Donate Help Contact The AHA Sign In Home
American Heart Association
Circulation
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Circulation. 2005;112:1763-1770
Published online before print September 12, 2005, doi: 10.1161/CIRCULATIONAHA.105.552174
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Clinical Perspective
Right arrow All Versions of this Article:
112/12/1763    most recent
CIRCULATIONAHA.105.552174v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gao, L.
Right arrow Articles by Zucker, I. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gao, L.
Right arrow Articles by Zucker, I. H.
Related Collections
Right arrow Cardio-renal physiology/pathophysiology
Right arrow Autonomic, reflex, and neurohumoral control of circulation
Right arrow ACE/Angiotension receptors
Right arrow Heart failure - basic studies

(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 (gainmax, 1.6±0.3 to 4.5±0.2 bpm/mm Hg, P<0.05), and increased RSNA (gainmax, 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




This article has been cited by other articles:


Home page
 CirculationHome page
B. Olshansky, H. N. Sabbah, P. J. Hauptman, and W. S. Colucci
Parasympathetic Nervous System and Heart Failure: Pathophysiology and Potential Implications for Therapy
Circulation, August 19, 2008; 118(8): 863 - 871.
[Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
L. Gao, W. Wang, and I. H. Zucker
Simvastatin Inhibits Central Sympathetic Outflow in Heart Failure by a Nitric-Oxide Synthase Mechanism
J. Pharmacol. Exp. Ther., July 1, 2008; 326(1): 278 - 285.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
T.-M. Lee, M.-S. Lin, and N.-C. Chang
Effect of pravastatin on sympathetic reinnervation in postinfarcted rats
Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3617 - H3626.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
L. Gao, W. Wang, D. Liu, and I. H. Zucker
Exercise Training Normalizes Sympathetic Outflow by Central Antioxidant Mechanisms in Rabbits With Pacing-Induced Chronic Heart Failure
Circulation, June 19, 2007; 115(24): 3095 - 3102.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
I. H. Zucker
Novel Mechanisms of Sympathetic Regulation in Chronic Heart Failure
Hypertension, December 1, 2006; 48(6): 1005 - 1011.
[Full Text] [PDF]


Circulation Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search
Copyright © 2005 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited.