Skip to main content
PMC home page
Biochemical Journal logoLink to Biochemical Journal
. 1972 Jun;128(1):147–159. doi: 10.1042/bj1280147

The effects of increased heart work on the tricarboxylate cycle and its interactions with glycolysis in the perfused rat heart

J R Neely 1, R M Denton 1, P J England 1,*, P J Randle 1
PMCID: PMC1173579  PMID: 5085551

Abstract

1. The work of the perfused rat heart was acutely increased by raising the aortic pressure in the Langendorff preparation from 50 to 120mmHg; within 1 min in perfusions with media containing glucose or glucose+acetate, rates of oxygen consumption and tricarboxylate-cycle turnover increased 2.5-fold, glycolysis rate doubled and oxidation of triglyceride fatty acid was strikingly enhanced. 2. Increased cardiac work had no significant effects on the heart concentrations of creatine phosphate, ATP, ADP or 5′-AMP. The only significant changes in tricarboxylate-cycle intermediates were a decrease in malate in perfusions with glucose and decreases in acetyl-CoA and citrate and an increase in aspartate in perfusions with glucose+acetate. 3. Measurements of intracellular concentrations of hexose phosphates, glucose and glycogen indicated that work accelerated glycolysis by activation of phosphofructokinase and subsequently hexokinase; the activation could not be accounted for by changes in the known effectors of phosphofructokinase. 4. Acetate at either perfusion pressure increased heart concentrations of acetyl-CoA, citrate, glutamate and malate and decreased that of aspartate; acetate increased tricarboxylate-cycle turnover by 50–60% and inhibited glycolysis and pyruvate oxidation. 5. In view of the markedly different effects of acetate and of cardiac work on the concentrations of cycle intermediates the changes that accompany acetate utilization may be specifically concerned with the regulatory functions of the cycle in control of glycolysis and pyruvate oxidation and not with the associated increase in cycle turnover. It is suggested that the concentrations of key metabolites controlling the rate of cycle turnover may fluctuate with each heart beat and that this may explain why no significant changes (for example, in adenine nucleotide concentrations) have been detected with increased work in the present study.

