Hideki Morioka

Effect of neuropeptide Y on the hypothalamic-pituitary-adrenal axis in the dog.

There is increasing evidence that neuropeptide Y (NPY) affects the release of pituitary hormones, including adrenocorticotropic hormone (ACTH). The present study was designed to clarify the mechanism by which NPY activates the hypothalamic-pituitary-adrenal (HPA) axis in the dog. Mongrel dogs were equipped with a chronic cannula allowing intra-third (i.t.v.) or intra-lateral (i.l.v.) cerebroventricular administration. A 1.19 nmol, i.t.v. dose of NPY produced as great an ACTH and cortisol response as did equimolar ovine corticotropin releasing factor (CRF). This action of NPY was dose-dependent and shared by peptide YY (PYY) and pancreatic polypeptide (PP), other members of the PP family peptide. Intravenously (i.v.) administered NPY (1.19-11.9 nmol) was much less potent than i.v. CRF in stimulating ACTH and cortisol secretion. However, i.v. NPY significantly increased plasma ACTH and cortisol concentrations, raising the possibility that NPY may modulate the activity of corticotrophs. We have next investigated the possible relationship between NPY and CRF on the HPA axis. Pretreatment with a novel CRF antagonist, alpha-helical CRF9-41 (130.9 nmol i.t.v. or 261.8 nmol i.v.), partly but significantly attenuated the ACTH and cortisol responses to i.t.v. NPY (1.19 nmol). Furthermore, adding a subthreshold dose of i.t.v. NPY (0.119 nmol) to i.t.v. CRF (1.19 nmol) or i.v. NPY (2.38 nmol) to i.v. CRF (0.595 nmol) resulted in the potentiation of CRF-induced ACTH secretion. These results indicate that NPY may activate the HPA axis in concert with CRF probably at hypothalamic and/or pituitary levels. The present findings that NPY evokes ACTH secretion and potentiates the effectiveness of CRF as a secretagogue, together with high concentrations of NPY in the hypothalamus and pituitary portal blood, suggest that NPY is involved in the multihormonal control of ACTH release.

Cross-reactivities of neuropeptide Y and peptide YY with pancreatic polypeptide antisera: evidence for the existence of pancreatic polypeptide in the brain

Highly purified neuropeptide Y (NPY) and peptide YY (PYY) did not cross-react in our human pancreatic polypeptide (hPP) radioimmunoassay, nor did 125I-labelled NPY and PYY, even with anti-hPP serum at low dilution (1:1000). However, both [125I]NPY and [125I]PYY significantly cross-reacted with anti-bovine PP (bPP) serum at low dilution (1:1000, similar to that used in immunohistochemistry). These results suggest that radioassayable hPP-like peptide in the porcine or canine brain is probably pancreatic polypeptide itself, otherwise immunohistochemically detected bPP-like peptide may represent both NPY and PP.

Peptide YY receptors in the brain

Radiolabelled ligand binding studies demonstrated that specific receptors for peptide YY are present in the porcine as well as the canine brains. Peptide YY was bound to brain tissue membranes via high-affinity (dissociation constant, 1.39 X 10(-10)M) and low-affinity (dissociation constant, 3.72 X 10(-8)M) components. The binding sites showed a high specificity for peptide YY and neuropeptide Y, but not for pancreatic polypeptide or structurally unrelated peptides. The specific activity of peptide YY binding was highest in the hippocampus, followed by the pituitary gland, the hypothalamus, and the amygdala of the porcine brain, this pattern being similarly observed in the canine brain. The results suggest that peptide YY and neuropeptide Y may regulate the function of these regions of the brain through interaction with a common receptor site.

The role of cholecystokinin octapeptide in the central control of food intake in the dog

Cholecystokinin octapeptide (CCK-8, 1, 190 pmol/5 min) decreased food intake and water consumption in two models of ingestive behavior, i.e., food deprivation-induced feeding and insulin-induced feeding, when administered into the third (3V) and lateral (LV) cerebral ventricles. In fasted dogs, the suppression of food intake was more prominent after 3V CCK-8, whereas intravenously administered CCK-8 was without effect. Neuropeptide Y (NPY, 1, 190 pmol) had no significant stimulatory effect on food intake and water consumption in fasted as well as satiated dogs, and actually reduced both food and water intake in insulin-treated dogs. There was a slight but significant decrease in food and water intake after 275 nmol naloxone administration in both feeding models, and some of the dogs vomited. In insulin-treated animals, CCK-8 reversed, but NPY potentiated the hypothermic phase of temperature response observed after saline administration, whereas naloxone failed to alter rectal temperature. These results suggest that the effect of CCK-8 on feeding seems to involve central mechanisms in the dog, and that the mechanisms by which CCK-8, NPY and naloxone affect feeding behavior are different.

Proglumide has access to brain and antagonizes the central satiety effect of cholecystokinin octapeptide in the dog

Intra-third cerebroventricularly administered cholecystokinin octapeptide (CCK-8) decreased food intake through central mechanisms in the dog. Proglumide, administered intravenously, did enter into cerebrospinal (ventricular) fluid, and partially, but significantly, reversed this effect. CR1409, one of the newly synthesized glutaramic derivatives, blocked CCK-8-induced satiety more strongly than proglumide. These results indicate that systemic proglumide and CR1409 result in antagonism of the central CCK receptor for satiety in the dog.

