SKELETAL MUSCLE LESION IN MALIGNANT HYPERTHERMIA

恶性高热是一种人和猪的药物遗传性疾病， 在一般情况下易患灾难性的，通常是致命的综合征 麻醉。这种综合征也可能是由易感人群中的应激源引起的。 猪和MH在人类中的一个可能的应激作用。一个 MH易感人群和猪的共同特征是存在异常 不同类型骨骼肌在体外的代谢和收缩反应 药物，尤指某些麻醉剂。的工作假说 这一建议是，这些异常的代谢和宫缩反应 MH肌肉是MH综合征的主要病因事件， 这是肌浆内钙离子持续增加的结果。 此外，据认为，引发MH的麻醉剂确实 因此，通过作用于骨骼肌膜，导致体内 肌浆内钙离子。该项目将调查生化和 骨骼钙摄取和释放的药理学特性 从患者肌肉分离的肌浆网(SR) 用于MH诊断筛查，以及来自患有不同诊断的猪 肌挛缩表型。肌挛缩症表型与MH的关系 易感性和SR功能将被探索。一种非侵入性检测方法 测量材料的机电耦合和收缩/松弛动力学 骨骼肌将在MH诊断患者和猪身上进行评估 有不同的痉挛表型。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。这个 所获得的信息将为理解 发病机制，形成诊断基础，并为预防提供理论基础 和/或全身麻醉期间恶性高热的治疗。

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.