title: Acetoacetate augments beta-adrenergic inotropism of stunned myocardium by an antioxidant mechanism.
abstract: 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.affiliation: Department of Integrative Physiology and Cardiovascular Research Institute, University of North Texas Health Science Center, Fort Worth, Texas 76107-2699, USA.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Squires
authors.forename: Jie
authors.initials: J
authors.lastname: Sun
authors.forename: James L
authors.initials: JL
authors.lastname: Caffrey
authors.forename: Darice
authors.initials: D
authors.lastname: Yoshishige
authors.forename: Robert T
authors.initials: RT
authors.lastname: Mallet
mesh_terms: D000090:Acetoacetates / Q000008:administration & dosage*; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage*; D001794:Blood Pressure / Q000187:drug effects; D019343:Citric Acid / Q000378:metabolism; D000242:Cyclic AMP / Q000032:analysis / Q000378:metabolism; D004357:Drug Synergism; D004734:Energy Metabolism; D019298:Glucose-6-Phosphate / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D007545:Isoproterenol / Q000008:administration & dosage; D007700:Kinetics; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D017682:Myocardial Stunning / Q000188:drug therapy / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D000090:Acetoacetates; D000318:Adrenergic beta-Agonists; D000975:Antioxidants; D011943:Receptors, Adrenergic, beta; D019343:Citric Acid; C016635:acetoacetic acid; D009249:NADP; D019298:Glucose-6-Phosphate; D000242:Cyclic AMP; D005978:Glutathione; D007545:Isoproterenol