3,5-Di-t-butyl catechol is a potent human ryanodine receptor 1 activator, not suitable for the diagnosis of malignant hyperthermia susceptibility

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• 作者：Caterina Lacava^a ; ¹ ; Andrea Michalek-Sauberer^a ; Birgit Kraft^a ; Giampietro Sgaragli^b ; Elisabeth Sipos^a ; Carmen Hö ; ller^a ; Hans Georg Kress^a ; Fabio Fusi^b ; Lukas G. Weigl^a ; ^{lukas.weigl@meduniwien.ac.at}
• 关键词：DTCAT ; 3 ; 5-di-t-butyl catechol ; SR ; sarcoplasmic reticulum ; MH ; malignant hyperthermia ; MHS ; malignant hyperthermia susceptible ; MHN ; malignant hyperthermia normal ; MHE ; malignant hyperthermia equivocal ; MHEH ; malignant hyperthermia equivocal for halothan
• 刊名：Pharmacological Research
• 出版年：2012
• 期刊代码：54_10436618
• 类别：pha
• 出版时间：July, 2012
• 卷：66
• 期：1
• 页码：80-87
• 文件大小：976 K

摘要

3,5-Di-t-butyl catechol (DTCAT) releases Ca²⁺ from rat skeletal muscle sarcoplasmic reticulum (SR) vesicles. Hence, it is a candidate for use as a substitute for halothane or caffeine in the in vitro contracture test for the diagnosis of susceptibility to malignant hyperthermia (MH).

To characterize the effect of DTCAT at cell level, Ca²⁺ release experiments were performed on cultured, human skeletal muscle myotubes using the fluorescent Ca²⁺ indicator fura2-AM. DTCAT was also assayed in the in vitro contracture test on human skeletal muscle bundles obtained from individuals diagnosed susceptible (MHS), normal (MHN) or equivocal for halothane (MHEH) and compared to the standard test substances caffeine and halothane.

DTCAT increased, in a concentration-dependent manner and with a higher efficacy as compared to caffeine, the free, intracellular Ca²⁺ levels of cultured MHN and MHS skeletal muscle myotubes. This effect was similar in both types of myotubes and involved the release of Ca²⁺ from SR stores as well as Ca²⁺-influx from the extracellular space. Inhibition of ryanodine receptors either with ryanodine or with ruthenium red markedly reduced DTCAT-induced increase in intracellular Ca²⁺ concentration while abolishing that induced by caffeine. In MHN skeletal muscle bundles, DTCAT induced contractures with an EC₅₀ value of 160 卤 91 渭M. However, the sensitivity of MHS or MHEH muscles to DTCAT was similar to that of MHN muscles.

In conclusion, DTCAT is not suitable for the diagnosis of MH susceptibility due to its failure to discriminate between MHN and MHS muscles.