Biomedical subjects

D H Coy

Publications and source records attributed to D H Coy.

At least 109 records · Page 6Linked to original sources

PubMed1995

Activation of somatostatin receptor subtype 2 inhibits acid secretion in rats.

Somatostatin is a potent inhibitor of gastric acid secretion. Recently, at least five distinct somatostatin receptor subtypes (SSTR) have been characterized and evaluated using relatively selective peptide analogues of somatostatin. We sought to determine which somatostatin receptor subtypes are involved in peripheral regulation of gastric acid secretion. Fasted, male Sprague-Dawley rats were anesthetized and were implanted with a double-lumen cannula in the stomach. Acid secretion was measured in gastric samples collected every 10 min by backtitration to pH 7. After a 30-min basal period, a 2-h intravenous infusion of pentagastrin (24 micrograms.kg-1.h-1 i.v.) was started. During the second pentagastrin hour, a 1-h intravenous infusion of either vehicle (0.1% canine serum albumin in 0.9% saline) or somatostatin receptor agonists was begun. The somatostatin receptor agonists included peptides with relative specificity for SSTR1-5 (somatostatin-14; 10 nmol.kg-1.h-1); SSTR2, SSTR3, and SSTR5 [SMS-(201-995); 10 nmol.kg-1.h-1]; SSTR2 (1-1,000 nmol.kg-1.h-1); SSTR3 (10-1,000 nmol.kg-1.h-1); and SSTR5 (10-1,000 nmol.kg-1.h-1). The SSTR2 agonist decreased pentagastrin-stimulated acid secretion dose dependently, from 82 +/- 7% of maximum acid output at 1 nmol.kg-1.h-1 to 4 +/- 7% of maximum at 100 nmol.kg-1.h-1. At 10 nmol.kg-1.h-1, the SSTR2 agonist inhibited acid secretion (40 +/- 7% of maximum) similarly to somatostatin (37 +/- 4% of maximum) and SMS-(201-995) (31 +/- 4% of maximum). The SSTR2 agonist inhibited acid secretion approximately 10- to 100-fold more potently than either the SSTR3 or the SSTR5 agonist. These results indicate that somatostatin regulates gastric acid secretion by activation of SSTR2 receptors.

Animals↗

PubMed1995

Somatostatin receptor subtype 3 mediates the inhibitory action of somatostatin on gastric smooth muscle cells.

Previous functional studies show that somatostatin (SS) interacts with specific receptors to inhibit relaxation in gastric smooth muscle cells. There are no ligand binding studies, and it is unknown which of the five subtypes of SS receptors mediates the action. Dispersed gastric smooth muscle cells from guinea pig bound both 125I-labeled SS-14 and 125I-D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-Nal-NH2 (where Nal indicates N-naphthylalanine) (cyclo-SS-8), a synthetic peptidase-resistant octapeptide SS analogue. SS-28 and SS-14, cyclo-SS-8, and SS analogue D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol [SMS-(201-995) (octreotide)] inhibited 125I-cyclo-SS-8 binding with relative potencies of SS-28 = cyclo-SS-8 = SMS-(201-995) (octreotide), and the binding was not affected by the addition of protease inhibitors. SS-14 caused inhibition only in the presence of protease inhibitors. Ligand analysis demonstrated a two-binding-site model. Analysis of the relationship between biological function and binding suggested the high-affinity sites mediated the relaxant action of SS. 5'-Guanylylimidodiphosphate [Gpp-(NH)p] inhibited binding by reducing the affinity of the high-affinity site. Six SS-8 analogues that distinguish SS subtypes showed that 125I-SS-14 bound to somatostatin receptor subtype 3 (SSTR3). The results demonstrated that gastric smooth muscle cells possess distinct receptors for SS of the SSTR3 subtype. Occupation of these sites inhibits relaxation in gastric smooth muscle cells. Modulation between the high- and low- affinity binding states of SSTR3 is at least partially mediated by activation of guanine nucleotide regulatory proteins.

Animals↗

PubMed1995

Expression of somatostatin receptor genes and their role in inhibiting Cl- secretion in HT-29cl.19A colonocytes.

