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Vol. 282, Issue 3, 1312-1318, 1997
Department of Medicine (S.P., T.K.L., J.D.),
Montreal Heart
Institute and Department of Medicine (P.C.), Royal Victoria Hospital,
Montreal, Quebec, Canada;
Vascular Biology Center (J.W.R.), Medical
College of Georgia, Augusta, Georgia
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.
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