Mitochondrial Function in Normal and Hypoxic States of the Myocardium

  • J. R. Williamson
  • T. L. Rich


The relationships among isometric tension development, the oxidation-reduction states of pyridine nucleotides and cytochrome c, and the oxygenation state of myoglobin have been assessed using the arterially perfused rabbit interventricular septum under different conditions of contraction rate, perfusate [Ca2+] and pH, catecholamine stress, and hypoxia. Hypoxia was produced either by decreasing oxygen availability with maintained flow (high-flow hypoxia) or by decreasing the flow rate (ischemia). Under normoxic conditions, increased work caused a fall of the cytosolic adenine nucleotide phosphorylation potential, ΔG (ATP)c, an oxidation of the pyridine nucleotides, and a reduction of cytochrome c; the opposite occurred with decreased work. Thus, the redox potential span from NADH to cytochrome c, ΔG h , varied with the energy demand such that ΔG h and ΔG (ATP)c changed in the same direction. Under hypoxic conditions, all respiratory components became more reduced, and myoglobin was partially deoxygenated. The percentage change of developed tension under hypoxic conditions was approximately proportional to the percentage change of oxidized cytochrome c. When high-flow hypoxia and ischemia were compared at the same rates of oxygen delivery, the developed tension at any level of cytochrome c reduction was always lower with ischemia than with high-flow hypoxia. This difference was attributed to the low intracellular pH of ischemic tissue. Myoglobin deoxygenation was linearly related to cytochrome c reduction under all conditions of hypoxia, indicating steep oxygen gradients. The results support the concept of heterogeneous oxygenation of the tissue with mixed populations of aerobic and anaerobic mitochondria in the hypoxic state. In the full aerobic state, the control of mitochondrial respiration in situ appears similar to that of isolated mitochondria.


