment (P < 0.005 and 0.01, respectively). The effect of PP on IGP during nutrient infusion was abolished in the presence of L-NAME and in the presence of atropine. In vagotomized rats, PP increased IGP compared with intact controls (P < 0.05). PP significantly delayed gastric emptying of both a noncaloric (P < 0.05) and a caloric (P < 0.005) meal. PP inhibits gastric accommodation and delays gastric emptying, probably through inhibition of nitric oxide release. These results indicate that, besides the well-known centrally mediated effects, PP might decrease food intake through peripheral mechanisms.

PYY3-36 and pancreatic polypeptide reduce food intake in an additive manner via distinct hypothalamic dependent pathways in mice.

OBJECTIVE: Peptide YY (PYY3-36) and pancreatic polypeptide (PP) potently inhibit food intake in rodents and humans, however, it is unclear whether they have any synergistic/additive interaction in decreasing food intake. DESIGN AND METHODS: Fasted WT, Y2(-) (/) (-) , Y4(-) (/) (-) , or Y2Y4(-) (/) (-) mice were i.p. administrated with saline, PYY3-36, and/or PP. RESULTS: Combined injection of PYY3-36 and PP reduces food intake in an additive manner was demonstrated in this study. This effect is mediated via Y2 and Y4 receptors, respectively. It was demonstrated that PYY3-36 and PP activate distinct neuronal pathways in the hypothalamus, as demonstrated by immunostaining for c-fos, which shows distinct patterns in response to either hormone. After PYY3-36 injection, neurons in the dorsal aspect of the arcuate nucleus (Arc), paraventricular nucleus, and dorso-medial nucleus of the hypothalamus (DMH) are activated with minimal responses seen in the ventro-medial nucleus of the hypothalamus (VMH) and lateral hypothalamic area (LHA) of WT mice. These effects are absent in Y2(-) (/) (-) mice. PP activates preferably the lateral aspect of the Arc, the DMH, VMH, and LHA in a Y4 receptor-dependent manner. Importantly, the expression pattern of c-fos immunoreactive neurons induced by combined treatment appears to be the sum of the effects of single treatments rather than a result of synergistic interaction. CONCLUSIONS: These findings demonstrate that PYY3-36 and PP activate distinct pathways in the hypothalamus to reduce food intake in an additive manner.

Pancreatic polypeptide administration enhances insulin sensitivity and reduces the insulin requirement of patients on insulin pump therapy.

INTRODUCTION: The effects of pancreatic polypeptide (PP) infusion were examined in patients on insulin pump therapy to determine whether PP administration can reduce insulin requirements in patients with type 1 diabetes mellitus (T1DM) or type 3c diabetes mellitus (T3cDM; pancreatogenic). METHODS: Ten subjects with long-standing T1DM (n = 7) or T3cDM (n = 3) on insulin pump treatment received a 72 h subcutaneous infusion of 2 pmol/kg/min bovine PP or saline by portable infusion pump in a single-blinded, randomized, crossover design. RESULTS: Pancreatic polypeptide infusion raised plasma PP levels to 450-700 pmol/liter. Daily insulin infusion requirements (I) fell from 48 ± 6.9 to 40 ± 7.5 U on day 2 (p < .05) and from 46 ± 7.7 to 37 ± 6.6 U on day 3 (p < .05) of PP infusion compared with saline. Corrected for average blood glucose concentration (G), I/G fell in 10/10 subjects during the second 24 h period and in 7/10 subjects during the third 24 h period; sensitivity to insulin, calculated as 1/(I/G), increased 45% ± 12% on day 2 (p < .01) and 34% ± 14% on day 3 (p < .05) of PP infusion. Pancreatic polypeptide responses to a test meal were compared with the change in insulin infusion requirements in 5 subjects; the reduction in insulin requirements seen during PP infusion correlated with the degree of baseline PP deficiency (p < .002). CONCLUSIONS: A concurrent subcutaneous infusion of PP enhances insulin sensitivity and reduces insulin requirements in patients with long-standing T1DM and T3cDM on insulin pump therapy. The benefit of PP infusion correlated with the degree of PP deficiency.

