SKELETAL MUSCLE LESION IN MALIGNANT HYPERTHERMIA

恶性高热中的骨骼肌损伤

• 批准号: 3271903
• 负责人: THOMAS E NELSON
• 金额: $ 10.87万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-08-01 至 1993-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3271903
• 关键词: anesthesia complication; biopsy; calcium channel; calcium metabolism; depolarizing neuromuscular blocking agent; disease /disorder model; disease /disorder proneness /risk; dogs; genetic disorder; human subject; malignant hyperthermia; membrane proteins; membrane structure; microspectrophotometry; muscle pharmacology; muscle rigidity; organelles; radiotracer; ryanodine; striated muscles; swine

Malignant Hyperthermia (MH) is a genetic disease in man and various animal species predisposing to a life-threatening hypermetabolic syndrome that is triggered by certain anesthetic agents. The experiments described in this project are designed to answer questions regarding the etiology and pathophysiology of MH in man. Studies will involve 3 different species (man, dog, pig) each with a genetic predisposition to MH. Comparative studies in the canine and porcine MH genetic models will be performed at varying levels of organization, i.e., purified protein subcellular organelle membrane, intact skeletal muscle tissue and the intact animal. Parallel membrane and muscle tissue levels of investigations will be performed on tissue obtained from human MH diagnostic muscle biopsy specimens. It is expected that comparison of animal and human data will provide a better basis for understanding MH in man. Etiologic studies focus on a hypothesis that MH is a consequence of sustained myoplasmic Ca2+, secondary to the action of anesthetics on Ca2+ regulation by the sarcoplasmic reticulum (SR) membrane system. Various sites of electromechanical (E-C) coupling will be investigated pharmacologically with intact skeletal muscle and biochemically in fragmented SR membrane vesicles and purified protein. The results are expected to determine where in the E-C coupling pathway a defect may occur in MH muscle and if the same defective site(s) is common to the 3 species studied. Such results may contribute to our understanding of mechanisms for other muscle diseases. The clinical syndrome of masseter muscle rigidity, often a symptom of MH onset, is a serious and unresolved problem associated with anesthesia. Experiments designed to study intact animals, biopsied skeletal muscle and isolated SR membranes will attempt to address the uniqueness of masseter muscle pharmacology and physiology in relation to this clinical syndrome. In addition to expanding our knowledge and understanding of the MH syndrome, these studies will also contribute to our understanding of the mechanism of action of volatile anesthetics at different levels of biological organization.

恶性高热（MH）是一种遗传性疾病， 易发生危及生命的高代谢的动物物种 由某些麻醉剂引起的综合症。 的 本项目中描述的实验旨在回答以下问题 关于人类MH的病因学和病理生理学。研究将 涉及3个不同的物种（人，狗，猪），每个物种都有一个基因， 易患MH。 犬和猪MH的比较研究 遗传模型将在不同的组织水平上进行， 也就是说，纯化蛋白质亚细胞器膜，完整骨骼 肌肉组织和完整的动物。 平行膜和肌肉 将对获得的组织进行组织水平的研究 来自人类MH诊断肌肉活检标本。 预计在 动物和人类数据的比较将为以下方面提供更好的基础： 了解人类的MH。病因学研究集中在一个假设， MH是持续的肌浆Ca 2+的结果，继发于 麻醉药对肌浆网Ca ~（2+）调节的作用 (SR)膜系统 各种机电耦合点 将在完整骨骼肌的情况下进行药理研究， 在片段化的SR膜囊泡和纯化的蛋白质中进行生物化学分析。 该结果有望确定E-C偶联途径中的 缺陷可能发生在MH肌肉中，并且如果相同的缺陷部位 这三个物种都有研究。 这些结果可能有助于我们 了解其他肌肉疾病的机制。 临床 咬肌强直综合症通常是MH发作的症状，是一种 与麻醉相关的严重且未解决的问题。 实验 旨在研究完整的动物，活组织检查骨骼肌和分离的 SR膜将试图解决咬肌的独特性 药理学和生理学与这种临床综合征有关。 在 除了扩大我们对MH的知识和理解之外， 这些研究也将有助于我们了解 挥发性麻醉药在不同水平的作用机制 生物组织。