Physiological antagonism between prostaglandin E2 and neuropeptide Y on thermoregulation in the dog

These experiments were undertaken to determine whether neuropeptide Y (NPY) could suppress a prostaglandin hyperthermia in conscious dogs. Prostaglandin E2 (PGE2) (5 micrograms), injected into the lateral cerebral ventricle (ILV), evoked a hyperthermia of approximately 1 degrees C. Addition of ILV NPY (5 micrograms) significantly attenuated the PGE2-induced hyperthermia, whereas pancreatic polypeptide (PP), another member of the PP family peptide, did not. These results provide evidence for a role of NPY on thermoregulation in the dog.

Mechanism of actions of cholecystokinin octapeptide on food intake and insulin and pancreatic polypeptide release in the dog.

We investigated the mechanism by which CCK-8 injected into the third cerebral ventricle (ITV administration) inhibits food intake and stimulates insulin and pancreatic polypeptide (PP) secretion in the dog. ITV administration of CCK-8 (4.08 micrograms/5 min) resulted in a significant elevation of plasma insulin and PP concentrations. This effect was abolished by truncal vagotomy and promptly inhibited by ITV administration of atropine (20 micrograms) and proglumide (10 mg). CCK-8 was less effective in increasing insulin and PP concentrations than in reducing feeding. Thus, 1.36 micrograms of ITV CCK-8 markedly reduced food intake to 14, 15, 29 and 31% of control values at 10, 30, 60 and 120 min, respectively. Atropine and naloxone (50 micrograms) had no blocking effect on CCK-8-induced satiety, whereas proglumide antagonized it. These results indicate that ITV CCK-8 effects the endocrine pancreas and food intake through atropine-sensitive and atropine-insensitive mechanisms, respectively, both of which are likely to be mediated by CNS CCK receptors. Intravenous CCK-8 also stimulated PP and insulin release, through mechanisms that were atropine-sensitive and atropine-insensitive, respectively. However, its mode of action, especially on insulin secretion, was quite different from that of ITV CCK-8. Therefore, exogenous CCK appears to act in the brain and the periphery in concert with and independently from cholinergic systems.

Effects of amino acids on pancreatic polypeptide before and after vagotomy in the dog

SummaryWe have previously indicated a marked influence of the vagus nerve on postprandial pancreatic polypeptide secretion. The present study was designed to determine whether the vagus nerve also plays a role in the regulation of pancreatic polypeptide secretion by absorbed nutrients. The pancreatic polypeptide responses to 17 intravenously administered amino acids, as well as arginine and glucose, were measured and compared with those 1 year after truncal vagotomy in conscious dogs. In response to the infusion of a mixture of amino acids (20 g during 60 min), plasma pancreatic polypeptide concentrations decreased in normal dogs. The effect was, however, completely reversed by vagotomy, with a significant pancreatic polypeptide release being observed (p < 0.05). Arginine (5 g during 60 min) also showed a similar, although not statistically significant, effect. After intravenous bolus-injection of glucose (0.5 g/kg body weight), a transient decrease of pancreatic polypeptide secretion was found; vagotomy abolished this response. These results suggest that the vagus nerve may have a suppressive role in the process of pancreatic polypeptide secretion induced by intravenous amino acid(s) and glucose.

Neuropeptide Y (NPY) の視床下部-下垂体-副腎系への作用に関する研究

There is increasing evidence that neuropeptide Y (NPY) affects the release of pituitary hormones, including adrenocorticotropic hormone (ACTH). The present study was designed to clarify the mechanism by which NPY activates the hypothalamic-pituitary-adrenal (HPA) axis in the dog. Mongrel dogs were equipped with a chronic cannula allowing intra-third (i.t.v.) or intra-lateral (i.l.v.) cerebroventricular administration. A 1.19 nmol, i.t.v. dose of NPY produced as great an ACTH and cortisol response as did equimolar ovine corticotropin releasing factor (CRF). This action of NPY was dose-dependent and shared by peptide YY (PYY) and pancreatic polypeptide (PP), other members of the PP family peptide. Intravenously (i.v.) administered NPY (1.19-11.9 nmol) was much less potent than i.v. CRF in stimulating ACTH and cortisol secretion. However, i.v. NPY significantly increased plasma ACTH and cortisol concentrations, raising the possibility that NPY may modulate the activity of corticotrophs. We next investigated the possible relationship between NPY and CRF on the HPA axis. Pretreatment with a novel CRF antagonist, alpha-helical CRF9-41 (130.9 nmol i.t.v. or 261.5 nmol i.v.), partly but significantly attenuated the ACTH and cortisol responses to i.t.v. NPY (1.19 nmol). Furthermore, adding a subthreshold dose of i.t.v. NPY (0.119 nmol) to i.t.v. CRF (1.19 nmol) or i.v. NPY (2.38 nmol) to i.v. CRF (0.595 nmol) resulted in the potentiation of CRF-induced ACTH secretion. These results indicate that NPY may activate the HPA axis in concert with CRF probably at hypothalamic and/or pituitary levels. The present findings that NPY evokes ACTH secretion and potentiates the effectiveness of CRF as a secretagogue, together with high concentrations of NPY in the hypothalamus and pituitary portal blood, suggest the NPY is involved in the multihormonal control of ACTH release.