Ca2+ Ion Shifts in Vivo in Reversible and Irreversible Ischemic Injury

  • Robert B. Jennings
  • Charles Steenbergen
Part of the Progress in Experimental Cardiology book series (PREC, volume 1)


The changes in ion content and H2O detectable in vivo in the intact canine heart in reversible and irreversible ischemic injury are described, with emphasis on the role Ca2+ movements may play in causing ischemic injury. Changes in extracellular ion concentrations and pH revealed by ion-specific electrodes in ischemia are reviewed, as are the contributions of nuclear magnetic resonance measurements of ionized Ca2+ to our understanding of Ca2+ ion homeostasis in ischemia.

During the reversible phase of ischemic injury in vivo, there is little evidence of significant failure of ion pumps. Nevertheless, substantial shifts in ions and water occur while the myocardium is ischemic. Moreover, after reperfusion with arterial blood, living reversibly injured myocytes exhibit altered volume regulation that persists for minutes to hours. Increases in intracellular Ca2+ ion are small (i.e., μM) during the reversible phase and are much larger (i.e., mM) during the irreversible phase of ischemic injury, at which time the so-called calcium overload is clearly present. It is not known whether the overload is an epiphenomenon or a primary cause of lethal injury in Ischemia and reperfusion.


Ischemic Injury Severe Ischemia Canine Heart Cell Volume Regulation Total Ischemia 
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.
    Barry WH, Hasin Y, Smith TW. 1985. Sodium pump inhibition, enhanced calcium influx via sodium-calcium exchange, and positive inotropic response in cultured heart cells. Circ Res 56:231–241.PubMedGoogle Scholar
  2. 2.
    Barry WH, Smith TW. 1984. Movement of Ca2+ across the sarcolemma: effects of abrupt exposure to zero external Na concentration. J Mol Cell Cardiol 16:155–164.PubMedCrossRefGoogle Scholar
  3. 3.
    Murphy E, Aiton JF, Horres R, Lieberman M. 1983. Calcium elevation in cultured heart cells: its role in cell injury. Am Physiol Soc 245:C316–C321.Google Scholar
  4. 4.
    Cala PM. 1980. Volume reation by Amphiuma red blood cells. The membrane potential and its implications regarding the nature of the ion-flux pathways. J Gen Physiol 76:683–708.PubMedCrossRefGoogle Scholar
  5. 5.
    Jennings RB, Steenbergen C Jr, Kinney RB, Hill ML, Reimer KA. 1983. Comparison of the effect of ischaemia and anoxia on the sarcolemma of the dog heart. Eur Heart J 4(Suppl):123–127.PubMedGoogle Scholar
  6. 6.
    Steenbergen C Jr, Murphy E, Levy L, London RE. 1987. Elevation in cytosolic free calcium concentration early in myocardial ischemia in perfused rat heart. Circ Res 60:700–707.PubMedGoogle Scholar
  7. 7.
    Steenbergen C Jr, Perlman ME, London RE, Murphy E. 1993. Mechanism of preconditioning. Ionic alterations. Circ Res 72:112–115.PubMedGoogle Scholar
  8. 8.
    Jennings RB, Reimer KA. 1979. Biology of experimental, acute myocardial ischaemia and infarction. In Hearse DJ, de Leiris J (eds), Enzymes in Cardiology: Diagnosis and Research. Great Britain/New York John Wiley & Sons, pp. 21–57.Google Scholar
  9. 9.
    Menick FJ, White FC, Bloor CM. 1971. Coronary collateral circulation: determination of an anatomical anastomotic index of functional collateral flow capacity. Am Heart J 82:503–510.PubMedCrossRefGoogle Scholar
  10. 10.
