Biomedical subjects

D H Coy

Publications and source records attributed to D H Coy.

At least 91 records · Page 5Linked to original sources

PubMed1996

Receptor-specific somatostatin analogs: correlations with biological activity.

A number of cyclic and linear somatostatin (SRIF) analogs have now been found to have promising levels of selectivity for rodent somatostatin receptors (rsst2,3,5), but not sst1 and sst4. Comparisons between binding affinities for these and transfected human receptors are just beginning to emerge and we present results from a comparison of affinities of several key families of peptides for sst2 present on rat AR42J cells and on cells transfected with human (h)sst2. The typical cyclic octapeptide analogs, octreotide, lanreotide, and RC-160, exhibited similar affinities to SRIF for rsst2, but somewhat lower affinities for the human receptor. Affinities of several analogs for transfected hsst5 were also measured. As with the rat receptor, octreotide-related analogs had low affinity for hsst5. The highly specific rsst5 analog, DC-23-99, was less so for the human receptor; however, a D-Tyr1 version of DC-23-99 had subnanomolar affinity (Ki, 0.68 nmol/L) and high selectivity. A new extended-ring analog, BIM-23268D, showed superior affinity to DC-23-99 and even to SRIF and SRIF-28 for hsst5 (K(i), 0.38 nmol/L), and had the highest sst5/sst2 selectivity ratio of any analog that we have tested thus far.

Amino Acid Sequence↗

PubMed1996

Role of endogenous bombesin-peptides during vagal stimulation of gastric acid secretion in the rat.

The stimulatory effect of exogenous bombesin and its related mammalian peptides on gastric acid secretion and gastrin release has been examined in detail, while the regulatory role of endogenously released bombesin-like peptides is largely unknown. Accordingly we have determined the effect of a specific bombesin receptor antagonist during vagal stimulation of gastric acid secretion and gastrin release. In anesthetized rats electrical stimulation of the vagal nerves (10 V, 10 Hz, 1 ms) significantly increased plasma gastrin levels by 82 +/- 11 pg/20 min (P < 0.01) and gastric acid output by 99.4 +/- 9.9 mueq/20 min (P < 0.01). Intravenous infusion of the specific bombesin receptor antagonist D-Phe6-BN(6-13)OMe (400 nmol/kg/h) significantly reduced vagally induced increase of plasma gastrin levels by 70% to 29 +/- 8 pg/20 min (P < 0.05 vs control) and vagally stimulated gastric acid output by 40% to 57.4 +/- 10.6 mueq/20 min (P < 0.05 vs control). To demonstrate that the residual gastrin and acid response is due to non-bombesinergic mechanisms and not to an inadequate dose of the receptor antagonist, the latter was tested against gastrin-releasing peptide (GRP) at the maximally effective concentration of 300 pmol/kg/h, which resulted in an even 50% higher increase of plasma gastrin levels compared to vagal stimulation. The dose of the antagonist employed (400 nmol/kg/h) was sufficient to abolish GRP-induced stimulation of gastrin and gastric acid secretion. Previously it has been postulated that endogenous bombesin-peptides can stimulate acid secretion via gastrin-independent mechanisms. To investigate this possibility further the effect of the antagonist was examined on vagally induced acid secretion while gastrin levels were restored to the range of the respective control experiments. In presence of the antagonist the infusion of gastrin-17 (15 pmol/kg/h) in addition to vagal stimulation elevated plasma gastrin to levels not different from those during vagal stimulation alone. With identical plasma gastrin levels the bombesin receptor antagonist had no effect on vagally stimulated acid secretion (86.3 +/- 10.7 mueq/20 min vs 99.4 +/- 9.9 mueq/20 min in the controls; n.s.). In conclusion, the present data demonstrate for the first time that in rats in vivo endogenous bombesin peptides contribute to vagal stimulation of gastrin release and gastric acid secretion. Furthermore, endogenous bombesin-peptides exert their action on parietal cell function via an increase of gastrin release, while non-gastrinergic mechanisms are unimportant under the experimental conditions employed.

