Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Jul 1;98(1):62–69. doi: 10.1172/JCI118778

Glucose metabolism distal to a critical coronary stenosis in a canine model of low-flow myocardial ischemia.

P H McNulty 1, A J Sinusas 1, C Q Shi 1, D Dione 1, L H Young 1, G C Cline 1, G I Shulman 1
PMCID: PMC507401  PMID: 8690805

Abstract

Myocardial regions perfused through a coronary stenosis may cease contracting, but remain viable. Clinical observations suggest that increased glucose utilization may be an adaptive mechanism in such "hibernating" regions. In this study, we used a combination of 13C-NMR spectroscopy, GC-MS analysis, and tissue biochemical measurements to track glucose through intracellular metabolism in intact dogs infused with [1-13C]glucose during a 3-4-h period of acute ischemic hibernation. During low-flow ischemia [3-13C]alanine enrichment was higher, relative to plasma [1-13C]glucose enrichment, in ischemic than in nonischemic regions of the heart, suggesting a greater contribution of exogenous glucose to glycolytic flux in the ischemic region (approximately 72 vs. approximately 28%, P < 0.01). Both the fraction of glycogen synthase present in the physiologically active glucose-6-phosphate-independent form (46 +/- 10 vs. 9 +/- 6%, P < 0.01) and the rate of incorporation of circulating glucose into glycogen (94 +/- 25 vs. 20 +/- 15 nmol/gram/min, P < 0.01) were also greater in ischemic regions. Measurement of steady state [4-13C)glutamate/[3-13C]alanine enrichment ratios demonstrated that glucose-derived pyruvate supported 26-36% of total tricarboxylic acid cycle flux in all regions, however, indicating no preference for glucose over fat as an oxidative substrate in the ischemic myocardium. Thus during sustained regional low-flow ischemia in vivo, the ischemic myocardium increases its utilization of exogenous glucose as a substrate. Upregulation is restricted to cytosolic utilization pathways, however (glycolysis and glycogen synthesis), and fat continues to be the major source of mitochondrial oxidative substrate.

