ZD1611, an Orally Active Endothelin-A Receptor Antagonist, Prevents Chronic Hypoxia-induced Pulmonary Hypertension in the Rat

Abstract

Endothelin-1 (ET-1) is a potent vasoconstrictor and comitogen implicated in the pathogenesis of pulmonary hypertension (PH). We evaluated the effects of an ETAreceptor-selective antagonist, ZD1611, on hypoxia-induced PH in rats. «Prophylactic» and «therapeutic» paradigms were established in which rats were administered placebo or ZD1611 (1–3 mg/kg, q.i.dpo) concomitant with hypoxic exposure (10% O21 ATM) for 14 days or beginning after 7-day hypoxic exposure for 21 days. Compared with normoxic controls, hypoxic exposure plus placebo increased (P<0.05) hematocrit, mass ratio of right ventricle over left ventricle plus septum (RV/LV+S), and right intraventricular peak systolic pressure (RVSP). These latter two effects were decreased (P<0.05) by ZD1611 in both experimental paradigms [RV/LV+S(%)::RVSP(%); prophylactic, 14::32; therapeutic, 28::37]. Hypoxic exposure did not change mean systemic arterial pressure (MSAP). ZD1611 did not affect MSAP, plasma ET-1 concentrations, or blood gases measured when rats respired room air. In mechanistic studies, ZD1611 decreased (P<0.01) smooth muscle hypertrophy of small pulmonary arteries and abolished hypoxia-induced decreases in sensitivity and maximum contraction to ET-1 in isolated extralobar branch pulmonary artery. In conclusion, the ETAreceptor-selective antagonist, ZD1611, attenuates hypoxia-induced PH in the rat.