Animals↗

PubMed1996

Proadrenomedullin NH2-terminal 20 peptide has cAMP-mediated vasodilator activity in the mesenteric vascular bed of the cat.

Responses to proadrenomedullin NH2-terminal 20 peptide (hPAMP), a truncated analogue [hPAMP(12-20)], and adrenomedullin (hADM) were investigated in the mesenteric vascular bed of the cat. Under constant-flow conditions, injections of hPAMP, hPAMP(12-20), and hADM caused dose-related decreases in mesenteric perfusion pressure. hADM was 100-fold more potent than hPAMP, and 1000-fold more potent than hPAMP(12-20). Vasodilator responses to hPAMP and hADM were not altered by adrenergic-blocking agents, were similar in innervated and denervated preparations, and were similar when tone was increased by sympathetic nerve stimulation or phenylephrine infusion. Vasodilator responses to hPAMP and hADM were increased in duration by rolipram, a cAMP phosphodiesterase inhibitor. The present data suggest that vasodilator responses to the hPAMP and hADM are mediated by an increase in cAMP and that an interaction with the adrenergic nervous system is not involved.

Adamantane↗

PubMed1996

Somatostatin receptor subtype 2 mediates somatostatin inhibition of ion secretion in rat distal colon.

BACKGROUND & AIMS: Somatostatin peptides are potent inhibitors of intestinal ion secretion, providing the rationale for their use in treating secretory diarrhea. However, the nature of the receptors that mediate these effects is unclear. The aims of this study were to investigate expression of somatostatin receptor subtypes (SSTRs) 1-5 in rat colonic epithelium and to identify which subtype(s) mediate inhibition of adenosine 3', 5'-cyclic monophosphate (cAMP)-activated secretion using SSTR-selective analogues. METHODS: SSTR expression was determined by reverse-transcription polymerase chain reaction and immunoblotting. Effects of somatostatin analogues on electrogenic ion secretion were studied in isolated colonic mucosa mounted in Ussing chambers. RESULTS: Crypt epithelium expressed messenger RNA for SSTR1 and SSTR2 and low levels of SSTR5. A splice variant of SSTR2 (SSTR2B) was also detected. The SSTR2 selective analogue NC-812 was a potent inhibitor of forskolin-activated secretion and cAMP accumulation. In contrast, peptides selective for SSTR3 (DC-25/12) and SSTR5 (DC-23/99) were weak inhibitors of secretion. NC-812 also inhibited dibutyryl cAMP-activated secretion, indicating a site of action distal to cAMP production. Immunoblot analysis confirmed expression of a 93-kilodalton SSTR2 protein in crypt cell membranes. CONCLUSIONS: SSTR2 receptors expressed by colonocytes mediate somatostatin's antisecretory actions in rat colon. Somatostatin analogues directed to specific SSTRs may provide the basis for more selective antidiarrheal drugs.

Animals↗

PubMed1996

Pituitary adenylate cyclase-activating polypeptide stimulates cholecystokinin secretion in STC-1 cells.

Secretion of cholecystokinin (CCK) from the endocrine cells of small intestinal mucosa and the murine intestinal tumor cell line STC-1 is known to involve both adenosine 3',5'-cyclic monophosphate (cAMP)-and Ca(2+)-dependent signal transduction pathways. However, the endogenous stimulant(s) that acts through the cAMP-dependent cascade has not been identified. We determined the effect of pituitary adenylate cyclase-activating polypeptide (PACAP) on CCK secretion and cAMP production and its interaction with other CCK secretagogues in STC-1 cells. At concentrations > 10 nM, PACAP-27 stimulated the release of large intestinal CCK from STC-1 cells in a time- and dose-dependent manner. The stimulatory effect of PACAP-27 was enhanced by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). PACAP-27, PACAP-38, and vasoactive intestinal polypeptide (VIP), with or without IBMX, were equally effective and potent to elicit CCK release with similar half-maximal doses and maximal levels of stimulation. Both forms of PACAP and VIP stimulated a transient but not significant increase in the cellular cAMP level. In the presence of IBMX, all three peptides increased significantly the cellular cAMP level between 2 and 5 min, but PACAP produced a two times higher level than VIP. The stimulatory effect of PACAP-27 on CCK release was also potentiated by bombesin and KCl but without a synergistic production of cAMP. With or without IBMX, PACAP-27-stimulated CCK secretion was not affected by the Ca2+ channel blocker diltiazem (1 microM), the cell-permeable Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA-AM; 25 microM), or by downregulation of protein kinase C. The stimulatory effects of KCl and bombesin were either reduced or abolished by these treatments. The synergistic effect of bombesin with PACAP was abolished by diltiazem and BAPTA-AM but not by downregulation of protein kinase C, whereas KCl remained synergistic with PACAP after these treatments. Taken together, these results indicate that PACAP may be a neuromodulator of CCK secretion that acts through activation of adenylate cyclase and may function as a coregulator with other CCK secretagogues that are known to increase intracellular Ca2+ concentration.

