ROLE OF B ADRENERGIC RECEPTOR ANTAGONISTS IN CARDIAC SURGERY PATIENTS

我们之前在犬模型中证明了体外循环（CPB）后心肌肾上腺素能（BAR）功能降低。CPB是否对成人冠状动脉搭桥术（CABG）或瓣膜手术中BAR功能产生类似影响尚不清楚。因此，我们在CABG患者中初步验证了两种假设：1)CPB后成人心肌AR信号减少，2)术前使用慢性AR拮抗剂可阻止这一过程。经知情同意后，纳入52例接受冠状动脉手术的患者。在CPB前和停止CPB之前立即进行心房活检。评估血浆儿茶酚胺浓度、心肌AR密度和功能反应性（基础、异丙肾上腺素、锌interol、NaF和mn刺激的腺苷酸环化酶活性）。CPB期间，儿茶酚胺水平显著升高（p<0.005）。心肌AR腺苷酸环化酶偶联在CPB期间降低，证明了异丙肾上腺素刺激的腺苷酸环化酶活性降低21% （750 [430]pmol cAMP/mg总蛋白/15分钟CPB前与540 [390]CPB后，p=0.0062，中位数[四分位数范围]）。沿着AR信号转导级联的差异激活将缺陷定位在腺苷酸环化酶部分。慢性术前BAR拮抗剂不能预防cpb诱导的急性心肌BAR功能障碍。这些数据表明，在需要CPB的成人冠状动脉手术期间，无论是否给予慢性BAR拮抗剂，心肌腺苷酸环化酶对AR激动剂的反应都会急剧下降。急性BAR功能障碍的机制似乎是腺苷酸环化酶部分的直接损伤。mn刺激活性的类似倍数增加表明，Pre-和End-CPB保留了腺苷酸环化酶的催化活性，这表明其他机制（例如蛋白质水平降低或异构体表达/功能改变）可能导致腺苷酸环化酶功能降低。由于心脏瓣膜疾病（CVD）患者经常有充血性心力衰竭（CHF）和慢性心肌β -肾上腺素能受体（BAR）脱敏，我们接下来研究了CVD患者CPB期间是否发生急性BAR功能障碍。经知情同意后，50名患者入组。在CPB开始和结束时进行右心房活检，以评估BAR密度和腺苷酸环化酶（AC）活性。CPB期间血浆儿茶酚胺浓度升高3倍（p< 0.01）。虽然BAR密度保持不变，但异丙肾上腺素刺激的AC活性显著降低（30%;p<0.005）。直接G蛋白（NaF）激活和AC（锰）激活分别使AC活性降低22%和24%。术前有/无CHF的患者在CPB期间表现出相似程度的急性心肌BAR功能障碍。急性心肌BAR功能障碍发生在需要手术矫正的严重CVD患者CPB期间，伴有/不存在CHF。主要的潜在机制涉及BAR信号转导途径在AC部分水平的功能解耦。这一信息将有助于开发预防CPB期间急性心肌BAR功能障碍的药物，有可能改善这一高危人群的预后。作为这些初步研究的结果，我们现在正在研究cpb诱导的人类BAR脱敏的机制。磷酸化激酶，G蛋白偶联和腺苷酸环化酶异构体正在被检查。我们还进行了一项介入性试验，以验证BAR拮抗剂在CPB心脏手术期间保护患者免受急性心肌BAR脱敏的假设。

We previously demonstrated that myocardial-adrenergic (BAR) function is reduced after cardiopulmonary bypass (CPB) in a canine model. Whether CPB results in similar effects on BAR function in adult humans during coronary artery bypass graft (CABG) surgery or valve surgery is not known. Therefore we initially tested two hypotheses in CABG patients: 1) myocardial AR signaling is reduced in adult humans after CPB, and 2) administration of chronic preoperative AR antagonists prevents this process. After informed consent, 52 patients undergoing aortocoronary surgery were enrolled. Atrial biopsies were obtained pre-CPB and immediately prior to discontinuation of CPB. Plasma catecholamine concentrations, myocardial AR density, and functional responsiveness (basal, isoproterenol, zinterol, NaF, and Mn-stimulated adenylyl cyclase activity) were assessed. Catecholamine levels increased significantly during CPB (p<0.005). Myocardial AR adenylyl cyclase coupling decreased during CPB as evidenced by 21% decrease in isoproterenol-stimulated adenylyl cyclase activity (750 [430] pmol cAMP/mg total protein/15 min Pre-CPB versus 540 [390] End-CPB, p=0.0062, median [interquartile range]) in spite of constant AR density. Differential activation along the AR signal transduction cascade localized the defect to the adenylyl cyclase moiety. Administration of chronic preoperative BAR antagonists did not prevent acute CPB-induced myocardial BAR dysfunction. These data demonstrate that myocardial adenylyl cyclase response to AR agonists decreases acutely in adults during aortocoronary surgery requiring CPB, regardless of administration of chronic preoperative BAR antagonists. The mechanism underlying acute BAR dysfunction appears to be direct impairment of the adenylyl cyclase moiety. Similar fold increase in Mn-stimulated activity Pre- and End-CPB demonstrates preserved adenylyl cyclase catalytic activity, suggesting other mechanisms (e.g. decreased protein levels or altered isoform expression/function) may be responsible for decreased adenylyl cyclase function. Since patients with cardiac valve disease (CVD) frequently have congestive heart failure (CHF) and chronic myocardial beta-adrenergic receptor (BAR) desensitization, we next examined whether acute bAR dysfunction occurs during CPB in patients with CVD. After informed consent, 50 patients were enrolled. Right atrial biopsies were obtained at initiation and conclusion of CPB to assess BAR density and adenylyl cyclase (AC) activity. Plasma catecholamine concentrations increased 3-fold during CPB (p< 0.01). Although BAR density remained constant, isoproterenol-stimulated AC activity decreased significantly ( 30%; p<0.005). AC activity decreased 22% and 24% with direct G protein (NaF) or AC (manganese) activation, respectively. Patients with/without preoperative CHF exhibited similar degrees of acute myocardial BAR dysfunction during CPB. Acute myocardial BAR dysfunction occurs during CPB in patients with severe CVD requiring surgical correction, with/without pre-existing CHF. The primary underlying mechanism involves functional uncoupling of the BAR signal transduction pathway at the level of the AC moiety. This information should facilitate development of agents designed to prevent acute myocardial BAR dysfunction during CPB, potentially leading to improved outcome in this high-risk population. As a result of these initial studies, we are now examining mechanisms underlying CPB-induced BAR desensitization in humans. Phosphorylation kinases, G protein-coupling, and adenylyl cyclase isoforms are being examined. We are also performing an interventional trial to test the hypothesis that BAR antagonists protect patients from acute myocardial BAR desensitization during heart surgery with CPB.