Duke Adrian M, Hopkins Philip M, Halsal Jane P, Steele Derek S
School of Biomedical Sciences, University of Leeds, United Kingdom.
Anesthesiology. 2004 Dec;101(6):1339-46. doi: 10.1097/00000542-200412000-00014.
Recent work suggests that impaired Mg(2+) regulation of the ryanodine receptor is a common feature of both pig and human malignant hyperthermia. Therefore, the influence of [Mg(2+)] on halothane-induced Ca(2+) release from the sarcoplasmic reticulum was studied in malignant hyperthermia-susceptible (MHS) or -nonsusceptible (MHN) muscle.
Vastus medialis fibers were mechanically skinned and perfused with solutions containing physiologic (1 mm) or reduced concentrations of free [Mg(2+)]. Sarcoplasmic reticulum Ca(2+) release was detected using fura-2 or fluo-3.
In MHN fibers, 1 mm halothane consistently did not induce sarcoplasmic reticulum Ca(2+) release in the presence of 1 mm Mg(2+). It was necessary to increase the halothane concentration to 20 mm or greater before Ca release occurred. However, when [Mg(2+)] was reduced below 1 mm, halothane became an increasingly effective stimulus for Ca(2+) release; e.g., at 0.4 mm Mg(2+), 58% of MHN fibers responded to halothane. In MHS fibers, 1 mm halothane induced Ca(2+) release in 57% of MHS fibers at 1 mm Mg(2+). Reducing [Mg(2+)] increased the proportion of MHS fibers that responded to 1 mm halothane. Further experiments revealed differences in the characteristics of halothane-induced Ca(2+) release in MHS and MHN fibers: In MHN fibers, at 1 mm Mg(2+), halothane induced a diffuse increase in [Ca(2+)], which began at the periphery of the fiber and spread slowly inward. In MHS fibers, halothane induced a localized C(2+)a release, which then propagated along the fiber. However, propagated Ca(2+) release was observed in MHN fibers when halothane was applied at an Mg(2+) concentration of 0.4 mm or less.
When Mg(2+) inhibition of the ryanodine receptor is reduced, the halothane sensitivity of MHN fibers and the characteristics of the Ca release process approach that of the MHS phenotype. In MHS fibers, reduced Mg(2+) inhibition of the ryanodine receptor would be expected to have a major influence on halothane sensitivity. The Mg dependence of the halothane response in MHN and MHS may have important clinical implications in circumstances where intracellular [Mg(2+)] deviates from normal physiologic concentrations.
近期研究表明，ryanodine受体的镁离子（Mg²⁺）调节功能受损是猪和人类恶性高热的共同特征。因此，研究了镁离子浓度对恶性高热易感（MHS）或非易感（MHN）肌肉中氟烷诱导的肌浆网钙释放的影响。
取股内侧肌纤维进行机械去膜，并灌注含有生理浓度（1 mmol/L）或降低浓度游离镁离子的溶液。使用fura-2或fluo-3检测肌浆网钙释放。
在MHN纤维中，在1 mmol/L镁离子存在的情况下，1 mmol/L氟烷始终不会诱导肌浆网钙释放。必须将氟烷浓度提高到20 mmol/L或更高才会发生钙释放。然而，当镁离子浓度降低到1 mmol/L以下时，氟烷对钙释放的刺激作用越来越强；例如，在0.4 mmol/L镁离子浓度下，58%的MHN纤维对氟烷有反应。在MHS纤维中，1 mmol/L镁离子浓度时，1 mmol/L氟烷可诱导57%的MHS纤维发生钙释放。降低镁离子浓度会增加对1 mmol/L氟烷有反应的MHS纤维比例。进一步实验揭示了MHS和MHN纤维中氟烷诱导的钙释放特征的差异：在MHN纤维中，1 mmol/L镁离子浓度时，氟烷诱导钙离子浓度在纤维周边开始并缓慢向内扩散增加。在MHS纤维中，氟烷诱导局部钙释放，然后沿纤维传播。然而，当氟烷在0.4 mmol/L或更低的镁离子浓度下应用时，在MHN纤维中观察到了钙的传播释放。
当ryanodine受体的镁离子抑制作用减弱时，MHN纤维的氟烷敏感性以及钙释放过程的特征接近MHS表型。在MHS纤维中，ryanodine受体的镁离子抑制作用减弱预计会对氟烷敏感性产生重大影响。在细胞内镁离子浓度偏离正常生理浓度的情况下，MHN和MHS中氟烷反应的镁离子依赖性可能具有重要的临床意义。
