Acetoacetate augments beta-adrenergic inotropism of stunned myocardium by an antioxidant mechanism

Am J Physiol Heart Circ Physiol. 2003 Apr;284(4):H1340-7. doi: 10.1152/ajpheart.00473.2002. Epub 2002 Dec 19.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetoacetates / administration & dosage*
  • Adrenergic beta-Agonists / administration & dosage
  • Animals
  • Antioxidants / administration & dosage*
  • Blood Pressure / drug effects
  • Citric Acid / metabolism
  • Cyclic AMP / analysis
  • Cyclic AMP / 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
  • Myocardial Stunning / physiopathology*
  • Myocardium / metabolism
  • NADP / metabolism
  • Oxidation-Reduction
  • Phosphorylation
  • Receptors, Adrenergic, beta / physiology*
  • Ventricular Function, Left / drug effects


  • Acetoacetates
  • Adrenergic beta-Agonists
  • Antioxidants
  • Receptors, Adrenergic, beta
  • Citric Acid
  • acetoacetic acid
  • NADP
  • Glucose-6-Phosphate
  • Cyclic AMP
  • Glutathione
  • Isoproterenol