Recent studies in a cultured model of the intestinal epithelium (HT-29cl.19A) have shown that somatostatin-14 (SS-14) inhibits the Cl- secretory process by acting at multiple G protein-dependent sites. These actions may underlie the antidiarrheal properties of SS peptides. This study has investigated the expression of specific SS receptor subtypes (SSTR) in HT-29cl.19A and examined their role in mediating SS antisecretory actions. Two predominant SSTR, SSTR1 and SSTR2, were identified by reverse transcriptase-polymerase chain reaction (RT-PCR) of mRNA from polarized HT-29cl.19A monolayers. Receptor binding studies showed evidence of two distinct populations of binding sites consistent with the known properties of SSTR1 and SSTR2. The role of SSTR in inhibition of secretion was investigated by comparing the effectiveness of native and synthetic SS peptides on adenosine 3',5'-cyclic monophosphate (cAMP)-dependent Cl- secretion. Secretion stimulated by the receptor-mediated agonist prostaglandin E2 (PGE2) was inhibited > 70% by SS-14 with a 50% effective concentration (EC50) of 32 nM. In contrast, SMS-201-995 (SMS) and RC-160 exhibited little or no antisecretory activity (maximum inhibition of 15 +/- 1.9 and 2.8 +/- 1.9%, respectively, at 100 microM; EC50 > 1.5 microM). Similar effects on PGE2-stimulated cAMP accumulation were also observed. SS-14, but not SMS, also inhibited secretion stimulated by dibutyryl cAMP, which acts independently of changes in cellular cAMP. Pretreatment with pertussis toxin reversed the antisecretory effects of SS peptides.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗

PubMed1995

A comparison of the effects of human and ovine corticotropin-releasing hormone on the pituitary-adrenal axis.

To compare the clinical efficacy of ovine and human sequence corticotropin-releasing hormone (CRH), we examined the effects of both peptides on ACTH and cortisol secretion in normal human volunteers, obese subjects, and patients with pituitary-dependent (Cushing's disease) and adrenal-dependent Cushing's syndrome. All subjects in each group were studied twice in random order. One hundred micrograms of CRH were administered as an iv bolus through an in-dwelling forearm cannula at 0930 h, and thereafter, blood was drawn every 15 min for 2 h for the measurement of ACTH and cortisol. In the normal subjects, the peak ACTH, peak incremental ACTH, and mean area under the curve after CRH treatment were greater with ovine CRH than human CRH, although there was no difference in the cortisol response, however it was analyzed. There was no difference in the ACTH or cortisol response to the two preparations in the obese subjects, and no significant difference was found, for either cortisol or ACTH, between obese subjects and normal volunteers. With both varieties of CRH, Cushing's disease resulted in greater responses for ACTH and cortisol than those seen in the other 2 groups (P < 0.001 for all comparisons), but there was no difference between the sequences. However, a significant cortisol response, defined as an increase of greater than 4 times the coefficient of variation of the assay (24%), was seen in all 10 Cushing's patients with human CRH, but in only 8 with ovine CRH. In 3 patients with adrenal tumors, serum cortisol did not change after the administration of either preparation, whereas plasma ACTH remained undetectable throughout the study. We suggest that although ovine sequence CRH causes more prolonged and greater ACTH, and possibly cortisol, secretion compared to human CRH, the discriminatory value of the CRH test, in terms of either the diagnosis or differential diagnosis of Cushing's syndrome, is comparable for the two peptide sequences.

Adrenocorticotropic Hormone↗

PubMed1995

Interaction of galanin fragments with galanin receptors on isolated smooth muscle cells from guinea pig stomach: identification of a novel galanin receptor subtype.

From structure-function studies it has been proposed that two subtypes of receptors may mediate galanin's actions in the gastrointestinal tract and other tissues and their effects can be either direct or neurally mediated. We have recently demonstrated that isolated gastric smooth muscle cells possess high-affinity galanin receptors, activation of which increases AMP and causes relaxation. Because this cell system contains no neural elements, contains a single class of galanin receptors and allows binding to be correlated with function, it is a good system to investigate peptide requirements for cell activation. Porcine galanin (p-Gal) and rat galanin (r-Gal) were equipotent to the NH2-terminal fragments r,p-Gal(1-10), r,p-Gal(1-15), r,p-Gal(1-20), p-Gal(2-29) and p-Gal(3-29) at inhibiting binding of 125I-galanin to gastric smooth muscle cells from guinea pig (Kd 5-8 nM). The midmolecule fragment p-Gal(9-25) and the long COOH-terminal fragment r-Gal(9-29) were equipotent and 25-fold less potent than p-Gal. Acetylation of r-Gal(9-29) increased potency to that of p-Gal. The short COOH-terminal fragment, p-Gal(21-29) and r-Gal(21-29), had very low affinity (Kd 3 microM). Each peptide alone (1 microM) caused no effect on cell length, but inhibited carbachol-induced contraction. The inhibition was 81% to 92% for r-Gal or p-Gal, r,p-Gal(1-10), r,p-Gal(1-15), r,p-Gal(1-20), p-Gal(2-29), p-Gal(3-29) and Ac-r-Gal(9-29); 47% for p-Gal(9-25) and r-Gal(9-29); and 16% to 17% for p-Gal(21-29).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Peptide structural requirements for antagonism differ between the two mammalian bombesin receptor subtypes.

