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The ETA-Receptor Antagonist LU 135252 Prevents the Progression of Established Pulmonary Hypertension Induced by Monocrotaline in Rats

Department of Medicine, Institut de Cardiologie de Montréal, Montreal, Quebec, Canada

Stéphane Prié

Department of Medicine, Institut de Cardiologie de Montréal, Montreal, Quebec, Canada

Background: An imbalance between the nitric oxide (NO) and endothelin systems may contribute to the development of pulmonary hypertension (PH). We evaluated the effect of the specific ETA-receptor antagonist LU 135252 (LU) in rats with established monocrota line (MCT)-induced PH and the involvement of NO in the control of pulmonary vascular tone.

Methods and Results: Two weeks after MCT, rats developed PH with a right ventricular pressure (RVP) of 42.3 ± 8.5 vs 28.2 ± 4.1 mmHg for controls (mean ± SD, P < .05). Daily oral therapy with LU (50 mg/kg) or saline was started 2 weeks post-MCT injection for 20 days. LU increased the survival rate nonsignificantly from 41.7% to 66.7%. The surviving MCT + saline rats showed severe PH (RVP of 82.5 ± 8.9 mmHg) and RV hypertrophy with a right-to-left ventricle + septum weight ratio of 69.6% ± 10.2%, which were improved by LU to 53.5 ± 11.1 mmHg and 53.7% ± 9.9%, respectively (P < .01). In isolated lungs, pul monary vascular compliance was reduced by PH and unaffected by LU therapy. After the NO synthase inhibitor N -nitro-L-arginine (10^-4 mol/L), compliance was further reduced, although much less so, in the LU-treated group (P < .01).

Conclusions: In this model, ETA antagonist therapy has a favorable effect on survival and pulmonary hemodynamics and reduces the dependency on NO for the attenuation of re duced vascular compliance.

Key Words: endothelins • endothelial receptors • pulmonary circulation • endothelial function • nitric oxide.

Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 4, No. 1, 33-39 (1999)
DOI: 10.1177/107424849900400106


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