Blunted pancreatic polypeptide-induced vasodilatation in mesenteric resistance vessels from spontaneously hypertensive rats.

The present study investigated the mechanisms of vasodilatation of the human pancreatic polypeptide [cPP(1-7), NPY(19-23),Ala(31),Aib(32),Gln(34)]hPP (hPP) in mesenteric small arteries from Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). The arteries were isolated and mounted in microvascular myographs for isometric tension recording. In vasopressin-contracted preparations with endothelium from WKY rats, hPP evoked concentration-dependent relaxations with maximal responses of 50+/-2% (n=5). hPP relaxation was reduced by endothelial cell removal and abolished in the presence of a nitric oxide (NO) synthase inhibitor, N(G)-nitro-L-arginine-methylester (L-NAME). hPP relaxation was blunted in segments with endothelium, and absent in segments without endothelium from SHR. The combined neuropeptide Y(1)- and Y(4)-receptor antagonist, GR23118 (Ile-Glu-Pro-Dpr-Tyr-Arg-Leu-Arg-Tyr-CONH(2)), and the neuropeptide Y(1) receptor antagonist, BIBP3226 ((R) -N2-(diphenylacetyl)-N-[(4-hydroxyphenyl)-methyl]-arginineamide), inhibited hPP-induced vasodilatation. Calcitonin gene-related peptide (CGRP) relaxation was reduced in arteries from SHR compared to WKY. The CGRP receptor antagonist, CGRP (8-37), antagonized vasodilatation induced by CGRP and rightward shifted concentration-response curves for hPP in arteries from WKY rats. There were no differences in nerves immunoreactive for CGRP in arteries from SHR compared to WKY rats. In contrast to neuropeptide Y which evokes contraction by activation of neuropeptide Y(1) and Y(2) receptors, the present results suggest hPP evokes relaxation of mesenteric small arteries by activation of prejunctional neuropeptide Y(1)-like receptors localized in CGRP-containing nerves followed by release of CGRP and of endothelium-derived NO. hPP relaxation is blunted in arteries from SHR probably as a consequence of endothelial cell dysfunction leading to reduced efficacy of CGRP.

Distribution of peripherally injected peptide YY ([125I] PYY (3-36)) and pancreatic polypeptide ([125I] hPP) in the CNS: enrichment in the area postrema.

The mechanism by which blood-borne peptide YY (3-36) (PYY(3-36)) and pancreatic polypeptide (PP) inhibit food intake is not clear and could implicate peripheral (vagal afferent pathways) and/or central (direct action on specific brain nuclei) mechanisms. To identify the primary brain structure(s) that could be activated after a peripheral injection of neuropeptide Y-related peptides, we investigated the distribution of radioactive materials using whole body autoradiography and coronal brain sections. Rats were injected with [125I] porcine (p) PYY(3-36) (i.p., 10 microCi) and killed after 30 min, 1, 2, or 4 h. After i.p. administration, significant amounts of radioactive materials were rapidly (<30 min) detected in the blood circulation and various tissues including the kidneys, liver, lung, heart, bone marrow, gastrointestinal tract, and thyroid gland, whereas in the brain, low but significant amounts of radioactive materials were detected at the level of the area postrema. Next, we investigated the distribution of radioactive labeling in the brain after i.v. injections of [125I]pPYY(3-36) (Y2 and Y5 subtypes), [125I] human (h) PP (Y4 and Y5 receptors), and [125I][Leu(31), Pro(34)] pPYY (Y1, Y4 and Y5 classes) in the rat brain. Fifteen minutes post injection, autoradiograms revealed positive signals only in the area postrema after the injection of [125I]-hPP and [125I][Leu(31), Pro(34)]pPYY. Whereas the presence of [125I]pPYY(3-36)-related labeling was detected in the area postrema, subfornical organ, and median eminence. In all other brain structures, including all hypothalamic nuclei and other circumventricular organs, near background level signals were detected. These data suggest that the inhibition of food intake observed after peripheral injections of pPYY(3-36) and hPP could involve receptor activation preferentially located at the level of the area postrema, a structure well-known to be involved in the modulation of food intake.

