Endothelin(B) receptor-mediated contraction in human pulmonary resistance arteries

1 Using wire myography, we have examined the endothelin (ET) receptor subtypes mediating vasoconstriction to ET peptides in human pulmonary resistance arteries (150-200 mu m, i.d.). 2 Cumulative concentration-response curves to ET-1, sarafotoxin 6c (SX6c) and ET-3 were constructed in the presence and absence of the selective antagonists FR 139317 (ET(A)-selective), EMS 182874 (ET(A)-selective) and BQ-788 (ET(B)-selective). 3 All agonists induced concentration-dependent contractions. However, the response curves to ET-1 were biphasic in nature. The first component demonstrated a shallow slope up to 1 nM ET-1. Above 1 nM ET-1 the response curve was markedly steeper. Maximum responses to ET-3 and SX6c were the same as those to 1 nM ET-1 and 30% of those to 0.1 mu M ET-1. The order of potency, taking 0.3 mu M as a maximum concentration was SX6c much greater than ET-3>ET-1 (pEC(50) values of: 10.75+/-0.27, 9.05+/-0.19, 8.32+/-0.08 respectively). Taking 1 nM ET-1 as a maximum, the EC(50) for ET-1 was 10.08+/-0.13 and therefore ET-1 was equipotent to ET-3 and SX6c over the first component of the response curve. 4 Responses to ET-1 up to 1 nM were resistant to the effects of the ET(A) receptor antagonists, FR 139317 and BMS 182874 but were inhibited by the ET(B) receptor antagonist, BQ-788. Conversely, responses to ET-1 over I nM were inhibited by the ET(A) receptor antagonists, FR 139317 and EMS 182874 but unaffected by the ET(B) receptor antagonist, BQ-788. 5 The results suggest that at concentrations up to 1 nM, responses to ET-1 are mediated via the ET(B) receptor, whilst the responses to higher concentrations are mediated by ET(A) receptors.