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 Nω -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.
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