Migita T, Mukaida K, Hamada H, Kobayashi M, Nishino I, Yuge O, Kawamoto M
Department of Anesthesiology and Critical Care, Hiroshima University, Hiroshima, Japan.
Anaesth Intensive Care. 2009 May;37(3):415-25. doi: 10.1177/0310057X0903700313.
Malignant hyperthermia is a pharmacogenetic skeletal muscle disorder of intracellular calcium (Ca2+) homeostasis with an autosomal dominant inheritance. The objective of this study was to investigate the safety of propofol by investigating its effects on calcium homeostasis and its effect sites in human skeletal muscles. Muscle specimens were obtained from 10 individuals with predisposition to malignant hyperthermia. In skinned fibre experiments, we measured the effects of propofol on the Ca(2+)-induced Ca2+ release and the uptake of Ca2+ into the sarcoplasmic reticulum. Ca2+ imaging in primary myotubes was employed to analyse propofol-mediated alternations in the Ca2+ regulation and propofol-induced Ca2+ responses in the presence of Ca2+ channel blocker or Ca(2+)-induced Ca2+ release inhibitor. Increased Ca2+ release from the sarcoplasmic reticulum and inhibition of Ca2+ uptake into the sarcoplasmic reticulum were not observed with 100 microM propofol. A rise of Ca2+ was not seen under 100 microM propofol and the EC50 value for propofol was 274.7 +/- 33.9 microM, which is higher than the clinical levels for anaesthesia. Propofol-induced Ca2+ responses were remarkably attenuated in the presence of Ca2+ channel blocker or Ca(2+)-induced Ca+ release inhibitor compared with the results obtained with caffeine. We conclude firstly that propofol is safe for individuals with predisposition to malignant hyperthermia when it is used within the recommended clinical dosage range, and secondly that its mode of action upon ryanodine receptors is likely to be different from that of caffeine.
恶性高热是一种具有常染色体显性遗传特征的、细胞内钙（Ca2+）稳态的药物遗传学骨骼肌疾病。本研究的目的是通过研究丙泊酚对人体骨骼肌钙稳态及其作用位点的影响，来探讨丙泊酚的安全性。从10名有恶性高热倾向的个体获取肌肉标本。在脱膜纤维实验中，我们测量了丙泊酚对Ca2+诱导的Ca2+释放以及Ca2+摄取到肌浆网中的影响。在原代肌管中进行Ca2+成像，以分析丙泊酚介导的Ca2+调节变化以及在存在Ca2+通道阻滞剂或Ca2+诱导的Ca2+释放抑制剂时丙泊酚诱导的Ca2+反应。100微摩尔丙泊酚未观察到肌浆网Ca2+释放增加以及Ca2+摄取到肌浆网受到抑制。在100微摩尔丙泊酚下未观察到Ca2+升高，丙泊酚的半数有效浓度（EC50）值为274.7±33.9微摩尔，高于临床麻醉水平。与咖啡因的结果相比，在存在Ca2+通道阻滞剂或Ca2+诱导的Ca+释放抑制剂时，丙泊酚诱导的Ca2+反应显著减弱。我们首先得出结论，当在推荐的临床剂量范围内使用时，丙泊酚对有恶性高热倾向的个体是安全的；其次得出结论，其对兰尼碱受体的作用方式可能与咖啡因不同。
