ROLE OF B ADRENERGIC RECEPTOR ANTAGONISTS IN CARDIAC SURGERY PATIENTS

B 肾上腺素能受体拮抗剂在心脏手术患者中的作用

• 批准号: 6415275
• 负责人: Debra Anne Schwinn
• 金额: $ 29.31万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-12-01 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6415275
• 关键词: acute disease /disorder; antiadrenergic agents; beta adrenergic receptor; clinical research; drug screening /evaluation; heart /lung bypass; human subject; human therapy evaluation; myocardium; pathologic process; phosphorylation; receptor sensitivity

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.

我们先前在犬的体外循环(CPB)模型中证明了心肌肾上腺素能(BAR)功能降低。目前尚不清楚在冠状动脉旁路移植术(CABG)或瓣膜手术中，CPB是否会对成人的BAR功能产生类似的影响。因此，我们最初在CABG患者中检验了两个假说：1)成人CPB后心肌AR信号减少，2)术前长期应用AR拮抗剂可阻止这一过程。经知情同意后，纳入52例行主动脉冠状动脉手术的患者。在CPB前和CPB停止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、氟化钠和锰刺激的腺苷环化酶活性)。体外循环期间儿茶酚胺水平显著升高(p&lt；0.005)。在体外循环期间，心肌AR腺酰环化酶偶联减少，表现为异丙肾上腺素刺激的腺酰环化酶活性降低21%(750pmolcAMP/mg总蛋白/15min比540[390]End-CPB，p=0.0062，中位数[四分位数范围])。沿着AR信号转导通路的差异激活将缺陷定位于腺苷环化酶部分。术前长期应用BAR拮抗剂并不能预防CPB所致的急性心肌BAR功能障碍。这些数据表明，在需要体外循环的冠状动脉手术中，成人心肌腺酰环化酶对AR激动剂的反应性急剧降低，而与术前长期使用BAR拮抗剂无关。急性酒吧功能障碍的机制似乎是腺酰环化酶部分的直接损伤。CPB前和CPB结束前锰刺激活性的相似倍数增加显示了腺酰环化酶催化活性的保留，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)可能是导致腺酰环化酶功能下降的原因。由于心脏瓣膜病(CVD)患者经常出现充血性心力衰竭(CHF)和慢性心肌β-肾上腺素能受体(BAR)脱敏，我们接下来检查CVD患者在体外循环期间是否发生急性BAR功能障碍。知情同意后，纳入50例患者。分别在CPB开始和结束时取右心房活检标本，以评估BAR密度和腺苷环化酶(AC)活性。体外循环期间，血浆儿茶酚胺浓度增加了3倍(p&lt；0.01)。尽管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&lt；0.005)。直接激活G蛋白(NaF)和激活AC(锰)后，AC活性分别下降22%和24%。术前有/无心衰的患者在体外循环期间表现出相似程度的急性心肌梗死。在CPB期间，需要手术矫正的严重心血管疾病患者中会出现急性心肌杆功能障碍，这些患者既有或不存在CHF。主要的潜在机制涉及AC部分水平上BAR信号转导通路的功能解偶联。这些信息应该有助于开发旨在预防体外循环期间急性心肌梗死功能障碍的药物，潜在地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诱导人类BAR脱敏的潜在机制。正在检测磷酸化激酶、G蛋白偶联和腺苷环化酶同工酶。我们还进行了一项干预性试验，以测试BAR拮抗剂在体外循环心脏手术期间保护患者免受急性心肌BAR脱敏的假设。