Document Detail

Superoxide mediates sympathoexcitation in heart failure: roles of angiotensin II and NAD(P)H oxidase.
MedLine Citation:
PMID:  15459075     Owner:  NLM     Status:  MEDLINE    
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.
Lie Gao; Wei Wang; Yu-Long Li; Harold D Schultz; Dongmei Liu; Kurtis G Cornish; Irving H Zucker
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.     Date:  2004-09-30
Journal Detail:
Title:  Circulation research     Volume:  95     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2004 Oct 
Date Detail:
Created Date:  2004-10-29     Completed Date:  2005-05-12     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  937-44     Citation Subset:  IM    
Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA.
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MeSH Terms
Angiotensin II / physiology*,  toxicity
Angiotensin II Type 1 Receptor Blockers / therapeutic use
Blood Pressure / drug effects
Ditiocarb / pharmacology
Heart Failure / drug therapy,  etiology,  metabolism*,  physiopathology
Heart Rate / drug effects
Injections, Intraventricular
Kidney / innervation
Losartan / therapeutic use
Medulla Oblongata / metabolism
NADPH Oxidase / biosynthesis,  genetics,  physiology*
Protein Subunits
RNA, Messenger / biosynthesis,  genetics
Reactive Oxygen Species
Receptor, Angiotensin, Type 1 / biosynthesis,  genetics
Superoxides / metabolism*
Sympathetic Nervous System / physiopathology*
Tachycardia, Ventricular / complications
Grant Support
Reg. No./Substance:
0/Angiotensin II Type 1 Receptor Blockers; 0/Protein Subunits; 0/RNA, Messenger; 0/Reactive Oxygen Species; 0/Receptor, Angiotensin, Type 1; 11062-77-4/Superoxides; 11128-99-7/Angiotensin II; 114798-26-4/Losartan; 147-84-2/Ditiocarb; EC Oxidase

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