ENDOTHELIN RECEPTORS MEDIATING CONTRACTION OF RAT AND HUMAN PULMONARYRESISTANCE ARTERIES - EFFECT OF CHRONIC HYPOXIA IN THE RAT

1 We examined the endothelin (ET) receptors mediating contractions to ET-1, ET-3 and sarafotoxin S6c (SX6c) in rat pulmonary resistance arte ries by use of peptide and non-peptide ET receptor antagonists. Change s induced by pulmonary hypertension were examined in the chronically h ypoxic rat. The effect of the mixed ETA/ETB receptor antagonist SB 209 670 on endothelin-mediated contraction was also examined in human pulm onary resistance arteries. 2 In rat vessels, the order of potency for the endothelin agonists was SX6c=ET-3>ET-1 (pEC(50) values in control rats: 9.12+/-0.10, 8.76+/-0.14 and 8.12+/-0.04, respectively). Maximum contractions induced by ET-3 and ET-1 were increased in vessels from chronically hypoxic rats. 3 The ETA receptor antagonist FR 139317 (1 m u M) had no effect on the potency of ET-1 in any vessel studied but ab olished the increased response to ET-1 in the chronically hypoxic vess els. The ETA receptor antagonist EMS 182874 (1 mu M) increased the pot ency of ET-1 in control rat vessels without effecting potency in the p ulmonary hypertensive rat vessels. 4 Bosentan (non-peptide mixed ETA/E TB receptor antagonist) increased the potency of ET-1 in control rat v essels but was without effect in the pulmonary hypertensive rat vessel s. Bosentan (1 mu M) inhibited responses to SX6c in control and chroni cally hypoxic rat vessels with pK(b) values of 5.84 and 6.11, respecti vely. The ETB receptor antagonist BQ-788 (1 mu M) did not inhibit resp onses to ET-1 in any vessel tested but did inhibit responses to both S X6c and ET-3 (pK(b) values in control and chronically hypoxic rat vess els respectively: SX6c 7.15 and 7.22; ET-3: 6.68 and 6.89). BQ-788 (1 mu M) added with EMS 182874 (10 mu M) did not inhibit responses to ET- 1 in control vessels but caused a significant inhibition of responses to ET-I in chronically hypoxic preparations. 5 SB 209670 inhibited res ponses to ET-1 in both control and chronically hypoxic vessels with pK (b) values of 7.36 and 7.39, respectively. SB 209670 (0.1 and 1 mu M) virtually abolished responses to ET-1 in the human pulmonary resistanc e artery. 6 In conclusion, in rat pulmonary resistance arteries, vasoc onstrictions induced by ET-1, SX6c and ET-3 are mediated predominantly by activation of an ETB-like receptor. However, lack of effect of som e antagonists on ET-1 induced vasoconstriction suggests that ET-1 stim ulates an atypical ETB receptor. The increase in potency of ET-1 in th e presence of some antagonists suggests the presence of an inhibitory ETA-like receptor. The influence of this is reduced, or absent, in the chronically hypoxic rats. Increased responses to ET-1 are observed in the chronically hypoxic rat and may be mediated by increased activati on of ETA receptors. SB 209670 is unique in its potency against respon ses to ET-1 in both control and chronically hypoxic rats, as well as h uman, isolated pulmonary resistance arteries.