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 endothe lin (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 prese nce of bosentan, a new nonpeptide mixed antagonist of ET(A) and ET(B) receptors. The effect of chronic treatment with bosentan was then exam ined in rats that were exposed to chronic hypoxia and developed pulmon ary hypertension. In lungs from normoxic rats, bosentan (10(-5) M) abo lished the vasodilator responses to ET-1 (10(-10) M) or to the ET(B)-s elective agonist IRL-1620 (10(-10) M) and attenuated the vasoconstrict or 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 previousl y exposed to hypoxia for 15 days, pretreatment with bosentan (100 mg.k g(-1) day(-1) by gavage) for 3 days attenuated the increase in systemi c 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 exp osed 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 t reated with vehicle. Body weight, hematocrit, and systemic arterial pr essure did not differ between the two groups. The degree of musculariz ation of pulmonary vessels at alveolar duct and alveolar wall levels w as lower (P < 0.01) in bosentan-treated rats than in their hypoxic con trols. The present findings suggest that endogenous ET contributes to the development of pulmonary hypertension in rats exposed to chronic h ypoxia.