Characterization of somatostatin receptors in guinea‐pig isolated ileum, vas deferens and right atrium

Abstract

1 Somatostatin14 (SS14) inhibits neurogenically mediated contractile responses in guinea-pig ileum and vas deferens and exerts a direct negative inotropic action in guinea-pig spontaneously beating right atrium. In this study, the receptors mediating these inhibitory effects have been characterized by comparing the potencies of several cyclic somatostatin analogues. 2 In the guinea-pig ileum, SS14, somatostatin28 (SS28), somatostatin25 (SS25) and several smaller cyclic somatostatin analogues including octreotide, angiopeptin and CGP 23996, inhibited neurogenically mediated contractile responses, each being of similar potency. 3 In contrast, in the guinea-pig vas deferens and right atrium, SS28 was about 30 times more potent than SS14. However, although angiopeptin was nearly as potent as SS14 as an agonist in the vas deferens, in guinea-pig atrium angiopeptin had low intrinsic activity and antagonized the negative inotropic action of both SS14 and SS28 (pKB values of 7.4 and 7.2, respectively). CGP 23996 was 2-7 times weaker than SS14 in guinea-pig vas deferens and atria.4 Phosphoramidon (1 AM) and amastatin (10 JAM) did not influence the potency of SS14 or SS28 in either the guinea-pig ileum or right atrium. In the guinea-pig vas deferens, phosphoramidon and amastatin did not affect the potency of SS28, but enhanced the potency of SS14 about 5 fold. Despite the presence of phosphoramidon and amastatin, SS28 was still more potent than SS14 in the vas deferens. 5 The putative somatostatin receptor blocking drug, cyclo(7-aminoheptanoyl Phe-D-Trp-Lys-Thr[Bzl]) (CPP; 1 JAM), did not antagonize the effects of either SS14 or SS28 in ileum, vas deferens or atrial preparations. 6 Somatostatin14 did not modify the contractile action of carbachol or ax,-methylene ATP in the ileum and vas deferens respectively, suggesting that the site of the inhibitory effects on neurogenically mediated contractile responses in both preparations was pre-junctional. Consistent with this conclusion was the observation that the inhibitory effect of SS14 was markedly and inversely related to the external Ca2+ concentration. The inhibitory effect of SS14 in guinea-pig atrium was only partly dependent on the external Ca2+ concentration. 7 The somatostatin receptors mediating the inhibitory effect of SS14 in the ileum and vas deferens can be distinguished by the differential relative potencies of SS14 and SS28. In the former, SS14 and SS28 have similar potency whilst in the latter SS28 is much more potent. In this respect, the somatostatin receptor mediating negative inotropy in the guinea-pig right atrium appears similar to that identified in the vas deferens.8 We suggest that the somatostatin receptor mediating inhibition of neurogenic contraction in the ileum is similar to the recently cloned SSTR2 receptor. In contrast, the somatostatin receptor mediating negative inotropy in the atrium and inhibition of neurotransmission in the vas deferens appears similar to the SSTR4 receptor which recognises SS28 with higher affinity than SS14.

Localization and pharmacological characterization of somatostatin sst2 sites in the rat cerebellum

“…Another correlate to sst2 binding is inhibition of tumor growth where again the short cyclic analogues of somatostatin are extremely potent agonists (see Buscail et al 1993). Finally, it has recently be suggested that sst2 receptors may be involved in mediating the inhibition of neurogenically mediated contraction in the guinea-pig ileum (Feniuk et al 1993) and contraction in the rat distal colon (McKeen et al 1994). However, the similar pharmacological characteristics of sst2 and ssts receptors do not allow to decide conclusively whether functional effects produced by short synthetic analogues of SRIF are mediated by one or the other of these two receptors.…”

Somatostatin sst2 receptors inhibit peristalsis in the rat and mouse jejunum

“…A similar neuronal interaction is suggested to regulate tachykinin release from longitudinal muscle motoneurones (22). Thus somatostatin is likely to act within the enteric circuits controling peristalsis rather than at the level of the neuromuscular junction, and this would explain the ability of SRIF to attenuate neurogenically mediated contraction of the guinea pig ileum (14,18,24,36,45).…”

“…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).…”

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

“…Following a 60 min interval a second cumulative curve to the test agonist was obtained as described above. Using such a protocol, it has previously been shown that concentration-effect curves to SRIF are highly reproducible Feniuk et al, 1993).…”