Animals↗

PubMed1996

Pulmonary vasodilator responses to adrenomedullin are reduced by NOS inhibitors in rats but not in cats.

Responses to and the mechanism of action of adrenomedullin (ADM), the carboxy-terminal fragments of ADM, and calcitonin gene-related peptide (CGRP), a structurally related peptide, were investigated in the pulmonary vascular bed of the rat. Under conditions of elevated tone and controlled pulmonary blood flow in the isolated blood-perfused rat lung, injections of ADM, the 15-52 amino acid carboxy-terminal ADM analogue (ADM15-52), and CGRP caused dose-related decreases in pulmonary arterial perfusion pressure. In contrast, the carboxy-terminal 22-52 and 40-52 amino acid fragments had no consistent vasodilator activity. After administration of the nitric oxide synthase inhibitors, N omega-nitro-L-arginine benzyl ester or N omega-nitro-L-arginine methyl ester (L-NAME), pulmonary vasodilator responses to ADM, to ADM15-52, to CGRP, to acetylcholine, and to bradykinin were significantly decreased in the rat, whereas vasodilator responses to isoproterenol and nitroglycerin were not changed. However, in the pulmonary vascular bed of the cat, L-NAME had no significant effect on vasodilator responses to ADM in doses that attenuated vasodilator responses to acetylcholine and bradykinin. L-NAME had no effect on responses to isoproterenol or nitric oxide. When the relative vasodilator activity of the active peptides was compared, ADM15-52 was approximately three-fold less potent than ADM, and ADM was threefold less potent than CGRP in decreasing pulmonary vascular resistance in the rat lung. When vasodilator responses were compared in the rat and cat, ADM was threefold more potent in decreasing pulmonary vascular vascular resistance in the cat than in the rat, and vasodilator responses to ADM were independent of the intervention used to raise tone in the rat. The present data demonstrate that ADM and ADM15-52 have significant vasodilator activity in the pulmonary vascular bed of the rat, and that responses to ADM, ADM15-52, and CGRP are dependent on the release of nitric oxide in the rat. The present results indicate that pulmonary vasodilator responses to ADM are not dependent on the release of nitric oxide in the cat and suggest that responses to the peptide are mediated by different mechanisms in the pulmonary vascular bed of the rat and cat.

Adrenomedullin↗

PubMed1996

Hindbrain GRP receptor blockade antagonizes feeding suppression by peripherally administered GRP.

Bombesin (BN)-like peptides injected peripherally or centrally suppress food intake in rats. The relationship between the central and peripheral actions of BN is unknown. However, experimental evidence supports a critical role for the caudal hindbrain in mediating the feeding effects of BN. To investigate this relationship further, we examined the ability of fourth ventricular infusion of a specific gastrin-releasing peptide (GRP) antagonist, [D-F5, Phe6, D-Ala11]BN-(6-13) methyl ester (BN-ME), to block suppression of glucose intake (0.5 kcal/ml) produced by intraperitoneal administration of GRP-(18-27) in 5-h food-deprived male Sprague-Dawley rats (n = 10). We found that fourth ventricular administration of 10, 32, and 100 ng BN-ME blocked the suppression of glucose intake produced by peripherally administered 10 nmol/kg GRP-(18-27). The most effective dose of BN-ME (100 ng) blocked the ability of peripheral injection of GRP-(18-27) to inhibit glucose intake but had no effect on intake when given alone. These results demonstrate that the availability of caudal hindbrain GRP receptors is necessary for peripherally administered GRP-(18-27) to reduce food intake in rats.

