Skip to main content
SpringerLink
Log in

Calcium channel blockers are inadequate for malignant hyperthermia crisis

  • Original Article
  • Published:
Journal of Anesthesia Aims and scope Submit manuscript

Abstract

Purpose

Malignant hyperthermia (MH) results from disordered calcium (Ca2+) homeostasis in skeletal muscle during general anesthesia. Although Ca2+ channel blockers may be given to treat the tachycardia and circulatory instability, coadministration of Ca2+ channel blockers and dantrolene is contraindicated during MH crisis. We evaluated the effect of Ca2+ channel blockers on Ca2+ homeostasis and their interactions with dantrolene in human skeletal muscle.

Methods

Human skeletal muscle samples were obtained by biopsy and divided into two groups according to the results of the Ca2+-induced Ca2+ release rate test. Differentiated myotubes were labeled with Fura-2, and changes in the 340/380-nm ratio were used to calculate changes in Ca2+ concentration following nifedipine treatment in the absence or presence of dantrolene.

Results

Nifedipine induced a transient increase in the intracellular Ca2+ concentration ([Ca2+]i) in a dose-dependent manner. The half-maximal concentration (EC50) for nifedipine was 0.718 ± 0.329 μM in the accelerated group and 1.389 ± 0.482 μM in the nonaccelerated group (P = 0.009). The addition of 50 μM dantrolene attenuated by 15.4% the increase in [Ca2+]i caused by the 0.5 μM nifedipine.

Conclusion

Ca2+ channel blockers led to increased [Ca2+]i in human skeletal muscle cells. The increase is thus scarcely affected by dantrolene treatment. Data provide a greater physiologic basis for avoiding the use of Ca2+ channel blockers during MH crisis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Hopkins PM. Malignant hyperthermia: advances in clinical management and diagnosis. Br J Anaesth. 2000;85:118–28.

    Article  PubMed  CAS  Google Scholar 

  2. Stowell KM. Malignant hyperthermia: a pharmacogenetic disorder. Pharmacogenomics. 2008;9:1657–72.

    Article  PubMed  CAS  Google Scholar 

  3. Larach MG, Gronert GA, Allen GC, Brandom BW, Lehman EB. Clinical presentation, treatment, and complications of malignant hyperthermia in North America from 1987 to 2006. Anesth Analg. 2010;110:498–507.

    Article  PubMed  Google Scholar 

  4. Rosenberg H, Davis M, James D, Pollock N, Stowell K. Malignant hyperthermia. Orphanet J Rares Dis. 2007;2:21–34.

    Article  Google Scholar 

  5. Saltzman LS, Kates RA, Corke BC, Norfleet EA, Heath KR. Hyperkalemia and cardiovascular collapse after verapamil and dantrolene administration in swine. Anesth Analg. 1984;63:473–8.

    Article  PubMed  CAS  Google Scholar 

  6. Lynch C 3rd, Durbin CG Jr, Fisher NA, Veselis RA, Althaus JS. Effects of dantrolene and verapamil on atrioventricular condition and cardiovascular performance in dogs. Anesth Analg. 1986;65:252–8.

    PubMed  CAS  Google Scholar 

  7. Freysz M, Timour Q, Bemaud C, Bertrix L, Faucon G. Cardiac implications of amlodipine-dantrolene combinations. Can J Anaesth. 1996;43:50–5.

    Article  PubMed  CAS  Google Scholar 

  8. Glahn KP, Ellis FR, Halsall PJ, Muller CR, Snoeck MMJ, Urwyler A, Wappler F; European Malignant Hyperthermia Group. Recognizing and managing a malignant hyperthermia crisis: guidelines from the European Malignant Hyperthermia Group. Br J Anasth. 2010;105:417–20.

    Google Scholar 

  9. Larach MG, Localio AR, Allen GC, Denborough MA, Ellis FR, Gronert, GA, Kaplan RF, Muldoon SM, Nelson T E, Ording H, Rosenberg H, Waud BE, Wedel DJ. A clinical grading scale to predict malignant hyperthermia susceptibility. Anesthesiology 1994;80:771–9.

