Superoxide Mediates Sympathoexcitation in Heart Failure

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Abstract
Chronic heart failure (CHF) is often associated with excitation of the sympathetic nervous system. This event is thought to be a negative predictor of survival in CHF. Sympathoexcitation and central angiotensin II (Ang II) have been causally linked. Recent studies have shown that NAD(P)H oxidase-derived reactive oxidant species (ROS) are important mediators of Ang II signaling. In the present study, we tested the hypothesis that central Ang II activates sympathetic outflow by stimulation of NAD(P)H oxidase and ROS in the CHF state. CHF was induced in male New Zealand White rabbits by chronic ventricular tachycardia. Using radio telemetry of arterial pressure and intracerebroventricular infusions, experiments were performed in the conscious state. Renal sympathetic nerve activity (RSNA) was recorded as a direct measure of sympathetic outflow. Intracerebroventricular Ang II significantly increased RSNA in sham (131.5±13.3% of control) and CHF (193.6±11.9% of control) rabbits. The increase in CHF rabbits was significantly greater than in sham rabbits (P1) receptor and subunits of NAD(P)H oxidase (p40phox, p47phox, and gp91phox) were demonstrated in CHF rabbits. These data demonstrate intense radical stress in autonomic areas of the brain in experimental CHF and provide evidence for a tight relationship between Ang II and ROS as contributors to sympathoexcitation in CHF.

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