Differences between endothelin receptors mediating contraction of guinea-pig aorta and pig coronary artery

Abstract

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 μM, respectively. Cyclo-( D-Trp- D-Asp-Pro- D-Val-Leu) (BQ-123; 0.1–1 μM) 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) ≥ sarafotoxin S6a (7.5) ≥ endothelin-1 (12.6) ≥ sarafotoxin S6b (14.8) ≥ VIC (18.3) = endothelin-2(19.3) ≥ [Ala 1,3,11,15]endothelin-1 (41.7) ≥ [Ala 3,11]endothelin-1 (55.2) > endothelin-3 (96.8) > sarafotoxin S6d (> 200). Endothelin-(16–21) was neither agonist nor antagonist at 10 μM. 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 μM) did not alter the concentration-response curve of endothelin-1. At 10 μM, 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 μM), 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 μM 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.