    Google Scholar 

  10. Endo M, Iino M. Measurement of Ca release in skinned fibers from skeletal muscle. Methods Enzymol. 1988;157:12–26.

    Article  PubMed  CAS  Google Scholar 

  11. Ohta T, Endo M, Nakano T, Morohoshi Y, Wanikawa K, Ohga A. Ca-induced Ca release in malignant hyperthermia-susceptible pig skeletal muscle. Am J Physiol. 1989;256:358–67.

    Google Scholar 

  12. Oku S, Mukaida K, Nosaka S, Sai Y, Maehara Y, Yuge O. Comparison of the in vitro caffeine-halothane contracture test with the Ca-induced Ca release rate test in patients suspected of having malignant hyperthermia susceptibility. J Anesth. 2000;14:6–13.

    Article  PubMed  CAS  Google Scholar 

  13. Ibarra MCA, Wu S, Murayama K, Minami M, Ichihara Y, Kikuchi H, et al. Malignant hyperthermia in Japan. Anesthesiology. 2006;104:1146–56.

    Article  Google Scholar 

  14. Migita T, Mukaida K, Kawamoto M, Kobayashi M, Yuge O. Fulminant-type malignant hyperthermia in Japan: cumulative analysis of 383 cases. J Anesth. 2007;21:285–8.

    Article  PubMed  Google Scholar 

  15. Migita T, Mukaida K, Hamada H, Kobayashi M, Nishino I, Yuge O, Kawamoto M. Effects of propofol on calcium homeostasis in human skeletal muscle. Anaesth Intensive Care. 2009;37:415–25.

    PubMed  CAS  Google Scholar 

  16. Liberona JL, Caviedes P, Tascon S, Hidalgo J, Giglio JR, Sampaio SV, Caviedes R, Jaimovich E. Expression of ion channels during differentiation of a human skeletal muscle cell line. J Muscle Res Cell Motil. 1997;18:587–98.

    Article  PubMed  CAS  Google Scholar 

  17. Squecco R, Bencini C, Piperio C, Francini F. L-type Ca2+ channel and ryanodine receptor cross-talk in frog skeletal muscle. J Physiol. 2004;555:137–52.

    Article  PubMed  CAS  Google Scholar 

  18. Yang T, Allen PD, Pessah IN, Lopez JR. Enhanced excitation-coupled calcium entry in myotubes is associated with expression of RyR1 malignant hyperthermia mutations. J Biol Chem. 2007;282:37471–8.

    Article  PubMed  CAS  Google Scholar 

  19. Hofmann F, Biel M, Flockerzi V. Molecular basis for Ca2+ channel diversity. Annu Rev Neurosci. 1994;17:399–418.

    Article  PubMed  CAS  Google Scholar 

  20. Opie LH. Pharmacological differences between calcium antagonists. Eur Heart J. 1997;18:71–9.

    Article  Google Scholar 

  21. Hockerman GH, Peterson BZ, Johnson BD, Catterall WA. Molecular determinants of drug binding and action on L-type calcium channels. Annu Rev Pharmacol Texicol. 1997;37:361–96.

    Article  CAS  Google Scholar 

  22. Yamaguchi S, Okamura Y, Nagao T, Adachi-Akahane S. Serine residue in the IIIS5-S6 linker of the L-type Ca2+ channel alpha 1C subunit is the critical determinant of the action of dihydropyridine Ca2+ channel agonists. J Biol Chem. 2000;275:41504–11.

    Article  PubMed  CAS  Google Scholar 

  23. Hirota K, Hashiba E, Yoshioka H, Kabara S, Matsuki A. Effects of three different L-type Ca2+ entry blockers on airway constriction induced by muscarinic receptor stimulation. Br J Anaesth. 2003;90:671–5.

    Article  PubMed  CAS  Google Scholar 

  24. Striessnig J, Grabner M, Mitterdorfer J, Hering S, Sinnegger MJ, Glossmann H. Structural basis of drug binding to L Ca2+ channels. Trends Pharmacol Sci. 1998;19:108–15.