    Schaper W, Wusten B. 1979. Collateral circulation. In Schaper W (ed), Pathophysiology of Myocardial Perfusion. Amsterdam: Elsevier/North Holland Biomedical Press, pp. 415–470.Google Scholar
  11. 11.
    Jennings RB, Murry CE, Steenbergen C Jr, Reimer KA. 1990. Development of cell injury in sustained acute ischemia. Circulation 82(Suppl):II-2–II-12.Google Scholar
  12. 12.
    Jennings RB, Reimer KA, Steenbergen C Jr. 1986. Myocardial ischemia revisited. The osmolar load, membrane damage, and reperfusion (editorial). J Mol Cell Cardiol 18:769–780.PubMedCrossRefGoogle Scholar
  13. 13.
    Jennings RB, Steenbergen C Jr. 1985. Nucleotide metabolism and cellular damage in myocardial ischemia. Annu Rev Physiol 47:727–749.PubMedCrossRefGoogle Scholar
  14. 14.
    Jennings RB, Kaltenbach JP, Smetters GW. 1957. Enzymatic changes in acute myocardial ischemic injury. Arch Pathol Lab Med 64:10–16.Google Scholar
  15. 15.
    Hill JL, Genes LS. 1980. Effect of acute coronary artery occlusion on local myocardial extracellular K+ activity in swine. Circulation 61:768–778.PubMedGoogle Scholar
  16. 16.
    Jennings RB, Reimer KA. 1973. The fate of the ischemic myocardial cell. In Corday E, Swan HJC (eds), Myocardial Infarction. New Perspectives in Diagnosis and Management. Baltimore: Williams and Wikins, pp. 13–24.Google Scholar
  17. 17.
    Jennings RB, Schaper J, Hill ML, Steenbergen C Jr, Reimer KA. 1985. Effect of reperfusion late in the phase of reversible ischemic injury. Changes in cell volume, electrolytes, metabolites, and ultrastructure. Circ Res 56:262–278.PubMedGoogle Scholar
  18. 18.
    Jennings RB, Reimer KA. 1992. Lethal reperfusion injury: fact or fancy? In Parratt JR (ed), Myocardial Response to Acute Injury. London: Macmillan Press, pp. 17–34.Google Scholar
  19. 19.
    Reimer KA, Jennings RB. 1982. Ion and water shifts, cellular. In Cowley RA, Trump BF (eds), Cellular Injury in Shock, Anoxia and Ishemia. Pathophysiology. Prevention and Treatment. Baltimore: Williams and Wilkins, pp. 132–147.Google Scholar
  20. 20.
    Jennings RB, Crout JR, Smetters GW. 1957. Studies on distribution and localization of potassium in early myocardial ischemic injury. Arch Pathol 63:586–592.Google Scholar
  21. 21.
    Jennings RB, Sommers HM, Kaltenbach JR, West JJ. 1964. Electrolyte alterations in acute myocardial ischemic injury. Circ Res 14:260–269.PubMedGoogle Scholar
  22. 22.
    Basuk WL, Reimer KA, Jennings RB. 1986. Effect of repetitive brief episodes of ischemia on cell volume, electrolytes and ultrastructure. J Am Coll Cardiol (Suppl):33A–41A.Google Scholar
  23. 23.
    Jennings RB, Ganote CE, Kloner RA, Whalen DA Jr, Hamilton DG. 1975. Explosive swelling of myocardial cells irreversibly injured by transient ischemia. In Fleckenstein F, Rona G (eds), Pathophysiology and Morphology of Myocardial Cell Alteration. Baltimore: University Park Press, pp. 405–413.Google Scholar
  24. 24.
    Jennings RB, Hawkins HK, Hill ML. 1977. Myocardial cell volume control in ischemic injury. In Lefer A, Kelliher G, Rovetto M (eds), Pathophysiology: Therapeutics of Myocardial Injury. New York: Spectrum Publications pp. 351–365.Google Scholar
  25. 25.
    Jennings RB, Shen AC. 1972. Calcium in experimental myocardial ischemia. In Bajusz E, Rona G (eds), Recent Advances in Studies on Cardiac Structure and Metabolism. Myocardiology. Baltimore: University Park Press, pp. 639–655.Google Scholar
  26. 26.
    Shen AC, Jennings RB. 1972. Myocardial calcium and magnesium in acute ischemic injury. Am J Pathol 67:417–440.PubMedGoogle Scholar
  27. 27.
    Shen AC, Jennings RB. 1972. Kinetics of calcium accumulation in acute myocardial ischemic injury. Am J Pathol 67:441–452.PubMedGoogle Scholar
  28. 28.
    Weiss J, Shine KI. 1982. Extracellular K+ accumulation during myocardial ischemia in isolated rabbit heart. Am J Physiol 242:H619–H628.PubMedGoogle Scholar
  29. 29.
    Fleet WF, Johnson TA, Graebner CA, Gettes LS. 1985. Effect of serial brief ischemic episodes on extracellular K+, pH, and activation in the pig. Circulation 72:922–932.PubMedGoogle Scholar
  30. 30.
    Pike MM, Luo CS, Clark MD, Kirk KA, Kitakaze M, Madden MC, Cragoe EJ, Pohost GM. 1993. NMR measurements of Na+ and cellular energy in ischemic rat heart: role of Na+-H+ exchange. Am J Physiol 265:H2017–H2026.PubMedGoogle Scholar
  31. 31.
    Whalen DA Jr, Hdton DG, Ganote CE, Jennings RB. 1974. Effect of a transient period of ischemia on myocardial cells. I. Effects on cell volume regulation. Am J Pathol 74:381–398.PubMedGoogle Scholar
  32. 32.
    Kloner RA, Ganote CE, Whalen D, Jennings RB. 1974. Effect of a transient period of ischemia on myocardial cells. II. Fine structure during the first few minutes of reflow. Am J Pathol 74:399–422.PubMedGoogle Scholar
  33. 33.
    Herdson PB, Sommers HM, Jennings RB. 1965. A comparative study of the fine structure of normal and ischemic dog myocardium with special reference to early changes following temporary occlusion of a coronary artery. Am J Pathol 46:367–386.PubMedGoogle Scholar
  34. 34.
    Lehninger AL. 1970. Mitochondria and calcium ion transport. Biochem J 119:129–138.PubMedGoogle Scholar
  35. 35.
    Kloner RA, Ganote CE, Jennings RB. 1974. The “no-reflow” phenomenon after temporary coronary occlusion in the dog. J Clin Invest 543:1496–1508.Google Scholar
  36. 36.
    Yellon DM, Jennings RB. 1991. Myocardial Protection: The Pathophysiology of Reperfusion and Reperfusion Injury. New York: Raven Press, pp. 1–214.Google Scholar
  37. 37.
    Fleckenstein A. 1971. Specific inhibitors and promotors of calcium action in the excitation contraction coupling of heart muscle and their role in the prevention or production of rnyocardial lesions. In Harris P, Opie L (eds), Calcium and the Heart. New York: Academic Press, pp. 135–189.Google Scholar
  38. 38.
    Fleckenstein A, Fleckenstein-Grun G. 1980. Cardiovascular protection by Ca antagonists. Eur Heart J 1(Suppl B):15–21.PubMedGoogle Scholar
  39. 39.
    Fleckenstein A, Janke J, Doring HJ, Leder O. 1975. Key role of Ca in the production of noncoronarogenic myocardial necroses. In Fleckenstein A, Rona G (eds), Recent Advances in Studies on Cardiac Structure and Metabolism. Baltimore: University Press, pp. 21–32.Google Scholar
  40. 40.
    Ganote CE, Nayler WG. 1985. Contracture and the Calcium Paradox (editorial review). J Mol Cell Cardiol 17:733–745.PubMedCrossRefGoogle Scholar
  41. 41.
    Bolli R. 1990. Mechanism of myocardial “stunning.” Circulation 82:723–738.PubMedGoogle Scholar
  42. 42.
    Murry CE, Richard VJ, Jennings RB, Reimer U. 1991. Myocardial protection is lost before contractile function recovers from ischemic preconditioning. Am J Physiol (Heart Circ Physiol) 260(29):H796–H804.Google Scholar
  43. 43.
    Murry CE, Richard VJ, Reimer KA, Jennings RB. 1990. Ischemic preconditioning slows energy metabolism and delays ultrastructural damage during sustained ischemia. Circ Res 66:913–931.PubMedGoogle Scholar
  44. 44.
    Swain JL, Sabina RL, Hines JJ, Greenfield JC Jr, Holmes EW. 1984. Repetitive episodes of brief ischemia (12 min) do not produce a cumulative depletion of high energy phosphate compounds. Cardiovasc Res 18:264–269.PubMedCrossRefGoogle Scholar
  45. 45.
    Metcalfe JC, Hesketh TR, Smith GA. 1985. Free cytosolic Ca+ measurements with fluorine labelled indicators using 19F NMR. Cell Calcium 6:183–195.PubMedCrossRefGoogle Scholar
  46. 46.
    Pike MM, Frazer JC, Dedrick DF, Ingwall JS, Allen PD, Springer CS, Smith TW. 1985. 23Na and 39K nuclear magnetic resonance studies of perfused rat hearts. Biophys J 48:159–173.PubMedGoogle Scholar
  47. 47.
    Malloy CR, Buster DC, Margarida M, Castro CA, Geraldes CFGC, Jeffrey FMH, Sherry AD. 1990. Influence of global ischemia on intracellular sodium in the perfused rat heart. Magn Reson Med 15:33–44.PubMedCrossRefGoogle Scholar
  48. 48.
    Steenbergen C, Murphy E, Levy L, London RE. 1987. Elevation in cytosolic free calcium concentration early in myocardial ischemia in pefused rat heart. Circ Res 60:700–707.PubMedGoogle Scholar
  49. 49.
    Marban E, Kitakaze M, Kusuoka H, Porterfield JK, Yue DT, Chacko VP. 1987. Intracellular free calcium concentration measured with 19F NMR spectroscopy in intact ferret hearts. Proc Natl Acad Sci USA 84:6005–6009.PubMedCrossRefGoogle Scholar
  50. 50.
    London RE, Rhee CK, Murphy E, Gabel S, Levy LA. 1994. NMR-sensitive fluorinated and fluorescent intracellular calcium ion indicators with high dissociation constants. Am J Physiol 266:C1313–C1322.PubMedGoogle Scholar
  51. 51.
    Murphy E, Steenbergen C, Levy LA, Gabel S, London RE. 1994. Measurement of cytosolic free calcium in perfused rat heart using TF-BAPTA. Am J Physiol 266:C1323–C1329.PubMedGoogle Scholar
  52. 52.
    Chen W, Steenbergen C, Levy LA, Vance J, London RE, Murphy E. 1996. Measurement of free Ca2+ in sarcoplasmic reticulum in perfused rabbit heart loaded with 1,2-bis(2-amino-5,6-difluorophenoxy)ethane-N,N,N′,N′-tetraacetic acid by 19F NMR. J Biol Chem 271:7398–7403.PubMedCrossRefGoogle Scholar
  53. 53.
    Murphy E, Perlman M, London RE, Steenbergen C. 1991. Amiloride delays the ischemia-induced rise in cytosolic free calcium. Circ Res 68:1250–1258.PubMedGoogle Scholar
  54. 54.
    Murphy E, Steenbergen C, Levy LA, Raju B, London RE. 1989. Cytosolic free magnesium levels in ischemic rat heart. J Biol Chem 264:5622–5627.PubMedGoogle Scholar
  55. 55.
    Westfall MV, Solaro RJ. 1992. Alterations in myofibrillar function and protein profiles after complete global ischemia in rat hearts. Circ Res 70:302–313.PubMedGoogle Scholar
  56. 56.
    Matsumura Y, Saeki E, Inoue M, Hori M, Kamada T, Kusuoka H. 1996. Inhomogeneous disappearance of myofilament-related cytoskeletal proteins in stunned myocardium of guinea pig. Circ Res 79:447–454.PubMedGoogle Scholar
  57. 57.
    Reimer KA, Jennings RB. 1992. Myocardial ischemia, hypoxia, and infarction. In Fozzard HA, Jennings RB, Haber E, Katz AM, Morgan HE (eds), The Heart and Cardiovascular System. New York: Raven Press, pp. 1875–1973.Google Scholar
  58. 58.
    Reimer KA, Hill ML, Jennings RB. 1981. Prolonged depletion of ATP and of the adenine nucleotide pool due to delayed resynthesis of adenine nucleotides following reversible myocardial ischemic injury in dogs. J Mol Cell Cardiol 13:229–239.PubMedCrossRefGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1998

Authors and Affiliations

  • Robert B. Jennings
    • 1
  • Charles Steenbergen
    • 1
  1. 1.Duke University Medical CenterUSA

Personalised recommendations