RT Journal Article SR Electronic T1 The Orally Active ETA Receptor Antagonist (+)-(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 Rats JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 1312 OP 1318 VO 282 IS 3 A1 Stéphane Prié A1 Tack Ki Leung A1 Peter Cernacek A1 James W. Ryan A1 Jocelyn Dupuis YR 1997 UL http://jpet.aspetjournals.org/content/282/3/1312.abstract AB 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 ± 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), 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,3H-benzoyl-phenylalanly-glycyl-proline. MCT reduced fractional 3H-benzoyl-phenylalanly-glycyl-proline hydrolysis (0.488 ± 0.051, P < .01) which was normalized by LU therapy (0.563 ± 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. The American Society for Pharmacology and Experimental Therapeutics