Animals↗

PubMed1996

Renal responses to intra-arterial administration of adrenomedullin in dogs.

The present study was undertaken to evaluate the renal responses to intra-arterial infusion (12.5 pmol.kg-1.min-1) for 30 min of adrenomedullin (ADM) in denervated kidneys of anesthetized dogs (n = 8). Total renal blood flow (RBF) was measured with an electromagnetic flow probe, and two single-fiber laser-Doppler needle flow probes were used to measure relative changes in cortical (CBF) and medullary blood flow (MBF). ADM administration resulted in decreases in renal vascular resistance (32.3 +/- 4.9 to 22.3 +/- 3.0 mmHg.ml-1.min.g) and increases in RBF (4.5 +/- 0.5 to 6.0 +/- 0.6 ml.min-1.g-1), CBF (33 +/- 1.3%, n = 41, and MBF (32 +/- 5.7%, n = 5) without changes in glomerular filtration rate. There were also substantial increases in urine flow (11.3 +/- 1.9 to 28 +/- 4.8 microliters.min-1.g-1), as well as in sodium excretion (1.8 +/- 0.2 to 4.2 +/- 0.6 microliter.min-1.g-1). After cessation of ADM infusion, partial recovery of these responses was observed within a 30-min period. Responses to ADM were attenuated during inhibition of nitric oxide (NO) synthesis by nitro-L-arginine (50 micrograms.kg-1.min-1). These findings indicate that renal vasodilator, diuretic, and natriuretic responses to ADM may be mediated by the release of endogenous NO and suggest that ADM could play a role in regulating water and electrolyte excretion by the kidney.

Adrenomedullin↗

PubMed1996

Catecholamine release mediates pressor effects of adrenomedullin-(15-22) in the rat.

Human adrenomedullin, a novel hypotensive peptide, contains a six-member ring structure similar to that found in calcitonin gene-related peptide and pancreatic amylin. Unlike the full-sequence peptide, human adrenomedullin-(15-22) [hADM-(15-22)], which contains the ring structure, increases systemic arterial pressure in the rat but not the cat. We undertook the present study to investigate the mechanism by which hADM-(15-22) increases systemic arterial pressure in the rat. Injection of hADM-(15-22) in doses of 10 to 300 nmol/kg i.v. increased systemic arterial pressure in a dose-dependent manner and was threefold less potent than norepinephrine when doses were compared on a nanomole basis. However, the ring structures of human calcitonin gene-related peptide and human amylin, human calcitonin gene-related peptide-(1-8) and human amylin-(1-8), respectively, had no significant effect on systemic arterial pressure in the rat. Pressor responses to hADM-(15-22) were reduced significantly after administration of phentolamine or reserpine. Responses to hADM-(15-22) were not altered by the angiotensin type 1 blocking agent DuP 753 or the endothelin-A/endothelin-B receptor blocking agent bosentan, and responses to hADM-(15-22) and the nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium (DMPP) were reduced after bilateral adrenalectomy. Pressor responses to DMPP were reduced by hexamethonium, whereas the nicotinic blocking agent had no effect on the pressor response to hADM-(15-22). These data suggest that increases in systemic arterial pressure in response to hADM-(15-22) in the rat are mediated by the activation of alpha-adrenergic receptors by catecholamines released from the adrenal medulla. The present data suggest that hADM-(15-22) releases catecholamines from the adrenal medulla by a noncholinergic mechanism.

Adrenalectomy↗

PubMed1995

Comparison of the peptide structural requirements for high affinity interaction with bombesin receptors.