Recently it has been established that both a gastrin-releasing peptide (GRP) receptor and a neuromedin B (NMB) receptor mediate the actions of bombesin-related peptides in mammals. Five different classes of peptides that function as GRP receptor antagonists have been identified; however, it is unknown whether similar strategies will yield antagonists for the closely related NMB receptor. In the present study we have used either native cells possessing only one bombesin (Bn) receptor subtype or cells stably transfected with one subtype to determine whether using the strategies that were used successfully for GRP receptors would allow NMB receptor antagonists to be identified. [DPhe12]Bn analogs; des Met14 amides, esters and alkylamides; psi 13-14 Bn pseudopeptides; and D-amino acid-substituted analogs of substance P (SP) or SP(4-11) were all synthesized and each functioned as a GRP receptor antagonist. All of these antagonists had low affinity for the NMB receptor. Application of similar strategies to NMB by formation of [DPhe8]NMB, [psi 9-10]NMB pseudopeptides, des-Met10 NMB amides, alkylamide or esters did not result in any potent NMB receptor antagonists. D-Amino acid SP and SP(4-11) analogs were weakly selective NMB receptor antagonists. No COOH-terminal fragments of NMB or GRP functioned as a GRP or NMB receptor antagonist. These results demonstrate that none of the known strategies used to prepare peptide GRP receptor antagonists are successful at the NMB receptor, suggesting that a different strategy will be needed for this peptide, such as the formation of somatostatin octapeptide or D-amino acid-substituted substance P analogs. These results suggest that even though there is a close homology between GRP and NMB and their receptors, their structure-function relations are markedly different. These results indicate that the development of receptor subtype-specific peptide agonists or peptide antagonists for newly discovered receptor subtypes of gastrointestinal hormones/neurotransmitters may be difficult because the strategies developed for one well-studied subtype may not apply to the other even though it is structurally closely related.

3T3 Cells↗

PubMed1995

Comparative effects of adrenomedullin, an adrenomedullin analog, and CGRP in the pulmonary vascular bed of the cat and rat.

Responses to synthetic human adrenomedullin (ADM), a novel hypotensive peptide initially isolated from human pheochromocytoma cells, an ADM analog (ADM15-52), and a structurally related peptide, calcitonin gene-related peptide (CGRP), were compared in the pulmonary vascular bed of the cat and rat under constant flow conditions. When tone was increased with U46619, intraarterial injections of ADM (0.03-0.3 nmol), ADM15-52 (0.03-0.3 nmol), and of CGRP (0.03-0.3 nmol) caused dose-related decreases in pulmonary arterial perfusion pressure. When the relative vasodilator activity of the peptides was compared on a nmol basis, ADM was approximately 10-fold more potent in the cat than in the rat, whereas vasodilator responses to CGRP were very similar in both species. CGRP was slightly more potent than ADM in the rat, whereas ADM was slightly more potent than CGRP in the cat. ADM and ADM15-52 had similar pulmonary vasodilator activity in the cat, whereas the full sequence peptide was slightly more potent than ADM15-52 in the rat. The present data demonstrate that ADM has significant vasodilator activity in the pulmonary vascular beds of the cat and of the rat, and that the relative potency of the vasodilator effects of ADM and ADM15-52 are different in the two species.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1994

Blockade of feeding inhibition by neuromedin B using a selective receptor antagonist.

The ability of a selective neuromedin B receptor antagonist, D-Nal-cyclo[Cys-Tyr-D-Trp-Orn-Val-Cys]-Nal-NH2 (BIM-23127), to block suppression of food intake produced by the mammalian bombesin-like peptides neuromedin B and neuromedin C was examined. BIM-23127 completely blocked suppression of intake produced by neuromedin B but not by neuromedin C. These results suggest an independent role for neuromedin B receptors in suppression of food intake by bombesin-like peptides and demonstrate the utility of this group of antagonists for in vivo experiments.

Animals↗

PubMed1994

Specific inhibition of rat pancreatic insulin or glucagon release by receptor-selective somatostatin analogs.

