THE ORALLY-ACTIVE ETA RECEPTOR ANTAGONIST YRIMIDIN-2-YLOXY)-3-METHOXY-3,3-DIPHENYL-PROPIONIC ACID (LU-135252) PREVENTS THE DEVELOPMENT OF PULMONARY-HYPERTENSION AND ENDOTHELIAL METABOLIC DYSFUNCTION IN MONOCROTALINE-TREATED RATS())

Pulmonary hypertension is associated with endothelial dysfunction that may mediate or contribute to the disease process; among those abnorma lities is an increase in circulating endothelin-1 levels. We investiga ted the effect of the orally active endothelin A receptor antagonist L U 135252 (LU) on the development of monocrotaline (MCT)-induced pulmon ary hypertension and endothelial metabolic dysfunction. Rats were assi gned to four groups by receiving a single dose of MCT or saline, follo wed by once-daily gavage with LU (50 mg/kg) or saline for 3 weeks. Pla sma immunoreactive endothelin-1 levels doubled after MCT and were unaf fected by LU therapy. The MCT-induced increase in right ventricular sy stolic pressure (72.5 +/- 15.9 mmHg) and hypertrophy (right ventricle/ [left ventricle plus septum weight]; 0.58 +/- 0.08) were reduced by LU to 42.7 +/- 8.5 mmHg (P <.01) and 0.42 +/- 0.05 (P <.01), respectivel y. LU, however, did not modify MCT-induced pulmonary artery medial hyp ertrophy. Pulmonary vascular endothelial metabolic activity was evalua ted in isolated lungs by measuring endothelium-bound angiotensin-conve rting enzyme activity using a synthetic angiotensin-converting enzyme substrate, H-3-benzoyl-phenylalanly-glycyl-proline. MCT reduced fracti onal H-3-benzoyl-phenylalanly-glycyl-proline hydrolysis (0.488 +/- 0.0 51, P <.01) which was normalized by LU therapy (0.563 +/- 0.050). LU t reatment alone had no significant effect on any of these parameters. W e conclude that the endothelin A antagonist LU reduces MCT-induced pul monary hypertension and right ventricular hypertrophy and restores end othelial metabolic function. These results support the development of endothelin antagonists for the treatment of pulmonary hypertension and associated endothelial metabolic abnormalities.