Acute depression of myocardial β-adrenergic receptor signaling during cardiopulmonary bypass. Impairment of the adenylyl cyclase moiety

Background: Previously the authors showed that myocardial β-adrenergic (βAR) function is reduced after cardiopulmonary bypass (CPB) in a canine model. Whether CPB results in similar effects on βAR function in adult humans is not known. Therefore the current study tested two hypotheses: (1) That myocardial AR signaling is reduced in adult humans after CPB, and (2) that administration of long-term preoperative βAR antagonists prevents this process. Methods: 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 βAR density, and functional responsiveness (basal, isoproterenol, zinterol, sodium fluoride, and manganese-stimulated adenylyl cyclase activity) were assessed. Results: Catecholamine levels increased significantly during CPB (P < 0.005). Myocardial βAR 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 βAR density. Differential activation along the βAR signal transduction cascade localized the defect to the adenylyl cyclase moiety. Administration of long-term preoperative βAR antagonists did not prevent acute CPB-induced myocardial βAR dysfunction. Conclusions: These data indicate that the myocardial adenylyl cyclase response to βAR agonists decreases acutely in adults during aortocoronary surgery requiring CPB, regardless of whether long-term preoperative βAR antagonists are administered. The mechanism underlying acute βAR 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.