SKELETAL MUSCLE LESION IN MALIGNANT HYPERTHERMIA

恶性高热是人和猪的一种药物遗传性疾病， 在一般情况下，易患上灾难性的，往往是致命的综合症。 麻醉 该综合症也可能是由易感人群的压力源诱发的 猪和可能的作用的压力MH在人已经提出。 一 MH易感人和猪的共同特点是存在异常的 体外骨骼肌对不同浓度钙离子代谢和挛缩反应 药物，特别是某些麻醉剂。 的工作假设 这一建议是，这些异常的代谢和挛缩反应， MH肌肉代表MH综合征的主要病因学事件， 这是肌浆Ca++持续增加的结果。 此外，有人提出，麻醉剂，触发MH不 所以通过作用于骨骼膜， 肌浆Ca++。 该项目将研究生物化学和 骨骼肌Ca ~（++）摄取和释放的药理学特性 肌浆网（SR）分离自人类患者的肌肉， 用于MH诊断筛查，以及来自具有不同诊断 挛缩表型 挛缩表型、MH 将探索敏感性和SR功能。 一种非侵入性的测试， 测量机电耦合和收缩/松弛动力学， 将在MH诊断患者和猪中评价骨骼肌 具有不同的挛缩表型。 将对这些测试进行评估， MH易感骨骼肌的诊断和病因学潜力。 的 所获得的信息将为了解 发病机制，形成诊断基础，并为预防提供理论依据 和/或治疗全身麻醉期间的恶性高热。

Malignant hyperthermia is a pharmacogenetic disease in man and pigs which predisposes to a catastrophic, often fatal syndrome during general anesthesia. The syndrome may also be induced by stressors in susceptible pigs and a possible role of stress for MH in man has been suggested. A common feature for MH susceptible man and pigs is the existence of abnormal in vitro metabolic and contracture responses of skeletal muscle to various drugs, especially to certain anesthetic agents. The working hypothesis of this proposal is that these abnormal metabolic and contracture responses of MH muscle represent the primary etiologic event in the MH syndrome and that these are the consequence of a sustained increase in myoplasmic Ca++. Furthermore, it is proposed that the anesthetic agents that trigger MH do so by acting on skeletal membranes to cause the abnormal increase in myoplasmic Ca++. This project will investigate biochemical and pharmacologic properties of Ca++ uptake and release by skeletal sarcoplasmic reticulum (SR) isolated from muscle of human patients referred for MH diagnostic screening, and from pigs with varying diagnostic contracture phenotypes. The relationships among contracture phenotype, MH susceptibility and SR function will be explored. A noninvasive test for measuring electromechanical coupling and contraction/relaxation kinetics in skeletal muscle will be evaluated in MH diagnostic patients and in pigs with varying contracture phenotypes. These tests will be evaluated for diagnostic and etiologic potential for MH susceptible skeletal muscle. The information obtained will provide a basis for understanding the pathogenesis, form a diagnostic base, and give rationale for prevention and/or treatment of malignant hyperthermia during general anesthesia.