Full Text

The Full Text of this article is available as a PDF (202.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arai A. E., Grauer S. E., Anselone C. G., Pantely G. A., Bristow J. D. Metabolic adaptation to a gradual reduction in myocardial blood flow. Circulation. 1995 Jul 15;92(2):244–252. doi: 10.1161/01.cir.92.2.244. [DOI] [PubMed] [Google Scholar]
  2. Arai A. E., Pantely G. A., Anselone C. G., Bristow J., Bristow J. D. Active downregulation of myocardial energy requirements during prolonged moderate ischemia in swine. Circ Res. 1991 Dec;69(6):1458–1469. doi: 10.1161/01.res.69.6.1458. [DOI] [PubMed] [Google Scholar]
  3. Braunwald E., Rutherford J. D. Reversible ischemic left ventricular dysfunction: evidence for the "hibernating myocardium". J Am Coll Cardiol. 1986 Dec;8(6):1467–1470. doi: 10.1016/s0735-1097(86)80325-4. [DOI] [PubMed] [Google Scholar]
  4. Brunken R., Tillisch J., Schwaiger M., Child J. S., Marshall R., Mandelkern M., Phelps M. E., Schelbert H. R. Regional perfusion, glucose metabolism, and wall motion in patients with chronic electrocardiographic Q wave infarctions: evidence for persistence of viable tissue in some infarct regions by positron emission tomography. Circulation. 1986 May;73(5):951–963. doi: 10.1161/01.cir.73.5.951. [DOI] [PubMed] [Google Scholar]
  5. Depré C., Vanoverschelde J. L., Melin J. A., Borgers M., Bol A., Ausma J., Dion R., Wijns W. Structural and metabolic correlates of the reversibility of chronic left ventricular ischemic dysfunction in humans. Am J Physiol. 1995 Mar;268(3 Pt 2):H1265–H1275. doi: 10.1152/ajpheart.1995.268.3.H1265. [DOI] [PubMed] [Google Scholar]
  6. Fedele F. A., Gewirtz H., Capone R. J., Sharaf B., Most A. S. Metabolic response to prolonged reduction of myocardial blood flow distal to a severe coronary artery stenosis. Circulation. 1988 Sep;78(3):729–735. doi: 10.1161/01.cir.78.3.729. [DOI] [PubMed] [Google Scholar]
  7. Ito B. R. Gradual onset of myocardial ischemia results in reduced myocardial infarction. Association with reduced contractile function and metabolic downregulation. Circulation. 1995 Apr 1;91(7):2058–2070. doi: 10.1161/01.cir.91.7.2058. [DOI] [PubMed] [Google Scholar]
  8. Janier M. F., Vanoverschelde J. L., Bergmann S. R. Ischemic preconditioning stimulates anaerobic glycolysis in the isolated rabbit heart. Am J Physiol. 1994 Oct;267(4 Pt 2):H1353–H1360. doi: 10.1152/ajpheart.1994.267.4.H1353. [DOI] [PubMed] [Google Scholar]
  9. Johnston D. L., Lewandowski E. D. Fatty acid metabolism and contractile function in the reperfused myocardium. Multinuclear NMR studies of isolated rabbit hearts. Circ Res. 1991 Mar;68(3):714–725. doi: 10.1161/01.res.68.3.714. [DOI] [PubMed] [Google Scholar]
  10. Kobayashi K., Neely J. R. Effects of ischemia and reperfusion on pyruvate dehydrogenase activity in isolated rat hearts. J Mol Cell Cardiol. 1983 Jun;15(6):359–367. doi: 10.1016/0022-2828(83)90320-6. [DOI] [PubMed] [Google Scholar]
  11. Leimer K. R., Rice R. H., Gehrke C. W. Complete mass spectra of N-trifluoroacetyl-n-butyl esters of amino acids. J Chromatogr. 1977 Aug 21;141(2):121–144. doi: 10.1016/s0021-9673(00)99131-3. [DOI] [PubMed] [Google Scholar]
  12. Lewandowski E. D., Johnston D. L. Reduced substrate oxidation in postischemic myocardium: 13C and 31P NMR analyses. Am J Physiol. 1990 May;258(5 Pt 2):H1357–H1365. doi: 10.1152/ajpheart.1990.258.5.H1357. [DOI] [PubMed] [Google Scholar]
  13. Lewandowski E. D. Metabolic heterogeneity of carbon substrate utilization in mammalian heart: NMR determinations of mitochondrial versus cytosolic compartmentation. Biochemistry. 1992 Sep 22;31(37):8916–8923. doi: 10.1021/bi00152a031. [DOI] [PubMed] [Google Scholar]
  14. Lewandowski E. D., White L. T. Pyruvate dehydrogenase influences postischemic heart function. Circulation. 1995 Apr 1;91(7):2071–2079. doi: 10.1161/01.cir.91.7.2071. [DOI] [PubMed] [Google Scholar]
  15. Liedtke A. J. Alterations of carbohydrate and lipid metabolism in the acutely ischemic heart. Prog Cardiovasc Dis. 1981 Mar-Apr;23(5):321–336. doi: 10.1016/0033-0620(81)90019-0. [DOI] [PubMed] [Google Scholar]
  16. Maes A., Flameng W., Nuyts J., Borgers M., Shivalkar B., Ausma J., Bormans G., Schiepers C., De Roo M., Mortelmans L. Histological alterations in chronically hypoperfused myocardium. Correlation with PET findings. Circulation. 1994 Aug;90(2):735–745. doi: 10.1161/01.cir.90.2.735. [DOI] [PubMed] [Google Scholar]
  17. McNulty P. H., Liu W. X., Luba M. C., Valenti J. A., Letsou G. V., Baldwin J. C. Effect of nonworking heterotopic transplantation on rat heart glycogen metabolism. Am J Physiol. 1995 Jan;268(1 Pt 1):E48–E54. doi: 10.1152/ajpendo.1995.268.1.E48. [DOI] [PubMed] [Google Scholar]
  18. McNulty P. H., Luba M. C. Transient ischemia induces regional myocardial glycogen synthase activation and glycogen synthesis in vivo. Am J Physiol. 1995 Jan;268(1 Pt 2):H364–H370. doi: 10.1152/ajpheart.1995.268.1.H364. [DOI] [PubMed] [Google Scholar]
  19. Randle P. J. Regulation of glycolysis and pyruvate oxidation in cardiac muscle. Circ Res. 1976 May;38(5 Suppl 1):I8–15. [PubMed] [Google Scholar]
