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Cardiac surgery results in significant impairment of β-adrenergic receptor (βAR) function and is a cause of depressed myocardial function after surgery. We previously demonstrated that acute administration of βAR blocker during cardiopulmonary bypass (CPB) in an animal model of coronary artery bypass grafting (CABG) surgery attenuates βAR desensitization, whereas chronic oral β-blockade therapy in patients undergoing CABG surgery does not prevent it. Therefore we hypothesized that acute administration of metoprolol during CABG surgery would prevent acute myocardial βAR desensitization. A placebo-controlled initial phase (n = 72) was performed whereby patients were randomized to either metoprolol 10 mg or placebo immediately before CPB. Then a second dose-finding study was performed where patients received 20 mg (n = 20) or 30 mg (n = 20) of metoprolol. Hemodynamic monitoring, atrial membrane adenylyl cyclase activity, atrial βAR density, and postoperative outcomes were measured. All groups showed similar decreases in isoproterenol-stimulated adenylyl cyclase activity (13%–24%). Cardiac output remained similar in all 4 groups throughout the intraoperative and postoperative period. In addition, patients receiving metoprolol 20 or 30 mg had less supraventricular arrhythmias 24 h postoperatively compared with patients receiving metoprolol 10 mg or placebo. Therefore, unlike our previous animal model of CABG surgery, metoprolol did not attenuate myocardial βAR desensitization.