ENDOTHELIN ET(A) RECEPTORS MEDIATE HUMAN UTERINE SMOOTH-MUSCLE CONTRACTION

Receptors mediating endothelin-induced contraction of myometrium were investigated in the human uterus. Endothelin-1 and endothelin-3 (10 pM to 0.3 mu M) caused concentration-dependent contraction of myometrial strips. Endothelin-1 was approximately ten times more potent than endothelin-3, with pD(2) values of 8.24 and 7.20, respectively. By contrast, two endothelin ET(B) receptor selective agonists, BQ 3020 (N-acetyl-[Ala(11,15)]endothelin-1-(6-21)) and sarafotoxin 6c (up to 0.3 mu M), did not induce contraction of human myometrium, The endothelin ET(A) receptor selective antagonist, FR139317 (1-hexahydroazepino-CO-Leu-D-Trp(CH3)-D-(2-pyridyl)alanine) (0.1, 0.3 and 1 mu M), competitively antagonized the endothelin-1-elicited contraction, with a pA(2) value of 7.10, whereas another endothelin ET(A) receptor-selective blocking drug, BQ 123 [cyclo(-D-Trp-D-Asp-Pro-D-Val-Leu)], behaved as a non-competitive antagonist. Pretreatment of myometrial strips with an endothelin ET(B) receptor selective antagonist, IRL 1038 ([Cys(11)-Cys(15)]endothelin-1-(11-21)), had no effect on contractions induced by endothelin-1. All these data indicate that only endothelin ET(A) receptors mediate endothelin-1-induced contractions of human myometrium.