A group of new peptide ligands displaying high selectivity for binding to somatostatin receptor subtypes 2, 3 or 5 have been used to characterize somatostatin receptor involvement in the inhibition of glucagon secretion in rats. It was found that NC-8-12 and DC-25-100, which have high affinity for SSTR2 and much less affinity for the type 5 receptor, were by far the most potent inhibitors of glucagon secretion with EC50s of 48 and 18 nmole, respectively, relative to somatostatin itself (EC50 131 nmole). These two analogs were actually much less potent than somatostatin in inhibiting glucose-stimulated insulin release. In contrast, DC-23-99 (a type 5 receptor selective analog), which was previously found to be a more potent inhibitor of insulin secretion than somatostatin, had considerably less potent (EC50 410 nmole) effects on glucagon release. The SSTR3-specific ligands, DC-25-12 and DC-25-20, were not effective at the doses tested. The differing spectra of activities of these analogs suggest that inhibition of insulin and glucagon secretion in rats is mediated by entirely different somatostatin receptor populations.

Amino Acid Sequence↗

PubMed1994

Gastrin releasing peptide-preferring bombesin binding sites in human lung.

Characterization of bombesin binding sites in healthy human lung was performed through direct binding techniques. There was limited binding in the absence of trypsin and chymotrypsin inhibitors, suggesting important activities of both enzymes in human lung and/or increased sensitivity of the bombesin sites toward them. In human lung membranes, bombesin, gastrin releasing peptide (GRP) and GRP-preferring bombesin receptor antagonists displaced [125I-Tyr4]bombesin binding with high affinities (36-177 nM), whereas neuromedin B possessed a lower affinity of 2878 nM. [D-F5Phe6,D-Ala11]bombesin-(6-13)-methyl ester, the most active GRP-preferring bombesin antagonist as yet reported, had the highest affinity among all antagonists tested whereas neuromedin B had the lowest affinity. These data demonstrate that the bombesin binding sites in the human lung are of the GRP-preferring type.

Binding Sites↗

PubMed1994

Comparison of responses to adrenomedullin and calcitonin gene-related peptide in the pulmonary vascular bed of the cat.

Pulmonary vascular responses to the newly discovered hypotensive peptide, adrenomedullin, were compared with responses to the structurally related peptides, calcitonin gene-related peptide (CGRP) and amylin, in the intact-chest cat. Under conditions of controlled blood flow, when tone in the pulmonary vascular bed had been raised to a high steady level, intralobar injections of adrenomedullin (0.03-1 nmol), CGRP (0.1-3 nmol), and amylin (0.1 and 0.3 nmol) caused dose-related decreases in lobar arterial pressure without changing left atrial pressure. In terms of relative vasodilator activity in the pulmonary vascular bed, the dose of the peptide that decreased lobar arterial pressure 7.5 mm Hg (ED7.5 mm Hg) was significantly lower for adrenomedullin than for CGRP. The duration of the pulmonary vasodilator responses to CGRP was longer than for adrenomedullin, and both peptides decreased systemic arterial pressure when injected into the perfused lobar artery in the higher doses studied. The present data demonstrate that synthetic human adrenomedullin and CGRP have potent but relatively short-lasting vasodilator activity in the pulmonary vascular bed. These data show also that amylin, a structurally related pancreatic peptide, also has significant pulmonary vasodilator activity.

Adrenomedullin↗

PubMed1994

The somatostatin receptor subtype on rat enterochromaffinlike cells.

BACKGROUND/AIMS: Gastric enterochromaffinlike (ECL) cells play an important role in peripheral regulation of acid secretion. This study investigated the somatostatin receptor subtype on ECL cells. METHODS: ECL cells were isolated from rat fundic mucosa to a purity of 90%-95% by combining enzymatic digestion, elutriation, density gradient centrifugation, and culture. RESULTS: Polymerase chain reaction performed with templates from an ECL cell complementary DNA library and primers specific to each of the five known somatostatin receptor subtypes showed that the somatostatin receptor type 2 was significantly enriched in ECL complementary DNA. Single cell videoimaging of highly purified ECL cells in culture showed that only the somatostatin receptor type 2 selective agonist, DC 32-87, inhibited the gastrin-induced calcium signal at 10(-11) mol/L. The type 3 and type 4 selective agonists, DC 25-12 and DC 32-92, and also somatostatin 14 required 100-1000 times higher concentrations (10(-8) mol/L). The somatostatin receptor type 2 analogue also inhibited gastrin-stimulated histamine release with a 50% inhibitory concentration (IC50) value of 2 x 10(-12) mol/L, whereas somatostatin 14 and the type 3 and 4 analogues showed IC50 values of 1 to 5 x 10(-9) mol/L. CONCLUSIONS: The predominant somatostatin receptors on rat gastric ECL cells are of the somatostatin receptor 2 subtype; they inhibit histamine secretion by interfering with the gastrin-induced calcium signal.

