Abstract 15998: Rho Kinase Inhibition Prevents the Pressor and Sympatho-Excitatory Effects of Central Angiotensin-II Infusion in Conscious Rabbits

Introduction: Elevated sympathetic tone and activation of the renin-angiotensin system are pathophysiologic hallmarks of diseases like chronic heart failure, hypertension, chronic kidney disease, and obstructive sleep apnea, all of which have compelling burdens and therapeutic needs. The RhoA/Rho kinase pathway is an important mediator of the effects of Angiotensin-II (AngII) in the periphery, but the functional role of this pathway in the brain in AngII-induced sympatho-excitation is not well-characterized. Hypothesis: We hypothesized that central inhibition of the RhoA/Rho kinase pathway prevents AngII-mediated autonomic dysfunction in rabbits. Methods: Each rabbit received all four of the following intracerebroventricular infusion treatments for two weeks in random order: AngII, the Rho kinase inhibitor Fasudil (Fas), AngII and Fas, and vehicle infusion via osmotic minipump. After two weeks, the treatment was washed out with vehicle infusion for 7-14 days. Baseline recordings of mean arterial pressure (MAP) and heart rate (HR) were acquired throughout treatment. After ten days of infusion, cardiac sympathetic tone and sympathetic vasomotor tone were assessed by the change in HR after metoprolol and change in MAP after hexamethonium, respectively. Results: AngII treatment resulted in a pressor effect that was blocked with Fas co-infusion (A). Both cardiac sympathetic tone (B) and sympathetic vasomotor tone (C) were increased with AngII infusion; this sympatho-excitation was abrogated by co-infusion of Fas. Each of these measures showed a significant interaction between AngII and Fas, indicating that the pressor and sympatho-excitatory responses of central AngII are mediated by the RhoA/Rho kinase pathway. Conclusions: These data indicate that inhibition of the Rho kinase pathway centrally could act as a therapeutic brake on the positive feedback between central renin-angiotensin system activation and sympathetic outflow in many diseases.