Regulation of myocardial carbohydrate metabolism under normal and ischaemic conditions. Potential for pharmacological interventions

Cardiovascular Research

Volumn 33, Issue 2, 1997, Pages 243-257

  Stanley, William C ^a,e   Lopaschuk, Gary D ^b   Hall, Jennifer L ^c   McCormack, James G ^d  

^a CV THERAPEUTICS INC   (United States)

^b UNIVERSITY OF ALBERTA   (Canada)

^c STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

^d NOVO NORDISK A S   (Denmark)

^e CASE WESTERN RESERVE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

cardiac metabolism; carnitine; fatty acids; glycolysis; heart; insulin; lactate; myocardial ischemia; pyruvate dehydrogenase; reperfusion

Indexed keywords

CARNITINE; DICHLOROACETIC ACID; ETOMOXIR; GLUCOSE; INSULIN; PROPIONYLCARNITINE; RANOLAZINE;

ANIMAL TISSUE; CARBOHYDRATE METABOLISM; CONTROLLED STUDY; GLUCOSE OXIDATION; HEART MUSCLE ISCHEMIA; HEART MUSCLE METABOLISM; HUMAN; NONHUMAN; PRIORITY JOURNAL; RAT; REVIEW;

ANIMALS; CARBOHYDRATE METABOLISM; FATTY ACIDS; GLUCOSE; HUMANS; INSULIN; MYOCARDIAL ISCHEMIA; MYOCARDIAL REPERFUSION INJURY; MYOCARDIUM;

EID: 0031036553     PISSN: 00086363     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0008-6363(96)00245-3     Document Type: Review

References (184)