Amino Acid Sequence↗

PubMed1994

Synthetic human adrenomedullin and ADM15-52 have potent short-lasting vasodilator activity in the pulmonary vascular bed of the cat.

Responses to synthetic human adrenomedullin, a novel hypotensive peptide localized in several organ systems, including the lung, and the carboxy terminal 15-52 amino acid fragment of adrenomedullin (ADM15-52) were investigated in the pulmonary vascular bed of the intact-chest cat. Under constant flow conditions when baseline tone in the pulmonary vascular bed was raised to a high steady level, injections of adrenomedullin and ADM15-52 into the perfused lobar artery in doses of 0.1-1 nmol, caused significant dose-related decreases in lobar arterial pressure. Since left atrial pressure was unchanged, the decreases in lobar arterial pressure reflect decreases in pulmonary lobar vascular resistance. Adrenomedullin and ADM15-52 exhibited similar vasodilator activity and were approximately 3-fold more potent than bradykinin in the pulmonary vascular bed of the cat. Pulmonary vasodilator responses to adrenomedullin and ADM15-52 were rapid in onset and lasted for 150-200 sec, depending on the dose of the peptide injected. The present results demonstrate that synthetic human adrenomedullin and ADM15-52 possess potent, short-lasting vasodilator activity in the pulmonary vascular bed of the cat and suggest that amino acids 15-52 in the peptide are important for the expression of vasodilator activity in the pulmonary vascular bed of the cat.

Adrenomedullin↗

PubMed1994

Synthetic human adrenomedullin and adrenomedullin 15-52 have potent short-lived vasodilator activity in the hindlimb vascular bed of the cat.

Responses to synthetic human adrenomedullin, a novel hypotensive peptide isolated from human pheochromocytoma cells, and the carboxy terminal 15-52 amino acid fragment of adrenomedullin (ADM15-52) were investigated in the hindlimb vascular bed of the cat under constant flow conditions. Intraarterial injections of the peptides in doses of 0.01-0.3 nmol caused dose-related decreases in hindlimb perfusion pressure. When compared on a nmol basis, adrenomedullin and ADM15-52 were similar to bradykinin in vasodilator potency and were approximately 10 fold less potent than acetylcholine. The half-life of the vasodilator response to adrenomedullin and ADM15-52 ranged from 55 to 80 sec and was greater than the half-life of vasodilator responses to bradykinin in doses of 0.01-0.3 nmol and acetylcholine in doses of 0.01-0.3 nmol. The present data demonstrate that synthetic human adrenomedullin and ADM15-52 have potent but relatively short-lasting vasodilator activity in the hindlimb vascular bed of the cat. These data suggest that amino acid residues 15-52 of adrenomedullin are important for the expression of vasodilator activity in the hindlimb vascular bed of the cat.

Adrenomedullin↗

PubMed1994

Effects of an LHRH antagonist on the time of occurrence and amplitude of the preovulatory LH surge, progesterone and estradiol secretion, and ovulation in superovulated Holstein heifers.

Beginning on Day 10 or 11 of the estrous cycle, mature Holstein heifers were given a superovulatory regimen of twice-daily injections of porcine FSH, together with injections of PG with the fifth and sixth FSH injections. Every 12 h from 24 to 60 h after PG administration, the animals received im injections of different doses of the LH releasing hormone antagonist [N-Ac-D-Nal(2)(1), D-pCl-Phe(2), D-Trp(3), D-Arg(6), D-Ala(10)]-LHRH or vehicle. Follicular development was monitored by transrectal ultrasonography every 12 h from 24 to 120 h after PG administration. All animals were given hCG at 72 h after PG injection, and were artificially inseminated. At Day 7 of gestation, the corpora lutea were counted by ultrasonography, and embryos were collected by nonsurgical flushing of the uterus. Treatment with the antagonist resulted in a dose-dependent decrease in the amplitude of the LH surge and in delays in the time of occurrence of the LH surge, ovulation and the shift from estradiol to progesterone production. These results indicate that LHRH antagonists can be used to delay the LH surge and ovulation in superovulated heifers. This finding may be beneficial to studies in the superovulation of cattle.

