NONSPECIFIC ENDOTHELIN-RECEPTOR ANTAGONIST BLUNTS MONOCROTALINE-INDUCED PULMONARY-HYPERTENSION IN RATS

Endothelin-l (ET-I), a potent vasoactive and mitogenic peptide, has be en implicated in the pathogenesis of several forms of pulmonary hypert ension. We hypothesized that nonspecific blockade of ET receptors woul d blunt the development of monocrotaline (MCT)-induced pulmonary hyper tension in rats. A single dose of the nonspecific ET blocker bosentan (100 mg/kg) given to intact rats by gavage completely blocked the pulm onary vasoconstrictor actions of Big ET-1 and partially blunted hypoxi c pulmonary vasoconstriction. After 3 wk, MCT-injected (105 mg/kg sc) rats gavaged once daily with bosentan (200 mg/kg) had lower right vent ricular (RV) systolic pressure (RVSP), RV-to-body weight (RV/BW) and R V-to-left ventricular (LV) plus septal (S) weight [RV/(LV+S)] ratios a nd less percent medial thickness of small pulmonary arteries than cont rol MCT-injected rats. Lower dose bosentan (100 mg/kg) had no effect o n these parameters after MCT or saline injection. Bosentan raised plas ma ET-1 levels but had no effect on lung ET-1 levels. Bosentan (200 mg /kg) also had no effect on wet-to-dry lung weight ratios 6 days after MCT injection. When given during the last 10 days, but not the first 1 1 days of a 3-wk period after MCT injection, bosentan reduced RV/(LV+S ) compared with MCT-injected controls. We conclude that ET-1 contribut es to the pathogenesis of MCT-induced pulmonary hypertension and acts mainly during the later inflammatory rather than the acute injury phas e after injection.