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This Article Full Text Full Text (PDF) All Versions of this Article: 293/5/L1306    most recent 00189.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Dhaliwal, J. S. Articles by Kadowitz, P. J. Search for Related Content PubMed PubMed Citation Articles by Dhaliwal, J. S. Articles by Kadowitz, P. J.

Rho kinase and Ca²⁺ entry mediate increased pulmonary and systemic vascular resistance in L-NAME-treated rats

¹Department of Pharmacology, Tulane University Health Sciences Center, New Orleans; and ²Department of Anesthesiology, Oschner Clinic Foundation, New Orleans, Louisiana

Submitted 11 May 2007 ; accepted in final form 23 August 2007

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 nitric oxide (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 an NO synthesis inhibitor. In the intact rat, intravenous 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 intravenous injections of fasudil after L-NAME caused dose-dependent decreases in pulmonary and systemic arterial pressure and 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 an NO donor.

HA-1077; Rho kinase pathway; Ca⁺⁺ sensitization; pulmonary vascular bed; sodium nitroprusside; isradipine; N-nitro-L-arginine methyl ester