1. Evans CL. The metabolism of cardiac muscle. In: Evans' Recent Advances in Physiology. Philadelphia: P. Blakiston's Son, 1939:157-215.
2. Bing RJ, Siegel A, Vitale A, Balboni FSE, Taeschler M, Klappe M, Edwards S. Metabolic studies on the human heart in vivo. I. Studies on carbohydrate metabolism of the human heart. Am J Med 1953;15:284-296.
3. Bing RJ. The metabolism of the heart. Harvey Lect 1955;50:27-70.
4. Camici P, Ferrannini E, Opie LH. Myocardial metabolism in ischemia heart disease: basic principles and application to imaging by positron emission tomography. Prog Cardiovasc Dis 1989;32:217-238.
5. Liedtke AJ. Alterations of carbohydrate and lipid metabolism in the acutely ischemia heart. Prog Cardiovasc Dis 1981;23:321-326.
6. Neely JR, Morgan HE. Relationship between carbohydrate and lipid metabolism and the energy balance of heart muscle. Annu Rev Physiol 1974;36:413-459.
7. Taegtmeyer H. Energy metabolism of the heart: from basic concepts to clinical applications. Curr Prob Cardiol 1994;19:59-113.
8. Bell GI, Kayano T, Buse JB, Burant CF, Takeda J, Lin D, Fukomoto H, Seino S. Molecular biology of mammalian glucose transporters. Diabetes Care 1990;13:198-208.
9. James DE, Strube M, Mueckler M. Molecular cloning and characterization of an insulin regulatable glucose transporter. Nature 1989;338:83-87.
10. Doria-Medina CL, Lund DD, Pasley A, Sandra A, Sivitz WI. Immunolocalization of GLUT-1 glucose transporter in rat skeletal muscle and in normal and hypoxic cardiac tissue. Am J Physiol 1993;265:E454-E464.
11. Kraegen EW, Sowden JA, Halstead MB, Clark PW, Rodnick KJ, Chisholm DJ, James DE. Glucose transporters and in vivo glucose uptake in skeletal and cardiac muscle: fasting, insulin stimulation and immunoisolation studies of GLUT 1 and GLUT 4. Biochem J 1993;295:287-293.
12. Ren-fu Y, Hu X, Russell R, Young L. Translocation of glucose transporter isoforms in vivo: effects of hyperinsulinemia and low flow ischemia in the canine heart. Circulation 1995;92 (suppl I):I-769, (Abstract).
13. Sun D, Nguyen N, DeGrado TJ, Schwaiger M, Brosius FC. Ischemia induces translocation of the insulin-responsive glucose transporter GLUT4 to the plasma membrane of cardiac myocytes. Circulation 1994;89:793-798.
14. Slot JW, Geuze HJ, Gigengack S, James DE, Lienhard GE. Translocation of the glucose transporter GLUT 4 in cardiac myocytes of the rat. Proc Natl Acad Sci USA 1991;88:7815-7819.
15. Wheeler TJ. Translocation of glucose transporters in response to anoxia in heart. J Biol Chem 1988;263:19447-19454.
16. Hall JL, Hernandez LA, Henderson J, Kellerman LA, Stanley WC. Decreased interstitial glucose and transmural gradient in lactate during ischemia. Basic Res Cardiol 1994;89:468-486.
17. Hall JL, Henderson J, Hernandez LA, Kellerman LA, Stanley WC. Hyperglycemia results in an increase in myocardial interstitial glucose and glucose uptake during ischemia. Metabolism 1996;45:542-549.
18. Russell RR, Mrus JM, Mommessin JI, Taegtmeyer. Compartmentation of hexokinase in rat heart. J Clin Invest 1992;90:1972-1977.
19. Manchester J, Kong X, Nerbonne J, Lowry OH, Lawrence JC. Glucose transport and phosphorylaton in single cardiac myocytes: rate-limiting steps in glucose metabolism. Am J Physiol;1994;266:E326-E333.
20. Alonso MD, Lomako J, Lomako WM, Whelan WJ. A new look at the biogenesis of glycogen. FASEB J 1995;9:1126-1137.
21. Das I. Effects of heart work and insulin on glycogen metabolism in the perfused rat heart. Am J Physiol 1973;224:7-12.
22. Goodwin GW, Arteaga JR, Taegtmeyer H. Glycogen turnover in the isolated working rat heart. J Biol Chem 1995;270:9234-9240.
23. Henning SL, Wambolt RB, Schonekess, Lopaschuk GD, Allard MF. Contribution of glycogen to aerobic myocardial glucose utilization. Circulation 1996;93:1549-1555.
24. Van der Vusse GJ, Reneman RS. Glycogen and lipids (endogenous substrates). In: Drake-Holland AJ, Noble MIM, eds. Cardiac Metabolism. New York: Wiley, 1983:215-237.
25. Wisneski JA, Gertz EW, Neese RA, Gruenke LD, Morris DL, Craig JC. Metabolic fate of extracted glucose in normal human myocardium. J Clin Invest 1985;76:1819-1827.
26. Wisneski JA, Stanley WC, Neese RA, Gertz EW. Effects of acute hyperglycemia on myocardial glycolytic activity in humans. J Clin Invest 1990;85:1648-1656.
27. Iyengar SRK, Charrette JP, Iyengar CKS, Wasan S. Myocardial glycogen in prevention of perioperative ischemia injury of the heart: a preliminary report. Can J Surg 1976;19:246-251.
28. Lolley DM, Ray JF, Myers WO, Tewksbury DA. Importance of preoperative myocardial glycogen levels in human cardiac preservation. J Thorac Cardiovasc Surg 1978;78:678-687.