    Article  PubMed  CAS  Google Scholar 

  25. Weigl LG, Hohenegger M, Kress HG. J. Dihydropyridine-induced Ca2+ release from ryanodine-sensitive Ca2+ pools in human skeletal muscle cells. Physiol. 2000;525 2:461–9.

    Google Scholar 

  26. Migita T, Mukaida K, Hamada H, Kawamoto M. Do Ca2+ channel blockers improve malignant hyperthermia crisis? Eur J Anaesth. 2009;26:124.

    Google Scholar 

  27. Paul-Pletzer K, Yamamoto T, Bhat MB, MA J, Ikemoto N, Jimenez LS, Morimoto H, Williams PG, Parness J. Identification of a dantrolene-binding sequence on the skeletal muscle ryanodine receptor. J Biol Chem. 2002;277:34918–23.

    Google Scholar 

  28. Fruen BR, Mickelson JR, Louis CF. Dantrolene inhibition of sarcoplasmic reticulum Ca2+ release by direct and specific action at skeletal muscle ryanodine receptors. J Biol Chem. 1997;272:26965–71.

    Article  PubMed  CAS  Google Scholar 

  29. Cherednichenko G, Ward CW, Feng W, Cabrales E, Michaelson L, Samso M, Lopez JR, Allen PD, Pessah IN. Enhanced excitation-coupled calcium entry in myotubes expressing malignant hyperthermia mutation R163C is attenuated by dantrolene. Mol Pharmacol. 2008;73:1203–12.

    Article  PubMed  CAS  Google Scholar 

  30. Cherednichenko G, Hurne AM, Fessenden JD, Lee EH, Allen PD, Beam KG, Pessah IN. Conformational activation of Ca2+ entry by depolarization of skeletal myotubes. Proc Natl Acad Sci USA. 2004;101(44):15793–8.

    Article  PubMed  CAS  Google Scholar 

  31. Dirksen RT. Checking your DOCCs and feet: molecular mechanisms of Ca2+ entry in skeletal muscle. J Physiol. 2009;587:3139–47.

    Article  PubMed  CAS  Google Scholar 

  32. Bannister RA, Pessah IN, Beam KG. The skeletal L-type Ca2+ current is a major contributor to excitation-coupled Ca2+ entry. J Gen Physiol. 2009;133:79–91.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Takako Migita received a research grant from a Grant-in-Aid (No. 17390428 and 21591973) for Scientific Research from the Japan Society for the Promotion of Science (Tokyo, Japan). Keiko Mukaida received a research grant from a Grant-in-Aid (No. 17390428 and 21591973) for Scientific Research from the Japan Society for the Promotion of Science (Tokyo, Japan). Toshimichi Yasuda received a research grant from a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (Tokyo, Japan). Hiroshi Hamada received a research grant from a Grant-in-Aid (No. 17390428) for Scientific Research from the Japan Society for the Promotion of Science (Tokyo, Japan). Masashi Kawamoto received a research grant from a Grant-in-Aid (No. 17390428 and 21591973) for Scientific Research from the Japan Society for the Promotion of Science (Tokyo, Japan).

Author information

Authors and Affiliations

  1. Division of Anesthesia, Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital, 1-9-6 Senda-machi, Naka-ku, Hiroshima, 730-8619, Japan

    Takako Migita

  2. Division of Anesthesia, Hiroshima Prefectural Rehabilitation Center, Higashi-Hiroshima, Japan

    Keiko Mukaida

  3. Department of Anesthesiology and Critical Care, Hiroshima University Graduate School of Medicine, Hiroshima, Japan

    Toshimichi Yasuda, Hiroshi Hamada & Masashi Kawamoto

Authors
  1. Takako Migita
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Keiko Mukaida
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Toshimichi Yasuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroshi Hamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Masashi Kawamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takako Migita.

About this article

Cite this article

Migita, T., Mukaida, K., Yasuda, T. et al. Calcium channel blockers are inadequate for malignant hyperthermia crisis. J Anesth 26, 579–584 (2012). https://doi.org/10.1007/s00540-012-1347-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00540-012-1347-0

Keywords

Search

Navigation