Recently it has been established that both a gastrin-releasing peptide (GRP)-preferring bombesin receptor and a neuromedin B-preferring bombesin receptor mediate the mammalian actions of bombesin-related peptides. Because many tissues used for studies of the structure-activity relationship of these peptides possess both receptor subtypes and none possess only the neuromedin B-preferring subtype, there is minimal information on the peptide structural features determining receptor selectivity and it is unknown whether the determinants of agonism at both bombesin receptor subtypes are similar. In the present study we have used native cells either possessing only one bombesin receptor subtype or stably transfected with one subtype to study in detail the peptide structural requirements for interacting and activating each receptor subtype. For the naturally occurring agonists, at the GRP-preferring bombesin receptor the relative affinities were litorin = ranatensin = bombesin > GRP >> neuromedin B, phyllolitorin and at the neuromedin B-preferring bombesin receptor were litorin = neuromedin B = ranatensin > bombesin, phyllolitorin >> GRP. For the GRP-preferring bombesin receptor the heptapeptide and for the neuromedin B-preferring bombesin receptor the octapeptide was the minimal carboxyl fragment interacting with the receptor/or causing biologic activity, and the nonapeptide and full decapeptide, respectively, were the minimal required for full affinity. Making neuromedin B more bombesin- or GRP-like by replacing amino acids in position 3, 6, and 9 demonstrated that position 3 was the most important, followed by position 9 for receptor subtype selectivity. A conformationally restricted GRP analogue, [D-Cys6,D-Ala11,Cys14]bombesin-(6-14) had a significantly higher affinity for GRP-preferring bombesin receptor than NMB receptor. These results demonstrate that: (1) the structure-function relations for the two mammalian bombesin receptors have important differences; (2) suggest that the active conformation of neuromedin B must differ markedly from the beta-sheet model proposed for GRP; and (3) suggest that one important function of the NH2 terminus of GRP and neuromedin B is determining receptor subtype selectivity.

Amino Acid Sequence↗

PubMed1995

Distinct receptors mediate gastrin-releasing peptide and neuromedin beta-induced delay of gastric of liquids in rats.

The present study was carried out to define which bombesin receptors are involved in the delay of gastric emptying induced by bombesin-like peptides. Adult male rats were fitted with gastric and jugular vein cannulas. Gastric emptying was determined 5 min after a 3-ml intragastric load of 0.9 M NaCl using phenol red as a marker. Mammalian bombesin-like peptides gastrin-releasing peptide-10 and neuromedin B both induced a delay of gastric emptying. When [Phe6]bombesin-(6-13)-methyl ester, a selective antagonist of the gastrin-releasing peptide-preferring subtype of bombesin receptors, was injected 5 min before the agonists, the effect of gastrin-releasing peptide-10 was competitively inhibited, whereas that of neuromedin B remained unaffected. Our results indicate that gastrin-releasing peptide-10 and neuromedin B delay gastric emptying by acting on distinct receptors in rats, in vivo.

Animals↗

PubMed1995

Galanin inhibits cholecystokinin secretion in STC-1 cells.

Neuropeptides such as gastrin releasing peptide and pituitary adenylate cyclase activating polypeptide (PACAP) stimulate CCK secretion from CCK producing cells. We hypothesized that in addition to somatostatin, galanin may also play an inhibitory role on CCK secretion. The effect of galanin on CCK secretion was studied in a CCK-producing murine neuroendocrine tumor cell line, STC-1. Galanin below 10 nM did not affect basal CCK secretion but dose- and time-dependently inhibited KCl-stimulated CCK secretion. Galanin also inhibited forskolin-, bombesin- and PACAP- but not dibutyryl cAMP- or beta-TPA-stimulated CCK secretion. The inhibitory effect of galanin was reduced partially by a blocker of ATP-sensitive K+ channel (K+ ATP), glibenclamide, and prevented by pretreatment of the cells with PTX. The results indicated galanin regulates CCK secretion by modulation of K+ ATP and cAMP production through receptors coupled to a PTX-sensitive G protein.

Adenylate Cyclase Toxin↗

PubMed1995

Pituitary adenylate cyclase activating peptide receptors regulate the growth of non-small cell lung cancer cells.

We have identified pituitary adenylate cyclase activating peptide (PACAP) receptors on small cell lung cancer cell line NCI-N417 in a previous study. In this study, the role of PACAP in the growth and signal transduction of non-small cell lung cancer cells was investigated. Northern blot analysis with a full-length human PACAP receptor cDNA probe revealed a major 7.5-kb hybridizing transcript when total RNA extracted from NCI-H838 cells was used. PACAP bound with high affinity (Kd = 1 nM) to a single class of sites (Bmax = 14,000/cell) when NCI-H838 cells were used. Specific 125I-labeled PACAP binding was inhibited with high affinity by PACAP-27 and PACAP-38, with moderate affinity by PACAP(6-38), and with low affinity by vasoactive intestinal polypeptide, PACAP(28-38), and PACAP(16-38). PACAP-27 elevated cAMP in a dose-dependent manner, and the increase in cAMP caused by PACAP was reversed by PACAP(6-38). PACAP-27, but not vasoactive intestinal polypeptide, elevated cytosolic Ca2+ in individual NCI-H838 cells. PACAP-27 stimulated arachidonic acid release, and the increase caused by PACAP was reversed by PACAP(6-38). PACAP-27 stimulated colony formation in NCI-H838 cells, whereas the PACAP antagonist PACAP(6-38) reduced colony formation in the absence or presence of exogenous PACAP-27. In nude mice bearing NCI-H838 xenografts, PACAP(6-38) slowed tumor growth significantly. These data suggest that biologically active type 1 PACAP receptors are present on human non-small cell lung cancer cells, which exhibit dual signal transduction pathways and regulate cell proliferation.

Animals↗

PubMed1995

Three-dimensional quantitative structure-activity relationships of somatostatin analogues. 1. Comparative molecular field analysis of growth hormone release-inhibiting potencies.

Somatostatin is a hypothalamic hormone that inhibits the release of growth hormone (GH). It has also been shown to inhibit the release of a broad range of hormones including insulin, glucagon, and gastrin. Presently, five different receptor subtypes of somatostatin have been characterized and cloned. Our previous work on the structure-activity relationship of somatostatin and that of many others has generated a large database of analogues with different biological activities and receptor affinities. This present work is an investigation of the growth hormone release-inhibiting potencies of somatostatin analogues by the three-dimensional quantitative structure-activity paradigm, comparative molecular field analysis (CoMFA). A total of 64 analogues were modeled in SYBYL using structural information from two NMR studies. The molecules were aligned by a root-mean-square fit of atoms and field-fit of the steric and electrostatic molecular fields and the resulting databases analyzed by partial least squares analysis with cross-validation to extract the optimum number of components. The analysis was then repeated without cross-validation to give the final QSAR models. Preliminary investigations with the CoMFA models led to the synthesis of a new somatostatin analogue. This compound together with five other newly synthesized compounds not included in the original training sets were used to test the predictive ability of the CoMFA models. Two models with good predictive powers are presented.

Amino Acid Sequence↗

PubMed1995

Influence of intracisternal injection of somatostatin analog receptor subtypes 2, 3 and 5 on gastric acid secretion in conscious rats.

Somatostatin (SST) and its analogs injected into the CSF induce different gastric acid response patterns. Five SST receptors have been characterized (SSTR-1 to -5). We studied the influence of selective SSTR-2, -3 and -5 ligands on basal gastric acid secretion after intracisternal (i.c.) injection in conscious rats equipped with chronic gastric and i.c. cannulae. Compared with pre-injection level, the SSTR-3 agonist, BIM-23056 (1 microgram) increased acid secretion by 274 +/- 43% while the SSTR-2 agonist, DC 32-87 (1 microgram) inhibited acid secretion by 50.7 +/- 13.3%. SST-14 (1 microgram), the SSTR-5 agonist, BIM-23052, (0.5-1 microgram), SSTR-3 (0.5 micrograms) and -2 (0.5 microgram) or vehicle injected i.c. did not modify basal acid secretion. These results show that the activation of brainstem SSTR-3 receptors stimulate and SSTR-2 inhibit basal gastric acid secretion in conscious rats with chronic gastric fistulae.

Amino Acid Sequence↗

PubMed1995

Comparison of responses to adrenomedullin and adrenomedullin analogs in the mesenteric vascular bed of the cat.

