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Circulation Research. 2004
Published online before print September 30, 2004, doi: 10.1161/01.RES.0000146676.04359.64
A more recent version of this article appeared on October 29, 2004
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Submitted on June 23, 2004
Revised on September 17, 2004
Accepted on September 21, 2004

Superoxide Mediates Sympathoexcitation in Heart Failure. Roles of Angiotensin II and NAD(P)H Oxidase

Lie Gao ; Wei Wang ; Yu-Long Li ; Harold D. Schultz ; Dongmei Liu ; Kurtis G. Cornish ; and Irving H. Zucker *

From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Nebraska Medical Center, Omaha.

* To whom correspondence should be addressed. E-mail: izucker{at}unmc.edu.

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 (P<0.01). These responses were abolished by intracerebroventricular losartan, tempol, or apocynin. Resting RSNA was significantly reduced by intracerebroventricular losartan, tempol, or apocynin in CHF rabbits but not in sham rabbits. Intracerebroventricular administration of the superoxide dismutase inhibitor diethyldithio-carbamic acid increased RSNA significantly more in sham compared with CHF rabbits. NADPH-dependent superoxide anion production in the rostral ventrolateral medulla (RVLM) was increased by 2.9-fold in CHF rabbits compared with sham rabbits. Finally, increases in the RVLM mRNA and protein expression of Ang II type 1 (AT1) 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.
Key words: free radicals • angiotensin receptors • RVLM • ventricular pacing




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