DIFFERENCES BETWEEN ENDOTHELIN RECEPTORS MEDIATING CONTRACTION OF GUINEA-PIG AORTA AND PIG CORONARY-ARTERY

Endothelin receptors mediating contraction were characterized and compared in rings from guinea-pig thoracic aorta and pig left circumflex coronary artery. In guinea-pig aorta, the following rank order of agonist potencies was found (mean EC(50) value, nM): endothelin-1 (5.0) = endothelin-2 (5.5) > vasoactive intestinal contractor (VIC; 11.0) > sarafotoxin S6b (39.8) > [Ala(3,11)]endothelin-1 (121) > sarafotoxin S6a (> 150) > endothelin-3 (> 500). [Ala(1,3,11,15)]Endothelin-1, endothelin-(16-21), sarafotoxin S6c and sarafotoxin S6d were neither agonists nor antagonists at concentrations up to 1, 10, 3 and 1 mu M, respectively. Cyclo-(D-Trp-D-Asp-Pro-D-Val-Leu) (BQ-123; 0.1-1 mu M) behaved as a competitive antagonist of endothelin-1 (pA(2) 7.4 +/- 0.1, slope factor 0.91 +/- 0.17, n = 4). In pig coronary artery, all endothelins and sarafotoxins were agonists, except for endothelin-(16-21). Sarafotoxin S6c, [Lys(4)]sarafotoxin S6c, [Nle(6)]sarafotoxin S6c and [Ala(1,3,11,15)]endothelin-1 acted as partial agonists (E(max) about 40% of that of endothelin-1). The rank order of agonist potencies was: sarafotoxin S6c (1.5)= [Lys(4)]sarafotoxin S6c (1.5) > [Nle(6)]sarafotoxin S6c (6.7) greater than or equal to sarafotoxin S6a (7.5) greater than or equal to endothelin-1 (12.6) greater than or equal to sarafotoxin S6b (14.8) <greater than endothelin-2 (19.3) greater than or equal to [Ala(1,3,11,15)]endothelin-1 (41.7) greater than or equal to [Ala(3,11)]endothelin-1 (55.2) > endothelin-3 (96.8) > sarafotoxin S6d (> 200). Endothelin-(16-21) was neither agonist nor antagonist at 10 mu M. The concentration-response curves of endothelin-3 and sarafotoxin S6a were biphasic, consisting of a higher sensitivity (40-45% of the total effect) and a lower sensitivity component. BQ-123 (0.1-1 mu M) did not alter the concentration-response curve of endothelin-1. At 10 mu M, BQ-123 shifted the curves of endothelin-1 and sarafotoxin S6c to the right, with mean pK(B) values of 5.21 and 5.04, respectively. Sarafotoxin S6c (0.3 mu M), used as an antagonist, abolished the effects of [Ala(1,3,11,15)]endothelin-1 and increased the threshold concentrations of endothelin-3, sarafotoxin S6a and, in the presence of 10 mu M BQ-123, of endothelin-1. The results show that endothelin receptors mediating contraction of guinea-pig aorta and pig coronary artery are different. In guinea-pig aorta, these receptors conformed to the ET(A) type. In pig coronary artery, receptors of the ET(B) type, and probably other receptors that are poorly sensitive to BQ-123, participated in the contraction.