29. Oldfiel GS, Commerford PJ, Opie LH. Effects of preoperative glucose-insulin-potassium on myocardial glycogen levels and on complications of mitral valve replacement. J Thorac Cardiovasc Surg 1986;91:874-878.
30. Gaesser GA, Brooks GA. Glycogen repletion following continuous and intermittent exercise to exhaustion. J Appl Physiol 1980;49:722-728.
31. Goldfarb AH, Bruno JF, Buckenmeyer PJ. Intensity and duration effects of exercise on heart cAMP, phosphorylase, and glycogen. J Appl Physiol 1986;60:1268-1273.
32. Kashiway Y, Sato K, Tsuchiya N, Thomas S, Fell DA, Veech RL, Passonneau JV. Control of glucose utilization in working perfused rat heart. J Biol Chem 1994;269:25502-25514.
33. Depre C, Rider MH, Veitch K, Hue L. Role of fructose 2,6-bis-phosphate in the control of heart glycolysis. J Biol Chem 1993;268:13274-13279.
34. Hue L, Depre C, Lefebvre V, Rider MH, Veitch K. Regulation of glucose metabolism in cardiac muscle. Biochem Soc Trans 1995;23:311-314.
35. Kobayashi K, Neely JR. Control of maximum rates of glycolysis in rat cardiac muscle. Circ Res 1979;44:166-175.
36. Opie LH. The Heart: Physiology and Metabolism, 2nd ed. New York: Raven Press, 1991.
37. Rovetto MJ, Lamberton WF, Neely JR. Mechanism of glycolytic inhibition in ischemic rat hearts. Circ Res 1975;37:742-751.
38. Jeremy RW, Koretsune Y, Marban E, Becker LC. Relationship between glycolysis and calcium homeostasis in postischemic myocardium. Circ Res 1992;70:1180-1190.
39. Kusuoka H, Marban E. Mechanism of the diastolic dysfunction induced by glycolytic inhibition. J Clin Invest 1994;93:1216-1223.
40. Weiss J, Hilderbrand B. Functional compartmentation of glycolytic versus oxidative metabolism in isolated rabbit heart. J Clin Invest 1985;75:436-447.
41. Entman ML, Kanike K, Goldstein MA, Nelson TP, Bornet EP, Futch TW, Schwartz A. Association of glycogenolysis with cardiac sarcoplasmic reticulum. J Biol Chem 1976;251:3140-3146.
42. Pierce GN, Philipson KD. Binding of glycolytic enzymes to cardiac sarcolemmal and sarcoplasmic reticular membranes. J Biol Chem 1985;260:6862-6870.
43. 2+ transport. Circ Res 1995;77:88-97.
44. Weiss JN, Lamp ST. Cardiac ATP-sensitive K+ channels. Evidence for preferential regulation by glycolysis. J Gen Physiol 1989;94:911-935.
45. + ATPase abolishes the protection afforded by glycolysis against myocardial ischemic injury. Circulation 1995;92(suppl I):I-631.
46. Gertz, EW, Wisneski JA, Stanley WC, Neese RA. Myocardial substrate utilization during exercise in humans: dual carbon-labeled carbohydrate isotope experiments. J Clin Invest 1988;82:2017-2025.
47. Stanley WC. Myocardial lactate metabolism during exercise. Med. Sci. Sport Exerc 1991;23:920-924.
48. Gertz EW, Wisneski JA, Neese RA, Bristow JD, Searle GL, Hanlon JT. Myocardial lactate metabolism: evidence of lactate release during net chemical extraction in man. Circulation 1981;63:1273-1279.
49. Garcia C, Goldstein JL, Pathak RK, Anderson RGW, Brown MS. Molecular characterization of a membrane transporter for lactate, pyruvate, and other monocarboxylates: Implication for the Cori cycle. Cell 1994;76:865-873.
50. i. Am J Physiol 1994;267:H1759-H1769.
51. Randle PJ. Fuel selection in animals. Biochem Soc Trans 1986;14:799-806.
52. Kerbey AL, Randle PJ, Cooper RH, Whitehouse S, Pask HT, Denton RM. Regulation of pyruvate dehydrogenase. Biochem J 1976;154:327-348.
53. Randle PJ, Hales CN, Garland PB, Newsholme EA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1963;ii:785-789.
54. Randle PJ, Newsholme EA, Garland PB. Regulation of glucose uptake by muscle. Effects of fatty acids, ketone bodies and pyruvate, and of alloxan diabetes and starvation, on the uptake and metabolic fate of glucose in rat heart and diaphragm muscles. Biochem J 1964;93:652-665.
55. Wieland O, Funcke HV, Loffler G. Interconversion of pyruvate dehydrogenase in rat heart muscle upon perfusion with fatty acids or ketone bodies. FEBS Lett 1971;15:295-298.
56. Wieland O, Siess E, Schulze-Wethmar FH, Funcke HG, Winton B. Active and inactive forms of pyruvate dehydrogenase in rat heart and kidney: effect of diabetes, fasting and refeeding on pyruvate dehydrogenase interconversion. Arch Biochem Biophys 1971;143:593-601.
57. Hansford RG, Cohen L. Relative importance of pyruvate dehydrogenase interconversion and feed-back inhibition in the effect of fatty acids on pyruvate oxidation by rat heart mitochondria. Arch Biochem Biophys 1978;191:65-81.
58. McCormack JG, Halestrap AP, Denton RM. Role of calcium ions in regulation of mammalian intramitochondrial metabolism. Physiol Rev 1990;70:391-425.
