Effects of endothelin ET(B) receptor agonists and antagonists on the biphasic response in the ileum.

In the guinea-pig ileum, both sarafotoxin S6c and IRL1620 (Suc-[Glu9,Ala11,15]endothelin-1-(8-21) induced a concentration-dependent biphasic effect (relaxation and contraction), but distinct tachyphylaxis of the tissue. Cross-tachyphylaxis and additivity experiments evidenced distinct receptors for these agonists. BQ-123 (cyclo[D-Trp-D-Asp-Pro-D-Val-Leu]), an endothelin ET(A) receptor antagonist, did not affect the response induced by either agonist. PD145065 [Ac-(D-Bhg-Leu-Asp-Ile-Ile-Trp) (D-Bhg = 5H-dibenzyl[a,d]cycloheptene-10,11-dihydroglycine)], an endothelin ET(A)/ET(B) receptor antagonist, inhibited the contractions induced by IRL1620 and sarafotoxin S6c in competitive and noncompetitive manner, respectively. RES-701-1 [cyclic(Gly1-Asp9)(Gly-Asn-Trp-His-Gly-Thr-Ala-Pro-Asp-Trp-P he-Phe-Asn-Tyr-Tyr-Trp)], an endothelin ET(B1) receptor antagonist, inhibited both components of the response induced by IRL1620, whereas it inhibited mainly the relaxation induced by low sarafotoxin S6c doses. Apamin and suramin had different effects towards the agonists. Our results suggest that two endothelin ET(B) receptors with distinct signal transduction mechanism mediate the biphasic response: (1) the endothelin ET(B1) receptor: sensitive to RES-701-1 and PD145065 and (2) the endothelin ET(B2) receptor: less sensitive to RES-701-1 and PD145065.

Distinct endothelin-B receptors mediate the effects of sarafotoxin S6c and IRL1620 in the ileum.

In the guinea pig ileum, both sarafotoxin S6c (S6c) and IRL1620 induced a biphasic effect (relaxation and contraction). S6c induced strong tachyphylaxis of both components of the response, but IRL1620 induced tachyphylaxis mainly of the contractile component. Whereas the tissues rendered tachyphylactic to S6c did not respond to IRL1620, a normal biphasic response to S6c was observed in the tissues rendered tachyphylactic to IRL1620. In the presence of IRL1620, S6c could induce its biphasic effect, whereas in the presence of S6c, IRL1620 was ineffective. BQ-123, a specific ETA antagonist, did not affect the biphasic response induced by either agonist. PD145065, a potent ETA/ETB antagonist, was a competitive and a noncompetitive antagonist, respectively, of the contractile components of IRL1620 and S6c. RES-701-1, a specific ETB1 antagonist, inhibited both components of the response induced by IRL1620. However, it inhibited mainly the relaxant component induced by low doses of S6c. Apamin had different effects on endothelin-1 (ET-1), S6c, and IRL1620. Our results suggest that there are at least two distinct populations of ETB receptors mediating the biphasic response: the ETB1 receptor, sensitive to RES-701-1 and PD145065, and the ETB2 receptor, less sensitive to RES-701-1 and PD145065.

Heterogeneous endothelin receptors mediate relaxation and contraction in the guinea-pig ileum.

IRL1620, a specific endothelin ETB receptor agonist, induced relaxation followed by contraction in the guinea-pig ileum, as did endothelin-1. Both components of the response were concentration-dependent in the range studied. Repeated administration of IRL1620 induced tachyphylaxis only of the contractile component, whereas endothelin-1 desensitized both components. BQ-123 (cyclo[D-Trp-D-Asp-Pro-D-Val-Leu]), a specific endothelin ETA receptor antagonist, did not inhibit the relaxation induced by either agonist, although it did inhibit the contraction induced by endothelin-1, but not by IRL1620. PD145065 (Ac-(D-Bhg-Leu-Asp-Ile-Ile-Trp) (D-Bhg = 5H-dibenzyl[a,d]cycloheptene-10,11-dihydroglycine)), a combined endothelin ETA/endothelin ETB receptor antagonist, inhibited the contractile effects of both endothelin-1 and IRL1620 and also inhibited the relaxation induced by IRL1620. Apamin, a Ca(2+)-activated K+ channel blocker, inhibited only the endothelin-1-induced relaxation. Our studies suggest that two endothelin ETB receptor subtypes mediate relaxation in the guinea-pig ileum: one is less sensitive to PD145065 but apamin-inhibitable, and the other is more sensitive to PD145065 but not apamin-inhibitable. Our results also suggest that both endothelin ETA and endothelin ETB receptor subtypes mediate contraction in the ileum.