Why Does Halothane Relax Cardiac Muscle but Contract Malignant Hyperthermic Skeletal Muscle?

  • S. Tsuyoshi Ohnishi
  • Masayuki Katsuoka
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 301)


We have studied the question of the possible role of sarcoplasmic reticulum (SR) in the interaction of volatile anesthetics (such as halothane, enflurane and isoflurane) with muscle. We used two cardiac muscle models, i.e., isolated rat myocytes and Langendorff perfused rat hearts. We compared the results with those for skeletal muscle SR from rabbits, rats and pigs susceptible to malignant hyperthermia (MH). In both skeletal and cardiac muscle SR, volatile anesthetics enhanced the calcium release from the SR. In cardiac muscle, these agents are known to decrease contracility (negative inotropism). We found that caffeine, a well-known agent which releases calcium from the SR, also had a negative inotropic effect in cardiac muscle, raising the possibility of an unexpected link between the potentiation of calcium release and mechanism underlying the observed negative inotropism. Current understanding of anesthetic mechanisms does not include this possibility. We further found that both volatile anesthetics and caffeine decrease the content of calcium in the SR, suggesting that the increase of calcium permeability results in the decrease of calcium ions in the SR which are available for excitation-contraction (E-C) coupling. In MH-susceptible skeletal muscle, a similar increase in calcium permeability does not cause a decrease of contractility, but rather may contribute to a fatal syndrome of temperature increase provoked by abnormal contracture. This difference may be because in skeletal myoplasm calcium ions recycle internally, while in the cardiac muscle cell they are in dynamic equilibrium with extracellular calcium ions.


Sarcoplasmic Reticulum Calcium Release Volatile Anesthetic Malignant Hyperthermia Malignant Hyperthermia 
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  1. 1.
    S. T. Ohnishi, Calcium-induced calcium release from fragmented sarcoplasmic reticulum, J Biochem 86:1147–1150 (1979).PubMedGoogle Scholar
  2. 2.
    S. T. Ohnishi, Calcium-Induced calcium release as a gated calcium transport, in: “Mechanism of Gated Calcium Transport Across Biological Membranes,” S. T. Ohnishi, M. Endo, eds., Academic Press, New York (1981).Google Scholar
  3. 3.
    S. T. Ohnishi, A. J. Waring, S. G. Fang, K. Horiuchi, J. L. Flick, K. K. Sadanaga, T. Ohnishi, Abnormal membrane properties of the sarcoplasmic reticulum of pigs susceptible to malignant hyperthermia: Modes of action of halothane, caffeine, dantrolene and two other drugs, Arch Biochem Biophys 247:294–301, (1986).PubMedCrossRefGoogle Scholar
  4. 4.
    S. T. Ohnishi, Effects of halothane, caffeine, dantrolene and tetracaine on the calcium permeability of skeletal sarcoplasmic reticulum of malignant hyperthermic pigs, Biochem Biophys Acta 897:261–268, (1987).PubMedCrossRefGoogle Scholar
  5. 5.
    S. T. Ohnishi, J. L. Flick, F. Rubin, Ethanol increases calcium permeability of heavy sarcoplasmic reticulum of skeletal muscle, Arch Biochem Biophys 233:588–594, (1984).PubMedCrossRefGoogle Scholar
  6. 6.
    S. T. Ohnishi, A. J. Waring, S. G. Fang, K. Horiuchi, T. Ohnishi, Sarcoplasmic reticulum membrane of rat skeletal muscle is disordered with chronic alcohol ingestion, Membr Biochem 6:49–63, (1984).CrossRefGoogle Scholar
  7. 7.
    S. T. Ohnishi, S. Taylor, G. A. Gronert, Calcium-induced calcium-release from sarcoplasmic reticulum of pigs susceptible to malignant hyperthermia: The effect of halothane and dantrolene, FEBS Lett 161:103–107 (1983).PubMedCrossRefGoogle Scholar
  8. 8.
    A. Fabiato, F. Fabiato, Contractions induced by a calcium triggered release of calcium from the sarcoplasmic reliculum of single skinned cardiac cells, J Physiol (Lond) 249:469–495 (1975).Google Scholar
  9. 9.
    W. R. Brewster, J. P. Isaacs, T. Waing-Anderson, Depressant effect of ether on myocardium of the dog and its modification by reflex release of epinephrine and norepinephrine, J Pharmacol Exp Ther 175:399–414 (1953).Google Scholar
  10. 10.
    H. L. Price, M. Helrich, The effect of cyclopropane, diethyl ether, nitrous oxide, thiopental and hydrogen ion concentration on the myocardial function of the dog heart-lung preparation, J Pharmacol Exp Ther 115:206–216 (1955).PubMedGoogle Scholar
  11. 11.
    B. R. Brown, J. R. Crout, A comparative study of the effect of five general anesthetics on myocardial contractility, Anesthesiology 34:236–245 (1971).PubMedCrossRefGoogle Scholar
  12. 12.