  20. Runnman E. M., Lamp S. T., Weiss J. N. Enhanced utilization of exogenous glucose improves cardiac function in hypoxic rabbit ventricle without increasing total glycolytic flux. J Clin Invest. 1990 Oct;86(4):1222–1233. doi: 10.1172/JCI114828. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Schaefer S., Schwartz G. G., Wisneski J. A., Trocha S. D., Christoph I., Steinman S. K., Garcia J., Massie B. M., Weiner M. W. Response of high-energy phosphates and lactate release during prolonged regional ischemia in vivo. Circulation. 1992 Jan;85(1):342–349. doi: 10.1161/01.cir.85.1.342. [DOI] [PubMed] [Google Scholar]
  22. Schulz R., Rose J., Martin C., Brodde O. E., Heusch G. Development of short-term myocardial hibernation. Its limitation by the severity of ischemia and inotropic stimulation. Circulation. 1993 Aug;88(2):684–695. doi: 10.1161/01.cir.88.2.684. [DOI] [PubMed] [Google Scholar]
  23. Schwaiger M., Neese R. A., Araujo L., Wyns W., Wisneski J. A., Sochor H., Swank S., Kulber D., Selin C., Phelps M. Sustained nonoxidative glucose utilization and depletion of glycogen in reperfused canine myocardium. J Am Coll Cardiol. 1989 Mar 1;13(3):745–754. doi: 10.1016/0735-1097(89)90621-9. [DOI] [PubMed] [Google Scholar]
  24. Shi C. Q., Sinusas A. J., Dione D. P., Singer M. J., Young L. H., Heller E. N., Rinker B. D., Wackers F. J., Zaret B. L. Technetium-99m-nitroimidazole (BMS181321): a positive imaging agent for detecting myocardial ischemia. J Nucl Med. 1995 Jun;36(6):1078–1086. [PubMed] [Google Scholar]
  25. Shulman G. I., Rossetti L., Rothman D. L., Blair J. B., Smith D. Quantitative analysis of glycogen repletion by nuclear magnetic resonance spectroscopy in the conscious rat. J Clin Invest. 1987 Aug;80(2):387–393. doi: 10.1172/JCI113084. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sinusas A. J., Bergin J. D., Edwards N. C., Watson D. D., Ruiz M., Makuch R. W., Smith W. H., Beller G. A. Redistribution of 99mTc-sestamibi and 201Tl in the presence of a severe coronary artery stenosis. Circulation. 1994 May;89(5):2332–2341. doi: 10.1161/01.cir.89.5.2332. [DOI] [PubMed] [Google Scholar]
  27. Tamm C., Benzi R., Papageorgiou I., Tardy I., Lerch R. Substrate competition in postischemic myocardium. Effect of substrate availability during reperfusion on metabolic and contractile recovery in isolated rat hearts. Circ Res. 1994 Dec;75(6):1103–1112. doi: 10.1161/01.res.75.6.1103. [DOI] [PubMed] [Google Scholar]
  28. Tan A. W., Nuttall F. Q. Characteristics of the dephosphorylated form of phosphorylase purified from rat liver and measurement of its activity in crude liver preparations. Biochim Biophys Acta. 1975 Nov 20;410(1):45–60. doi: 10.1016/0005-2744(75)90206-5. [DOI] [PubMed] [Google Scholar]
  29. Thomas J. A., Schlender K. K., Larner J. A rapid filter paper assay for UDPglucose-glycogen glucosyltransferase, including an improved biosynthesis of UDP-14C-glucose. Anal Biochem. 1968 Oct 24;25(1):486–499. doi: 10.1016/0003-2697(68)90127-9. [DOI] [PubMed] [Google Scholar]
  30. Tillisch J., Brunken R., Marshall R., Schwaiger M., Mandelkern M., Phelps M., Schelbert H. Reversibility of cardiac wall-motion abnormalities predicted by positron tomography. N Engl J Med. 1986 Apr 3;314(14):884–888. doi: 10.1056/NEJM198604033141405. [DOI] [PubMed] [Google Scholar]
  31. Vanoverschelde J. L., Wijns W., Depré C., Essamri B., Heyndrickx G. R., Borgers M., Bol A., Melin J. A. Mechanisms of chronic regional postischemic dysfunction in humans. New insights from the study of noninfarcted collateral-dependent myocardium. Circulation. 1993 May;87(5):1513–1523. doi: 10.1161/01.cir.87.5.1513. [DOI] [PubMed] [Google Scholar]
  32. Weiss J., Hiltbrand B. Functional compartmentation of glycolytic versus oxidative metabolism in isolated rabbit heart. J Clin Invest. 1985 Feb;75(2):436–447. doi: 10.1172/JCI111718. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Weiss R. G., Chacko V. P., Gerstenblith G. Fatty acid regulation of glucose metabolism in the intact beating rat heart assessed by carbon-13 NMR spectroscopy: the critical role of pyruvate dehydrogenase. J Mol Cell Cardiol. 1989 May;21(5):469–478. doi: 10.1016/0022-2828(89)90787-6. [DOI] [PubMed] [Google Scholar]
  34. Weiss R. G., Chacko V. P., Glickson J. D., Gerstenblith G. Comparative 13C and 31P NMR assessment of altered metabolism during graded reductions in coronary flow in intact rat hearts. Proc Natl Acad Sci U S A. 1989 Aug;86(16):6426–6430. doi: 10.1073/pnas.86.16.6426. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Weiss R. G., Gloth S. T., Kalil-Filho R., Chacko V. P., Stern M. D., Gerstenblith G. Indexing tricarboxylic acid cycle flux in intact hearts by carbon-13 nuclear magnetic resonance. Circ Res. 1992 Feb;70(2):392–408. doi: 10.1161/01.res.70.2.392. [DOI] [PubMed] [Google Scholar]
  36. Xu K. Y., Zweier J. L., Becker L. C. Functional coupling between glycolysis and sarcoplasmic reticulum Ca2+ transport. Circ Res. 1995 Jul;77(1):88–97. doi: 10.1161/01.res.77.1.88. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES