FURTHER EVIDENCE FROM FUNCTIONAL-STUDIES FOR SOMATOSTATIN RECEPTOR HETEROGENEITY IN GUINEA-PIG ISOLATED ILEUM, VAS-DEFERENS AND RIGHT ATRIUM

1 Somatostatin (SRIF) causes a concentration-dependent inhibition of n eurotransmission in guinea-pig ileum and vas deferens as well as negat ive inotropy in guinea-pig isolated right atrium. The SRIF receptors m ediating these effects have now been further characterized by use of t he peptides BIM-23027, BIM-23056 and L-362855, reported as selective f or the recombinant SRIF receptor types, sst(2), sst(3) and sst(5), res pectively. 2 BIM-23027 was a highly potent agonist at causing an inhib ition of neurotransmission in the guineapig ileum (EC(50) value 1.9 nM ), being about 3 times more potent than SRIF (EC(50) value 6.8 nM). In contrast, in both guinea-pig vas deferens and right atrial preparatio ns, BIM-23027 was a relatively weak agonist being at least 30-100 time s weaker than SRIF. In guinea-pig atria, BIM-23027 (3 mu M) antagonize d the negative inotropic action of SRIF(28) (apparent pK(B) = 5.9 +/- 0.1) but had no effect on the negative inotropic action of cyclohexyla denosine. 3 The inhibitory effect of BIM-23027 in the guinea-pig ileum was readily desensitized. Prior exposure to BIM-23027 (0.3 mu M) mark edly attenuated the inhibitory effect of SRIF but had no effect on the inhibitory action of clonidine suggesting that BIM-23027 and SRIF act via a common receptor mechanism. 4 L-362855 caused a concentration-de pendent inhibition of neurotransmission in both the guinea-pig ileum a nd vas deferens as well as causing negative inotropy in the guinea-pig atrium but was at least 30-100 times weaker than SRIF. In guinea-pig isolated atria, L-362855 (3 mu M) did not antagonize the negative inot ropic action of SRIF(28). 5 BIM-23056 in concentrations up to 1 mu M w as inactive as an agonist in guinea-pig isolated ileum, vas deferens a nd atrium and did not antagonize the inhibitory actions of SRIF in any of these preparations. 6 The results from this study support our prev ious contention that the sst(2) receptor type mediates inhibition of n eurotransmission by SRIF in the guinea-pig ileum. The SRIF receptor ty pe mediating inhibition of neurotransmission in the guinea-pig vas def erens appears different, but similar, to that mediating negative inotr opy in the atrium. However the characteristics of these latter recepto rs appear different from that of the recombinant sst(2), sst(3) and ss t(5) receptors for SRIF described for rat and man.