OPIOID HIBERNATION FACTORS FOR MYOCARDIAL PROTECTION

阿片类药物保护心肌的冬眠因素

• 批准号: 6151354
• 负责人: Steven F Bolling
• 金额: $ 22.6万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-08 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6151354
• 关键词: chemoprevention; disease /disorder model; enzyme activity; heart arrest; heart circulation; heart function; heart metabolism; heart pharmacology; hibernation; histopathology; hypothermia; immunoprecipitation; laboratory rabbit; membrane permeability; myocardial ischemia /hypoxia; myocardium; opioid receptor; postoperative state; protein kinase C; protein structure function; receptor binding; reperfusion; tissue /cell culture

DESCRIPTION: (Adapted from investigator's abstract) Many patients have advanced cardiac disease, necessitating complicated cardiac surgery or transplantation. During cardiac surgery, including transplantation, the heart is rendered ischemic; and blood flow to the heart is stopped either to undertake the surgery or to transport the organ, which is currently limited to 4-6 hours. In order for the patient to be removed from cardiopulmonary bypass and return to activity, the heart has to function well following cardiac surgery. Any enhancement in myocardial energy preservation will increase the number of positive outcomes for patients and improve the quality of patient care. Interestingly, hibernating animals can preserve up to 90% of the energy required during normal euthermic metabolism. The mechanism of this energy preservation during hibernation is currently unknown; however, many studies point to an opioid "trigger" molecule, which has been termed the hibernation induction trigger or HIT. The opiate nature of HIT is well established, as HIT can be reversed or retarded by opiate antagonists. Evidence indicates that HIT initiates its potential metabolic inhibitory effects through specific membrane opioid receptors, particularly delta receptors. Delta opioids have been shown in many models and the investigators' preliminary results to produce profound behavioral, physiological and metabolic inhibitory effects favoring survival at the whole animal, the organ and the cellular level. The proposed study will investigate the mechanisms of action of delta opioids at both the organ and subcellular levels. These studies could result in extended safe cardiac ischemic time with potential application to cardiac surgery and cardiac transplantation. In these proposed isolated heart studies, the investigators will determine if delta opioids provide enhanced myocardial protection during ischemia. The investigators will also seek to elucidate the intracellular mechanism by which the delta opioids protect the ischemic myocardium. The ability of the delta opioids to effect myocardial protection suggests that the use of these molecules may be valuable in many clinical scenarios resulting in ischemia.

描述：（改编自研究者摘要） 许多患者患有晚期心脏病， 心脏手术或移植。在心脏手术期间，包括 移植时，心脏缺血;血液流向心脏， 心脏停止进行手术或运输 器官，目前仅限于4-6小时。为了让病人 从心肺转流中取出并恢复活动， 心脏手术后心脏必须功能良好。任何增强 在心肌能量保存中， 为患者提供更好的服务，提高患者护理质量。 有趣的是，冬眠动物可以保存高达90%的能量， 在正常的体温代谢过程中所需要的。的机理 冬眠期间的能量保存目前是未知的;然而， 许多研究指出，阿片类药物的“触发”分子， 称为休眠感应触发器或HIT。鸦片的性质 HIT已得到证实，因为HIT可被阿片类药物逆转或延迟 对手。证据表明，HIT启动了其潜力 通过特异性膜阿片受体的代谢抑制作用， 特别是δ受体。δ阿片类药物已被证明在许多 模型和研究人员的初步结果， 行为、生理和代谢抑制作用， 在整个动物，器官和细胞水平上的生存。的 拟议的研究将调查三角洲的作用机制， 阿片类药物在器官和亚细胞水平。这些研究可以 延长安全心脏缺血时间，具有潜在应用价值 心脏手术和心脏移植。在这些建议中， 研究人员将确定， 阿片类药物在局部缺血期间提供增强的心肌保护。的 研究人员还将寻求阐明细胞内机制 δ阿片类药物通过其保护缺血心肌。的能力 δ阿片类药物对心肌保护的作用表明， 这些分子的使用在许多临床情况下可能是有价值的 导致局部缺血。