Oxygen Tension Pyridine Nucleotide Tension Development Contraction Rate Isometric Tension 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Akerboom, T. M. M., Bookelman, H., and Tager, J. M. 1977. Control of ATP transport across the mitochondrial membrane of isolated rat liver cells. FEBS Lett. 74:50–54.PubMedCrossRefGoogle Scholar
  2. 2.
    Berne, R. M., and Rubio, R. 1979. Coronary circulation. In: R. M. Berne, N. Sperelakis, and S. R. Geiger (eds.), Handbook of Physiology: The Cardiovascular System, Vol. 1, pp. 873–952. American Physiological Society, Bethesda.Google Scholar
  3. 3.
    Chance, B., Legallais, V., Sorge, J., and Graham, N. 1975. A versatile time-sharing multichannel spectrophotometer, reflectometer and fluorometer. Anal. Biochem. 66:498–514.PubMedCrossRefGoogle Scholar
  4. 4.
    Dutton, P. L., Leigh, J. S., and Scarpa, A. 1978. Frontiers of Biological Energetics, Vol. II, pp. 1341–1554. Academic Press, New York.Google Scholar
  5. 5.
    Dutton, P. L., Wilson, D. F., and Lee, C. P. 1970. Oxidation reduction potentials of cytochromes in mitochondria. Biochemistry 9:5077–5082.PubMedCrossRefGoogle Scholar
  6. 6.
    Erecinska, M., and Wilson, D. F. 1978. Cytochrome c oxidase: A synopsis. Arch. Biochem. Biophys. 188:1–14.PubMedCrossRefGoogle Scholar
  7. 7.
    Erecinska, M., Wilson, D. F., and Nishiki, K. 1978. Homeostatic regulation of cellular energy metabolism: Experimental characterization in vivo and fit to a model. Am. J. Physiol. 234:C82-C89.PubMedGoogle Scholar
  8. 8.
    Franke, H., Barlow, C. H., and Chance, B. 1976. Oxygen delivery in perfused rat kidney: NADH fluorescence and renal functional state. Am. J. Physiol. 231:1082–1089.PubMedGoogle Scholar
  9. 9.
    Garlick, P. B., Radda, G. K., and Seeley, P. J. 1979. Studies of acidosis in the ischemic heart by phosphorus nuclear magnetic resonance. Biochem. J. 184:547–554.PubMedGoogle Scholar
  10. 10.
    Harbig, K., Chance, B., Kovách, A. G. B., and Reivich, M. 1976. In vivo measurement of pyridine nucleotide fluorescence from cat brain cortex. J. Appl. Physiol. 41:480–488.PubMedGoogle Scholar
  11. 11.
    Hempel, F. G., Jöbsis, F. F., La Manna, J. C, Rosenthal, M. R., and Saltzman, H. A. 1977. Oxidation of ceregral cytochrome aa 3 by oxygen plus carbon dioxide at hyperbaric pressure. J. Appl. Physiol. 43:872–877.Google Scholar
  12. 12.
    Jöbsis, F. F. 1977. What is a molecular oxygen sensor? What is a transduction process? Adv. Exp. Med. Biol. 78:3–18.PubMedCrossRefGoogle Scholar
  13. 13.
    Klingenberg, M., and Rottenberg, H. 1977. Relationship between the gradient of the ATP/ ADP ratio and the membrane potential across the mitochondrial membrane. Eur. J. Biochem. 73:125–130.PubMedCrossRefGoogle Scholar
  14. 14.
    Langer, G. A., and Brady, A. F. 1968. The effects of temperature upon contraction and ionic exchange in rabbit ventricular myocardium: Relation to control of active state. J. Gen. Physiol. 52:682–713.CrossRefGoogle Scholar
  15. 15.
    Lemasters, J. J., and Sowers, A. E. 1979. Phosphate dependence and atractyloside inhibition of mitochondrial oxidative phosphorylation. J. Biol. Chem. 254:1248–1251.PubMedGoogle Scholar
  16. 16.
    Letko, G., and Küster, U. 1979. Competition between extramitochondrial and intramitochondrial ATP-consuming processes. Acta Biol. Med. Germ. 38:1379–1385.PubMedGoogle Scholar
  17. 17.
    Longmuir, I. S. 1957. Respiration rate of rat liver cells at low oxygen concentrations. Biochem. J. 65:378–382.PubMedGoogle Scholar
  18. 18.
    Mitchell, P. 1976. Vectorial chemistry and the molecular mechanics of chemiosmotic coupling: Power transmission by proticity. Biochem. Soc. Trans. 4:399–430.PubMedGoogle Scholar
  19. 19.
    Neely, J. R., Whitmer, J. T., and Rovetto, M. J. 1975. Effect of coronary blood flow on glycolytic flux and intracellular pH in isolated rat hearts. Circ. Res. 37:733–741.PubMedCrossRefGoogle Scholar
  20. 20.
    Oshino, N., Sugano, T., Oshino, R., and Chance, B. 1974. Mitochondrial function under hypoxic conditions: The steady states of cytochrome a + aa 3 and their relation to mitochondrial energy states. Biochim. Biophys. Acta 368:298–310.PubMedCrossRefGoogle Scholar
  21. 21.
    Rich, T. L., and Brady, A. J. 1974. Potassium contracture and utilization of high energy-phosphates in rabbit hearts. Am. J. Physiol. 226:105–113.PubMedGoogle Scholar