59. Higgins AJ, Morville M, Burges RA, Gardiner DG, Page MG, Blackburn KJ. Oxfenicine diverts rat muscle metabolism from fatty acid to carbohydrate oxidation and protects the ischemia rat heart. Life Sci 1980;27:963-970.
60. Higgins AJ, Morville M, Burges RA, Blackburn KJ. Mechanism of action of oxfenicine on muscle metabolism. Biochem Biophys Res Commun 1981;100:291-296.
61. Lopaschuk GD, Belke DD, Gamble J, Itoi T, Schonekess BO. Regulation of fatty acid oxidation in the mammalian heart in health and disease. Biochim Biophys Acta 1994;1213:263-276.
62. Lopaschuk GD, Spafford M. Response of isolated working hearts to fatty acids and carnitine palmitoyltransferase I inhibition during reduction of coronary flow in acutely and chronically diabetic rats. Circ Res 1989;65:378-387.
63. Randle PJ, Priesman DA. 151-161, MS Patel, TE Roche and RA Harris, eds. Alpha-Keto Acid Dehydrogenase Complexes. Basel: Birkhauser Verlag, 1996.
64. Newsholme EA, Randle PJ. Regulation of glucose uptake by muscle. Effects of fatty acids, ketone bodies and pyruvate, and of alloxan diabetes, starvation, hypophysectomy and adrenalectomy, on the concentrations of hexose phosphates, nucleotides and inorganic phosphate in perfused rat heart. Biochem J 1964;93:641-651.
65. Gertz EW, Wisneski JA, Neese RA, Houser MS, Korte R, Bristow JD. Myocardial lactate extraction: multi-determined metabolic function. Circulation 1980, 61:256-261.
66. Lopaschuk GD, Wambolt RB, Barr RL. An imbalance between glycolysis and glucose oxidation is a possible explanation for the detrimental effects of high levels of fatty acids during aerobic reperfusion of ischemia hearts. J Pharmacol Exp Ther 1993;264:135-144.
67. Newsholme EA, Randle PJ, Manchester KL. Inhibition of the phosphofructokinase reaction in perfused rat heart by respiration of ketone bodies, fatty acids and pyruvate. Nature 1962;193:270-271.
68. Chappell JD, Robinson BH. Penetration of the mitochondrial membrane by tricarboxylic acid anions. Biochem Soc Symp 1968;27:123-133.
69. Kruszynska YT, McCormack JG, McIntyre N. Effects of glycogen stores and non-esterified fatty acid availablity on insulin-stimulated glucose metabolism and tissue pyruvate dehydrogenase activity in the rat. Diabetologia 1991;34:205-211.
70. Awan AA, Saggerson ED. Malonyl-CoA metabolism in cardiac myocytes and its relevance to the control of fatty acid oxidation. Biochem J 1993;295:61-66.
71. Saddik M, Gamble J, Witters LA, Lopaschuk GD. Acetyl-CoA carboxylase regulation of fatty acid oxidation in the heart. J Biol Chem 1993;268:25836-25845.
72. Stanley WC, Hernandez LA, Spires DA, Bringas J, Wallace S, McCormack JG. Pyruvate dehydrogenase activity and malonyl CoA levels in normal and ischemia swine myocardium: effects of dichloroacetate. J Mol Cell Cardiol 1996;28:905-914.
73. Wang D, Buja LM, McMillin JG. Acetyl coenzyme A carboxylase activity in neonatal rat cardiac myocytes in culture: citrate dependence and effects of hypoxia. Arch Biochem Biophys 1996;325:249-255.
74. Bianchi A, Evans JL, Iverson AJ, Nordlund AC, Watts TD, Witters LA. Identification of an isozymic form of acetyl-CoA carboxylase. J Biol Chem 1990;265:1502-1509.
75. Thampy, K.G. Formation of malonyl-CoA in rat heart. J Biol Chem 1989;264:17631-17634.
76. Whitehouse S, Cooper RH, Randle PJ. Mechanism of activation of pyruvate dehydrogenase by dichloroacetate and other halogenated carboxylic acids. Biochem J 1974;141: 761-774.
77. Broderick TL, Quinney HA, Lopaschuk GD. Carnitine stimulation of glucose oxidation in the fatty acid perfused isolated working rat heart. J. Biol. Chem. 1992;267:3758-3763.
78. Broderick TL, Quinney, HA, Barker CC Lopaschuk GD. Beneficial effect of carnitine on mechanical recovery of rat hearts reperfused after a transient period of global ischemia is accompanied by a stimulation of glucose oxidation. Circulation 1993;87:972-981.
79. Lysiak W, Toth PP, Suelter CH, Bieber LL. Quantification of the efflux of acylcarnitines on the levels of acid-soluble short-chain acyl-CoA and CoASH on rat heart and liver mitochondria. J Biol Chem 1986;261:10698-13703.
80. Schneider CA, Taegtmeyer H. Fasting in vivo delays myocardial cell damage after brief periods of ischemia in the isolated working rat heart. Circ Res 1991;68:1045-1050.
81. Laughlin MR, Taylor J, Chesnick AS, Balaban RS. Nonglucose substrates increase glycogen synthesis in vivo in dog heart. Am J Physiol 1994;267:H219-H223.
82. Lassers BW, Wahlqvist ML, Kaijser L, Carlson LA. Effect of nicotinic acid on myocardial metabolism in man at rest and during exercise. J Appl Physiol 1972;33:72-80.