Influence of central and peripheral administration of pancreatic polypeptide on gastric mucosa growth.

UNLABELLED: Previous studies have shown that pancreatic polypeptide (PP) inhibits exocrine pancreatic secretion. The aim of present study was to determine the influence of PP administration on gastric growth and blood flow. METHODS: Study was performed on regularly fed, fasted or fasted and subsequently refed rats. Rats were treated with saline (intraperitoneally - i.p.), caerulein (0.24 nmol/kg/dose, i.p.), pentagastrin (0.38 micromol/kg/dose, i.p.) or PP (5 nmol/kg/dose, i.p. or 10 pmol/dose intracerebroventricularly - i.c.v.). Saline, caerulein, pentagastrin and PP were administered alone or in combination, 3 times daily during last 48 h of experiment. RESULTS: Treatment with pentagastrin increased gastric mucosa weight, mucosal DNA synthesis and gastric blood flow in all group tested. Intraperitoneal and i.c.v administration of PP alone reduced mucosal DNA synthesis in regularly fed and refed animals, and decreased gastric blood flow in refed animals. Combination of PP i.p. or i.c.v plus pentagastrin significantly reduced the pentagastrin-evoked increase in gastric mucosa weight, gastric DNA synthesis and gastric blood flow in fasted animals, as well as regularly fed animals. In refed animals, influence of PP administration on the pentagastrin-evoked increase in gastric mucosa weight was weak and statistically insignificant, but still i.p or i.c.v administration of PP significantly reduced gastric blood flow and mucosal DNA synthesis in this group of animals. Administration of caerulein caused weak, but significant increase in gastric DNA synthesis, gastric mucosa weight and gastric blood flow in fasted rats. In regularly fed animals, caerulein significantly increased only gastric DNA synthesis and gastric blood flow. In fasted animals with subsequent refeeding, caerulein was without effect on parameters tested in the stomach. Neither i.p. nor i.c.v administration of PP affected the caerulein-evoked effects in the stomach. CONCLUSIONS: Peripheral and central administration of PP inhibits food- and pentagastrin-stimulated growth of gastric mucosa. Similar effects of low central doses of PP as the high peripheral doses of PP suggests a crucial role of the central nervous system in the inhibitory effect of PP on gastric mucosa growth.

The area postrema lesions alter the inhibitory effects of peripherally infused pancreatic polypeptide on pancreatic secretion.

Circulating PP binds to specific receptors in the DVC through the AP, but the mechanism through which these brain receptors affect pancreatic secretion is not clear. We hypothesize that the removal of the AP (APX) will alter the effects of PP on pancreatic secretion. APX or sham procedures were performed in anesthetized male Wistar rats. After a 1-month recovery, one group of rats were infused with either PP (30 or 100 pmol/kg per h) or vehicle under basal or 2-DG-stimulated (75 mg/kg, i.v. bolus) conditions for studying pancreatic exocrine secretion. A second parallel group was sacrificed for examination of PP receptor binding in the brain stem. A third group received an intraperitoneal injection of PP at the dose of 4.15x10(4) pmol/kg (200 microg/kg) and c-fos expression in the brain stem was examined. APX eliminated PP binding sites in the DVC as assessed by autoradiography. PP infusion caused a dose-dependent decrease in basal protein secretion. APX partially reversed PP inhibition of basal protein secretion when infused at 30 pmol/kg per h, and at 100 pmol/kg per h stimulated pancreatic fluid secretion and reversed the inhibition of protein secretion. During 2-DG stimulation the effects of PP and 2-DG on pancreatic fluid and protein secretion were parallel. PP dose-dependently inhibited 2-DG-stimulated secretion in sham rats. APX reduced the pancreatic fluid (54%) and protein (46%) secretory response to 2-DG. However, PP at 30 pmol/kg per h remained a potent inhibitor of 2-DG-stimulated pancreatic secretion in APX rats. This effect was blunted with PP at 100 pmol/kg per h in APX rats, possibly related to the stimulatory effect of high-dose PP in APX rats without 2-DG. Furthermore, i.p. PP induced significantly greater c-fos activation of NTS neurons in APX rats than sham rats, despite the apparent absence of PP binding sites in the DVC. We conclude that in awake rats, PP inhibits basal secretion, in part, through the AP. Furthermore, and unlike PYY, PP inhibits 2-DG-stimulated pancreatic secretion, and it does so through an AP-independent mechanism. The possibility that the mechanism may involve the DVC cannot be excluded since i.p. injection of PP activates c-fos expression in DVC neurons. Thus, PP and PYY may regulate different components of the pancreatic secretory control system through unique pathways.

