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The Rho kinase inhibitor azaindole-1 has long-acting vasodilator activity in the pulmonary vascular bed of the intact chest rat

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Responses to a selective azaindole-based Rho kinase (ROCK) inhibitor (azaindole-1) were investigated in the rat. Intravenous injections of azaindole-1 (10–300 µg/kg), produced small decreases in pulmonary arterial pressure and larger decreases in systemic arterial pressure without changing cardiac output. Responses to azaindole-1 were slow in onset and long in duration. When baseline pulmonary vascular tone was increased with U46619 or L-NAME, the decreases in pulmonary arterial pressure in response to the ROCK inhibitor were increased. The ROCK inhibitor attenuated the increase in pulmonary arterial pressure in response to ventilatory hypoxia. Azaindole-1 decreased pulmonary and systemic arterial pressures in rats with monocrotaline-induced pulmonary hypertension. These results show that azaindole-1 has significant vasodilator activity in the pulmonary and systemic vascular beds and that responses are larger, slower in onset, and longer in duration when compared with the prototypical agent fasudil. Azaindole-1 reversed hypoxic pulmonary vasoconstriction and decreased pulmonary and systemic arterial pressures in a similar manner in rats with monocrotaline-induced pulmonary hypertension. These data suggest that ROCK is involved in regulating baseline tone in the pulmonary and systemic vascular beds, and that ROCK inhibition will promote vasodilation when tone is increased by diverse stimuli including treatment with monocrotaline.
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Keywords: L-NAME; ROCK; Rho kinase; U46619; azaindole-1; circulation pulmonaire et systémique; fasudil; hypoxia; hypoxie; monocrotaline; pulmonary and systemic circulation; réponses vasodilatatrices; vasodilator responses

Document Type: Research Article

Affiliations: 1: Department of Pharmacology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112-2699, USA. 2: Institute of Cardiovascular Research, Pharma Research Centre, Bayer AG, D-42096 Wuppertal, Germany.

Publication date: July 4, 2012

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