Acute hibernation decreases myocardial pyruvate carboxylation and citrate release.

In the well-perfused heart, pyruvate carboxylation accounts for 3-6% of the citric acid cycle (CAC) flux, and CAC carbon is lost via citrate release. We investigated the effects of an acute reduction in coronary flow on these processes and on the tissue content of CAC intermediates. Measurements were made in an open-chest anesthetized swine model. Left anterior descending coronary artery blood flow was controlled by a extracorporeal perfusion circuit, and flow was decreased by 40% for 80 min to induce myocardial hibernation (n = 8). An intracoronary infusion of [U-(13)C(3)]lactate and [U-(13)C(3)]pyruvate was given to measure the entry of pyruvate into the CAC through pyruvate carboxylation from the (13)C-labeled isotopomers of CAC intermediates. Compared with normal coronary flow, myocardial hibernation resulted in parallel decreases of 65% and 79% in pyruvate carboxylation and net citrate release by the myocardium, respectively, and maintenance of the CAC intermediate content. Elevation of the arterial pyruvate concentration by 1 mM had no effect. Thus a 40% decrease in coronary blood flow resulted in a concomitant decrease in pyruvate carboxylation and citrate release as well as maintenance of the CAC intermediates.

[1]  B. Corkey,et al.  [65] Assays of intermediates of the citric acid cycle and related compounds by fluorometric enzyme methods , 1969 .

[2]  I. Hassinen,et al.  Pyruvate carboxylation as an anaplerotic mechanism in the isolated perfused rat heart. , 1982, The Biochemical journal.

[3]  M. Gibala,et al.  Anaplerosis of the citric acid cycle: role in energy metabolism of heart and skeletal muscle. , 2000, Acta physiologica Scandinavica.

[4]  Opie Lh.  Effects of regional ischemia on metabolism of glucose and fatty acids. Relative rates of aerobic and anaerobic energy production during myocardial infarction and comparison with effects of anoxia. , 1976 .

[5]  H. Brunengraber,et al.  Partitioning of pyruvate between oxidation and anaplerosis in swine hearts. , 2000, American journal of physiology. Heart and circulatory physiology.

[6]  Portland Press Ltd.  Role of NAD+-linked malic enzymes as regulators of the pool size of tricarboxylic acid-cycle intermediates in the perfused rat heart , 1987 .

[7]  A. Liedtke.  Alterations of carbohydrate and lipid metabolism in the acutely ischemic heart. , 1981, Progress in cardiovascular diseases.

[8]  J. Hiltunen,et al.  Pyruvate carboxylation in the rat heart. Role of biotin-dependent enzymes. , 1989, The Biochemical journal.

[9]  G. Shulman,et al.  Glucose metabolism distal to a critical coronary stenosis in a canine model of low-flow myocardial ischemia. , 1996, The Journal of clinical investigation.

[10]  C. Des Rosiers,et al.  Effects and metabolism of fumarate in the perfused rat heart. A 13C mass isotopomer study. , 1997, The American journal of physiology.

[11]  A. Arai,et al.  Active downregulation of myocardial energy requirements during prolonged moderate ischemia in swine. , 1991, Circulation research.

[12]  A. Sherry,et al.  13C isotopomer model for estimation of anaplerotic substrate oxidation via acetyl-CoA. , 1996, The American journal of physiology.

[13]  T. Nielsen,et al.  Myocardial exchanges of glutamate, alanine and citrate in controls and patients with coronary artery disease. , 1983, Clinical science.

[14]  R. C. Lin,et al.  Malic enzymes of rabbit heart mitochondria. Separation and comparison of some characteristics of a nicotinamide adenine dinucleotide-preferring and a nicotinamide adenine dinucleotide phosphate-specific enzyme. , 1974, The Journal of biological chemistry.

[15]  S. Rahimtoola.  A perspective on the three large multicenter randomized clinical trials of coronary bypass surgery for chronic stable angina. , 1985, Circulation.

[16]  H. Taegtmeyer,et al.  Propionyl-L-carnitine-mediated improvement in contractile function of rat hearts oxidizing acetoacetate. , 1995, The American journal of physiology.

