Canadian Anaesthetists’ Society Journal

, Volume 31, Issue 2, pp 130–154

Dantrolene -In vitro studies in malignant hyperthermia susceptible (MHS) and normal skeletal muscle

  • Beverley A. Britt
  • Elizabeth Scott
  • Wanda Frodis
  • Mary-Jean Clements
  • Laszlo Endrenyi


Dantrolene sodium, a hydantoin analogue, is efficacious in the therapy of malignant hyperthermia (MH). In order to improve our knowledge of the mode of action of dantrolene, we have examined the influence of dantrolene sodium on; (1) twitch and resting tensions, in the absence and the presence of caffeine, of intact skeletal muscle fascicles; and (2) caffeine induced tension rises of single chemically skinned skeletal muscle fascicles.

We have found that dantrolene appears to exert its beneficial action on malignant hyperthermia susceptible (MHS) skeletal muscle by an indirect action on the sarcoplasmic reticulum (SR). Thus dantrolene inhibits twitch tensions of skeletal muscle fascicles, probably by indirectly preventing the release of calcium from the SR. To a lesser extent dantrolene inhibits caffeine induced contractures of skeletal muscle fascicles, probably by indirectly accelerating the uptake of calcium into the SR. Because the former effect is greater than the latter in vivo dantrolene sodium is effective only when given prior to total loss of calcium from the SR. Vigilant temperature and EKG monitoring of all patients during anaesthesia is, therefore, essential.

Key words

hyperthermia malignant dantrolene muscle skeletal caffeine twitch tension contracture resting tension 


Le dantrolène sodique, un analogue de l’hydantoin, est efficace dans le traitement de VHyperthermie maligne. Pour améliorer notre connaissance du mode d’action du dantrolène, nous avons étudié l’influence du dantrolène sodique sur: 1) la tension de contraction et de repos avec ou sans caféine sur des faisceaux de muscle squelettique intacts; et 2) l’augmentation de la tension induite par la caféine sur des faisceaux de muscle squelettique enrobés chimiquements. Nous avons trouvé que le dantrolène semble exercer son action bénéfique sur le muscle squelettique susceptible à l’Hyperthermie maligne par une action indirecte sur le réticulum sarcoplasmique (RS). Le dantrolène inhibe les tensions de contraction des faisceaux de muscle squelettique, probablement en prévenant indirectement le largage du calcium du RS. A un moindre degré, le dantrolène inhibe les contractures des faisceaux du muscle squelettique induites par la caféine probablement en accélérant indirectement la captation du calcium dans le RS.

Parce que le premier effet est plus important que le deuxième in-vivo, le dantrolène est efficace uniquement lorsqu’il est administré avant le largage total du calcium par le RS, Une surveillance vigilante de la température et de V électrocardiogramme pendant l’anesthésie est essentielle.