Full text

PDF
147

Selected References

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

  1. Boerth R. C., Covell J. W., Seagren S. C., Pool P. E. High-energy phosphate concentrations in dog myocardium during stress. Am J Physiol. 1969 May;216(5):1103–1106. doi: 10.1152/ajplegacy.1969.216.5.1103. [DOI] [PubMed] [Google Scholar]
  2. CAIN D. F., DAVIES R. E. Breakdown of adenosine triphosphate during a single contraction of working muscle. Biochem Biophys Res Commun. 1962 Aug 7;8:361–366. doi: 10.1016/0006-291x(62)90008-6. [DOI] [PubMed] [Google Scholar]
  3. CARLSON L. A., EKELUND L. G., ORO L. Studies on blood lipids during exercise. IV. Arterial concentration of plasma free fatty acids and glycerol during and after prolonged exercise in normal men. J Lab Clin Med. 1963 May;61:724–729. [PubMed] [Google Scholar]
  4. CHEN R. F., PLAUT G. W. ACTIVATION AND INHIBITION OF DPN-LINKED ISOCITRATE DEHYDROGENASE OF HEART BY CERTAIN NUCLEOTIDES. Biochemistry. 1963 Sep-Oct;2:1023–1032. doi: 10.1021/bi00905a020. [DOI] [PubMed] [Google Scholar]
  5. Chase J. F. pH-dependence of carnitine acetyltransferase activity. Biochem J. 1967 Aug;104(2):503–509. doi: 10.1042/bj1040503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Denton R. M., Randle P. J. Concentrations of glycerides and phospholipids in rat heart and gastrocnemius muscles. Effects of alloxan-diabetes and perfusion. Biochem J. 1967 Aug;104(2):416–422. doi: 10.1042/bj1040416. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. GARLAND P. B., RANDLE P. J., NEWSHOLME E. A. CITRATE AS AN INTERMEDIARY IN THE INHIBITION OF PHOSPHOFRUCTOKINASE IN RAT HEART MUSCLE BY FATTY ACIDS, KETONE BODIES, PYRUVATE, DIABETES, AND STARVATION. Nature. 1963 Oct 12;200:169–170. doi: 10.1038/200169a0. [DOI] [PubMed] [Google Scholar]
  8. HAVEL R. J., NAIMARK A., BORCHGREVINK C. F. Turnover rate and oxidation of free fatty acids of blood plasma in man during exercise: studies during continuous infusion of palmitate-1-C14. J Clin Invest. 1963 Jul;42:1054–1063. doi: 10.1172/JCI104791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. HOCHREIN H., DOERING H. J., WELTEKEN J., LOENNE E. [Energy-rich phosphate of the myocardium in variation of the loading conditions. Experiments on heart-lung preparation in the guinea pig]. Pflugers Arch Gesamte Physiol Menschen Tiere. 1960;271:548–563. [PubMed] [Google Scholar]
  10. KOSICKI G. W., SRERE P. A. Kinetic studies on the citrate-condensing enzyme. J Biol Chem. 1961 Oct;236:2560–2565. [PubMed] [Google Scholar]
  11. Kosicki G. W., Lee L. P. Effect of divalent metal ions on nucleotide inhibition of pig heart citrate synthase. J Biol Chem. 1966 Aug 10;241(15):3571–3574. [PubMed] [Google Scholar]
  12. MORGAN H. E., HENDERSON M. J., REGEN D. M., PARK C. R. Regulation of glucose uptake in muscle. I. The effects of insulin and anoxia on glucose transport and phosphorylation in the isolated, perfused heart of normal rats. J Biol Chem. 1961 Feb;236:253–261. [PubMed] [Google Scholar]
  13. Neely J. R., Bowman R. H., Morgan H. E. Effects of ventricular pressure development and palmitate on glucose transport. Am J Physiol. 1969 Apr;216(4):804–811. doi: 10.1152/ajplegacy.1969.216.4.804. [DOI] [PubMed] [Google Scholar]
  14. Neely J. R., Liebermeister H., Battersby E. J., Morgan H. E. Effect of pressure development on oxygen consumption by isolated rat heart. Am J Physiol. 1967 Apr;212(4):804–814. doi: 10.1152/ajplegacy.1967.212.4.804. [DOI] [PubMed] [Google Scholar]
  15. Neely J. R., Whitfield C. F., Morgan H. E. Regulation of glycogenolysis in hearts: effects of pressure development, glucose, and FFA. Am J Physiol. 1970 Oct;219(4):1083–1088. doi: 10.1152/ajplegacy.1970.219.4.1083. [DOI] [PubMed] [Google Scholar]
  16. Newsholme E. A., Randle P. J. Regulation of glucose uptake by muscle. 7. 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 Dec;93(3):641–651. doi: 10.1042/bj0930641. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Opie L. H., Mansford K. R., Owen P. Effects of increased heart work on glycolysis and adenine nucleotides in the perfused heart of normal and diabetic rats. Biochem J. 1971 Sep;124(3):475–490. doi: 10.1042/bj1240475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. PARMEGGIANI A., BOWMAN R. H. REGULATION OF PHOSPHOFRUCTOKINASE ACTIVITY BY CITRATE IN NORMAL AND DIABETIC MUSCLE. Biochem Biophys Res Commun. 1963 Aug 1;12:268–273. doi: 10.1016/0006-291x(63)90294-8. [DOI] [PubMed] [Google Scholar]
  19. PERRY S. V. Creatine phosphokinase and the enzymic and contractile properties of the isolated myofibril. Biochem J. 1954 Jul;57(3):427–434. doi: 10.1042/bj0570427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Pogson C. I., Randle P. J. The control of rat-heart phosphofructokinase by citrate and other regulators. Biochem J. 1966 Sep;100(3):683–693. doi: 10.1042/bj1000683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. REGEN D. M., DAVIS W. W., MORGAN H. E., PARK C. R. THE REGULATION OF HEXOKINASE AND PHOSPHOFRUCTOKINASE ACTIVITY IN HEART MUSCLE. EFFECTS OF ALLOXAN DIABETES, GROWTH HORMONE, CORTISOL, AND ANOXIA. J Biol Chem. 1964 Jan;239:43–49. [PubMed] [Google Scholar]
  22. Randle P. J., England P. J., Denton R. M. Control of the tricarboxylate cycle and its interactions with glycolysis during acetate utilization in rat heart. Biochem J. 1970 May;117(4):677–695. doi: 10.1042/bj1170677. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Randle P. J., Newsholme E. A., Garland P. B. Regulation of glucose uptake by muscle. 8. 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 Dec;93(3):652–665. doi: 10.1042/bj0930652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. WILLIAMSON J. R. GLYCOLYTIC CONTROL MECHANISMS. I. INHIBITION OF GLYCOLYSIS BY ACETATE AND PYRUVATE IN THE ISOLATED, PERFUSED RAT HEART. J Biol Chem. 1965 Jun;240:2308–2321. [PubMed] [Google Scholar]
  25. WOLLENBERGER A., RISTAU O., SCHOFFA G. [A simple technic for extremely rapid freezing of large pieces of tissue]. Pflugers Arch Gesamte Physiol Menschen Tiere. 1960;270:399–412. [PubMed] [Google Scholar]
  26. Wieland O., Funcke H. v., Löffler G. Interconversion of pyruvate dehydrogenase in rat heart muscle upon perfusion with fatty acids or ketone bodies. FEBS Lett. 1971 Jul 1;15(4):295–298. doi: 10.1016/0014-5793(71)80641-5. [DOI] [PubMed] [Google Scholar]
  27. Zingaro R. A., Uziel M. Preparation and properties of active, insoluble alkaline phosphatase. Biochim Biophys Acta. 1970 Aug 8;213(2):371–379. doi: 10.1016/0005-2787(70)90045-6. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES