Further evidence from functional studies for somatostatin receptor heterogeneity in guinea‐pig isolated ileum, vas deferens and right atrium

Feniuk, W.; Dimech, J.; Jarvie, Emma M.; Humphrey, P. P. A.

doi:10.1111/j.1476-5381.1995.tb15906.x

Cited by 15 publications

(12 citation statements)

References 14 publications

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“…Although EC 50 values could not be calculated, lower concentrations of octreotide and BIM-23027 than of SRIF were necessary to inhibit MMCs, consistent with an action at sst 2 receptors. BIM-23027 was about three times more potent than SRIF at inhibiting neurogenic contractions of the guinea pig ileum (15), and a similar potency order was observed for sst 2 -mediated inhibition of rat parietal cell secretion (43) and rat colon contractions (33).…”

Section: Discussionmentioning

confidence: 78%

“…Octreotide and BIM-23027 are agonists with some selectivity for the sst 2 receptor, but each has additional agonist activity at sst 5 receptors, whereas Cyanamid154806 (Cyn) and BIM-23056 are antago-nists for sst 2 and sst 5 receptors, respectively (2,42). In this respect, BIM-23027 has been shown to inhibit neurogenically mediated contraction in the guinea pig ileum (15), whereas octreotide modulates gastrointestinal motility in both animals and human tissue (29,40). The aims of this study were therefore to characterize the spontaneous peristaltic activity observed in isolated preparations of rat and mouse small intestine and to examine its modulation by SRIF and selective sst-receptor ligands.…”

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confidence: 99%

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Somatostatin sst₂ receptors inhibit peristalsis in the rat and mouse jejunum

Abdu

Hicks

Hennig

et al. 2002

American Journal of Physiology-Gastrointestinal and Liver Physi

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Somatostatin [somatotropin release-inhibitory factor (SRIF)] has widespread actions throughout the gastrointestinal tract, but the receptor mechanisms involved are not fully characterized. We have examined the effect of selective SRIF-receptor ligands on intestinal peristalsis by studying migrating motor complexes (MMCs) in isolated segments of jejunum from rats, mice, and sst 2-receptor knockout mice. MMCs were recorded in 4-to 5-cm segments of jejunum mounted horizontally in vitro. MMCs occurred in rat and mouse jejunum with intervals of 104.4 Ϯ 10 and 131.2 Ϯ 8 s, respectively. SRIF, octreotide, and BIM-23027 increased the interval between MMCs, an effect fully or partially antagonized by the sst2-receptor antagonist Cyanamid154806. A non-sst2 receptor-mediated component was evident in mouse as confirmed by the observation of an inhibitory action of SRIF in sst2 knockout tissue. Blocking nitric oxide generation abolished the response to SRIF in rat but not mouse jejunum. sst2 Receptors mediate inhibition of peristalsis in both rat and mouse jejunum, but a non-sst2 component also exists in the mouse. Nitrergic mechanisms are differentially involved in rat and mouse jejunum. knockout; migrating motor complex; enteric nervous system; somatotropin release-inhibitory factor ISOLATED SEGMENTS OF BOWEL can perform complex and coordinated contractile activity, which is dependent on interactions between myogenic and local neural mechanisms. The polarized reflex responses to intestinal stimuli, first described by Bayliss and Starling (3), are now recognized to involve activation of ascending and descending enteric pathways leading to contraction and relaxation of smooth muscle (6). A variety of different transmitters and neuromodulators in these enteric pathways contributes to the coordination of this peristaltic activity. Somatostatin [somatotropin release-inhibitory factor (SRIF)] is present in a subpopulation of descending interneurones that project caudally within the myenteric plexus but not into either the longitudinal or circular muscle layers of the intestine (10,31,35). SRIF is also found in submucous plexus neurones, around submucosal blood vessels, and is present in mucosal endocrine cells in human (31), guinea pig (10), and rodent intestine (12, 13). SRIF is released by intestinal distension (11) and participates in the coordination of descending relaxation (21). The effects of exogenous SRIF on intestinal motility are complex. In the guinea pig ileum, both excitatory and inhibitory effects, operating through prejunctional mechanisms (14,18,24,36,45), have been described. The contractile response of the rat colon to SRIF also appears to involve activation of noncholinergic nerves (33), possibly by a process of disinhibition of vasoactive intestinal peptide (VIP) ergic/nitrergic interneurones supplying longitudinal muscle motoneurones (22). In contrast, the activity of VIPergic/nitregic neurons supplying the circular muscle layer is augmented by SRIF leading to relaxation (21). Thus SRIF plays a neuromodulat...

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Section: Discussionmentioning

confidence: 78%

mentioning

confidence: 99%

Somatostatin sst₂ receptors inhibit peristalsis in the rat and mouse jejunum

Abdu

Hicks

Hennig

et al. 2002

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Similarly our experiments were designed on the basis of establishing equieective concentrations of the antagonists prior to assessing their potential to elicit contractions During the course of our experiments it became evident that both CTOP and MR-2266 caused a transient inhibition of the electrically-evoked contractions. In light of the report that CTOP (but not CTAP) possesses agonist activity at somatostatin receptors (Connor et al, 1997a), and that these receptors are present in the ileum (Fenuik et al, 1995), we investigated whether co-activation of a non-opioid receptor could account for the reduced responses to CTOP in overnight, morphine-exposed preparations of the ileum. Our results showed that somatostatin produced qualitatively similar responses to CTOP and that subsequent desensitization of the receptor reduced the eect of CTOP on electrically-evoked contractions.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological examination of contractile responses of the guinea‐pig isolated ileum produced by μ‐opioid receptor antagonists in the presence of, and following exposure to, morphine

Mundey

Ali

Mason

et al. 2000

British J Pharmacology

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1 We have assessed the potential of several m-opioid receptor antagonists to elicit a response in the guinea-pig isolated ileum in the presence of, and following overnight exposure to, morphine. 2 Naloxone, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH 2 (CTOP), (7)-5,9a-diethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomorphan (MR2266), but not D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH 2 (CTAP), produced a transient inhibition of electrically-evoked contractions of the guinea-pig ileum. The eect of 1 mM CTOP, but not that to MR2266, was inhibited by 1 mM somatostatin. 3 Naloxone (0.3 mM), CTOP (3 mM), CTAP (3 mM) and MR2266 (0.3 mM) antagonized the inhibitory eect of morphine on electrically-evoked contractions of the guinea-pig to a similar degree and, following 60 min exposure to morphine, produced non-sustained contractions. The response to 3 mM CTOP was signi®cantly smaller than that to 3 mM CTAP. None of the antagonists produced a response in the absence of morphine. 4 Following overnight exposure of the ileum to 0.3 mM morphine (48C), and repeated washing to remove the agonist, all four antagonists elicited non-sustained contractions. However, the responses to 3 mM CTOP and 0.3 mM MR2266 were signi®cantly smaller than those elicited by 0.3 mM naloxone and 3 mM CTAP. Somatostatin (1 mM) signi®cantly reduced naloxone-induced contractions, but not those to CTAP. 5 While all four m-opioid antagonists elicited contractions in the presence of, and following prolonged exposure to, morphine, dierences between them were noted which may be a consequence of non-opioid actions.

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“…Such compounds include BIM-23027, BIM-23056, and L-362855 which selectively bind with subnanomolar affinities to sst2, sst3, and sst5 receptors, respectively (Raynor et al 1993a, b). Currently, however, few studies have investigated the effect of these SRIF analogues in gastrointestinal preparations naturally expressing SRIF receptors (McKeen et al 1994a;Feniuk et al , 1995. In the present study, the pharmacological properties of the SRIF receptor type mediating the antisecretory action of SRIF in rat colonic mucosa were studied by examining the actions of several selective SRIF analogues including BIM-23027, BIM-23056 and L-362855.…”

Section: Introductionmentioning

confidence: 99%

Somatostatin receptors mediating inhibition of basal and stimulated electrogenic ion transport in rat isolated distal colonic mucosa

