Desensitization of myocardial β-adrenergic receptors during cardiopulmonary bypass: Evidence for early uncoupling and late downregulation

Abstract

Background. Cardiopulmonary bypass (CPB), a process routinely used during cardiac surgery, is a potent stimulant to the release of endogenous catecholamines. Hence, we tested the hypothesis that CPB results in myocardial β-adrenergic receptor (βAR) 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 βAR density, proportion of β1AR to β2AR, and βAR coupling capacity to adenylyl cyclase. βAR 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 β1AR to β2AR (determined by two-site fit for [125I]-iodocyanopindolol competition binding with the β1AR 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 β1AR and β2AR 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 β2AR 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 βAR density or adenylyl cyclase activity. Conclusions. These data suggest that myocardial βAR 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 βAR 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.