Journal Article↗

PubMed1994

Structure-activity relationships for relaxation of smooth muscle by VIP.

Utilizing VIP and five VIP analogues, concentration-response curves for relaxation of rat mesenteric artery and rat gastric longitudinal muscle were determined for comparison with our previously published radioligand binding data on rat smooth muscle and other tissues. The biological potency of the VIP analogues in the present study compared more closely with their potency for VIP receptor binding in smooth muscle tissue (arteries) vs. other tissues (pituitary, brain, liver).

Animals↗

PubMed1994

Bombesin receptor subtype mediation of gastroenteropancreatic hormone secretion in rats.

Bombesin is a potent releaser of many gut and pancreatic hormones including gastrin, glucose-dependent insulinotropic polypeptide (GIP), pancreatic polypeptide (PP), cholecystokinin (CCK), enteroglucagon, and insulin. Three mammalian bombesin-like peptides, gastrin-releasing peptide (GRP), neuromedin C (NMC or GRP-10), and neuromedin B (NMB), and two bombesin receptor subtypes, GRP preferring and NMB preferring, have been characterized. We used a highly potent, selective antagonist of the GRP-preferring receptor, [D-Phe6]bombesine(6-13)-methylester ([D-Phe6]Bn(6-13)OMe), to determine the receptor subtype mediating bombesin-induced secretion of gastrin, GIP, PP, peptide YY (PYY), and insulin, as well as the importance of endogenous bombesin-like peptides in controlling basal secretion of these hormones. Unanesthetized rats received femoral vein infusion of saline, bombesin (10 nmol/kg/h), [D-Phe6]Bn(6-13)OMe (1000 nmol/kg/h), or bombesin plus [D-Phe6]Bn(6-13)OMe. Blood was withdrawn from jugular vein catheters before and 30 min after the start of infusions. Plasma gastrin, GIP, PP, PYY, and insulin were measured by specific radioimmunoassays. [D-Phe6]Bn(6-13)OMe alone reduced basal insulin levels by 28% (p < 0.05) but did not alter basal levels of plasma PP, GIP, PYY, or gastrin (p > 0.05 for each). Bombesin infusion significantly increased plasma levels of each hormone (p < 0.0001 for each). [D-Phe6]Bn(6-13)OMe completely blocked bombesin-induced increases in PP, insulin, and gastrin, and almost completely blocked increases in GIP and PYY (p < 0.01 for each). Our results suggest that (a) exogenous bombesin significantly stimulates PP, insulin, GIP, PYY, and gastrin secretion, (b) bombesin-induced secretion of these hormones is primarily mediated by the GRP-preferring receptor, and (c) an endogenous bombesin-like peptide acting at this receptor subtype plays an important physiological role in control of basal secretion of insulin but not PP, GIP, PYY, or gastrin.

Animals↗

PubMed1994

Characterization of somatostatin receptor subtypes controlling rat gastric acid and pancreatic amylase release.

An examination of the binding characteristics of a large number of somatostatin analogues with respect to the five known somatostatin receptor subtypes has recently resulted in the discovery of several peptides with some selectivity for types 2, 3, and 4 and little affinity for type 1 or 5 receptor. A panel of these peptides has thus far implicated type 2 receptors in the inhibition of release of pituitary growth hormone and type 4 receptors in inhibiting pancreatic insulin release. In the present article, we have examined the inhibitory effects of the same group of peptides on in vivo rat gastric acid and pancreatic amylase release and binding to rat pancreatic acinar cells. The type 2-selective ligand NC-8-12 was a potent inhibitor of gastric acid release (EC50s in the 1.5 nM region) whereas the type 4-selective ligand, DC-23-99, elicited little response. However, some involvement of type 3 receptors could not be ruled out because the type 3-selective analogue, DC-25-20, exhibited inhibitory effects at higher dose levels (EC50 > 10 nM). Conversely, the type 4 analogue was a potent inhibitor of amylase release (EC50 1.1 nM) whereas the type 3 analogue had no significant effects at doses tested. DC-23-99 also bound with high affinity to rat acinar cells (EC50 3.8 nM), whereas DC-25-20 exhibited more than 10-fold less affinity. Thus, these two major biological functions of somatostatin appear to be controlled by different receptors and, furthermore, effects on both endocrine and exocrine pancreas appear to be type 4 receptor mediated.

Amino Acid Sequence↗