CENTRAL RHO KINASE INHIBITION RESTORES BAROREFLEX SENSITIVITY AND AT1R PROTEIN IMBALANCE IN CONSCIOUS RABBITS WITH CHRONIC HEART FAILURE

The small GTPase RhoA and its associated kinase ROCKII are involved in vascular smooth muscle cell contraction and endothelial nitric oxide synthase (eNOS) mRNA destabilization. Overactivation of the RhoA/ROCKII pathway is implicated in a number of pathologies including chronic heart failure (CHF) and may contribute to the enhanced sympathetic outflow seen in CHF due to decreased nitric oxide (NO) availability. Thus, we hypothesized that central ROCKII blockade would improve the sympatho-vagal 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 ICV cannula and osmotic minipump (rate: 1 µL/h) containing sterile saline, 1.5 µg/kg/day fasudil (Fas, a ROCKII inhibitor) for 4 days or Fas + 100 µg/kg/day L-NAME, a NOS inhibitor. Arterial baroreflex control was assessed by IV infusion of sodium nitroprusside and phenylephrine. Fas infusion significantly lowered resting HR 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 HR in response to IV metoprolol was similar to sham and was reversed by L-NAME. Fas decreased AT1R and phospho-RhoA protein expression and increased eNOS expression in the brainstem of CHF animals. These data strongly suggest that central ROCKII activation contributes to cardiac sympatho-excitation 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.