CPU0213, A NON-SELECTIVE ETA/ETB RECEPTOR ANTAGONIST, IMPROVES PULMONARY ARTERIOLAR REMODELING OF MONOCROTALINE-INDUCED PULMONARY HYPERTENSION IN RATS

The aim of the present study was to explore the effects of CPU0213, a dual endothelin ETA/ETB receptor antagonist, and nifedipine, a calcium antagonist, in relieving pulmonary hypertension (PH). Both endothelin receptor and calcium antagonists have been reported to be effective in alleviating the remodelling of pulmonary arteries induced by monocrotaline (MCT) in rats. After an initial single dose of 60 mg/kg, s.c., MCT, CPU0213 was administered to rats at doses of 25, 50 or 100 mg/kg, p.o., for 28 days. In addition, nifedipine was administered to another group of rats at a dose of 10 mg/kg, p.o., for 28 days. The haemodynamics of the right ventricle, pulmonary vascular activity, remodelling of the pulmonary arterioles (< 150 mu m) and biochemical changes were evaluated. Right ventricular systolic pressure (RVSP), central venous pressure (CVP), the maximum rate of uprising pressure (dP/dT(max)) and the weight index of the right ventricle were significantly elevated in MCT-treated rats. In addition, increases in pulmonary endothelin-1, malonyldialdehyde (MDA) and hydroxyproline content and a reduction in superoxide dismutase activity was found after MCT treatment. The thickness and area of the pulmonary arterial wall were significantly increased in MCT-treated rats compared with control rats. At all three doses tested, CPU0213 ameliorated these changes in a dose-dependent manner and the effects were associated with a greater reduction in the remodelling of pulmonary arterioles. However, nifedipine was only partially effective in amelerioating biochemical and haemodynamic changes induced by MCT, significantly reducing RVSP, CVP, +dp/dt(max), tissue MDA, inducible nitric oxide synthase and hydroxyproline content, increasing -dp/dt(min) and having no effect on the other parameters investigated. In addition, nifedipine had no effect on remodelling of the arterial wall. In conclusion, CPU0213 is more effective than nifedipine in suppressing the remodelling of pulmonary arterioles in PH induced by MCT treatment of rats. Furthermore, CPU0213 may have promise in treating PH secondary to connective tissue disease.