    B. F. Rusy, H. Komai, Anesthetic depression of myocardial contractility: A review of possible mechanisms, Anesthesiology 67:745–766 (1987).PubMedCrossRefGoogle Scholar
  13. 13.
    H. L. Price, Calcium reverses myocardial depression caused by halothane: Site of action, Anesthesiology 218:576–579 (1974).CrossRefGoogle Scholar
  14. 14.
    H. L. Price, Myocardial depression by nitrous oxide and its reversal by Ca++, Anesthesiology 44:211–215 (1976).PubMedCrossRefGoogle Scholar
  15. 15.
    C. Lynch, S. Vogel, N. Sperelakis, Halothane depression of myocardial slow aciton potentials, Anesthesiology 55:360–368 (1981).PubMedCrossRefGoogle Scholar
  16. 16.
    Z. J. Bosnjak, J. P. Kampine, Effects of halothane, enflurane, and isoflurane on the SA node, Anesthesiology 58:314–321 (1983).PubMedCrossRefGoogle Scholar
  17. 17.
    Z. J. Bosnjak, J. P. Kampine, Effects of halothane on transmembrane potentials, Ca2+ transients, and papillary muscle tension in the cat, Am J Physiol 251:H374–H381 (1986).PubMedGoogle Scholar
  18. 18.
    C. Lynch III, Differential depression of myocardial contractility by halothane and isoflurane in vitro, Anesthesiology 64:620–631 (1986).PubMedCrossRefGoogle Scholar
  19. 19.
    G. A. Langer, S. D. Serena, L. M. Nudd, Cation exchange in heart cell culture: Correlation with effects on contractile force, J Mol Cell Cardiol 6:149–161 (1974).PubMedCrossRefGoogle Scholar
  20. 20.
    W. G. Nayler, J. Szeto, Effect of sodium pentobarbilal on calcium in mammalian heart muscle, Am J Physiol 222:339–344 (1972).PubMedGoogle Scholar
  21. 21.
    E. S. Casella, N. D. A. Suite, Y. I. Fisher, T. J. J. Blanck, The effect of volatile anesthetics on the pH dependence of calcium uptake by cardiac sarcoplasmic reticulum, Anesthesiology 67:386–390 (1987).PubMedCrossRefGoogle Scholar
  22. 22.
    J. Y. Su, W. G. L. Kcrrick, Effects of halothane on caffeine-induced tension transients in functionally skinned myocardial fibers, Pflugers Arch 380:29–34 (1979).PubMedCrossRefGoogle Scholar
  23. 23.
    S. T. Ohnishi, C. A. DiCamillo, M. Singer, H. L. Price, Correlation between halothane-indueed myocardial depression and decreases in La3+-displaceable Ca2+ in cardiac muscle cells, J Cardiovasc Pharmacol 2:67–75 (1980).PubMedCrossRefGoogle Scholar
  24. 24.
    S. T. Ohnishi, D. M. Obzansky, H. L. Price, The increase in calcium binding of cardiac plasma membrane lipoprotein caused by general anesthetics and alcohol, Can J Physiol Pharmacol 58:525–530 (1980).PubMedCrossRefGoogle Scholar
  25. 25.
    B. Drenger, T. J. J. Blanck, Volatile anesthetics depress the binding of calcium channel blocker to purified cardiac sarcolemma (abstract), Anesthesiology 69:A16 (1988).CrossRefGoogle Scholar
  26. 26.
    Z. J. Bosnjak, F. D. Supan, N. J. Rusch, The effects of halothane, enflurane and isoflurane on calcium current in isolated canine ventricular cells, Anesthesiology 74:340–345 (1991).PubMedCrossRefGoogle Scholar
  27. 27.
    M. Endo, Calcium release from the sarcoplasmic reticulum, Physiol Rev 57:71–108 (1977).PubMedGoogle Scholar
  28. 28.
    J. L. Sutko, L. J. Thompson, A. A. Kort, E. G. Lakatta, Comparison of effects of ryanodine and caffeine on rat ventricular myocardium, Am J Physiol 250:H786–H795 (1986).PubMedGoogle Scholar
  29. 29.
    D. M. Wheeler, R. T. Rice, R. C. Hansford, E. G. Lakatta, The effect of halothane on the free intracellular calcium concentration of isolated rat heart cells, Anesthesiology 69:578–583 (1988).PubMedCrossRefGoogle Scholar
  30. 30.
    J. S. Herland, D. G. Stephenson, F. J. Julian, Halothane affects the contractile apparatus and sarcoplasmic reticulum of mechanically skinned rat ventricular fibers (abstract), Biophys J 53:335a (1988).Google Scholar
  31. 31.
    H. L. Price, S. T. Ohnishi, Effects of anesthetics on the heart, Fed Proc 39:575–1579 (1980).Google Scholar
  32. 32.
    M. Katsuoka, S. T. Ohnishi, Volatile anesthetics decrease calcium content of isolated myocytcs, Anesthesiology 70:954–960 (1989).PubMedCrossRefGoogle Scholar
  33. 33.
    M. Katsuoka, S. T. Ohnishi, Inhalation anaesthetics decrease calcium content of cardiac sarcoplasmic reticulum, Br J Anaesth 62:669–673 (1989).PubMedCrossRefGoogle Scholar
  34. 34.
    R. L. Kao, E. W. Christman, S. L. Luh, J. M. Kraubs, G. F. Tylers, G. H. Williams, The effects of insulin and anoxia on the metabolism of isolated mature rat cardiac myocytes, Arch Biochem Biophys 203:587–599 (1980).PubMedCrossRefGoogle Scholar
  35. 35.
    G. Grynkiewiez, M. Poenie, R. Y. Tsien, A new generation of Ca2+ indicators with greatly improved fluorescence properties, J Biol Chem 260:3440–3450 (1985).Google Scholar
  36. 36.
    F. Renzi, B. E. Waud, Partition coefficients of volatile anesthetics in Krebs’Solution, Anesthesiology 47:62–63 (1977).PubMedCrossRefGoogle Scholar
  37. 37.
    M. Endo, Mechanism of action of caffeine on the sarcoplasmic reticulum of skeletal muscle, Proc Japan Acad 51:479–484 (1975).Google Scholar
  38. 38.
    R. S. V. Heide, R. A. Altschuld, K. G. Lamka, C. E. Ganote, Modification of caffeine-induced injury in calcium-free perfused rat hearts, Am J Pathol 123:351–364 (1986).Google Scholar
  39. 39.
    E. I. Eger, Isoflurane: A review. Anesthesiology 55:559–576 (1981).PubMedCrossRefGoogle Scholar
  40. 40.
    P. R. Housmans, I. Murat, Comparative effects of halothane, enflurane, and isoflurane at equipotent anesthetic concentrations on isolated ventricular myocardium of the ferret: I. Contractility, Anesthesiology 69:451–463 (1988).PubMedCrossRefGoogle Scholar
  41. 41.
    M. Morad, Y. Goldman, Excitation-contraction coupling in the sarcoplasmic reticulum skinnet of tension, Prog Biophys Mol Biol 27:259–313 (1973).CrossRefGoogle Scholar
  42. 42.
    G. B. McClellan, S. Winegrad, The regulation of the calcium sensitivity of the contractile system in mammalian cardiac muscle. J Gen Physiol 72:737–764 (1978).PubMedCrossRefGoogle Scholar
  43. 43.
    H. Reuter, C. F. Stevens, R. W. Tsien, G. Ycllin, Properties of single calcium channels in cardiac cell culture, Nature 297:501–504 (1982).PubMedCrossRefGoogle Scholar
  44. 44.
    R. A. Chapman, Excitation-contraction coupling in heart muscle, Prog Biophys Mol Biol 35:1–52 (1979).PubMedCrossRefGoogle Scholar
  45. 45.
    H. Reuter, Exchange of calcium ions in the mammalian myocardium: Mechanisms and physiological significance, Circ Res 34:599–606 (1974).PubMedGoogle Scholar
  46. 46.
    P. Caroni, E. Carafoli, An ATP-dependent Ca2+-pumping system in dog heart sarcolemma, Nature 283:765–767 (1980).PubMedCrossRefGoogle Scholar
  47. 47.
    E. Caraboeuf, P. Gautier, P. Guiraudou, Potential and tension changes induced by sodium removal in dog Purkinje fibers: Role of an electrogenic sodium-calcium exchange, J Physiol (Land) 311:605–622 (1981).Google Scholar
  48. 48.
    E. Carafoli, The homcostasis of calcium in heart cells, J Mol Cell Cardiol 17:203–212 (1985).PubMedCrossRefGoogle Scholar
  49. 49.
    F. F. Jobsis, M. J. O’Connor, Calcium release and reasborption in the sartorius muscle of the toad, Biochem Biophys Res Commun 25:246–252 (1966).PubMedCrossRefGoogle Scholar
  50. 50.
    S. Winegrad, Autoradiographic studies of intracellular calcium in frog skeletal muscle, J Gen Physiol 48:455–479 (1965).PubMedCrossRefGoogle Scholar
  51. 51.
    S. Wincgrad, Intracellular calcium movements of frog skeletal muscle during recovery from tetanus, J Gen Physiol 51:65–83 (1968).CrossRefGoogle Scholar
  52. 52.
    A. J. Sweetman, A. F. Esmail, Evidence for the role of calcium ions and mitochondria in the maintenance of anesthesia in the rat, Biochem Biophys Res Commun 64:885–890 (1975).PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • S. Tsuyoshi Ohnishi
    • 1
  • Masayuki Katsuoka
    • 2
  1. 1.Philadelphia Biomedical Research InstituteKing of PrussiaUSA
  2. 2.Ihara Chemical CompanyShizuokaJapan

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