Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1993 Aug;92(2):831–839. doi: 10.1172/JCI116657

Effects of amino acids on substrate selection, anaplerosis, and left ventricular function in the ischemic reperfused rat heart.

M E Jessen 1, T E Kovarik 1, F M Jeffrey 1, A D Sherry 1, C J Storey 1, R Y Chao 1, W S Ring 1, C R Malloy 1
PMCID: PMC294921  PMID: 8102382

Abstract

The effect of aspartate and glutamate on myocardial function during reperfusion is controversial. A beneficial effect has been attributed to altered delivery of carbon into the citric acid cycle via substrate oxidation or by stimulation of anaplerosis, but these hypotheses have not been directly tested. 13C isotopomer analysis is well suited to the study of myocardial metabolism, particularly where isotopic and metabolic steady state cannot be established. This technique was used to evaluate the effects of aspartate and glutamate (amino acids, AA) on anaplerosis and substrate selection in the isolated rat heart after 25 min of ischemia followed by 30 or 45 min of reperfusion. Five groups of hearts (n = 8) provided with a mixture of [1,2-13C]acetate, [3-13C]lactate, and unlabeled glucose were studied: control, control plus AA, ischemia followed by 30 min of reperfusion, ischemia plus AA followed by 30 min of reperfusion, and ischemia followed by 45 min of reperfusion. The contribution of lactate to acetyl-CoA was decreased in postischemic myocardium (with a significant increase in acetate), and anaplerosis was stimulated. Metabolism of 13C-labeled aspartate or glutamate could not be detected, however, and there was no effect of AA on functional recovery, substrate selection, or anaplerosis. Thus, in contrast to earlier reports, aspartate and glutamate have no effect on either functional recovery from ischemia or on metabolic pathways feeding the citric acid cycle.