83. Nuutila P, Knuuti MJ, Raitakari M, Ruotsalainen U, Teras M, Vioppio-Pulkki L, Haaparantaa M, Solin O, Wegelius U, Vki-Jarvinen H. Effect of antilipolysis on heart and skeletal muscle glucose uptake in overnight fasted humans. Am J Physiol 1994;267:E941-946.
84. Stone CK, Holden J, Stanley WC, Perlman SB. Effect of substrate availability upon cardiac glucose uptake. J Nuclear Med 1995;36:996-1002.
85. Keul J. Myocardial metabolism in athletes. Adv Exp Med Biol 1971;11:447-467.
86. Barrett EJ, Schwartz RG, Francis CK, Zaret BL. Regulation by insulin of myocardial glucose and fatty acid metabolism in the conscious dog. J Clin Invest 1984;74:1073-1079.
87. Zaninetti D, Greco-Perotto R, Jeanrenaud B. Heart glucose transport and transporters in rat heart: regulation by insulin, workload, and glucose. Diabetologia 1988;31:108-113.
88. Guth BD, Wisneski JA, Neese RA, White FC, Heusch G, Mazer CD. Myocardial lactate release during ischemia in swine. Relation to regional blood flow. Circulation 1990;81:1948-1958.
89. Marshall RC, Nash WW, Shine KI, Phelps ME, Ricchiuti N. Glucose metabolism during ischemia due to excessive oxygen demand or altered coronary flow in the isolated arterially perfused rabbit septum. Circ Res 1981;49:640-648.
90. Stanley WC, Hall JL, Stone CK, Hacker TA. Acute myocardial ischemia causes a transmural gradient in glucose extraction but not glucose uptake. Am J Physiol 1992;262:H91-H96.
91. Fedele FA, Gewirtz H, Cappone RJ, Sharaf B, Most AS. Metabolic response to prolonged reduction of myocardial blood flow distal to a severe conronary artery stenosis. Circulation 1988;78:729-735.
92. Pantely GA, Malone SA, Rhen WS, Anselone CG, Arai A, Bristow J, Bristow JD. Regeneration of myocardial phosphocreatine in pigs despite continued moderate ischemia. Circ Res 1990;67:1481-1493.
93. Ramatoola SH. A perspective on the three large multicenter randomized clinical trials of coronary bypass surgery for chronic stable angina. Circulation 1985;72 (Suppl V):V-123-125.
94. Arai AE, Pantely GA, Anselone CG, Bristow J, Bristo DJ. Active down regulation of myocardial energy requirements during prolonged moderate ischemia in swine. Circ Res 1991;69:1458-1469.
95. Schultz R, Guth BD, Pieper K, Martin C, Heusch G. Recruitment of an inotropic reserve in moderately ischemia myocardium at the expense of metabolic recovery. Circ Res 1992;70:1282-1295.
96. Mazer CD, Cason BA, Stanley WC, Wisneski JA, Shnier CB, Hickey RF. Dicholoracetate reduces lactate production but does not improve function in ischemia swine myocardium. Am J Physiol 1995;268:H879-H885.
97. Liedtke AJ, Nellis SH, Neely JR. Effects of excess free fatty acids on mechanical and metabolic function in normal and ischemia myocardium in swine. Circ Res 1978;43:652-661.
98. Liedtke AJ, Nellis SH, Mjos OD. Effects of reducing fatty acid metabolism on mechanical function in regionally ischemia hearts. Am J Physiol 1984;247:H387-H394.
99. Vatner SF. Correlation between acute reductions in myocardial blood flow and function in conscious dogs. Circ Res 1980;81:1948-1958.
100. Hoffman JIE. Transmural myocardial perfusion. Prog Cardiovasc Dis 1987;29:429-464.
101. Ichihara K, Abiko Y. Inhibition of endo- and epicardial glycogenolysis by propranolol in ischemia hearts. Am J Physiol 1977;232:H249-H253.
102. Kobayashi K, Neely JR. Effects of ischemia and reperfusion on pyruvate dehydrogenase activity in isolated rat hearts. J Mol Cell Cardiol 1983;15:359-367.
103. Patel TB, Olsen MS. Regulation of pyruvate dehydrogenase complex in ischemic rat heart. Am J Physiol 1984;246:H858-864.
104. Clarke B, Spedding M, Patmore L, McCormack JG. Protective effects of ranolazine in guinea pig hearts during low-flow ischemia and their association with increases in active pyruvate dehydrogenase. Br J Pharmacol 1993;109:748-750.
105. Stanley WC, Hall JL, Smith KR, Cartee GD, Hacker TA, Wisneski JA. Myocardial glucose transporters and glycolytic metabolism during ischemia in hyperglycemic diabetic swine. Metabolism 1994;43:61-69.
106. van der Vusse GJ, Arts T, Glatz JFC, Reneman RS. Transmural differences in energy metabolism of the left ventricular myocardium: fact or fiction? J Mol Cell Cardiol 1990;22:23-37.
107. 13C3] lactate: a new approach for investigating human myocardial metabolism during ischemia. J Am Coll Cardiol 1985;5:1138-1146.
108. Vrobel TR, Jorgensen CR, Bache RJ. Myocardial lactate and adenosine metabolite production as indicators of exercise-induced myocardial ischemia in the dog. Circulation 1982;66:555-561.
109. Dennis SC, Gevers W, Opie LH. Protons in ischemia: where do they come from; where do they go to? J Mol Cell Cardiol 1991;23:1077-1086.
