Booth J V, Landolfo K P, Chesnut L C, Bennett-Guerrero E, Gerhardt M A, Atwell D M, El-Moalem H E, Smith M S, Funk B L, Kuhn C M, Kwatra M M, Schwinn D A
Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Anesthesiology. 1998 Sep;89(3):602-11. doi: 10.1097/00000542-199809000-00008.
Previously the authors showed that myocardial beta-adrenergic (betaAR) function is reduced after cardiopulmonary bypass (CPB) in a canine model Whether CPB results in similar effects on betaAR function in adult humans is not known. Therefore the current study tested two hypotheses: (1) That myocardial betaAR signaling is reduced in adult humans after CPB, and (2) that administration of long-term preoperative betaAR antagonists prevents this process.
After they gave informed consent, 52 patients undergoing aortocoronary surgery were enrolled. Atrial biopsies were obtained before CPB and immediately before discontinuation of CPB. Plasma catecholamine concentrations, myocardial betaAR density, and functional responsiveness (basal, isoproterenol, zinterol, sodium fluoride, and manganese-stimulated adenylyl cyclase activity) were assessed.
Catecholamine levels increased significantly during CPB (P < 0.005). Myocardial betaAR adenylyl cyclase coupling decreased during CPB, as evidenced by a 21% decrease in isoproterenol-stimulated adenylyl cyclase activity (750 [430] pmol cyclic adenosine monophosphate per milligram total protein 15 min before CPB compared with 540 [390] at the end of CPB, P = 0.0062, medians [interquartile range]) despite constant betaAR density. Differential activation along the betaAR signal transduction cascade localized the defect to the adenylyl cyclase moiety. Administration of long-term preoperative betaAR antagonists did not prevent acute CPB-induced myocardial betaAR dysfunction.
These data indicate that the myocardial adenylyl cyclase response to betaAR agonists decreases acutely in adults during aortocoronary surgery requiring CPB, regardless of whether long-term preoperative betaAR antagonists are administered. The mechanism underlying acute betaAR dysfunction appears to be direct impairment of the adenylyl cyclase moiety. Similar increases in manganese-stimulated activity before and at the end of CPB show preserved adenylyl cyclase catalytic activity, suggesting that other mechanisms (such as decreased protein levels or altered isoform expression or function) may be responsible for decreased adenylyl cyclase function.
此前作者在犬类模型中发现，体外循环（CPB）后心肌β-肾上腺素能（βAR）功能降低。CPB是否会对成年人类的βAR功能产生类似影响尚不清楚。因此，本研究检验了两个假设：（1）CPB后成年人类心肌βAR信号传导减少；（2）术前长期给予βAR拮抗剂可预防这一过程。
52例接受主动脉冠状动脉手术的患者在签署知情同意书后入组。在CPB前及即将停止CPB时获取心房活检组织。评估血浆儿茶酚胺浓度、心肌βAR密度及功能反应性（基础状态、异丙肾上腺素、辛特罗、氟化钠及锰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）。CPB期间心肌βAR-腺苷酸环化酶偶联减少，异丙肾上腺素刺激的腺苷酸环化酶活性降低21%可证明这一点（CPB前15分钟每毫克总蛋白为750[430]pmol环磷酸腺苷，CPB结束时为540[390]pmol环磷酸腺苷，P = 0.0062，中位数[四分位间距]），尽管βAR密度保持不变。βAR信号转导级联反应中的差异激活将缺陷定位至腺苷酸环化酶部分。术前长期给予βAR拮抗剂并不能预防CPB引起的急性心肌βAR功能障碍。
这些数据表明，在需要CPB的主动脉冠状动脉手术期间，成年人心肌对βAR激动剂的腺苷酸环化酶反应急性降低，无论术前是否长期给予βAR拮抗剂。急性βAR功能障碍的潜在机制似乎是腺苷酸环化酶部分的直接损伤。CPB前后锰刺激活性的类似增加表明腺苷酸环化酶催化活性保持，提示其他机制（如蛋白质水平降低或同工型表达或功能改变）可能是腺苷酸环化酶功能降低的原因。
