CPU0123, a novel endothelin receptor antagonist, relieves hypoxic pulmonary hypertension in rats by suppressing excessive ET‐ROS pathway

Abstract

AbstractPulmonary artery hypertension (PAH, PH) is a chronic and progressive disease with high morbidity and mortality and is resistant to vasodilative drugs in the clinic due to remodeling of pulmonary arterioles involved in PAH. The endothelin (ET) receptor antagonist bosentan is an effective oral medication in relieving PAH due to its antiproliferative effects. The dual ETA/ETB antagonist receptor antagonist, CPU0213, was compared with nifedipine in treating hypoxic PAH in SD rats that were exposed to 28 days of hypoxia (O2 10±0.5%). In untreated animals, elevated right ventricular systolic pressure (RVSP), central vein pressure (CVP), and remodeling of pulmonary arterioles were predominant. In the pulmonary tissue of PAH rats, the ET‐ROS pathway was over‐activated in association with a reduced NO level, increased iNOS activity and hydroxyproline contents. Following oral treatment with CPU0213, (50 mg/mg, 100 mg/kg, and 200 mg/kg, p.o.), the hemodynamic indices and pulmonary arteriole remodeling were significantly improved in a dose‐dependent manner. Elevated ET‐1 levels, iNOS activity, and maladjustment of pulmonary redox system were reversed, accompanied by a reduction of hydroxyproline in pulmonary tissue. An antiproliferative effect of CPU0213 was superior to that of nifedipine. The efficacy of 50 mg/kg CPU0213 was reduced. It is concluded that the low‐selective ETA/ETB receptor antagonist, CPU0213, is effective in relieving hypoxia‐induced pulmonary hypertension by suppressing an over‐activated ET‐ROS pathway in pulmonary tissue. Drug Dev Res 68:42–50, 2007. © 2007 Wiley‐Liss, Inc.