110. 2+ overload in isolated perfused rabbit heart. Circulation 1994;89:2787-2798.
111. 2+ homeostasis in hearts reperfused after prolonged episodes of ischemia. Ann New York Acad Sci 1994;723:38-50.
112. Opie LH. Reperfusion injury and its pharmacologic modification. Circulation 1989;80:1049-1062.
113. 2+ exchange. Circ Res 1989;65:1045-1056.
114. + exchange in cardiac physiology and pathophysiology: mediation of myocardial reperfusion injury by the pH paradox. Cardiovasc Res 1993;27:915-924.
115. + exchange and its inhibition in cardiac ischemia and reperfusion. Basic Res Cardiol 1993;88:443-455.
116. Murphy E, Perlman M, London RE, Steenbergen C. Amiloride delays the ischemia-induced rise in cytosolic free calcium. Circ Res 1991;68:1250-1258.
117. 2+ overload in reperfused ischemia myocardium. Annu Rev Physiol 1990;52:543-559.
118. 2 consumption during reperfusion of ischemia rat hearts. Am J Physiol 1996;270:H72-H80.
119. Lerch R, Tamm C, Papageorgiou I, Benzi RH. Myocardial fatty acid oxidation during ischemia and reperfusion. Mol Cell Biochem 1992;116:103-109.
120. Lewandowski ED, White LT. Pyruvate dehydrogenase influences postischemia heart function. Circulation 1995;91:2071-2079.
121. Lopaschuk GD, Spafford MA, Davies NJ, Wall SR. Glucose and palmitate oxidation in isolated working rat hearts reperfused after a period of transient global ischemia. Circ Res 1990;66:546-553.
122. Liedtke AJ, DeMaison L, Eggleston AM, Cohen LM, Nellis SH. Changes in substrate metabolism and effects of excess fatty acids in reperfused myocardium. Circ Res 1988;62:535-542.
123. Saddik M, Lopaschuk GD. Myocardial triglyceride turnover during reperfusion of isolated rat hearts subjected to a transient period of global ischemia. J Biol Chem 1992;267:3825-3831.
124. Schwaiger M, Neese RA, Araujo L, Sustained nonoxidative glucose utilization and depletion of glycogen in reperfused canine myocardium. J Am Coll Cardiol 1989;13:745-754.
125. Allard MF, Schonekess BO, Henning SL, Englisn DR, Lopaschuk GD. Contribution of oxidative metabolism and glycolysis to ATP production in hypertrophied hearts. Am J Physiol 1994;267:H742-H750.
126. Saddik M, Lopaschuk GD. Myocardial triglyceride turnover and contribution to energy substrate utilization in isolated working rat hearts. J Biol Chem 1991;266:8162-8170.
127. Benzi RH, Lerch R. Dissociation between contractile function and oxidative metabolism in postischemia myocardium. Circ Res 1992;71:567-576.
128. Stacpoole PW. The pharmacology of dichloroacetate. Metabolism 1989;38:112-1144.
129. Kudo N, Barr AJ, Barr RL, Desai S, Lopaschuk GD. High rates of fatty acid oxidation during reperfusion of ischemic hearts are associated with a decrease in malonyl CoA levels due to an increase in 5″-AMP-activated protein kinase inhibitoin of acetyl CoA carboxylase. J Biol Chem 1995;270:17513-17520.
130. Lopaschuk GD. Abnormal mechanical function in diabetes: relationship to altered myocardial carbohydrate/lipid metabolism. Coron. Artery Dis 1996;7:116-123.
131. Berggren H., R. Ekroth, J. Herlit, A Hjalmarson, A. Waldenstrom, J. Waldensstrom, and G. William-Olsson. Improved myocardial protection during cold cardioplegia by means of increased myocardial glycogen stores. Thorac. Cardiovasc. Surg. 1982;30:389-392.
132. Vanoverschelde J-LJ, Janier MF, Bakke JE, Marshall DR, Bergmann SR. Rate of glycolysis during ischemia determines extent of ischemia injury and functional recovery after reperfusion. Am J Physiol 1994;267:H1785-1795.
133. Neely JR, Grotyohann LE. Role of glycolytic products in damage to ischemia myocardium. Circ Res 1984;55:816-824.
134. Cross HR, Opie LH, Radda GK, Clarke K. Is a high glycogen content beneficial or deterimental to the ischemic rat heart? A controversy resolved. Circ Res 1996;78:482-491.
135. Budingen T. Ueber die Möglichkeit einer Ernährungsbehandlung des Herzmuskels durch Einbringen von Traubenzuckerlösungen in den großen Kreislauf. Dtsch Arch Klin Med 1914;114:534-579.
136. Goulston A. The beneficial effect of ingestion of cane sugar in certain forms of heart disease. Br J Med 1911;i:615.
137. Sodi-Pallares D, Bisteni A, Medrano GA, Testelli MR, DeMicheli A. The polarizing treatment of acute myocardial infarction. Dis Chest 1963;43:424-432.
138. Sodi-Pallares D, Testelli MR, Fishleder BL, Bisteni A, Medrano GA, Friedland C, DeMicheli A. Effects of an intravenous infusion of a potassium-glucose-insulin solution on the electrocardiographic signs of myocardial infarction. Am J Cardiol 1962;9:166-181.
