EndothelinB receptor-mediated contraction of human and rat pulmonary resistance arteries and the effect of pulmonary hypertension on endothelin responses in the rat.

We investigated the endothelin (ET) receptor subtypes that mediate vasoconstriction in human and rat pulmonary resistance arteries and the effect of pulmonary hypertension on endothelin (ET)-induced contractile responses in rat vessels. In human vessels, sarafotoxin S6c (SXS6c) was more potent than ET-1, but its maximal contractile response was only 20-30% of that to ET-1. Responses to ET-1 were resistant to the ETA antagonist FR 139317, and another, BMS 182874, inhibited responses only to high concentrations of ET-1. In all rat vessels, ET-1, ET-3, and the ETB receptor agonist SXS6c showed the following order of potency: SXS6c = ET-3 > ET-1, and responses to SXS6c were inhibited by the ETB receptor antagonist BQ 788 (1 microM). Maximal responses to ET-1 were greatest in chronic hypoxic (CH) pulmonary-hypertensive rats. In control rats, responses to ET-1 were unaffected by FR 139317 (1 microM) and were potentiated by BMS 182874 (1 microM) and by the mixed ETA/ETB receptor antagonist bosentan (1 microM). A combination of BMS 182874 (10 microM) and the ETB receptor antagonist BQ 788 (1 microM) had no effect on responses to ET-1. In the CH rats, responses to ET-1 were unaffected by FR 139317, BMS 182874, or bosentan. The results suggest the presence of an inhibitory ETA receptor in these vessels that may inhibit ET-1 activation of ETB receptors, and also suggest that the influence of this inhibitory ETA receptor is reduced in CH rat vessels. The results indicate a role for ETB receptors in ET-1-mediated vasoconstriction in both human and rat pulmonary resistance arteries.