TY - JOUR
T1 - Acetoacetate augments β-adrenergic inotropism of stunned myocardium by an antioxidant mechanism
AU - Squires, Jeffrey E.
AU - Sun, Jie
AU - Caffrey, James L.
AU - Yoshishige, Darice
AU - Mallet, Robert T.
PY - 2003/4/1
Y1 - 2003/4/1
N2 - Blunted β-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 β-adrenergic signaling has never been reported. To test the hypothesis that acetoacetate restores contractile performance and β-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 acetoacetatevs. 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 β-adrenergic mechanisms. Thus acetoacetate increased contractile performance and potentiated β-adrenergic inotropism in stunned myocardium without increasing energy reserves, suggesting its antioxidant character is central to its beneficial actions.
AB - Blunted β-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 β-adrenergic signaling has never been reported. To test the hypothesis that acetoacetate restores contractile performance and β-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 acetoacetatevs. 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 β-adrenergic mechanisms. Thus acetoacetate increased contractile performance and potentiated β-adrenergic inotropism in stunned myocardium without increasing energy reserves, suggesting its antioxidant character is central to its beneficial actions.
KW - Adenosine 3′,5′-cyclic monophosphate
KW - Citrate
KW - Glutathione
KW - Isoproterenol
KW - Nicotinamide adenine dinucleotide phosphate
UR - http://www.scopus.com/inward/record.url?scp=0037377564&partnerID=8YFLogxK
U2 - 10.1152/ajpheart.00473.2002
DO - 10.1152/ajpheart.00473.2002
M3 - Article
C2 - 12595283
AN - SCOPUS:0037377564
SN - 0363-6135
VL - 284
SP - H1340-H1347
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 4 53-4
ER -