139. Maroko PR, Libby P, Sobel BE, Bloor CM, Sybers HD, Shell WE, Covell JW, Braunwald E. Effect of glucose-insulin-potassium infusion on myocardial infarction following experimental coronary artery occlusion. Circulation 1972;45:1160-1175.
140. Opie LH, Owen P. Effect of glucose-insulin-potassium infusions on arteriovenous difference of glucose and of free fatty acids and on tissue metabolic changes in dogs with developing myocardial infarction. Am J Cardiol 1976;38:310-321.
141. Coleman GM, Gradinac S, Taegtmeyer H, Sweeney M, Frazier H. Efficacy of metabolic support with glucose-insulin-potassium for left ventricular pump failure after aortocoronary bypass surgery. Circulation 1989;80(suppl I):I-91-I-96.
142. Rogers WJ, Stanley AW, Breinig JB, Prather JW, McDaniel HG, Moraski RE, Mantle JA, Russell RO, Rackley CE. Reduction of hospital mortality rate of acute myocardial infarction with glucose-insulin-potassium infusion. Am Heart J 1976;92:441-454.
143. Gradinak S, Coleman GM, Taegtmeyer H, Sweeney MS, Frazier OH. Improved cardiac function with glucose-insulin-potassium after coronary bypass surgery. Ann Thorac Surg 1989;48:484-489.
144. Wargovich TJ, MacDonald RG, Hill JA, Feldman RL, Stacpoole PW, Pepine CJ. Myocardial metabolic and hemodynamic effects of dichloroacetate in coronary artery disease. Am J Cardiol 1988;61:65-70.
145. McVeigh JJ, Lopaschuk GD. Dichloroacetate stimulation of glucose oxidation improves recovery of ischemia rat hearts. Am J Physiol 1990;259:H1079-H1085.
146. Racey-Burns LA, Burns AH, Summer WR, Shepherd RE. The effect of dichloroacetate on the isolated no flow arrested rat heart. Life Sci 1989;44:2015-2023.
147. Wahr JA, Childs KF, Bolling SF. Dichloroacetate enhances myocardial functional and metabolic recovery following global ischemia. J Cardiothor Vascular Anesth. 1994;8:192-197.
148. Lopaschuk GD, Wall SR, Olley PM, Davies NJ. Etomoxir, a carnitine palmitoyltransferase I inhibitor, protects hearts from fatty acid-induced ischemia injury independent of changes in long chain acylcarnitine. Circ Res 1988;63:1036-1043.
149. Lopaschuk GD, Spafford M, Davies, NJ, Wall SR. Glucose and palmitate oxidation in isolated working rat hearts reperfused following a period of transient global ischemia. Circ Res 1990;66:546-553.
150. Schwartz GG, Greyson C, Wisneski JA, Garcia J. Inhibition of fatty acid metabolism alters myocardial high-energy phosphates in vivo. Am J Physiol 1994;267:H224-H231.
151. Rupp H, Schultze W, Vetter R. Dietery medium-chain triglyerides can prevent changes in myosine and SR due to CPT I inhibition by etomoxir. Am J Physiol 1995;269:R630-R640.
152. Rupp H, Brilla CG, Maisch B, Turcani M. Effects of CPT I inhibition on myocyte gene expression in overloaded hearts. J Mol Cell Cardiol 1995;27:A276 (Abstract).
153. McGarry JD. The mitochondrial carnitine palmitoyltransferase system: its broadening role in fuel homeostatis and new insights into its molecular features. Biochem Soc Trans 1995;23:321-324.
154. Schönekess, B.O., Allard, M.F., and Lopaschuk, G.D. Propionyl L-carnitine improvement of hypertrophied heart function is accompanied by an increase in carbohydrate oxidation. Circ Res 1995;77:726-734.
155. Russell RR, Mommessin JI, Taegtmeyer H. Propionyl-L-carnitine-mediated improvement in contractile function of rat hearts oxidizing acetoacetate. Am J Physiol 1995;268:H441-H447.
156. Iliceto, S., Scrutinio, D., Bruzzi, P., D'Ambrosio, G., Boni, L., Di Biase, M., Biasco, G., Hugenholtz, P.G. and Rizzon, P. on behalf of the CEDIM investigators. Effects of L-carnitine administration on left ventricular remodeling after acute anterior myocardial infarction: the L-carnitine ecocardiografia digitalizzata infarto miocardico (CEDIM). J Am Coll Cardiol 1995;26:380-387.
157. Michaletti R, Schianone A, Biachi G. Effect of propionyl-L-carnitine on rats with experimentally induced cardiomyopathies. In: De Jong JW, Ferarri R, eds. The Carnitine System: a new therapeutical approach to cardiovascular diseases. Dordrecht: Kluwer Academic Publishers, 1995:307-322.
158. Ferrari R, Anard I. Utilization of propionyl L-carnitine for the treatment of heart failure. In: De Jong JW, Ferarri R, eds. The Carnitine System: a new therapeutical approach to cardiovascular diseases. Dordrecht: Kluwer Academic Publishers, 1995:323-336.
159. Pepine CJ, Welsch MA. Therapeutic potential of L-carnitine in patients with angina pectoris. In: De Jong JW, Ferarri R, eds. The Carnitine System: a new therapeutical approach to cardiovascular diseases. Dordrecht: Kluwer Academic Publishers, 1995:225-244.
