Central Rho Kinase Inhibition Restores Baroreflex Sensitivity and Angiotensin II Type 1 Receptor Protein Imbalance in Conscious Rabbits With Chronic Heart Failure

Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE.
Hypertension (Impact Factor: 6.48). 01/2013; 61(3). DOI: 10.1161/HYPERTENSIONAHA.111.00396
Source: PubMed


The small GTPase RhoA and its associated kinase ROCKII are involved in vascular smooth muscle cell contraction and endothelial NO synthase mRNA destabilization. Overactivation of the RhoA/ROCKII pathway is implicated in several pathologies, including chronic heart failure (CHF), and may contribute to the enhanced sympathetic outflow seen in CHF as a result of decreased NO availability. Thus, we hypothesized that central ROCKII blockade would improve the sympathovagal imbalance in a pacing rabbit model of CHF in an NO-dependent manner. CHF was induced by rapid ventricular pacing and characterized by an ejection fraction of ≤45%. Animals were implanted with an intracerbroventricular cannula and osmotic minipump (rate, 1 μL/h) containing sterile saline, 1.5 µg/kg per day fasudil (Fas, a ROCKII inhibitor) for 4 days or Fas+100 µg/kg per day Nω-Nitro-l-arginine methyl ester hydrochloride, a NO synthase inhibitor. Arterial baroreflex control was assessed by intravenous infusion of sodium nitroprusside and phenylephrine. Fas infusion significantly lowered resting heart rate by decreasing sympathetic and increasing vagal tone. Furthermore, Fas improved baroreflex gain in CHF in an NO-dependent manner. In CHF Fas animals, the decrease in heart rate in response to intravenous metoprolol was similar to Sham and was reversed by Nω-Nitro-l-arginine methyl ester hydrochloride. Fas decreased angiotensin II type 1 receptor and phospho-ERM protein expression and increased endothelial NO synthase expression in the brain stem of CHF animals. These data strongly suggest that central ROCKII activation contributes to cardiac sympathoexcitation in the setting of CHF and that central Fas restores vagal and sympathetic tone in an NO-dependent manner. ROCKII may be a new central therapeutic target in the setting of CHF.

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Available from: Alicia (Diener) Schiller, Jul 21, 2015
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    • "We have previously shown that simvastatin lowers sympathetic tone in experimental chronic heart failure, another condition characterized by sympathoexcitation [18,19]. Also ROCK inhibition (ROKI) by Fasudil was shown to improve baroreflex sensitivity in experimental chronic heart failure when given in to the intracerebroventricular space [20]. This effect was blunted by intracerebroventricular application of L-NAME, an inhibitor of endothelial nitric oxide synthase, suggesting direct central effects and a contribution of central nitric oxide in this process. "
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