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

Abstract

T. Mallet. Acetoacetate augments ␤-adrenergic inotropism of stunned myocardium by an antioxidant mechanism. Am J Physiol Heart Circ Physiol 284: H1340-H1347, 2003. First published December 19, 2002 10.1152/ajpheart.00473.2002.-Blunted ␤-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 ␤-adrenergic signaling has never been reported. To test the hypothesis that acetoacetate restores contractile performance and ␤-adrenergic inotropism of stunned myocardium, postischemic Krebs-Henseleitperfused 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 ϩ 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 acetoacetatevs. isoproterenol-treated hearts (P Ͻ 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 ␤-adrenergic mechanisms. Thus acetoacetate increased contractile performance and potentiated ␤-adrenergic inotropism in stunned myocardium without increasing energy reserves, suggesting its antioxidant character is central to its beneficial actions.isoproterenol; glutathione; adenosine 3Ј,5Ј-cyclic monophosphate; nicotinamide adenine dinucleotide phosphate; citrate POSTISCHEMIC MYOCARDIAL STUNNING is produced in large part by cytotoxic oxygen and nitrogen metabolites generated upon coronary reperfusion (6). The resulting superoxide, H 2 O 2 , hydroxyl radical, and peroxynitrite (2, 12, 39) modify a variety of cellular components (5) to produce stunning. Inotropic responses to ␤-adrenergic stimulation are dampened in stunned myocardium (38, 44), perhaps resulting from oxidative damage to protein components of the ␤-adrenergic signaling cascade.Pyruvate, a natural metabolic fuel in myocardium, markedly increased ␤-adrenergic responsiveness of stunned myocardium and preserved energy stores (44). Pyruvate also restored GSH/GSSG redox potential (43), the princ...

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