Abstract 80: Central Rho Kinase Inhibition Lowers Sympathetic Nerve Activity and Restores Baroreflex Sensitivity and AT1R Protein Expression in Conscious Rabbits with Chronic Heart Failure
Rho-Associated protein kinase (RhoK) is a serine/threonine kinase involved in calcium sensitization and vascular smooth muscle cell contraction. RhoK overactivation is implicated in chronic heart failure (CHF) and a potential contributor to the heightened sympathetic nerve activity seen in CHF. Thus, we investigated the effect of central RhoK blockade on renal sympathetic nerve activity (RSNA) in a pacing rabbit model of CHF. CHF was induced by rapid ventricular pacing and characterized by an ejection fraction of ∼45%. Renal nerve recording electrodes, an ICV cannula and osmotic minipump (rate: 1 μL/h) containing sterile saline or 1.5 mg/kg/mL fasudil (Fas, a RhoK inhibitor) were implanted. Arterial baroreflex control was determined by IV infusion of sodium nitroprusside (100μg/kg) until mean arterial pressure (MAP) was lowered to ∼40 mmHg and phenylephrine (80μg/kg) until MAP was raised to ∼100 mm Hg. Fas infusion significantly lowered resting heart rate and improved maximal HR/MAP baroreflex gain in CHF (Fas:2.20 ± 0.13 vs Veh:2.84 ± 0.12). Administration of metoprolol prior to performing baroreflex analysis restored HR to sham levels and increased slope in the Fas group, suggesting Fas improves vagal tone. Change in RSNA response to oropharyngeal smoke was increased in CHF Fas animals vs CHF Veh. Fas decreased AT1R and phospho-RhoA (a readout of RhoK activity) protein expression and increased eNOS expression in the RVLM of CHF animals. These data suggest that central RhoK activation may contribute to sympatho-excitation in the setting of CHF and that Fas restores vagal tone and decreases sympathetic outflow. *p<0.05 vs sham groups, †p<0.05 vs Sham Fas, ‡p<0.05 vs CHF Veh.
- © 2012 by American Heart Association, Inc.