Schwinn D A, Leone B J, Spahn D R, Chesnut L C, Page S O, McRae R L, Liggett S B
Department of Anesthesiology, Duke University Medical Center, Durham, N.C.
Circulation. 1991 Dec;84(6):2559-67. doi: 10.1161/01.cir.84.6.2559.
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 beta-adrenergic receptor (beta AR) desensitization.
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 [125I]-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.
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.
体外循环（CPB）是心脏手术中常规使用的一种操作，是内源性儿茶酚胺释放的强效刺激因素。因此，我们检验了体外循环导致心肌β-肾上腺素能受体（βAR）脱敏的假说。
我们在体外循环前、期间（155分钟）和后（分别为CPB前、CPB期间和CPB后）获取犬经心肌左心室活检组织，测定βAR密度、β1AR与β2AR的比例以及βAR与腺苷酸环化酶的偶联能力。βAR密度在CPB前稳定在112±14 fmol/mg，CPB期间为103±9 fmol/mg，但CPB后降至84±7 fmol/mg。β1AR与β2AR的比例（通过[125I]-碘氰吲哚洛尔与β1AR选择性拮抗剂ICI89.406竞争结合的两点拟合测定）在整个过程中保持恒定（CPB前为60±3:40±3，CPB期间为55±3:44±3，CPB后为61±2:39±2），表明β1AR和β2AR亚型均下调。在体外循环期间，这些受体的功能特性呈现出不同的模式。在停止体外循环时，异丙肾上腺素刺激的腺苷酸环化酶最大活性（从252±14降至216±12 pmol/30分钟/mg）、次最大异丙肾上腺素刺激的腺苷酸环化酶活性（从183±10降至157±11 pmol/30分钟/mg）以及齐特罗尔刺激的腺苷酸环化酶活性（从187±11降至159±11 pmol/30分钟/mg，β2AR亚型激活的一种测量指标）均降低。然而，这种脱敏模式在CPB后30分钟被发现完全逆转，腺苷酸环化酶活性恢复到CPB前水平或略高。未接受体外循环的对照犬βAR密度或腺苷酸环化酶活性无变化。
这些数据表明，在健康、非缺血的犬心肌中，体外循环期间确实会发生心肌βAR脱敏，且这种模式在停止体外循环30分钟后逆转。此外，停止体外循环后，βAR下调的过程仍在缓慢进行。由于成功脱离体外循环是心脏手术中的关键过程，这些发现对此类患者的管理可能具有重要意义。
