ET(A)-RECEPTOR ANTAGONIST PREVENTS AND REVERSES CHRONIC HYPOXIA-INDUCED PULMONARY-HYPERTENSION IN RAT

The selective endothelin-A (ET(A))-receptor antagonist BQ-123 has been shown to prevent chronic hypoxia-induced pulmonary hypertension in the rat. Therefore in the current study we utilized BQ-123 to test the hypothesis that blockade of the ET(A) receptor can reverse as well as prevent the increase in mean pulmonary artery pressure, right ventricle-to-left ventricle plus septum ratio, and percent wall thickness in small. (50-100 mu m) pulmonary arteries observed in male Sprague-Dawley rats exposed to normobaric hypoxia (10% O-2, 2 wk). Infusion of BQ-123 (0.4 mg . 0.5 mu l(-1) . h(-1) for 2 wk in 10% O-2) begun after 2 wk of hypoxia significantly reversed the established pulmonary hypertension and prevented further progression of right ventricular hypertrophy during the third and fourth week of hypoxia. BQ-123 infusion instituted before exposure to hypoxia completely prevented the hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular remodeling. These findings suggest that, in the lung, hypoxia induced an increase synthesis of endothelin-l, which acts locally on ET(A) receptors to cause pulmonary hypertension, right heart hypertrophy, and pulmonary vascular remodeling, while ET(A)-receptor blockade can both prevent and reverse these processes.