부산대학교 도서관

OBJECTIVE:: Transient left ventricular dysfunction can occur after hypothermic, hyperkalemic cardioplegic arrest and is associated with decreased β-adrenergic receptor responsiveness. Occupancy of the β-adrenergic receptor activates adenylate cyclase, which phosphorylates the L-type Ca channel-enhancing myocyte contractility. The goal of this study was to identify potential mechanisms that contribute to the defects in the β-adrenergic receptor signaling cascade after cardioplegic arrest. METHODS:: Isolated left ventricular porcine myocytes were assigned to one of two treatment groups: (1) cardioplegic arrest (24 mEq/L K, 4°C × 2 hours, then 5 minutes in 37°C cell media; n = 130) or (2) normothermic control (cell media, 37°C × 2 hours; n = 222). Myocyte contractility was assessed at baseline and after either β-adrenergic receptor occupancy (25 nmol/L isoproterenol [INN: isoprenaline]), activation of adenylate cyclase (0.5 μmol forskolin), or direct activation of the L-type Ca-channel (10 nmol/L or 100 nmol/L (−)BayK 8644). RESULTS:: Myocyte velocity of shortening (μm/sec) was increased with β-adrenergic receptor occupancy or direct adenylate cyclase stimulation compared with baseline in the normothermic group (187.3 ± 6.9, 181.7 ± 10.2, and 73.9 ± 2.9, respectively; 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 response after cardioplegic arrest was significantly reduced compared with normothermic values under all conditions (p = 0.012). Direct activation of the L-type Ca-channel, which eliminates β-adrenergic receptor-dependent events, increased myocyte contractility in the normothermic group (161.90 ± 12.0, p < 0.0001) and after cardioplegic arrest (92.78 ± 6.8, p < 0.0001), but the positive inotropic response appeared reduced compared with normothermic control values (p = 0.003). CONCLUSION:: These findings suggest that contributory mechanisms for the reduced β-adrenergic receptor-mediated response after hypothermic, hyperkalemic cardioplegic arrest lie downstream from these specific components of the transduction pathway and likely include defects in Ca homeostasis, myofilament Ca sensitivity, or both.