TY - JOUR T1 - Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/09031936.00140309 SP - erj01403-2009 AU - B.K. Dahal AU - D. Kosanovic AU - P.K. Pamarthi AU - A. Sydykov AU - Y-J. Lai AU - R. Kast AU - H. Schirok AU - J-P. Stasch AU - H.A. Ghofrani AU - N. Weissmann AU - F. Grimminger AU - W. Seeger AU - R.T. Schermuly Y1 - 2010/01/01 UR - http://erj.ersjournals.com/content/early/2010/06/07/09031936.00140309.abstract N2 - Accumulating body of evidence incriminate Rho-kinase (ROCK) in the pathogenesis of pulmonary hypertension (PH). Therapeutic efficacy of azaindole-1, a novel highly selective and orally active ROCK inhibitor, has not yet been investigated in PH.This study aimed to investigate the effects of azaindole-1 on 1) acute hypoxic pulmonary vasoconstriction (HPV), 2) proliferation of pulmonary arterial smooth muscle cells (PASMCs) and 3) animal models of PH.Azaindole-1 significantly inhibited HPV in isolated, ventilated and buffer-perfused murine lungs and proliferation of primary rat PASMCs in vitro. Azaindole-1 was administered orally from 21 to 35 days after monocrotaline injection in rats (MCT-rats) and hypoxic exposure in mice. Azaindole-1 (10 and 30 mg·kg−1 body weight·day−1 in rats and mice, respectively) significantly improved hemodynamics and right ventricular hypertrophy. Moreover, the medial wall thickness and muscularization of peripheral pulmonary arteries were ameliorated. Azaindole-1 treatment resulted in a decreased immunoreactivity for phospho-myosin phosphatase target subunit 1 (p-MYPT1) and proliferating cell nuclear antigen (PCNA) in pulmonary vessels of MCT-rats, suggesting an impaired ROCK activity and reduced proliferating cells.Azaindole-1 provided therapeutic benefit in experimental PH, and this may be attributable to its potent vasorelaxant and antiproliferative effects. Azaindole-1 may offer a useful approach for treatment of PH. ER -