IN-VIVO EFFECTS OF ENDOTHELIN A-RECEPTOR AND B-RECEPTOR ANTAGONISTS IN GUINEA-PIGS

Endothelin (ET)-1, a novel 21-amino acid constrictor peptide, has been recently reported to have a potential pathophysiological role in asthma. We hypothesized that ET-1 might affect guinea pig lung via different ET receptor subtypes, i.e., ET(A) and ET(B), in vivo. To test this hypothesis, we investigated the effects of ET-1 on airways in anesthetized, open-chest, mechanically ventilated [frequency (f) = 1 Hz; tidal volume (V-T) = 9 ml/kg; positive end-expiratory pressure (PEEP) = 4 cmH(2)O] guinea pigs in the absence or the presence of ET(A) and ET(B) selective antagonists, i.e., BQ-123 and BQ-788, respectively. We affixed alveolar capsules to the lungs to measure alveolar pressure and calculated the elastance of lung (E(L)) and the resistance of lung (R(L)), tissue (R(ti)), and airway (R(aw)) under control conditions and after intravenous administration of ET-1 (10(-8) mol/kg). ET-1 induced a concentration-dependent increase in R(L), R(ti), R(aw), and E(L). BQ-123 (2 mg/kg) partially blocks Delta R(L) and Delta R(aw) during ET-1 induced constriction, while Delta R(ti) and Delta E(L) were not significantly affected. BQ-788 (2 mg/kg) significantly inhibited Delta R(L), Delta R(ti), Delta R(aw), and Delta E(L) during ET-l-induced constriction. The combination of BQ-123 and BQ-788 completely ablated the response to ET-1. These data suggest that both ET receptor subtypes, i.e., ET(A) and ET(B), may have physiological roles in guinea pig airways in response to ET-1, a potential mediator of asthma.