Effect of novel mixed ETA/ETB antagonists on responses to ET-1 in human small muscular pulmonary arteries

Selective ETA and ETB receptor antagonists do not fully inhibit responses to ET-1 in human small pulmonary arteries. Here, we have compared the influence of the novel mixed ETA/ETB antagonists SB/217242, SB/234551 and SB/209670 on ET-1-mediated vasoconstriction in these vessels. ET-1 was a potent vasoconstrictor (pEC(50): 8.14+/-0.05, n=5) and the concentration-response curve to ET-1 was biphasic in nature. All three mixed antagonists (1 mu M) inhibited the responses to ET-1, abolishing the biphasic form of the concentration response curve. The order of potency was SE 209670>SB 234551 greater than or equal to SB 217242 with estimated pKb values of 8.0+/-0.20, 6.8+/-0.17 and 6.6+/-0.11 respectively (n=3-5). (C) 1998 Academic Press.