FK506 (tacrolimus) increases halothane-induced Ca2+ release from skeletal muscle sarcoplasmic reticulum

Eduardo N. Chini, S. S. Henry Walker

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Background: FK506 binding protein is closely associated with the sarcoplasmic reticulum ryanodine receptor-channel and can modulate its function. The ryanodine receptor is stabilized by its association with FK506 binding protein. The immunosuppressant drugs FK506 (tacrolimus) and rapamycin can promote dissociation of FK506 binding protein from the ryanodine receptor 1 and by this mechanism increase sensitivity of ryanodine receptor 1 to agonists such as caffeine. Furthermore, it was shown recently that treatment of normal human skeletal muscle with FK506 and rapamycin increased halothane- induced contracture. The authors investigated the effect of the immunosuppressants FK506 and rapamycin on halothane-induced Ca2+ release in skeletal muscle sarcoplasmic reticulum vesicles. Methods: Skeletal muscle terminal cisterns were isolated from New Zealand White rabbits. Ca2+ uptake and release was monitored in skeletal muscle sarcoplasmic reticulum vesicles using the fluo-3 fluorescent technique. Western Blot analysis of FK506 binding protein was performed using standard protocol. Results: The authors observed that treatment of skeletal muscle sarcoplasmic reticulum vesicles with FK506 and rapamycin enhances halothane-induced Ca2+ release by about five times. Furthermore, the Ca2+ release induced by halothane in the presence of FK506 was inhibited by several antagonists of the ryanodine receptor, such as ruthenium red, spermine, and Mg2+. Conclusion: Dissociation of FK506 binding protein from its binding site in skeletal muscle sarcoplasmic reticulum vesicles can modulate halothane-induced Ca2+ release through the ryanodine receptor. Data are discussed in relation to the role of the FK506 binding protein in modulating the effect of halothane on the ryanodine receptor and the development of malignant hyperthermia phenotype.

Original languageEnglish (US)
Pages (from-to)1361-1365
Number of pages5
JournalAnesthesiology
Volume92
Issue number5
DOIs
StatePublished - May 2000

Keywords

  • Immunosuppression
  • Malignant hypothermia
  • Ryanodine channel

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

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