Full text

PDF
831

Selected References

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

  1. Armbrecht J. J., Buxton D. B., Brunken R. C., Phelps M. E., Schelbert H. R. Regional myocardial oxygen consumption determined noninvasively in humans with [1-11C]acetate and dynamic positron tomography. Circulation. 1989 Oct;80(4):863–872. doi: 10.1161/01.cir.80.4.863. [DOI] [PubMed] [Google Scholar]
  2. Armbrecht J. J., Buxton D. B., Schelbert H. R. Validation of [1-11C]acetate as a tracer for noninvasive assessment of oxidative metabolism with positron emission tomography in normal, ischemic, postischemic, and hyperemic canine myocardium. Circulation. 1990 May;81(5):1594–1605. doi: 10.1161/01.cir.81.5.1594. [DOI] [PubMed] [Google Scholar]
  3. Bergman G., Atkinson L., Metcalfe J., Jackson N., Jewitt D. E. Beneficial effect of enhanced myocardial carbohydrate utilisation after oxfenicine (L-hydroxyphenylglycine) in angina pectoris. Eur Heart J. 1980 Aug;1(4):247–253. doi: 10.1093/oxfordjournals.eurheartj.a061126. [DOI] [PubMed] [Google Scholar]
  4. Bittl J. A., Shine K. I. Protection of ischemic rabbit myocardium by glutamic acid. Am J Physiol. 1983 Sep;245(3):H406–H412. doi: 10.1152/ajpheart.1983.245.3.H406. [DOI] [PubMed] [Google Scholar]
  5. Brown M. A., Myears D. W., Bergmann S. R. Noninvasive assessment of canine myocardial oxidative metabolism with carbon-11 acetate and positron emission tomography. J Am Coll Cardiol. 1988 Oct;12(4):1054–1063. doi: 10.1016/0735-1097(88)90476-7. [DOI] [PubMed] [Google Scholar]
  6. Brown M. A., Myears D. W., Bergmann S. R. Validity of estimates of myocardial oxidative metabolism with carbon-11 acetate and positron emission tomography despite altered patterns of substrate utilization. J Nucl Med. 1989 Feb;30(2):187–193. [PubMed] [Google Scholar]
  7. Bush L. R., Warren S., Mesh C. L., Lucchesi B. R. Comparative effects of aspartate and glutamate during myocardial ischemia. Pharmacology. 1981;23(6):297–304. doi: 10.1159/000137565. [DOI] [PubMed] [Google Scholar]
  8. Buxton D. B., Nienaber C. A., Luxen A., Ratib O., Hansen H., Phelps M. E., Schelbert H. R. Noninvasive quantitation of regional myocardial oxygen consumption in vivo with [1-11C]acetate and dynamic positron emission tomography. Circulation. 1989 Jan;79(1):134–142. doi: 10.1161/01.cir.79.1.134. [DOI] [PubMed] [Google Scholar]
  9. Challoner D. R., Steinberg D. Effect of free fatty acid on the oxygen consumption of perfused rat heart. Am J Physiol. 1966 Feb;210(2):280–286. doi: 10.1152/ajplegacy.1966.210.2.280. [DOI] [PubMed] [Google Scholar]
  10. Choong Y. S., Gavin J. B., Armiger L. C. Effects of glutamic acid on cardiac function and energy metabolism of rat heart during ischaemia and reperfusion. J Mol Cell Cardiol. 1988 Nov;20(11):1043–1051. doi: 10.1016/0022-2828(88)90581-0. [DOI] [PubMed] [Google Scholar]
  11. Cole P. L., Beamer A. D., McGowan N., Cantillon C. O., Benfell K., Kelly R. A., Hartley L. H., Smith T. W., Antman E. M. Efficacy and safety of perhexiline maleate in refractory angina. A double-blind placebo-controlled clinical trial of a novel antianginal agent. Circulation. 1990 Apr;81(4):1260–1270. doi: 10.1161/01.cir.81.4.1260. [DOI] [PubMed] [Google Scholar]
  12. Drake A. J., Haines J. R., Noble M. I. Preferential uptake of lactate by the normal myocardium in dogs. Cardiovasc Res. 1980 Feb;14(2):65–72. doi: 10.1093/cvr/14.2.65. [DOI] [PubMed] [Google Scholar]
  13. Galiñanes M., Chambers D. J., Hearse D. J. Effect of sodium aspartate on the recovery of the rat heart from long-term hypothermic storage. J Thorac Cardiovasc Surg. 1992 Mar;103(3):521–531. [PubMed] [Google Scholar]
