Published Online
on January 19, 2004

A more recent version of this article appeared on February 1, 2004

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Submitted on June 12, 2003
Revised on June 30, 2003

Rho/Rho-Kinase Pathway in the Brainstem Contributes to Hypertension Caused by Chronic Nitric Oxide Synthase Inhibition

Koji Ito; Yoshitaka Hirooka^*; Takuya Kishi; Yoshikuni Kimura; Kozo Kaibuchi; Hiroaki Shimokawa; and Akira Takeshita

From Department of Cardiovascular Medicine (K.I., Y.H., T.K., Y.K., H.S., A.T.), Kyushu University Graduate School of Medical Sciences, Fukuoka, and the Department of Cell Pharmacology (K.K.), Nagoya University Graduate School of Medicine, Nagoya, Japan.

^* To whom correspondence should be addressed. E-mail: hyoshi{at}cardiol.med.kyushu-u.ac.jp.

Abstract--Central nervous system mechanisms are involved in hypertension caused by chronic inhibition of nitric oxide (NO) synthesis. Chronic inhibition of NO synthesis might also activate the Rho/Rho-kinase pathway in the vasculature. We recently demonstrated that activation of the Rho/Rho-kinase pathway in the nucleus tractus solitarii (NTS) contributes to hypertensive mechanisms in spontaneously hypertensive rats. The aim of the present study was to determine whether activation of this pathway also contributes to neurogenic hypertensive mechanisms caused by chronic NO synthesis inhibition. The NO synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) was administered to Wistar-Kyoto rats in their drinking water (1 mg/mL) for 2 weeks. Bilateral microinjection of Y-27632, a specific Rho-kinase inhibitor, into the NTS elicited decreases in arterial pressure, heart rate, and renal sympathetic nerve activity in control rats and L-NAME-treated rats. The magnitude of the decrease, however, was significantly greater in L-NAME-treated than in control rats. In another group of rats, the specific Rho-kinase inhibitor, Y-27632, was administered intracisternally for 2 weeks with a mini-osmotic pump from the beginning of treatment with L-NAME. Y-27632 co-treatment significantly attenuated the increase in arterial pressure. Furthermore, the expression level of membranous RhoA and phosphorylation of the target proteins of Rho-kinase, the ERM (ezrin, radixin, moesin) family members, was significantly greater in L-NAME-treated rats than in control rats. These results indicate that activation of the Rho/Rho-kinase pathway in the NTS contributes to neurogenic hypertension caused by chronic NO synthase inhibition.

Key words: nitric oxide • blood pressure • sympathetic nervous system • hypertension • brain

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