  1. 1.
    Ellis KO, Castellion AW, Honkomp LI, Wessels FL, Carpenter JF, Halliday RP Dantrolene, a direct acting skeletal muscle relaxant. J Pharm Sci 1973; 62: 948–51.PubMedCrossRefGoogle Scholar
  2. 2.
    Colton CA, Cotton JS The action of dantrolene sodium on the lobster neuromuscular junction. Comp Biochem Physiol 1979; 64C: 153–6.Google Scholar
  3. 3.
    Durant NN, Lee C, Kotz RL. The action of dantrolene on transmitter mobilization at the rat neuromuscular junction. EurJ Pharmacol 1980; 68: 403–8.CrossRefGoogle Scholar
  4. 4.
    Ellis KO, Bryant SH. Excitation-contraction uncoupling in skeletal muscle by dantrolene sodium. Naunyn Schmiedegerg’s Arch Pharmacol 1972; 274: 107–9.CrossRefGoogle Scholar
  5. 5.
    Desmedt JE, Hainaut K. Inhibition of the intracellular release of calcium by dantrolene in barnacle giant muscle fibres. J Physiol 1977; 265: 565–85.PubMedGoogle Scholar
  6. 6.
    Ellis KO, Carpenter JF, Studies on the mechanism of action of dantrolene sodium. A skeletal muscle relaxant. Naunyn-Schmiedeberg’s Arch Pharmacol 1972; 275: 83–94.CrossRefGoogle Scholar
  7. 7.
    Putney JW, Jr, Bianchi CP. Effect of dantrolene in E-C coupling in skeletal muscle. FEBS 1973; 32: 772.Google Scholar
  8. 8.
    Moulds R. Comparison of the effect of sodium thiocyanate and dantrolene sodium on a mammalian isolated Skeletal muscle. B? J Pharmacol 1977; 59: 129–33.Google Scholar
  9. 9.
    Fairhurst AS, Hamamoto V, Macri J. Modification of ryanodine toxicity by dantrolene and halothane in a model of malignant hyperthermia. Anesthesiology 1980; 53: 199–204.PubMedCrossRefGoogle Scholar
  10. 10.
    Okumura F, Crocker BD, Denborough MA. Site of the muscle cell abnormality in swine susceptible to malignant hyperpyrexia. Br J Anaesth 1980; 52: 377–83.PubMedCrossRefGoogle Scholar
  11. 11.
    Brocklehurst L. Dantrolene sodium and “skinned” muscle fibres. Nature 1975; 254: 364.PubMedCrossRefGoogle Scholar
  12. 12.
    Oba T. Influence of temperature and external Ca2+ concentration upon dantrolene action on excitation-contraction coupling in frog skeletal muscle. Can J Physiol Pharmacol 1981; 59: 358–63.PubMedGoogle Scholar
  13. 13.
    Ellis KO, Carpenter JF. The effect of dantrolene sodium (F440) on skeletal muscle. Fed Proc 1971; 30: 670.Google Scholar
  14. 14.
    Morgan KG, Bryant SH. The mechanism of action of dantrolene sodium. J Pharmacol Exp Therap 1977; 201: 138–47.Google Scholar
  15. 15.
    Desmedt JE, Hainaut K. Dantrolene and A23187 ionophore: specific action on calcium channels revealed by the aequorin method. Biochem Pharmacol 1979; 28: 957–64.PubMedCrossRefGoogle Scholar
  16. 16.
    Nelson TE. Excitation-contraction coupling: a common etiologic pathway for malignant hyperthermia susceptible muscle. In: Second International Symposium on Malignant Hyperthermia (eds. Aldrete, LA. and Britt, B.A.), Grune & Stratton, New York, p. 23–36(1978).Google Scholar
  17. 17.
    Ellis KO, Butterfield JL, Wessels FL, Carpenter JF. A comparison of skeletal, cardiac, and smooth muscle actions of dantrolene sodium-a skeletal muscle relaxant. Arch Int Pharmacodyn Ther 1976; 224: 118–32.PubMedGoogle Scholar
  18. 18.
    Hatae J, Ohba M, Kawata H. Effects of dantrolene sodium on the excitation-contraction coupling of the mammalian and amphibian cardiac muscle. J Mol Cell Cardiol 1980; 12: 857–67.PubMedCrossRefGoogle Scholar
  19. 19.
    Krarup, C. The effect of dantrolene on the enhancement and diminution of tension evoked by staircase and by tetanus in rat muscle. J. Physiol. 311: 389–400 (1981).PubMedGoogle Scholar
  20. 20.
    Leslie, G.C.andPart, N.J. Effect of dantrolene sodium on twitch contractions of individual motor units in the rat. J. Physiol, 318: 24 (1981).Google Scholar
  21. 21.
    Nott, M.W. andBowman, W.C. Actions of dantrolene sodium on contractions of the tibialis anterior and soleus muscles of cats under chloralose anaesthesia. Clin. Exp. Pharmacol. Physiol. 1: 113–122 (1974).PubMedCrossRefGoogle Scholar
  22. 22.
    Flewellen EH, Nelson TE, Bee DE. Effect of dantrolene on neuromuscular block by d-tubocurarine and subsequent antagonism by neostigmine in the rabbit. Anesthesiology 1980; 52: 126–30.PubMedGoogle Scholar
  23. 23.
    Flewellen EH, Nelson TE. A comparison of dantrolene and procainamide on in vivo muscle twitch of malignant hyperthermia susceptible pigs. FEBS 1978; 37:331,Google Scholar