  14. Hoekenga D. E., Brainard J. R., Hutson J. Y. Rates of glycolysis and glycogenolysis during ischemia in glucose-insulin-potassium-treated perfused hearts: A 13C, 31P nuclear magnetic resonance study. Circ Res. 1988 Jun;62(6):1065–1074. doi: 10.1161/01.res.62.6.1065. [DOI] [PubMed] [Google Scholar]
  15. Horowitz J. D., Sia S. T., Macdonald P. S., Goble A. J., Louis W. J. Perhexiline maleate treatment for severe angina pectoris--correlations with pharmacokinetics. Int J Cardiol. 1986 Nov;13(2):219–229. doi: 10.1016/0167-5273(86)90146-4. [DOI] [PubMed] [Google Scholar]
  16. Jeffrey F. M., Rajagopal A., Malloy C. R., Sherry A. D. 13C-NMR: a simple yet comprehensive method for analysis of intermediary metabolism. Trends Biochem Sci. 1991 Jan;16(1):5–10. doi: 10.1016/0968-0004(91)90004-f. [DOI] [PubMed] [Google Scholar]
  17. Kjekshus J. K., Mjos O. D. Effect of free fatty acids on myocardial function and metabolism in the ischemic dog heart. J Clin Invest. 1972 Jul;51(7):1767–1776. doi: 10.1172/JCI106978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lazar H. L., Buckberg G. D., Manganaro A. J., Becker H., Maloney J. V., Jr Reversal of ischemic damage with amino acid substrate enhancement during reperfusion. Surgery. 1980 Nov;88(5):702–709. [PubMed] [Google Scholar]
  19. Lear J. L. Relationship between myocardial clearance rates of carbon-11-acetate-derived radiolabel and oxidative metabolism: physiologic basis and clinical significance. J Nucl Med. 1991 Oct;32(10):1957–1960. [PubMed] [Google Scholar]
  20. Lerch R. A., Ambos H. D., Bergmann S. R., Welch M. J., Ter-Pogossian M. M., Sobel B. E. Localization of viable, ischemic myocardium by positron-emission tomography with 11C-palmitate. Circulation. 1981 Oct;64(4):689–699. doi: 10.1161/01.cir.64.4.689. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. Malloy C. R., Sherry A. D., Jeffrey F. M. Analysis of tricarboxylic acid cycle of the heart using 13C isotope isomers. Am J Physiol. 1990 Sep;259(3 Pt 2):H987–H995. doi: 10.1152/ajpheart.1990.259.3.H987. [DOI] [PubMed] [Google Scholar]
  23. Malloy C. R., Sherry A. D., Jeffrey F. M. Evaluation of carbon flux and substrate selection through alternate pathways involving the citric acid cycle of the heart by 13C NMR spectroscopy. J Biol Chem. 1988 May 25;263(15):6964–6971. [PubMed] [Google Scholar]
  24. Malloy C. R., Thompson J. R., Jeffrey F. M., Sherry A. D. Contribution of exogenous substrates to acetyl coenzyme A: measurement by 13C NMR under non-steady-state conditions. Biochemistry. 1990 Jul 24;29(29):6756–6761. doi: 10.1021/bi00481a002. [DOI] [PubMed] [Google Scholar]
  25. Mickle D. A., del Nido P. J., Wilson G. J., Harding R. D., Romaschin A. D. Exogenous substrate preference of the post-ischaemic myocardium. Cardiovasc Res. 1986 Apr;20(4):256–263. doi: 10.1093/cvr/20.4.256. [DOI] [PubMed] [Google Scholar]
  26. Patel T. B., Olson M. S. Regulation of pyruvate dehydrogenase complex in ischemic rat heart. Am J Physiol. 1984 Jun;246(6 Pt 2):H858–H864. doi: 10.1152/ajpheart.1984.246.6.H858. [DOI] [PubMed] [Google Scholar]
  27. Paulson D. J., Traxler J., Schmidt M., Noonan J., Shug A. L. Protection of the ischaemic myocardium by L-propionylcarnitine: effects on the recovery of cardiac output after ischaemia and reperfusion, carnitine transport, and fatty acid oxidation. Cardiovasc Res. 1986 Jul;20(7):536–541. doi: 10.1093/cvr/20.7.536. [DOI] [PubMed] [Google Scholar]
  28. Peuhkurinen K. J., Nuutinen E. M., Pietiläinen E. P., Hiltunen J. K., Hassinen I. E. Role of pyruvate carboxylation in the energy-linked regulation of pool sizes of tricarboxylic acid-cycle intermediates in the myocardium. Biochem J. 1982 Dec 15;208(3):577–581. doi: 10.1042/bj2080577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Peuhkurinen K. J. Regulation of the tricarboxylic acid cycle pool size in heart muscle. J Mol Cell Cardiol. 1984 Jun;16(6):487–495. doi: 10.1016/s0022-2828(84)80637-9. [DOI] [PubMed] [Google Scholar]
