The Orally Active ET A Receptor Antagonist (ϩ)-(S)-2-(4,6- dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenyl- propionic acid (LU 135252) Prevents the Development of Pulmonary Hypertension and Endothelial Metabolic Dysfunction in Monocrotaline-Treated Ra

ABSTRACT Pulmonary hypertension is associated with endothelial dysfunction that may mediate or contribute to the disease process; among those abnormalities is an increase in circulating endothelin-1 levels. We investigated the effect of the orally active endothelin A receptor antagonist LU 135252 (LU) on the development of monocrotaline (MCT)-induced pulmonary hypertension and endothelial metabolic dysfunction. Rats were assigned to four groups by receiving a single dose of MCT or saline, followed by once-daily gavage with LU (50 mg/kg) or saline for 3 weeks. Plasma immunoreactive endothelin-1 levels doubled after MCT and were unaffected by LU therapy. The MCT-induced increase in right ventricular systolic pressure (72.5 Ϯ 15.9 mmHg) and hypertrophy (right ventricle/[left ventricle plus septum weight]; 0.58 Ϯ 0.08) were reduced by LU to 42.7 Ϯ 8.5 mmHg (P Ͻ .01) and 0.42 Ϯ 0.05 (P Ͻ .01), respectively. LU, however, did not modify MCT-induced pulmonary artery medial hypertrophy. Pulmonary vascular endothelial metabolic activity was evaluated in isolated lungs by measuring endothelium-bound angiotensin-converting enzyme activity using a synthetic angiotensin-converting enzyme substrate, 3 Hbenzoyl-phenylalanly-glycyl-proline. MCT reduced fractional 3 H-benzoyl-phenylalanly-glycyl-proline hydrolysis (0.488 Ϯ 0.051, P Ͻ .01) which was normalized by LU therapy (0.563 Ϯ 0.050). LU treatment alone had no significant effect on any of these parameters. We conclude that the endothelin A antagonist LU reduces MCT-induced pulmonary hypertension and right ventricular hypertrophy and restores endothelial metabolic function. These results support the development of endothelin antagonists for the treatment of pulmonary hypertension and associated endothelial metabolic abnormalities. ET-1 is a potent vasoconstrictor peptide with strong mitogenic activity for smooth muscle cells. Circulating ET-1 levels are increased in humans who have primary and secondary pulmonary hypertensio