Document Detail


Acetoacetate augments beta-adrenergic inotropism of stunned myocardium by an antioxidant mechanism.
MedLine Citation:
PMID:  12595283     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Blunted beta-adrenergic inotropism in stunned myocardium is restored by pharmacological (N-acetylcysteine) and metabolic (pyruvate) antioxidants. The ketone body acetoacetate is a natural myocardial fuel and antioxidant that improves contractile function of prooxidant-injured myocardium. The impact of acetoacetate on postischemic cardiac function and beta-adrenergic signaling has never been reported. To test the hypothesis that acetoacetate restores contractile performance and beta-adrenergic inotropism of stunned myocardium, postischemic Krebs-Henseleit-perfused guinea pig hearts were treated with 5 mM acetoacetate and/or 2 nM isoproterenol at 15-45 and 30-45 min of reperfusion, respectively, while cardiac power was monitored. The myocardium was snap frozen, and its energy state was assessed from phosphocreatine phosphorylation potential. Antioxidant defenses were assessed from GSH/GSSG and NADPH/NADP(+) redox potentials. Stunning lowered cardiac power and GSH redox potential by 90 and 70%, respectively. Given separately, acetoacetate and isoproterenol each increased power and GSH redox potential three- to fivefold. Phosphocreatine potential was 70% higher in acetoacetate- vs. isoproterenol-treated hearts (P < 0.01). In combination, acetoacetate and isoproterenol synergistically increased power and GSH redox potential 16- and 7-fold, respectively, doubled NADPH redox potential, and increased cAMP content 30%. The combination increased cardiac power four- to sixfold vs. the individual treatments without a coincident increase in phosphorylation potential. Potentiation of isoproterenol's inotropic actions endured even after acetoacetate was discontinued and GSH potential waned, indicating that temporary enhancement of redox potential persistently restored beta-adrenergic mechanisms. Thus acetoacetate increased contractile performance and potentiated beta-adrenergic inotropism in stunned myocardium without increasing energy reserves, suggesting its antioxidant character is central to its beneficial actions.
Authors:
Jeffrey E Squires; Jie Sun; James L Caffrey; Darice Yoshishige; Robert T Mallet
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2002-12-19
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  284     ISSN:  0363-6135     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2003 Apr 
Date Detail:
Created Date:  2003-03-10     Completed Date:  2003-04-15     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H1340-7     Citation Subset:  IM    
Affiliation:
Department of Integrative Physiology and Cardiovascular Research Institute, University of North Texas Health Science Center, Fort Worth, Texas 76107-2699, USA.
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MeSH Terms
Descriptor/Qualifier:
Acetoacetates / administration & dosage*
Adrenergic beta-Agonists / administration & dosage
Animals
Antioxidants / administration & dosage*
Blood Pressure / drug effects
Citric Acid / metabolism
Cyclic AMP / analysis,  metabolism
Drug Synergism
Energy Metabolism
Glucose-6-Phosphate / metabolism
Glutathione / metabolism
Guinea Pigs
Heart Rate / drug effects
Isoproterenol / administration & dosage
Kinetics
Male
Muscle Contraction / drug effects*
Myocardial Stunning / drug therapy,  physiopathology*
Myocardium / metabolism
NADP / metabolism
Oxidation-Reduction
Phosphorylation
Receptors, Adrenergic, beta / physiology*
Ventricular Function, Left / drug effects
Grant Support
ID/Acronym/Agency:
HL-71684/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Acetoacetates; 0/Adrenergic beta-Agonists; 0/Antioxidants; 0/Receptors, Adrenergic, beta; 53-59-8/NADP; 541-50-4/acetoacetic acid; 56-73-5/Glucose-6-Phosphate; 60-92-4/Cyclic AMP; 70-18-8/Glutathione; 7683-59-2/Isoproterenol; 77-92-9/Citric Acid

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