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 ET(A)-receptor antagonist LU 135252 (LU) in rats with established monocrotaline (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, pulmonary vascular compliance was reduced by PH and unaffected by LU therapy. After the NO synthase inhibitor N(omega)-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, ET(A) antagonist therapy has a favorable effect on survival and pulmonary hemodynamics and reduces the dependency on NO for the attenuation of reduced vascular compliance.
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 ET(A)-receptor antagonist LU 135252 (LU) in rats with established monocrotaline (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 + salinerats 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, pulmonary vascular compliance was reduced by PH and unaffected by LU therapy. After the NO synthase inhibitor N(omega)-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, ET(A) antagonist therapy has a favorable effect on survival and pulmonary hemodynamics and reduces the dependency on NO for the attenuation of reduced vascular compliance.
Authors: M Kavanagh; B Battistini; S Jean; J Crochetière; L Fournier; J Wessale; T J Opgenorth; R Cloutier; D Major Journal: Br J Pharmacol Date: 2001-12 Impact factor: 8.739
Authors: I P Temple; O Monfredi; G Quigley; H Schneider; M Zi; E J Cartwright; M R Boyett; V S Mahadevan; G Hart Journal: Int J Cardiol Date: 2014-10-11 Impact factor: 4.164