160. Paulson DJ, Shug AL. Experimental evidence for the anti-ischemic effects of L-carnitine. In: De Jong JW, Ferarri R, eds. The Carnitine System: a new therapeutical approach to cardiovascular diseases. Dordrecht: Kluwer Academic Publishers, 1995:183.
161. Brevetti, G., Perna, S., Sabba, C., Martone, D., and Condorelli, M. Propionyl L-carnitine in intermittent claudification: double-blind, placebo-controlled, dose titration, multicenter study. J Am Coll Cardiol 1995;26:1411-1416.
162. Dalla-Volta S, Maraglino G, Delia-Valentina P, Viena P, Desideri A. Comparison of trimetazidine with nifedipine in effort angina: a double-blind, crossover study. Cardiovasc Drugs Ther 1990;4:853-860.
163. Detry JM, Sellier P, Pennaforte S, Cokkinos D, Dargie H, Mathes P. Trimetazidine: a new concept in the treatment of angina. Comparison with propranolol in patients with stable angina. Br J Clin Pharmacol 1994;37:279-288.
164. Sellier P. Chronic effects of trimetazidine on ergometric parameters in effort angina. Cariovasc Drugs Ther 1990;4:822-823.
165. Sellier P, Harpy C, Corona P, Audouin P, Ourbak P. Acute effects of trimetazidine on ergometric parameters in effort angina. Cardiovasc Drugs Ther 1990;4:820-821.
166. 31P-NMR spectroscopy in the isolated rat heart. Arch Int Pharmacodyn 1987;286:97-110.
167. Boucher, F.R., D.J. Hearse, and L.H. Opie. Effects of trimetazidine on ischemic contracture in isolated perfused rat hearts. J Cardiovasc Pharmacol 1994;24:45-49.
168. Fantini E, Demaison L, Sentex E, Grynberg A, Athias P. Some biochemical aspects of the protective effect of trimetazidine on rat cardiomyocytes during hypoxia and reoxygenation. J Mol Cell Cardiol 1994;26:949-958.
169. +] and pH in a canine model of transient myocardial ischemia. Biochem Soc Trans 1987;15:1057-1058.
170. Allely MC, Alps BJ. Prevention of myocardial enzyme release by ranolazine in a primate model of ischemia with reperfusion. Br J Pharmacol 1990;99:5-6.
171. 1-adrnoceptors in the rat left ventricle by ischemia and acyl carnitines: protection by ranolazine. J Cardiovasc Pharmacol 1993;21:869-873.
172. Ferrandon P, Pascal J-C, Armstrong JM. Protective effects of the novel anti-ischemia agent ranolazine (RS-43285) in the reperfused rat heart. Br J Pharmacol 1988;93:247.
173. Gralinski MR, Black SC, Kilgore KS, Chou AY, McCormack JG, Lucchesi. Cardioprotective effects of ranolazine (RS-43285) in the isolated perfused rabbit heart. Cardiovasc Res 1994;28:1231-1237.
174. Rousseau MF, Visser, FG, Bax JJ, Dubrey S, Cocco G, Pouleur H, Harris SR, Wolff AA. Ranolazine: anti-anginal therapy with a novel mechanism: controlled comparison versus atenolol. Eur Heart J 1994;15:95 (Abstract).
175. Smith WB, Chrysant S, Garland WT, Parker S, Walpole HT, Mokatrin A, Gennevois D, Pepine CJ. A multicenter controlled trial of a novel metabolic active compound (ranolazine) in chronic stable angina patients. J Am Coll Cardiol 1995;26:24A-25A (Abstract).
176. Thadani U, Ezekowitz M, Fenney L, Chiang Y-K. Double-blind efficacy and safety study of a novel anti-ischemic agent, ranolazine, versus palcebo in patients with chronic stable angina pectoris. Circulation 1994;90:726-734.
177. Bouvy T, Rousseau MF, Cocco G, Cheron P, Williams GJ, Detry JMR. Improvement in exercise tolerance and left ventricular filling dynamics in patients with angina pectoris with the novel metabolic modulator, ranolazine. Acta Cardiol 1993;48:98-99.
178. Cocco G, Rousseau MF, Bouvy T, Cheron P, Williams G, Detry JMR. Effects of a new metabolic modulator, ranolazine, on exercise tolerance in angina pectoris patients treated with beta-blocker or diltiazem. J Cardiovasc Pharmacol 1992;20:131-138.
179. McCormack JG, Barr RL, Wolff AA, Lopaschuk GD. Ranolazine stimulates glucose oxidation in normoxic, ischemic, and reperfused ischemic rat hearts. Circulation 1996;93:135-142.
180. Aaker A, McCormack JG, Hirai T, Musch TI. Effects of ranolazine on the exercise capacity of rats with chronic heart failure induced by myocardial infarction. J Cardiovasc Pharmacol 1996;28:353-362.
181. Black SC, Gralinski MR, McCormack JG, Driscoll, Lucchesi BR. Effect of ranolazine on infarct size in a canine model of regional myocardial ischemia/reperfusion. J Cardiovasc Pharmacol 1994;24:921-928.
182. McCormack JG, Baracos VE, Barr R, Lopaschuk GD. Effects of ranolazine on oxidative substrate preferences in epitrochlearis muscle. J Appl Physiol 1996;81:905-910.
183. Clarke B, Wyatt KM, McCormack JG. Ranolazine increases active pyruvate dehydrogenase in perfused normoxic rat hearts: evidence for an indirect mechanism. J Mol Cell Cardiol 1996;28:341-350.
184. Wall SR, Lopaschuk GD. Biochim Biophys Acta 1989;1006:97-103.