BQ123, AN ET(A)-RECEPTOR ANTAGONIST, ATTENUATES HYPOXIC PULMONARY-HYPERTENSION IN RATS

To investigate the role of endothelin-1 (ET-1) in the pathogenesis of hypoxic pulmonary hypertension, we studied the effects of a recently d escribed endothelin-receptor antagonist (ET(A)), BQ123, on the develop ment of this process. Intraperitoneal osmotic pumps were placed into 8 -wk-old Sprague-Dawley rats that received either saline or BQ123 (0.15 mg/h). The rats were maintained in room air normoxia or placed in a h ypobaric chamber (380 Torr) for 2 wk to induce hypoxic pulmonary hyper tension. There were no hemodynamic differences between normoxic rats t reated with either saline or BQ123. However, treatment with BQ123 atte nuated the hypoxia-induced increase in pulmonary arterial mean pressur e and total pulmonary resistance index by 60 and 87% respectively. The re was also a reduction in hypoxia-induced right ventricular hypertrop hy in the BQ123 group. Histological studies performed using a barium-g elatin fixation technique in hypoxic BQ123-treated animals demonstrate d a decrease in medial wall thickness in arteries corresponding to the respiratory and terminal bronchioles, respectively. Similarly, there was a significant reduction in the degree of mascularization of more d istal vessels at the level of alveolar ducts in BQ123-treated hypoxic rats. We conclude that the ET(A)-receptor antagonist BQ123 attenuates the development of hypoxic pulmonary hypertension in rats in vivo, the reby suggesting a possible contributing role for ET-1 and the ET(A) re ceptor in the pathogenesis of this process.