BETA-ADRENERGIC SIGNAL-TRANSDUCTION AND CONTRACTILITY IN THE CANINE HEART AFTER CARDIOPULMONARY BYPASS

Objective: Impaired beta-adrenergic signal transduction has been propo sed as a mechanism contributing to myocardial depression after cardiac surgery. This study determined the changes in the beta-adrenergic sys tem in a model of postoperative myocardial dysfunction induced by myoc ardial ischaemia and reperfusion under cardiopulmonary bypass (CPB). T hose changes were then related to contractility and responsiveness to beta-adrenergic stimulation. Methods: Four groups of dog hearts were s tudied: 7 hearts harvested immediately after anaesthesia induction (co ntrol group representing the preoperative cardiac condition); 6 hearts harvested after three hours of chest opening by sternotomy (open ches t group serving as control for the effects of anaesthesia and surgery) ; 7 hearts harvested during CPB after 30 minutes of global ischaemia ( ischaemia group); and 10 hearts from dogs submitted to one hour of CPB involving 30 minutes of global cardiac ischaemia, harvested 30 minute s after CPB (ischaemia-reperfusion group). Myocardial membranes were p repared to assess: (1) beta-adrenergic receptor density using the radi oligand [I-125]iodocyanopindolol; (2) GTP-sensitive adenylate cyclase activity and its regulation by isoprenaline and forskolin; (3) G prote in levels, using an immunoblotting technique. Ventricular trabeculae o r papillary muscles served to assess contractility and responsiveness to isoprenaline. Results: The control and open chest groups had compar able beta-adrenergic receptor density, adenylate cyclase activity and cardiac contractility. In the ischaemia group, the left ventricular me mbranes had a 55% decrease in receptor density as compared to the cont rols (P < 0.005), similar GTP-sensitive adenylate cyclase activity and significantly lower adenylate cyclase responses to stimulation with i soprenaline and forskolin. In the ischaemia-reperfusion group, a 144% increase in the left ventricular receptor density was found as compare d to the controls (P < 0.005), with a 70% increase in GTP-sensitive ad enylate cyclase activity (P < 0.05), a similar adenylate cyclase respo nse to isoprenaline and a 61% increase in response to forskolin (P < 0 .005), As compared to the controls, the ischaemia and ischaemia-reperf usion groups had comparable G(s alpha) levels, but markedly decreased G(i alpha-2) and G(i alpha-3) levels. The baseline tension of the isol ated muscles in the ischaemia and ischaemia-reperfusion groups was com parable, but was 61% and 47% lower than the controls, respectively (P < 0.05). The maximal isoprenaline stimulated tension in the ischaemia and ischaemia-reperfusion groups was 66% and 36% lower than the contro ls, respectively(P < 0.05 between all groups). Conclusions: The beta-a drenergic system is severely depressed during global cardiac ischemia under CPB, but recovers to supranormal values after CPB. However the i ncreased cAMP generation by myocardial membranes after CPB is associat ed with decreased tension generation by corresponding cardiac muscles. Thus decreased contractility after CPB may be better explained by cel lular alterations distal to cAMP generation rather than by changes in the beta-adrenergic system. (C) 1997 Elsevier Science B.V.