Mouse pancreatic polypeptide modulates food intake, while not influencing anxiety in mice.

This study was designed to investigate the effects of synthetic mouse pancreatic polypeptide (mPP) on feeding and anxiety in mice. The intracerebroventricular (i.c.v.) injection of mPP (0.003-3 nmol) dose-dependently increased food intake. A significant increase was observed 20 min after i.c.v. injection and continued for 4 h. The intraperitoneal (i.p.) injection of mPP (0.03-30 nmol) dose-dependently decreased food intake. A significant decrease was observed 20 min after i.p. injection and continued for 4 h. In the elevated plus maze test, the i.c.v. injection of mPP (0.003-3 nmol) did not affect anxiety behavior. These results suggest that mPP modulates food intake and the Y4 receptor in the brain may contribute to the regulation of feeding, whereas appearing not to influence anxiety in mice.

Thioperamide, a histamine H3 receptor antagonist, suppresses NPY-but not dynorphin A-induced feeding in rats.

Whether or not neuropeptide Y (NPY)-induced feeding in rats is influenced by the histaminergic system in the brain was investigated by intracerebroventricular (i.c.v.) administration of a selective histamine H3 receptor antagonist prior to i.c.v. administration of NPY. NPY (10 microg/10 microl) strongly induced feeding in sated rats during the light phase of the day. Dynorphin A1-17 (10 microg/10 microl), a kappa-opioid agonist, and rat pancreatic polypeptide (rPP, 30 microg/10 microl) also stimulated ingestive behavior in sated rats, but food intake in both cases was less than that induced by NPY. Thioperamide maleate, a specific histamine H3 receptor antagonist (408.5 microg/10 microl) reduced the feeding response to NPY by 52% (P < 0.0001), but not to dynorphin A1-17 and rPP. Thioperamide at i.c.v. doses of 40.8-408.5 microg/10 microl had no effect on food intake in sated rats. These results suggest that the thioperamide may have a specific effect on NPY receptor-mediated neuronal systems related to feeding.

Role of the Y5 neuropeptide Y receptor in feeding and obesity.

Neuropeptide Y (NPY), a 36-amino-acid neuromodulator abundantly expressed in the brain, has been implicated in the regulation of food intake and body weight. Pharmacological data suggest that NPY's stimulatory effect on appetite is transduced by the G-protein-coupled NPY Y5 receptor (Y5R). We have inactivated the Y5R gene in mice and report that younger Y5R-null mice feed and grow normally; however, they develop mild late-onset obesity characterized by increased body weight, food intake and adiposity. Fasting-induced refeeding is unchanged in younger Y5R-null mice and they exhibit normal sensitivity to leptin. Their response to intracerebroventricular (i.c.v.) administration of NPY and related peptides is either reduced or absent. NPY deficiency attenuates the obesity syndrome of mice deficient for leptin (ob/ob), but these effects are not mediated by NPY signaling through the Y5R because Y5R-null ob/ob mice are equally obese. These results demonstrate that the Y5R contributes to feeding induced by centrally administered NPY and its analogs, but is not a critical physiological feeding receptor in mice.

Pancreatic polypeptide administration improves abnormal glucose metabolism in patients with chronic pancreatitis.

Chronic pancreatitis (CP) is associated with lowered plasma levels and a blunted nutrient-induced release of pancreatic polypeptide (PP). To investigate the possible role of PP on glucose metabolism, we studied male patients with documented CP (n = 5) and obesity-matched control subjects (NL) (n = 6). Hepatic glucose production (HGP) and overall glucose disposal rates were determined by [3-3H]glucose infusion during a hyperinsulinemic-euglycemic clamp during three separate admissions. Basal rates of HGP were higher in CP patients. In response to an infusion of insulin (60 pmol.m-2.min-1), HGP fell 91 +/- 5% in NL subjects but only 68 +/- 8% in CP subjects (P < 0.05). One month later, the clamp was repeated during the final 2 h of an 8-h infusion of bovine PP (2 pmol.kg-1.min-1). HGP before the insulin infusion and its subsequent suppression (NL: 83 +/- 5%; CP: 86 +/- 15%) were nearly identical between groups. In follow-up studies 1 month after the PP infusion, HGP both basally and in response to insulin alone were similar to the first study. During oral glucose tolerance tests (OGTT) performed 18 h after the PP infusion, subjects with normal (n = 7) baseline OGTT responses showed no effect. All patients with diabetic (n = 3) or nondiagnostic (n = 1) OGTT responses, however, demonstrated lowered mean plasma glucose levels (approximately -2.3 mmol/L; range: -0.6 to -7.2 mmol/L). OGTTs repeated 1 month after the PP treatment showed a return to pretreatment responses. We conclude that chronic pancreatitis accompanied by PP deficiency is associated with partial hepatic resistance both in the basal state and in response to hyperinsulinemia. This impairment is reversed after iv PP administration. PP deficiency may therefore play a role in the development of pancreatogenic diabetes caused by pancreatic injury.

Effect of the C-terminal tetrapeptide amide of gastrin (CCK-4) and pancreatic polypeptide on gastrointestinal electrical activity in the conscious miniature pig.

The effect of IV infusion of CCK-4, 33.2 and 332 pM/kg/min, and pancreatic polypeptide (PP), 4.8 and 48 pM/kg/min, on gastrointestinal electrical activity was studied in conscious miniature pigs with electrodes implanted in the wall of the antrum pylori and small intestine. In the antrum pylori infusion of the higher dose of both peptides provoked an increase in frequency of the basic electrical rhythm together with a decrease in frequency of spike bursts. In the studied dose range CCK-4 and PP were without influence on small intestinal electrical activity.

Intracisternal rat pancreatic polypeptide stimulates gastric emptying in the rat.

Pancreatic polypeptide (PP) has been shown to alter gastrointestinal functions, including increased gastric acid secretion and motility following brain stem injections of PP. The present study investigated the effect of an intracisternal injection of PP on the rate of gastric emptying. Additionally, the efficacy of the rat and bovine forms of the peptide was compared. Rats anesthetized with ether received an intracisternal injection of rat PP, bovine PP, or vehicle and, upon regaining consciousness, were fed a liquid test "meal." Intracisternal rat PP produced a marked enhancement in gastric emptying compared with control animals. Bovine PP, at doses equimolar to or three times greater than the effective rat PP dose, produced no change in gastric emptying. Pretreatment with systemic atropine prior to central injection of rat PP eliminated the stimulation of emptying, suggesting that PP acts through a cholinergic mechanism. When equimolar doses of rat or bovine PP were microinjected directly into the dorsal vagal complex, the region containing PP receptors, both were capable of stimulating antral motility. The response to bovine PP, however, was delayed and reduced compared with that seen following rat PP. The results suggest that rat PP strongly stimulates gastric emptying in rats and that bovine PP, depending on the route of administration, is either ineffectual or a weaker agonist for central PP receptors.

Pancreatic polypeptide microinjection into the dorsal motor nucleus inhibits pancreatic secretion in rats.

