DESENSITIZATION OF MYOCARDIAL BETA-ADRENERGIC RECEPTORS DURING CARDIOPULMONARY BYPASS - EVIDENCE FOR EARLY UNCOUPLING AND LATE DOWN-REGULATION

Background. Cardiopulmonary bypass (CPB), a process routinely used during cardiac surgery, is a potent stimulant to the release of endogeneous catecholamines. Hence, we tested the hypothesis that CPB results in myocardial beta-adrenergic receptor (beta-AR) desensitization. Methods and Results. We obtained canine transmyocardial left ventricular biopsies before, during (155 minutes), and after CPB (pre-CPB, CPB, and post-CPB, respectively) and determined beta-AR density, proportion of beta-1AR to beta-2AR, and beta-AR coupling capacity to adenylyl cyclase. beta-AR density was stable at 112 +/- 14 fmol/mg (pre-CPB) and 103 +/- 9 fmol/mg (CPB) but decreased post-CPB to 84 +/- 7 fmol/mg. The ratio of beta-1AR to beta-2AR (determined by two-site fit for [I-125]-iodocyanopindolol competition binding with the beta-1AR selective antagonist ICI89.406) remained constant throughout (60 +/- 3:40 +/- 3 pre-CPB, 55 +/- 3:44 +/- 3 CPB, and 61 +/- 2:39 +/- 2 post-CPB), revealing that both beta-1AR and beta-2AR subtypes were downregulated. A different pattern was noted in the functional properties of these receptors during CPB. Decreased maximal isoproterenol-stimulated adenylyl cyclase activity (252 +/- 14 to 216 +/- 12 pmol/30 min/mg), submaximal isoproterenol-stimulated adenylyl cyclase activity (183 +/- 10 to 157 +/- 11 pmol/30 min/mg), and zinterol-stimulated adenylyl cyclase activity (187 +/- 11 to 159 +/- 11 pmol/30 min/mg, a measure of beta-2AR subtype activation) were noted during CPB, at the time when weaning from CPB takes place. However, this desensitized pattern was found to be completely reversed by 30 minutes post-CPB, with adenylyl cyclase activities returning to pre-CPB levels or slightly higher. Control dogs that did not receive CPB showed no change in beta-AR density or adenylyl cyclase activity. Conclusions. These data suggest that myocardial beta-AR desensitization does occur during CPB in healthy, nonischemic canine myocardium and that this pattern is reversed 30 minutes after discontinuation of CPB. In addition, a slower process of beta-AR downregulation persists after discontinuation of CPB. Because successful weaning from CPB is a critical process during myocardial surgery, these findings have potentially important implications in the management of such patients.