Document Detail


Cardiac nitric oxide production due to angiotensin-converting enzyme inhibition decreases beta-adrenergic myocardial contractility in patients with dilated cardiomyopathy.
MedLine Citation:
PMID:  11499734     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVES: This study tested the hypothesis that angiotensin-converting enzyme (ACE) inhibitors attenuate beta-adrenergic contractility in patients with idiopathic dilated cardiomyopathy (DCM) through nitric oxide (NO) myocardial signaling. BACKGROUND: The ACE inhibitors increase bradykinin, an agonist of NO synthase (NOS). Nitric oxide inhibits beta-adrenergic myocardial contractility in patients with heart failure. METHODS: The study patients were given the angiotensin-1 (AT-1) receptor antagonist losartan for one week. The hemodynamic responses to intravenous dobutamine were determined before and during intracoronary infusion of enalaprilat (0.2 mg/min) with and without the NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA, 5 mg/min). RESULTS: In patients with DCM (n = 8), dobutamine increased the peak rate of rise of left ventricular pressure (+dP/dt) by 49 +/- 8% (p < 0.001) and ventricular elastance (Ecs) by 53 +/- 16% (p < 0.03). Co-infusion with enalaprilat decreased +dP/dt to 26 +/- 12% and Ecs to -2 +/- 17% above baseline (p < 0.05), and this anti-adrenergic effect was reversed by L-NMMA co-infusion (p < 0.05 vs. enalaprilat). In addition, intracoronary enalaprilat reduced left ventricular end-diastolic pressure (LVEDP), but not left ventricular end-diastolic volume, consistent with increased left ventricular distensibility. Infusion with L-NMMA before enalaprilat in patients with DCM (n = 5) prevented the reduction in +dP/dt, Ecs and LVEDP. In patients with normal left ventricular function (n = 5), enalaprilat did not inhibit contractility or reduce LVEDP during dobutamine infusion. CONCLUSIONS: Enalaprilat attenuates beta-adrenergic contractility and enhances left ventricular distensibility in patients with DCM, but not in subjects with normal left ventricular function. This response is NO modulated and occurs in the presence of angiotensin receptor blockade. These findings may have important clinical and pharmacologic implications for the use of ACE inhibitors, AT-1 receptor antagonists and their combination in the treatment of heart failure.
Authors:
I S Wittstein; D A Kass; P H Pak; W L Maughan; B Fetics; J M Hare
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of the American College of Cardiology     Volume:  38     ISSN:  0735-1097     ISO Abbreviation:  J. Am. Coll. Cardiol.     Publication Date:  2001 Aug 
Date Detail:
Created Date:  2001-08-13     Completed Date:  2001-10-04     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  8301365     Medline TA:  J Am Coll Cardiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  429-35     Citation Subset:  AIM; IM    
Affiliation:
Division of Cardiology, The Johns Hopkins Hospital, Baltimore, Maryland 21287, USA.
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MeSH Terms
Descriptor/Qualifier:
Adrenergic beta-Antagonists / pharmacology*
Angiotensin-Converting Enzyme Inhibitors / pharmacology*
Blood Pressure / drug effects
Cardiomyopathy, Dilated / metabolism*,  physiopathology*
Compliance
Depression, Chemical
Diastole
Dobutamine / pharmacology
Enalaprilat / pharmacology*
Enzyme Inhibitors / pharmacology
Female
Heart / physiopathology
Hemodynamics / drug effects
Humans
Losartan / pharmacology
Male
Middle Aged
Myocardial Contraction / drug effects*
Myocardium / metabolism
Nitric Oxide / biosynthesis*
Ventricular Dysfunction, Left / metabolism,  physiopathology
omega-N-Methylarginine / pharmacology
Grant Support
ID/Acronym/Agency:
HL-03238/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Adrenergic beta-Antagonists; 0/Angiotensin-Converting Enzyme Inhibitors; 0/Enzyme Inhibitors; 10102-43-9/Nitric Oxide; 114798-26-4/Losartan; 17035-90-4/omega-N-Methylarginine; 34368-04-2/Dobutamine; 84680-54-6/Enalaprilat

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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