Effects of endothelin ETB receptor agonists and antagonists on the biphasic response in the ileum

In the guinea-pig ileum, both sarafotoxin S6c and IRL1620 (Suc-[Glu(9),Ala( 11,15)]endothelin-1-(8-21) induced a concentration-dependent biphasic effec t (relaxation and contraction), but distinct tachyphylaxis of the tissue. C ross-tachyphylaxis and additivity experiments evidenced distinct receptors for these agonists, BQ-123 (cyclo[D-Trp-D-Asp-Pro-D-Val-Leu]), an endotheli n ETA receptor antagonist, did not affect the response induced by either ag onist. PD145065 [Ac-(D-Bhg-Leu-Asp-Ile-Ile-Trp) (D-Bhg = SH-dibenzyl[a, d]c ycloheptene-10,11-dihydroglycine)], an endothelin ETA/ETB receptor antagoni st, inhibited the contractions induced by IRL1620 and sarafotoxin S6c in co mpetitive and noncompetitive manner, respectively. RES-701-1 [cyclic(Gly(1) -Asp(9))(Gly-Asn-Trp-His-Gly-Thr-Ala-Pro-Phe-Asn-Tyr-Tyr-Trp)], an endothel in ETB1 receptor antagonist, inhibited both components of the response indu ced by LRL1620, whereas it inhibited mainly the relaxation induced by low s arafotoxin S6c doses. Apamin and suramin had different effects towards the agonists. Our results suggest that two endothelin ETB receptors with distin ct signal transduction mechanism mediate the biphasic response: (1) the end othelin ETB1 receptor: sensitive to RES-701-1 and PD145065 and (2) the endo thelin ETB2 receptor: less sensitive to RES-701-1 and PD145065. (C) 1999 El sevier Science B.V. All rights reserved.