PROTECTION FROM PULMONARY-HYPERTENSION WITH AN ORALLY-ACTIVE ENDOTHELIN RECEPTOR ANTAGONIST IN HYPOXIC RATS

The aim of this study was to investigate the potential role of endothelin (ET) in the development of chronic hypoxic pulmonary hypertension. Pulmonary vascular reactivity to ET-1 was first examined in isolated perfused lungs from normoxic and chronically hypoxic rats in the presence of bosentan, a new nonpeptide mixed antagonist of ET(A) and ET(B) receptors. The effect of chronic treatment with bosentan was then examined in rats that were exposed to chronic hypoxia and developed pulmonary hypertension. In lungs from normoxic rats, bosentan (10(-5) M) abolished the vasodilator responses to ET-1 (10(-10) M) or to the ET(B)-selective agonist IRL-1620 (10(-10) M) and attenuated the vasoconstrictor responses to 10(-9) M ET-1 (from 8.7 +/- 0.7 to 1.8 +/- 0.3 mmHg, P < 0.01) or 10(-9) M IRL-1620 (from 1.5 +/- 0.4 to 0.4 +/- 0.1 mmHg, P < 0.05). In lungs from chronically hypoxic rats, the presser response to 3 x 10(-10) M ET-1 was abolished by bosentan and partially reduced by the selective ET(A) antagonist BQ-123. In conscious rats previously exposed to hypoxia for 15 days, pretreatment with bosentan (100 mg.kg(-1) day(-1) by gavage) for 3 days attenuated the increase in systemic arterial pressures and the concomitant decrease of cardiac output in response to an intravenous bolus of ET-1 (3 x 10(-10) M). In rats exposed to hypoxia for 15 days and simultaneously treated with bosentan, pulmonary arterial pressure was lower (P < 0.05) and right ventricular hypertrophy was less severe (P < 0.01) than in control hypoxic rats treated with vehicle. Body weight, hematocrit, and systemic arterial pressure did not differ between the two groups. The degree of muscularization of pulmonary vessels at alveolar duct and alveolar wall levels was lower (P < 0.01) in bosentan-treated rats than in their hypoxic controls. The present findings suggest that endogenous ET contributes to the development of pulmonary hypertension in rats exposed to chronic hypoxia.