B ADRENOCEPTORS DURING CARDIOPULMONARY BYPASS

描述：（改编自研究者摘要） 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） 心肺转流术（CPB）期间的脱敏。 两个假设是 测试，即，1)CPB期间急性心肌β AR增敏是 定位于β AR部分，由受体磷酸化引起， 2)在开始CPB时静脉内美托洛尔干预将 防止CPB期间心肌β AR脱敏。 的假设是 PI之前的工作结果报告了急性心肌梗死 β AR脱敏发生在CPB后3小时内。 私家侦探现在希望 为了阐明β AR脱敏的机制， 所述激酶（GRK 1 -6和PKA）存在于人心室中， 心房，然后定量的变化与CPB在mRNA水平上使用 定量PCR和蛋白质水平使用功能测定。 的PI 还建议进行一项干预性试验，以确定是否 通过静脉注射预防术中β AR脱敏 美托洛尔在开始心肺转流时将防止或限制 旁路术后心肌功能障碍。 β AR信号的检测 使用心房活检的有和没有美托洛尔的转导通路 体外循环前后的β AR数分析， 亚型，受体与G蛋白的功能性偶联，以及 腺苷酸环化酶水平的测定。 待评估的临床结局 包括通过经食管回波确定射血分数的变化， CPB后正性肌力支持水平、ICU住院时间和总体 发病率和死亡率。 预计预防心肌梗死 心脏手术期间β AR脱敏应导致增强 从CPB分离时的心肌性能和使用较少的 正性肌力药

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.