Abstract

It has been proposed that endothelin-1 (ET-1), a potent endogenous vasoactive peptide, may play an important role in the regulation of pulmonary blood flow. The purpose of the present study was to characterize the effects of ET-1 and a nonpeptide mixed ET_Aand ET_B receptor antagonist, SB 209670, in isolated segments of the canine pulmonary artery and to examine the effects of SB 209670 in a canine model of acute hypoxia-induced pulmonary hypertension. In isolated segments of the pulmonary artery, SB 209670 (3–300 nM) produced a concentration-dependent antagonism of contraction elicited by ET-1 (pA₂ = 8.9; slope = 0.9) and had no effect on phenylephrine responses. In addition, SB 209670 antagonized the small, endothelium-dependent relaxation induced by sarafotoxin 6c in phenylephrine (10 μM)-precontracted vessels (pK_B = 8.6). In anesthetized dogs, the driving pressure across the pulmonary circulation increased approximately 100% during the hypoxic period (area under the curve [AUC] = 267.1 ± 25.3 mm Hg·min). SB 209670 treatment (3 and 30 μg/kg/min i.v.) reduced pulmonary vascular resistance and produced a profound dose-related inhibition of hypoxia-induced pulmonary hypertension (AUC = 158.3 ± 22.7 mm Hg·min and 50.1 ± 4.9 mm Hg·min, respectively). None of the other hemodynamic or arterial blood gas parameters differed significantly in the vehicle and treatment groups. In addition, SB 209670 produced a significant reversal of hypoxia-induced pulmonary hypertension (AUC = 267.1 ± 25.3 mm Hg·min vs. 167.8 ± 23.4 mm Hg·min) when administered at the plateau of the hypoxic response. It was found that SB 209670 administration significantly elevated plasma levels of ET-1-LI (≥25-fold). These results suggest that ET-1 is an important mediator of hypoxia-induced pulmonary hypertension in the dog and that SB 209670, a potent and selective mixed ET_A and ET_B receptor antagonist in the pulmonary circulation, may represent an important therapeutic approach to the treatment of pulmonary hypertension.