  22. 22.
    Rich, T. L., and Williamson, J. R. 1978. Correlation of isometric tension and redox state in perfused rabbit interventricular septum. In: P. L. Dutton, J. S. Leigh, and A. Scarpa (eds.), Frontiers of Biological Energetics, Vol. 2, pp. 1523–1532. Academic Press, New York.CrossRefGoogle Scholar
  23. 23.
    Rich, T. L., and Williamson, J. R. 1982. Assessment of oxygen gradients in cells and perfused interventricular septum by optical techniques. Am. J. Physiol. (submitted).Google Scholar
  24. 24.
    Rottenberg, H. 1979. Non-equilibrium thermodynamics of energy conversion in bioener-getics. Biochim. Biophys. Acta 549:225–253.PubMedCrossRefGoogle Scholar
  25. 25.
    Salhany, J. M., Peiper, G. M., Wu, S., Todd, G. L., Clayton, F. C, and Eliot, R. S. 1979. 31P nuclear magnetic resonance measurements of cardiac pH in perfused guinea pig hearts. J. Mol. Cell. Cardiol. 11:601–610.PubMedCrossRefGoogle Scholar
  26. 26.
    Steenbergen, C, Deleeuw, G., Barlow, C, Chance, B., and Williamson, J. R. 1977. Heterogeneity of the hypoxic state in perfused rat heart. Circ. Res. 41:606–615.PubMedCrossRefGoogle Scholar
  27. 27.
    Steenbergen, C, Deleeuw, G., Rich, T., and Williamson, J. R. 1977. Effects of acidosis and ischemia on contractility and intracellular pH of rat heart. Circ. Res. 41:849–858.PubMedCrossRefGoogle Scholar
  28. 28.
    Steenbergen, C, Deleeuw, G., and Williamson, J. R. 1978. Analysis of control of glycolysis in ischemic hearts having heterogeneous zones of anoxia. J. Mol. Cell. Cardiol. 10:617–639.PubMedCrossRefGoogle Scholar
  29. 29.
    Steenbergen, C, and Williamson, J. R. 1980. Heterogeneous coronary perfusion during myocardial hypoxia. In: M. Tajuddin, B. Bhatia, H. H. Siddiqui, and G. Rona (eds.), Advances in Myocardiology, Vol. 2, pp. 271–284. University Park Press, Baltimore.Google Scholar
  30. 30.
    Sugano, T., Oshino, N., and Chance, B. 1974. Mitochondrial functions under hypoxic conditions: The steady states of cytochrome c reduction and of energy metabolism. Biochim. Biophys. Acta 347:340–358.PubMedCrossRefGoogle Scholar
  31. 31.
    Tamura, M., Oshino, N., Chance, B., and Silver, I. A. 1978. Optical measurements of intracellular oxygen concentration of rat hearts in vitro. Arch. Biochem. Biophys. 191:8–22.CrossRefGoogle Scholar
  32. 32.
    Wikström, M., and Krab, K. 1979. Proton pumping cytochrome c oxidase. Biochim. Biophys. Acta 549:177–222.PubMedCrossRefGoogle Scholar
  33. 33.
    Wikström, M. F., and Saari, H. T. 1975. Conformational change in cytochrome aa 3 and ATP synthetase of the mitochondrial membrane and their role in mitochondrial energy transduction. Mol. Cell. Biochem. 11:17–33.CrossRefGoogle Scholar
  34. 34.
    Williamson, J. R. 1979. Mitochondrial function in the heart. Annu. Rev. Physiol. 41:485–506.PubMedCrossRefGoogle Scholar
  35. 35.
    Williamson, J. R., Safer, B., Rich, T., Schaffer, S., and Kobayashi, K. 1975. Effects of acidosis on myocardial contractility and metabolism. Acta Med. Scand. [Suppl.] 587:95–111.Google Scholar
  36. 36.
    Wilson, D. F., Erecinska, M., Drown, C, and Silver, I. A. 1979. The oxygen dependence of cellular energy metabolism. Arch. Biochem. Biophys. 195:485–493.PubMedCrossRefGoogle Scholar
  37. 37.
    Wilson, D. F., Owen, C. S., and Erencinska, M. 1979. Quantitative dependence of mitochondrial oxidative phosphorylation on oxygen concentration: A mathematical model. Arch. Biochem. Biophys. 195:494–504.PubMedCrossRefGoogle Scholar
  38. 38.
    Wilson, D. F., Owen, C. S., and Holian, A. 1977. Control of mitochondrial respiration: A quantitative evaluation of the roles of cytochrome c and oxygen. Arch. Biochem. Biophys. 182:749–762.PubMedCrossRefGoogle Scholar
  39. 39.
    Van der Meer, R., Akerboom, T. P. M., Groen, A. K., and Tager, J. M. 1978. Relationship between oxygen uptake of perfused rat liver cells and the cytosolic phosphorylation state calculated from indicator metabolites and a redetermined equilibrium constant. Eur. J. Biochem. 84:421–428.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1983

Authors and Affiliations

  • J. R. Williamson
    • 1
  • T. L. Rich
    • 1
  1. 1.Department of Biochemistry and BiophysicsUniversity of Pennsylvania School of MedicinePhiladelphiaUSA

Personalised recommendations