DIFFERENT ENDOTHELIN RECEPTORS INVOLVED IN ENDOTHELIN-1-INDUCED AND SARAFOTOXIN-S6B-INDUCED CONTRACTIONS OF THE HUMAN ISOLATED CORONARY-ARTERY

1 Endothelin receptors, that mediate contraction of the human isolated coronary artery, were characterized by use of a number of agonists and antagonists. Contraction induced by the non-selective agonists, endothelin (ET)-1 and sarafotoxin S6b, was compared in endothelium-intact and endothelium-denuded ring segments. The effects of ET-1 and BQ-123 (an ET(A) receptor antagonist) were investigated both in ring segments and in spirally cut strips. Lastly, the effect of phosphoramidon was studied on, contraction induced by big-ET-1. 2 The order of agonist potency (pD(2)) in endothelium-intact coronary artery ring segments was: ET-1 (8.27)approximate to sarafotoxin S6b (8.16)>big-ET-1 (<7.1)approximate to ET-3 (<6.9). [Ala(1,3,11,15)]ET-1 (ET(B) receptor agonist) caused significant contraction only at 1 mu M, whereas 0.3 mu M big-ET-3 had no effect. Removal of the endothelium in ring segments did not affect the contractile response to ET-1 or to sarafotoxin S6b. 3 After a full concentration-response curve had been obtained to ET-1 or sarafotoxin S6b, further contractions of the endothelium-intact coronary artery segments could only be achieved by applying ET-1 in segments exposed to sarafotoxin S6b, and not the reverse. 4 BQ-123 (0.1 mu M) antagonized contractions of endothelium-intact ring segments induced by sarafotoxin S6b (pK(B) 7.86). Only 10 mu M BQ-123 antagonized contractions induced by ET-1 (pK(B) 5.75). FR139317 was also more potent against sarafotoxin S6b (pK(B) 8.24- 8.47) than against ET-1 (pK(B) 6.11). [Ala(1,3,11,15)]ET-1 (1 mu M) had no effect on the contractile response to ET-1 or to sarafotoxin S6b. 5 In strip preparations with intact endothelium, the pD(2) of ET-1 increased to 9.04 +/- 0.16 (vs. 8.50 +/- 0.07 in rings), and BQ-123 (1 mu M) caused a rightward shift of the ET-1 induced concentration-response curve (pK(B) 6.62 vs. 5.75 in rings). 6 Contractile responses to big-ET-1 of endothelium-intact coronary artery segments were attenuated in the presence of phosphoramidon (100 mu M), indicating conversion of big-ET-1 to ET-1 within the coronary artery segment. 7 The present study indicates that ET-1 and sarafotoxin S6b contract the human isolated coronary artery via different receptors, which can probably be best characterized as subtypes of the ET(A) receptor. Furthermore, it is demonstrated that the type of preparation (ring or strip) may affect the potency of ET-1 as an agonist and of BQ-123 as an antagonist.