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1 Pharmacology SL83, Tulane University, Health Sciences Center, New Orleans, Louisiana, United States
2 Department of Anesthesiology, Oschner Clinic Foundation, New Orleans, Louisiana, United States
* To whom correspondence should be addressed. E-mail: pkadowi{at}tulane.edu.
The small GTP-binding protein and its downstream effector Rho-kinase play an important role in the regulation of vasoconstrictor tone. Rho-kinase activation maintains increased pulmonary vascular tone and mediates the vasoconstrictor response to NO synthesis inhibition in chronically hypoxic rats and in the ovine fetal lung. However the role of Rho-kinase in mediating pulmonary vasoconstriction after NO synthesis inhibition has not been examined in the intact rat. To address this question cardiovascular responses to the Rho-kinase inhibitor fasudil were studied at baseline and after administration of a NO synthesis inhibitor. In the intact rat iv injections of fasudil cause dose dependent decreases in systemic arterial pressure, small decreases in pulmonary arterial pressure and increases in cardiac output. L-NAME caused a significant increase in pulmonary and systemic arterial pressures and a decrease in cardiac output. The iv injections of fasudil after L-NAME caused dose-dependent decreases in pulmonary and systemic arterial pressure, increases in cardiac output and the percent decreases in pulmonary arterial pressure in response to the lower doses of fasudil were greater than decreases in systemic arterial pressure. The Ca++ entry blocker isradipine also decreased pulmonary and systemic arterial pressure in L-NAME treated rats. Infusion of sodium nitroprusside restored pulmonary arterial pressure to baseline values after administration of L-NAME. These data provide evidence in support of the hypothesis that increases in pulmonary and systemic vascular resistance following L-NAME treatment are mediated by Rho-kinase and Ca++ entry through L-type channels and that responses to L-NAME can be reversed by a NO donor.
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