[17]  F. Fedele,et al.  Metabolic response to prolonged reduction of myocardial blood flow distal to a severe coronary artery stenosis. , 1988, Circulation.

[18]  J. Mccormack,et al.  Regulation of myocardial carbohydrate metabolism under normal and ischaemic conditions Potential for pharmacological interventions , 1997 .

[19]  J K Kelleher,et al.  Applications of mass isotopomer analysis to nutrition research. , 1997, Annual review of nutrition.

[20]  C. Rosiers,et al.  Citrate release by perfused rat hearts: a window on mitochondrial cataplerosis. , 2000, American journal of physiology. Endocrinology and metabolism.

[21]  J. Hiltunen,et al.  Role of NADP+ (corrected)-linked malic enzymes as regulators of the pool size of tricarboxylic acid-cycle intermediates in the perfused rat heart. , 1987, The Biochemical journal.

[22]  H. Taegtmeyer,et al.  Pyruvate carboxylation prevents the decline in contractile function of rat hearts oxidizing acetoacetate. , 1991, The American journal of physiology.

[23]  G. Heusch,et al.  Progressive loss of perfusion-contraction matching during sustained moderate ischemia in pigs. , 2001, American journal of physiology. Heart and circulatory physiology.

[24]  P. Attwood.  The structure and the mechanism of action of pyruvate carboxylase. , 1995, The international journal of biochemistry & cell biology.

[25]  J. Mccormack,et al.  Pyruvate dehydrogenase activity and malonyl CoA levels in normal and ischemic swine myocardium: effects of dichloroacetate. , 1996, Journal of molecular and cellular cardiology.

[26]  B. Cason,et al.  Dichloroacetate stimulates carbohydrate metabolism but does not improve systolic function in ischemic pig heart. , 1995, The American journal of physiology.

[27]  L. Opie.  Effects of Regional Ischemia on Metabolism of Glucose and Fatty Acids: Relative Rates of Aerobic and Anaerobic Energy Production during Myocardial Infarction and Comparison with Effects of Anoxia , 1976, Circulation research.

[28]  R. Bünger,et al.  Pyruvate-enhanced phosphorylation potential and inotropism in normoxic and postischemic isolated working heart. Near-complete prevention of reperfusion contractile failure. , 1989, European journal of biochemistry.

[29]  K. Shine,et al.  Protection of ischemic rabbit myocardium by glutamic acid. , 1983, The American journal of physiology.

[30]  A. Arai,et al.  Regeneration of myocardial phosphocreatine in pigs despite continued moderate ischemia. , 1990, Circulation research.

[31]  H. Brunengraber,et al.  Isotopomer Analysis of Citric Acid Cycle and Gluconeogenesis in Rat Liver , 1995, The Journal of Biological Chemistry.

[32]  T. Takala,et al.  Tricarboxylic acid cycle metabolites during ischemia in isolated perfused rat heart. , 1983, The American journal of physiology.

[33]  G. Heusch,et al.  Recruitment of an inotropic reserve in moderately ischemic myocardium at the expense of metabolic recovery. A model of short-term hibernation. , 1992, Circulation research.

[34]  J. Caffrey,et al.  Antioxidant properties of pyruvate mediate its potentiation of beta-adrenergic inotropism in stunned myocardium. , 1999, Journal of molecular and cellular cardiology.

[35]  R. Sh.  A perspective on the three large multicenter randomized clinical trials of coronary bypass surgery for chronic stable angina. , 1985, Circulation.

[36]  S. Rahimtoola.  Some unexpected lessons from large multicenter randomized clinical trials. , 1985, Circulation.

[37]  C. Stone,et al.  Acute myocardial ischemia causes a transmural gradient in glucose extraction but not glucose uptake. , 1992, The American journal of physiology.

[38]  C. Rosiers,et al.  A 13C Mass Isotopomer Study of Anaplerotic Pyruvate Carboxylation in Perfused Rat Hearts* , 1997, The Journal of Biological Chemistry.

[39]  C. Rosiers,et al.  Probing the Origin of Acetyl-CoA and Oxaloacetate Entering the Citric Acid Cycle from the 13C Labeling of Citrate Released by Perfused Rat Hearts* , 1997, The Journal of Biological Chemistry.