McKeen

Feniuk

Humphrey

1995

Naunyn-Schmiedeberg's Arch Pharmacol

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The aim of this study was to examine the potencies of several recently identified selective somatostatin (SRIF)-receptor ligands as inhibitors of electrogenic ion transport in the rat distal colonic mucosa with the view to identifying the SRIF receptor type involved. Under basal conditions, cumulative administration of SRIF and SRIF28 decreased short circuit current (SCC), a measure of electrogenic ion transport, with EC50 values of 4 nM and 9 nM respectively. The peptidase inhibitors, phosphoramidon (1 microM) and amastatin (10 microM), has no effect on the potencies of either SRIF or SRIF28. The inhibitory action of SRIF on basal SCC was suppressed by piretanide and diphenylamine-2-carboxylate, compatible with the assumption that the Na+K+2Cl- co-transporter and Cl- channels, respectively, may be involved in this antisecretory action of SRIF. Tetrodotoxin (1 microM) had no effect on the antisecretory action of SRIF, suggesting that the process was not neuronally mediated. All of the SRIF analogues examined, with the exception of BIM-23056, maximally inhibited basal SCC to a similar extent as SRIF. Seglitide and octreotide were both more potent antisecretory agents than SRIF (respective EC50 values, 0.4 nM and 1.5 nM) suggesting that this effect was mediated by a receptor belonging to the SRIF1 receptor group. The most distinguishing feature of the rank order of agonist potencies was the high potency of the selective sst2 receptor ligand, BIM-23027 (EC50 value 0.32 nM), the weaker potency exhibited by the selective sst5 receptor ligand, L-362855 (EC50 value 21 nM), and the lack of agonist activity displayed by the selective sst3 receptor ligand, BIM-23056 (EC50 value > 1000 nM). This profile is comparable with that observed in binding studies on the recombinant sst2 receptor. Forskolin-stimulated secretion was suppressed by SRIF analogues with the rank order of agonist potencies BIM-23027 > SRIF > L-362855 >> BIM-23056 which resembled that exhibited under basal conditions. However, the absolute potencies of these agonists were lower (respective EC50 values 2 nM, 14 nM< 38 nM and > 1000 nM) whilst the magnitude of inhibition was about three fold greater. BIM-23027 and SRIF (both 30 nM) also inhibited carbachol-stimulated increases in basal SCC by 60-70%, while a similar concentration of L-362855 inhibited these responses by 11%. BIM-23056 (1 microM) had no effect on carbachol-simulated secretion. Radioligand binding studies on rat colonic mucosal membranes using [125I]-Tyr11-SRIF suggested heterogeneity of SRIF binding sites. Thus, SRIF and SRIF28 competed for binding (IC50 values, 0.32 and 0.63 nM, respectively) with Hill slopes less than unity; while seglitide and BIM-23027 both maximally displaced only 30-40% of specific binding with apparent high affinity (respective pIC50 values, 10.1 nM and 10.0). In conclusion, SRIF decreases basal as well as both cAMP and Ca(2+)-dependent Cl- secretion in rat colonic mucosa. The rank order of agonist potencies suggests that receptors resembling the recombinant sst2 recept...

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Further evidence from functional studies for somatostatin receptor heterogeneity in guinea‐pig isolated ileum, vas deferens and right atrium

Cited by 15 publications

References 14 publications

Somatostatin sst₂ receptors inhibit peristalsis in the rat and mouse jejunum

Somatostatin sst₂ receptors inhibit peristalsis in the rat and mouse jejunum

Pharmacological examination of contractile responses of the guinea‐pig isolated ileum produced by μ‐opioid receptor antagonists in the presence of, and following exposure to, morphine

Somatostatin receptors mediating inhibition of basal and stimulated electrogenic ion transport in rat isolated distal colonic mucosa

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Further evidence from functional studies for somatostatin receptor heterogeneity in guinea‐pig isolated ileum, vas deferens and right atrium

Cited by 15 publications

References 14 publications

Somatostatin sst2 receptors inhibit peristalsis in the rat and mouse jejunum

Somatostatin sst2 receptors inhibit peristalsis in the rat and mouse jejunum

Pharmacological examination of contractile responses of the guinea‐pig isolated ileum produced by μ‐opioid receptor antagonists in the presence of, and following exposure to, morphine

Somatostatin receptors mediating inhibition of basal and stimulated electrogenic ion transport in rat isolated distal colonic mucosa

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Somatostatin sst₂ receptors inhibit peristalsis in the rat and mouse jejunum

Somatostatin sst₂ receptors inhibit peristalsis in the rat and mouse jejunum