  24. 24.
    Anderson IL, Lipicky RJ, Jones EW. Dantrolene sodium in porcine malignant hyperthermia: studies on isolated muscle strips. In: Second International Symposium on Malignant Hyperthermia (eds. Aldrete, J.A. and Britt, B.A.), Grune & Stratton, New York, p. 509–34 (1978).Google Scholar
  25. 25.
    Leslie GC, Part NJ. The action of dantrolene sodium on rat fast and slow muscle in vivo, Br J Pharmac 1981;72:665–72.Google Scholar
  26. 26.
    Anderson IL, Jones EW, Porcine malignant hyperthermia: effect of dantrolene sodium on in-vitro halo-thane-induced contraction of susceptible muscle, Anesthesiology 1976; 44; 57–61.PubMedCrossRefGoogle Scholar
  27. 27.
    Anderson IL, Rawstron RE, Dunlop DJ. Screening for malignant hyperthermia susceptibility. NZ Med J 1980;91:417–19.Google Scholar
  28. 28.
    Rosenberg H. Dantrolene and caffeine contracture test (letter to the editor), Can Anaesth Soc J 1980; 27: 303–4.PubMedGoogle Scholar
  29. 29.
    Butterfield JL, Ellis KO. Effects of dantrolene sodium, a skeletal muscle relaxant, on the contractility of cardiac and smooth muscle. Fed Proc 1973; 32: 772.Google Scholar
  30. 30.
    Britt BA, Kalow W, Gordon A, Humphrey JG, Rew-castle NB. Malignant hyperthermia - an investigation of five patients. Can Anaesth Soc J 1973; 20: 431–67.PubMedCrossRefGoogle Scholar
  31. 31.
    Britt BA, Prodis W, Scott E, Endrenyi L. Comparison of the caffeine skinned fibre tension (CSFT) test with the caffeine-halothane contracture (CHC) test in the diagnosis of malignant hyperthermia. Can Anaesth Soc J 1982; 29: 550–62,PubMedCrossRefGoogle Scholar
  32. 32.
    Korczyn AD, Shavit S, Schlosberg I. The chick as a model for malignant hyperpyrexia. Eur J Pharmacol 1980; 61:187–89.PubMedCrossRefGoogle Scholar
  33. 33.
    Nelson TE, Flewellen EH. Rationale for dantrolene vs. procainamide for treatment of malignant hyperthermia, Anesthesiology 1979; 50; 118. 34 Gronert GA. Malignant hyperthermia. Anesthesiology 1980; 53: 395–423.CrossRefGoogle Scholar
  34. 35.
    Hall GM, Lucke JN, Lister D. Treatment of porcine malignant hyperthermia. The successful use of dantrolene in the Pietrain pig. Anaesthesia 1977; 32: 472,PubMedCrossRefGoogle Scholar
  35. 36.
    Gronert GA, Milde JH, Theye RA. Dantrolene in porcine malignant hyperthermia. Anesthesiology 1976; 44: 488–95.PubMedGoogle Scholar
  36. 37.
    Hall LW, Trim CM, Woolfe N. Further studies on porcine malignant hyperthermia. Br Med J 1972; 2: 145.PubMedGoogle Scholar
  37. 38.
    Ryan JF. Treatment of acute hyperthermia crises. In: International Anesthesiology Clinics: Malignant Hyperthermia (ed. Britt, B,A,) 1979; 17: 153–68.Google Scholar
  38. 39.
    Mathieu A, Bogosian AJ, Ryan JF, Crone RK, Crocker D. Recrudescence after survival of an initial episode of malignant hyperthermia. Anesthesiology 1979; 51:454–55.PubMedCrossRefGoogle Scholar
  39. 40.
    Harrison GG. Dantrolene sodium in the treatment of MH: a case report. S Afr Med J 1981; 60: 909–10.PubMedGoogle Scholar
  40. 41.
    Gronert GA, Thompson RL, Onofrio BM. Human malignant hyperthermia: awake episodes and correction by dantrolene. Anesth Anaig 1980; 59: 377–78.Google Scholar
  41. 42.
    Lydiatt JS, Hill GE, Treatment of heat stroke with dantrolene. Letter to the Editor. JAMA 1981; 246: 41–2.PubMedCrossRefGoogle Scholar
  42. 43.
    Delacour JL, Daoudal P, Chapoutot JL, Rocq B. Traitement du syndrome mal in des neuroleptiques par 1e dantrolene. La Nouvelle Presse Médicale 1981 ; 10: 3572–3.PubMedGoogle Scholar
  43. 44.
    Britt BA. Dantrolene-A review. Can Anaesth Soc J 1984;31:61–75.PubMedCrossRefGoogle Scholar
  44. 45.
    Britt BA. Malignant hyperthermia-a review. In: Handbook of Experimental Pharmacology, Pyretics and Antipyretics (ed, Milton, A.S.), Springer-Verlag, Heidelberg 1982; p. 547–615.Google Scholar
  45. 46.
    Sandow A. Skeletal muscle. Ann Rev Physiol 1970; 32: 1040.Google Scholar
  46. 47.
    Hoyle G. How is muscle turned on and off Sci Am 1970; 222: 85.CrossRefGoogle Scholar
  47. 48.
    Hasselbach W. Relaxing factor and the relaxation of muscle. Progress in Biophysics 1964; 14: 1.CrossRefGoogle Scholar
  48. 49.
    Huxley HE. Structural evidence concerning the mechanism of contraction in striated muscle. In: Muscle (eds. Paul, W.M., Daniel, E.E., Kay, C.M. and Monckton, G.). Pergamon Press, Oxford, p. 3, 1965.Google Scholar
