DOWNSTREAM DEFECTS IN BETA-ADRENERGIC SIGNALING AND RELATION TO MYOCYTE CONTRACTILITY AFTER CARDIOPLEGIC ARREST

Objective: Transient left ventricular dysfunction can occur after hypo thermic, hyperkalemic cardioplegic arrest and is associated with decre ased beta-adrenergic receptor responsiveness, Occupancy of the beta-ad renergic receptor activates adenylate cyclase, which phosphorylates th e L-type Ca2+ channel-enhancing myocyte contractility, The goal of thi s study was to identify potential mechanisms that contribute to the de fects in the beta-adrenergic receptor signaling cascade after cardiopl egic arrest. Methods: Isolated left ventricular porcine myocytes were assigned to one of two treatment groups: (1) cardioplegic arrest (24 m Eq/L K+, 4 degrees C x 2 hours, then 5 minutes in 37 degrees C cell me dia; n = 130) or (2) normothermic control (cell media, 37 degrees C x 2 hours; n = 222), Myocyte contractility was assessed at baseline and after either beta-adrenergic receptor occupancy (25 nmol/L isoproteren ol [INN: isoprenaline]), activation of adenylate cyclase (0.5 mu mol f orskolin), or direct activation of the L-type Ca2+-channel (10 nmol/L or 100 nmol/L (-)BayK 8644), Results: Myocyte velocity of shortening ( mu m/sec) was increased with beta-adrenergic receptor occupancy or dir ect adenylate cyclase stimulation compared with baseline in the normot hermic group (187.3 +/- 6.9, 181.7 +/- 10.2, and 73.9 +/- 2.9, respect ively; p < 0.0001) and after cardioplegic arrest (128.6 +/- 8.9, 124.3 +/- 9.4, and 46.1 +/- 2.6, respectively; p < 0.0001), However, the re sponse after cardioplegic arrest was significantly reduced compared wi th normothermic values under all conditions (p = 0.012), Direct activa tion of the L-type Ca2+-channel, which eliminates beta-adrenergic rece ptor-dependent events, increased myocyte contractility in the normothe rmic group (161.90 +/- 12.0, p < 0.0001) and after cardioplegic arrest (92.78 +/- 6.8, p < 0.0001), but the positive inotropic response appe ared reduced compared with normothermic control values (p = 0.003), Co nclusion: These findings suggest that contributory mechanisms for the reduced beta-adrenergic receptor-mediated response after hypothermic, hyperkalemic cardioplegic arrest lie downstream from these specific co mponents of the transduction pathway and likely include defects in Ca2 + homeostasis, myofilament Ca2+ sensitivity, or both.