B ADRENOCEPTORS DURING CARDIOPULMONARY BYPASS

描述：(改编自调查人员的摘要)目的 建议是确定潜在的机制和治疗或 预防急性心肌β-肾上腺素能受体(β-AR) 体外循环(CPB)中的脱敏。两个假设是为了 接受测试，即1)CPB期间急性心肌β-AR敏化 定位于β-AR部分，由受体磷酸化和 2)CPB开始时静脉注射美托洛尔干预 防止CPB期间心肌β-AR脱敏。这些假设是 PI之前的工作结果报告说，急性心肌梗死 β-AR脱敏在体外循环后三小时内发生。私人侦探现在希望 通过研究阐明β-AR脱敏的潜在机制 哪些激酶(GRK1-6和PKA)存在于人的心室和 然后在mRNA水平上定量测定CPB对心脏的影响 定量聚合酶链式反应和在蛋白质水平上使用功能分析。《少年派》 还提议进行一项干预性试验，旨在确定 静脉注射预防术中β-AR脱敏 美托洛尔在开始体外循环时将阻止或限制 搭桥后心肌功能障碍。BetaAR信号的检测 使用美托洛尔和不使用美托洛尔进行心房活检的转导途径 CPB前后得到的数据包括BetaAR数的分析， 亚型，受体与G蛋白的功能性偶联，以及 腺苷环化酶水平的测定。临床结果有待评估 包括由经食道回波确定的射血分数的变化， 体外循环术后肌力支持水平、ICU住院天数和总体 发病率和死亡率。预计预防心肌梗死 心脏手术中的β-AR脱敏应导致增强 停用CPB时的心肌功能和使用较少的药物 变力药。

DESCRIPTION: (Adapted from the investigator's abstract) The purpose of this proposal is to determine the underlying mechanism and the treatment or prevention of acute myocardial beta-adrenergic receptor (betaAR) desensitization during cardiopulmonary bypass (CPB). Two hypotheses are to be tested, i.e., 1) acute myocardial betaAR sensitization during CPB is localized to the betaAR moiety and results from receptor phosphorylation and 2) intervention with intravenous metoprolol upon initiation of CPB will prevent myocardial betaAR desensitization during CPB. The hypotheses are the result of previous work by the PI who has reported that acute myocardial betaAR desensitization occurs within three hours of CPB. The PI now wishes to elucidate the mechanisms underlying betaAR desensitization by examining which kinases (GRK1-6, and PKA) are present in the human ventricle and atrium and then quantitate changes with CPB at the mRNA level using quantitative PCR and at the protein level using functional assays. The PI also proposes to perform an interventional trial designed to determine if prevention of intraoperative betaAR desensitization by administering IV metoprolol upon initiating cardiopulmonary bypass will prevent or limit postbypass myocardial dysfunction. The examination of the betaAR signal transduction pathway with and without metoprolol using atrial biopsies obtained before and after CPB include the analysis of betaAR number, subtype, functional coupling of receptors to G-proteins, and the determination of adenyl cyclase levels. Clinical outcomes to be assessed include changes in ejection fraction determined by transesophageal echo, level of post-CPB inotropic support, ICU hospital stay, and overall morbidity and mortality. It is anticipated that prevention of myocardial betaAR desensitization during cardiac surgery should lead to enhanced myocardial performance at the time of separation from CPB and use of fewer inotropic drugs.