  49. 50.
    Porter KR, Franzini-Armstrong C. The sarcoplasmic reticulum. Sci Am 1965; 212: 73.Google Scholar
  50. 51.
    Endo M. Role of calcium in control of muscle contraction and muscle metabolism. Presented at the International Workshop of Malignant Hyperthermia Researchers, Banff, Alberta, October, 1982.Google Scholar
  51. 52.
    Gallant EM, Godt RD, Gronert GA. Role of plasma membrane defect of skeletal muscle in malignant hyperthermia. Muscle and Nerve 1979; 2; 491–4.PubMedCrossRefGoogle Scholar
  52. 53.
    Nelson TE, Flewellen EH. Does prior dantrolene affect the in vitro diagnosis of malignant hyperthermia susceptibility? Can Anaesth Soc J 1979; 26: 484–88.PubMedCrossRefGoogle Scholar
  53. 54.
    Britt BA. Etiology and pathophysiology of malignant hyperthermia. Fed Proc 1979; 38: 44–8.PubMedGoogle Scholar
  54. 55.
    Thorpe W, Seeman P. Drug-induced contracture of muscle. In: International Symposium on Malignant Hyperthermie (eds. Gordon, R.A., Britt, B.A., and Kalow, W.), Charles C. Thomas, Springfield, 1973, p. 152–62.Google Scholar
  55. 56.
    Thorens S, Endo M. Calcium-induced calcium release and “depolarization”-induced calcium release: their physiological significance. Proc Japan Acad 1975; 51:473.Google Scholar
  56. 57.
    Endo M, Tanaka M, Ogawa Y. Calcium induced release of calcium from the sarcoplasmic reticulum of skinned skeletal muscle fibres, Nature 1970; 228: 34.PubMedCrossRefGoogle Scholar
  57. 58.
    Miyamoto H, Racker E. Mechanism of calcium release from skeletal sarcoplasmic reticulum. J. Membrane Biol 1982; 66:193.CrossRefGoogle Scholar
  58. 59.
    Nelson T. Personal communication. International Workshop of Malignant Hyperthermia Researchers, Banff, Alberta, October, 1982.Google Scholar
  59. 60.
    Taylor S, Calcium movements in relation to muscle contraction, Proc Western Pharmacol Soc 1979; 22:321.Google Scholar
  60. 61.
    Taylor S. Personal communication, New York, N.Y. 1983.Google Scholar
  61. 62.
    Campbell KP, Shamoo AE. Chloride-induced release of actively loaded calcium from light and heavy sarcoplasmic reticulum vesicles. J Membrane Biol 1980; 54:73.CrossRefGoogle Scholar
  62. 63.
    Britt BA, Endrenyi L, Cadman DL, Ho MF, Fung HYK. Porcine malignant hyperthermia-effects of halothane on mitochondrial respiration and calcium accumulation. Anesthesiology 1975; 42:292–300.PubMedCrossRefGoogle Scholar
  63. 64.
    Britt BA, Kalow W, Endrenyi L. Malignant hyperthermia and the mitochondria in human patients. In: International Symposium on Malignant Hyperthermia (eds, Gordon, R.A., Britt, B.A, and Kalow,W.), Charles C. Thomas, Springfield, 1973, p. 387–98.Google Scholar
  64. 65.
    Cheah KS. Phospholipases in MH. Presented at the International Workshop of Malignant Hyperthermia Researchers. Banff, Alberta, October, 1982.Google Scholar
  65. 66.
    Weiss B, Wallace TL. Mechanisms and pharmacological implications of altering calmodulin activity. Calcium and Cell Function 1980; 1:331.Google Scholar
  66. 67.
    Britt BA. Unpublished data (1981).Google Scholar
  67. 68.
    Hull MJ, Webster WW,Gatz E. The effects of pento-barbital on 2,4-dinitrophenol induced malignant hyperthermia during halothane general anaesthesia in dogs. J Oral Surg 1971; 29:640.PubMedGoogle Scholar
  68. 69.
    Wilson RD, Nichols RJ, Dent TE, Allen CR. Distal bances of the oxidative-phosphorylation mechanisms as a possible etiological factor in sudden unexplained hyperthermia. Anesthesiology 1966; 26:232.Google Scholar
  69. 70.
    Eikelenboom G, Sybesma M. A possible mechanism for induction of porcine malignant hyperthermia syndrome. J Animal Sci 1974; 38:504.Google Scholar
  70. 71.
    Eikelenboom G, van den BergkSG. Mitochondrial metabolism in stress-susceptible pigs. J Animal Sei 1973; 37:692.Google Scholar

Copyright information

© Canadian Anaesthesiologists 1984

Authors and Affiliations

  • Beverley A. Britt
    • 1
    • 2
  • Elizabeth Scott
    • 1
  • Wanda Frodis
    • 1
  • Mary-Jean Clements
    • 1
  • Laszlo Endrenyi
    • 1
  1. 1.Departments of Anaesthesia and PharmacologyPreventative Medicine and Biostatistics, University of TorontoToronto
  2. 2.Dept. of AnaesthesiaUniversity of TorontoToronto

Personalised recommendations