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

Area of Science:

• Cardiovascular Physiology
• Vascular Biology
• Pharmacology

Background:

• Rho kinase is crucial for regulating vascular tone, particularly in response to vasoconstrictors.
• Rho kinase activation contributes to elevated pulmonary vascular tone following nitric oxide (NO) synthesis inhibition.
• Its specific role in mediating pulmonary vasoconstriction in intact rats after NO synthesis inhibition remains unclear.

Purpose of the Study:

• To investigate the role of Rho kinase in mediating pulmonary vasoconstriction after NO synthesis inhibition in intact rats.
• To examine the effects of the Rho kinase inhibitor fasudil on cardiovascular responses before and after NO synthesis inhibition.

Main Methods:

• Cardiovascular responses to fasudil were assessed in intact rats at baseline and after administration of L-NAME (an NO synthesis inhibitor).
• Effects of the calcium channel blocker isradipine and the NO donor sodium nitroprusside were also evaluated.

Main Results:

• Fasudil administration caused dose-dependent decreases in systemic and pulmonary arterial pressures and increased cardiac output.
• L-NAME significantly increased pulmonary and systemic arterial pressures and decreased cardiac output.
• Fasudil administration after L-NAME reversed these increases, with greater effects on pulmonary than systemic pressure.
• Isradipine also reduced pressures in L-NAME-treated rats, and sodium nitroprusside restored pulmonary arterial pressure.

Conclusions:

• Increases in pulmonary and systemic vascular resistance after L-NAME treatment are mediated by Rho kinase and calcium entry via L-type channels.
• These findings demonstrate that Rho kinase plays a significant role in maintaining elevated vascular tone post-NO synthesis inhibition.
• Responses to L-NAME can be effectively reversed by administering an NO donor.