  30. Peuhkurinen K. J., Takala T. E., Nuutinen E. M., Hassinen I. E. Tricarboxylic acid cycle metabolites during ischemia in isolated perfused rat heart. Am J Physiol. 1983 Feb;244(2):H281–H288. doi: 10.1152/ajpheart.1983.244.2.H281. [DOI] [PubMed] [Google Scholar]
  31. Pisarenko O. I., Novikova E. B., Serebryakova L. I., Tskitishvili O. V., Ivanov V. E., Studneva I. M. Function and metabolism of dog heart in ischemia and in subsequent reperfusion: effect of exogenous glutamic acid. Pflugers Arch. 1985 Dec;405(4):377–383. doi: 10.1007/BF00595691. [DOI] [PubMed] [Google Scholar]
  32. Pisarenko O. I., Oleynikov O. D., Shulzhenko V. S., Studneva I. M., Ryff I. M., Kapelko V. I. Association of myocardial glutamate and aspartate pool and functional recovery of postischemic heart. Biochem Med Metab Biol. 1989 Oct;42(2):105–117. doi: 10.1016/0885-4505(89)90046-7. [DOI] [PubMed] [Google Scholar]
  33. Pisarenko O. I., Solomatina E. S., Studneva I. M., Ivanov V. E., Kapelko V. I., Smirnov V. N. Effect of glutamic and aspartic acids on adenine nucleotides, nitrogenous compounds and contractile function during underperfusion of isolated rat heart. J Mol Cell Cardiol. 1983 Jan;15(1):53–60. doi: 10.1016/0022-2828(83)90307-3. [DOI] [PubMed] [Google Scholar]
  34. Renstrom B., Nellis S. H., Liedtke A. J. Metabolic oxidation of pyruvate and lactate during early myocardial reperfusion. Circ Res. 1990 Feb;66(2):282–288. doi: 10.1161/01.res.66.2.282. [DOI] [PubMed] [Google Scholar]
  35. Rosenkranz E. R., Buckberg G. D., Laks H., Mulder D. G. Warm induction of cardioplegia with glutamate-enriched blood in coronary patients with cardiogenic shock who are dependent on inotropic drugs and intra-aortic balloon support. J Thorac Cardiovasc Surg. 1983 Oct;86(4):507–518. [PubMed] [Google Scholar]
  36. 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]
  37. Scrutton M. C., White M. D. Pyruvate carboxylase. Inhibition of the mammalian and avian liver enzymes by alpha-ketoglutarate and L-glutamate. J Biol Chem. 1974 Sep 10;249(17):5405–5415. [PubMed] [Google Scholar]
  38. Sherry A. D., Malloy C. R., Zhao P., Thompson J. R. Alterations in substrate utilization in the reperfused myocardium: a direct analysis by 13C NMR. Biochemistry. 1992 May 26;31(20):4833–4837. doi: 10.1021/bi00135a014. [DOI] [PubMed] [Google Scholar]
  39. 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]
  40. Thomassen A., Nielsen T. T., Bagger J. P., Henningsen P. Effects of intravenous glutamate on substrate availability and utilization across the human heart and leg. Metabolism. 1991 Apr;40(4):378–384. doi: 10.1016/0026-0495(91)90148-p. [DOI] [PubMed] [Google Scholar]
  41. Thomassen A., Nielsen T. T., Bagger J. P., Pedersen A. K., Henningsen P. Antiischemic and metabolic effects of glutamate during pacing in patients with stable angina pectoris secondary to either coronary artery disease or syndrome X. Am J Cardiol. 1991 Aug 1;68(4):291–295. doi: 10.1016/0002-9149(91)90821-2. [DOI] [PubMed] [Google Scholar]
  42. Vik-Mo H., Mjøs O. D. Influence of free fatty acids on myocardial oxygen consumption and ischemic injury. Am J Cardiol. 1981 Aug;48(2):361–365. doi: 10.1016/0002-9149(81)90621-4. [DOI] [PubMed] [Google Scholar]
  43. Wargovich T. J., MacDonald R. G., Hill J. A., Feldman R. L., Stacpoole P. W., Pepine C. J. Myocardial metabolic and hemodynamic effects of dichloroacetate in coronary artery disease. Am J Cardiol. 1988 Jan 1;61(1):65–70. doi: 10.1016/0002-9149(88)91306-9. [DOI] [PubMed] [Google Scholar]

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

RESOURCES