Responses to adrenomedullin, a newly discovered hypotensive peptide isolated from human pheochromocytoma cells, and the carboxy terminal 15-52 (adrenomedullin-(15-52)) and 22-52 (adrenomedullin-(22-52)) amino acid fragments of adrenomedullin were investigated in the mesenteric vascular bed of the cat. Under constant flow conditions, injections of adrenomedullin, adrenomedullin-(15-52), and calcitonin gene-related peptide (CGRP) in doses of 0.003-1 nmol into the perfused superior mesenteric artery caused significant dose-related decreases in mesenteric arterial perfusion pressure. Mesenteric vasodilator responses to adrenomedullin and adrenomedullin-(15-52) were similar in magnitude and duration, while vasodilator responses to CGRP were greater in magnitude and longer in duration than those produced by adrenomedullin or adrenomedullin-(15-52) when these agents were injected in doses of 0.1-1 nmol. Adrenomedullin-(22-52) caused no significant change in mesenteric arterial perfusion pressure when injected in doses up to 10 nmol. These results suggest that amino acids 15-52 and the six-membered ring structure of adrenomedullin are important for the expression of vasodilator activity in the mesenteric vascular bed of the cat.

Adrenomedullin↗

PubMed1995

Somatostatin analogues and multiple receptors: possible physiological roles.

The availability of transfected cell lines expressing the five cloned somatostatin receptors has allowed extensive families of synthetic analogues to be screened for their binding affinities to these receptors. Cyclic octapeptides in the octreotide series have high affinity for sstr2 and low affinity for sstr1 and sstr4. Modifications to these analogues can have profound effects on their residual affinity for sstr3 and sstr5. Several linear peptides, incorporating the critical core-D-Trp-Lys-sequence of all active analogues, exhibit selectivity for either sstr3, sstr5 or both, but little affinity for the other three. From these analogues we have assembled a panel of compounds with a useful degree of specificity for sstr2, sstr3 and sstr5 and these have been used to evaluate receptor involvement in various physiological processes. Inhibition of pituitary growth hormone release correlates completely with sstr2 affinity and it appears from preliminary results that inhibition of pancreatic glucagon release is also sstr2 mediated. Effects on gastric acid secretion show a high degree of dependence on sstr2 affinity. Inhibition in vivo by somatostatin of insulin release, amylase release and binding to rat pancreatic acinar cells is highly correlated with sstr5 receptor affinity. Gastric smooth muscle cells have particularly high affinity for sstr3 receptor ligands. The availability of receptor-specific ligands is proving to be of great value in elucidating the physiological roles of each receptor. It is anticipated that these and future generations of analogues will have distinct therapeutic advantages over somatostatin itself and presently available cyclic octapeptides.

Amino Acid Sequence↗

PubMed1995

Fourth ventricular injection of the bombesin receptor antagonist [D-Phe6]bombesin(6-13)methyl ester, but not BW2258U89, increases food intake in rats.

To investigate the role of endogenous bombesin-like peptides in the caudal brainstem for the short-term control of food intake, we evaluated the effects of fourth-ventricular injections of two different bombesin (BN) receptor antagonists, [D-Phe6]BN(6-13) methyl ester and BW2258U89, on intake of sweetened, condensed milk in male rats. Although fourth-ventricular administration of BW2258U89 (0.125-20 ng) had no effect on food intake, fourth-ventricular injections of 1.0-20.0 ng of [D-Phe6BN(6-13) methyl ester resulted in an inverted U-shaped, dose-response curve with a maximal effect at 2.5 ng. Microstructural analysis of the licking behavior indicated that the increase in intake was primarily the result of an increased number of licks and an increase in lick efficiency. Behavioral time sampling demonstrated that these changes in intake occurred without the appearance of any competing behavior or significant change in the overall pattern of behavior. Because [D-Phe6BN(6-13) methyl ester appears to be a preferential antagonist at the GRP-preferring receptor, the increased intake that occurred after its administration suggests that an endogenous GRP-mechanism in the caudal brainstem is necessary for the normal, short-term control of sweet milk intake under these conditions.

Animals↗