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(Circulation. 2005;112:1763-1770.)
© 2005 American Heart Association, Inc.

Heart Failure

Simvastatin Therapy Normalizes Sympathetic Neural Control in Experimental Heart Failure

Roles of Angiotensin II Type 1 Receptors and NAD(P)H Oxidase

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

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

Correspondence to Irving H. Zucker, PhD, Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, 985850 Nebraska Medical Center, Omaha, NE 68198-5850. E-mail izucker{at}unmc.edu

Received March 27, 2005; revision received May 31, 2005; accepted June 28, 2005.

Background— In a previous study, we showed that simvastatin (SIM) therapy normalized sympathetic outflow and cardiovascular reflex regulation in chronic heart failure (CHF). However, the precise neural and cellular pathways for these effects are unknown. We hypothesized that SIM exerts its beneficial effect on autonomic function in CHF by downregulating central angiotensin II (Ang II) and superoxide mechanisms.

Methods and Results— Experiments were carried out on 36 male New Zealand White rabbits, 13 normal and 23 CHF. All rabbits were identically instrumented to record mean arterial pressure, heart rate, and renal sympathetic nerve activity (RSNA). Echocardiography was used to monitor cardiac function. Reverse transcription–polymerase chain reaction, Western blotting, and lucigenin-enhanced chemiluminescence were used to measure gene expression of Ang II type 1 receptor and NAD(P)H oxidase subunits and NAD(P)H oxidase activity in the rostral ventrolateral medulla. Compared with the CHF control group, SIM significantly reduced the central Ang II–induced pressor and sympathoexcitatory responses, decreased baseline RSNA (57.3±3.2% to 22.4±2.1% of maximum, P<0.05), increased baroreflex control of heart rate (gain_max, 1.6±0.3 to 4.5±0.2 bpm/mm Hg, P<0.05), and increased RSNA (gain_max, 1.7±0.2% to 4.9±0.6% of maximum/mm Hg, P<0.01). Importantly, SIM improved left ventricular function (EF, 32.4±4.1% to 51.7±3.2%, P<0.05). SIM also downregulated mRNA and protein expression of Ang II type 1 receptor and NAD(P)H oxidase subunits and inhibited NAD(P)H oxidase activity in the rostral ventrolateral medulla of CHF rabbits. Chronic intracerebroventricular infusion of Ang II completely abolished the aforementioned effects of SIM in CHF rabbits.

Conclusions— These data strongly suggest that SIM normalizes autonomic function in CHF by inhibiting central Ang II mechanisms and therefore the superoxide pathway. These data also demonstrate that SIM improves left ventricular function in pacing-induced CHF rabbits.

Key Words: angiotensin • free radicals • statins • nervous system, sympathetic • heart failure

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