BACKGROUND/AIMS: Pancreatic polypeptide (PP), a hormone released from the pancreas, inhibits pancreatic secretion in vivo but not in vitro, suggesting that the inhibitory action of PP on pancreatic secretion is indirect. Circulating PP in physiological concentrations binds to specific receptors in the dorsal vagal complex in the brainstem. Therefore, the hypothesis of this study was that PP acts centrally and inhibits pancreatic secretion by modulating vagal tone. METHODS: The effects of microinjection of PP into the dorsal motor nucleus on 2-deoxy-D-glucose-stimulated and cholecystokinin octapeptide (CCK-8)-stimulated pancreatic secretion were examined in urethane-anesthetized rats. RESULTS: Microinjection of PP to the dorsal motor nucleus but not brainstem sites outside it inhibited 2-deoxy-D-glucose-stimulated pancreatic flow and protein output. CCK-8-stimulated pancreatic protein output was inhibited by PP in the dorsal motor nucleus in dose-dependent and site-specific manners. The inhibitory effect of PP on CCK-8-stimulated protein output was eliminated by vagotomy. CONCLUSIONS: The results suggest that PP acts in the dorsal motor nucleus to modulate vagal tone on the pancreas, thereby inhibiting pancreatic secretion. This study shows for the first time that the dorsal motor nucleus is involved in central feedback inhibition of the exocrine pancreas.

Pancreatic polypeptide stimulates gastric motility through a vagal-dependent mechanism in rats.

The present study examined the influence of peripherally administered pancreatic polypeptide (PP) on vagal control of gastric motility. The jugular vein was cannulated in urethane-anesthetized rats and a strain gauge was sewn onto the antrum to monitor motility. Intravenous infusion of rat PP (2-200 pmol over 45 min) resulted in a dose-dependent increase in antral contraction amplitude. The motility response to i.v. PP was eliminated by pretreatment with atropine or bilateral vagotomy. In contrast to i.v. infusion, close intra-arterial infusion of PP into the gastric circulation had no effect on motility suggesting that PP does not act upon peripheral afferent terminals or directly within the stomach. These results support the hypothesis that circulating PP indirectly enhances gastric motility through a vagal cholinergic mechanism.

Intracisternal injection of pancreatic polypeptide stimulates gastric emptying in rats.

In the present study, we evaluated the effects of central administration of pancreatic polypeptide (PP) on gastric emptying of a liquid meal in conscious rats using a phenol red method. Intracisternal injection of PP (0.5-2.0 micrograms) speeds gastric emptying of a test meal in a dose-dependent manner. In contrast, i.p. injection of PP at the same doses inhibited gastric emptying in a dose-related fashion. Bilateral gastric branch vagotomy abolished the increase in gastric emptying evoked by intracisternal PP. These results demonstrate that PP speeds gastric emptying through the vagal system when given centrally but slows emptying when given peripherally.

Pancreatic polypeptide in dorsal vagal complex stimulates gastric acid secretion and motility in rats.

High concentrations of receptors for pancreatic polypeptide (PP), a pancreatic hormone, were recently discovered in the dorsomedial region of the dorsal vagal complex (DVC). We hypothesized that gastric acid secretion and motility, digestive functions strongly influenced by vagovagal reflexes organized within the DVC, would be affected by PP applied directly to this vagal sensorimotor integration area. After urethan-anesthetized rats were prepared for antral motility recording or titrometric analysis of gastric acid output, phosphate-buffered saline or various doses of PP in phosphate-buffered saline were micropressure injected into the medial DVC. Injections of PP into the DVC produced significant, long-lasting, and dose-dependent increases in gastric acid secretion and antral motility. These gastric responses were blocked by bilateral cervical vagotomy and by atropine, suggesting that intramedullary PP stimulates vagal cholinergic pathways, resulting in enhanced gastric functions. Because PP is not synthesized within the central nervous system, these results point to a new mechanism whereby the digestive tract may modulate its own autonomic control: direct humoral action on vagovagal reflex circuits within the brain stem.