CONTRIBUTORY MECHANISMS FOR THE BENEFICIAL-EFFECTS OF MYOCYTE PRECONDITIONING DURING CARDIOPLEGIC ARREST

Background Preconditioning protects the myocardium from ischemia and m ay be a potent means of endogenous cardioprotection during cardioplegi c arrest and rewarming. However, fundamental mechanisms that potential ly contribute to the beneficial effects of preconditioning during card ioplegic arrest and rewarming remain unclear. Accordingly, the overall goal of the present study was to examine the potential mechanisms by which preconditioning protects myocyte contractile function during sim ulated cardioplegic arrest and rewarming. Methods and Results Left ven tricular isolated porcine myocyte contractile function was examined wi th the use of videomicroscopy under three conditions: (1) normothermia , maintained in cell medium (37 degrees C) for 2 hours; (2) simulated cardioplegic arrest and rewarming, incubated in crystalloid cardiopleg ic solution (24 mEq/L K+, 4 degrees C) for 2 hours followed by normoth ermic reperfusion; and (3) preconditioning/cardioplegic arrest and rew arming, hypoxia (20 minutes) and reoxygenation (20 minutes) followed b y simulated cardioplegic arrest and rewarming. Cardioplegic arrest and rewarming caused a decline in steady-state myocyte shortening velocit y compared with normothermic controls (22.0 +/- 1.6 versus 57.2 +/- 2. 6 mu m/s, respectively, P<.05), which was significantly improved with preconditioning (36.1 +/- 1.7 mu m/s, P<.05). In the next series of ex periments, the influence of nonmyocyte cell populations with respect t o preconditioning and cardioplegic arrest was examined. Endothelial or smooth muscle cell cultures were subjected to a period of hypoxia (20 minutes) and reoxygenation (20 minutes) and the eluent incubated with naive myocytes, which were then subjected to simulated cardioplegic a rrest and rewarming. Pretreatment with the eluent from endothelial cul tures followed by cardioplegic arrest and rewarming improved myocyte f unction compared with cardioplegia-alone values (31.7 +/- 2.2 versus 2 4.7 +/- 1.6 mu m/s, respectively, P<.05), whereas smooth muscle cultur e eluent pretreatment resulted in no change (23.7 +/- 4.0 mu m/s, P=.8 1). Molecular mechanisms for the protective effects of preconditioning on myocyte contractile processes with cardioplegic arrest and rewarmi ng were examined in a final series of experiments. Adenosine-mediated pathways or ATP-sensitive potassium channels were activated by augment ing cardioplegic solutions with adenosine (200 mu mol/L) or the potass ium channel opener aprikalim (100 mu mol/L), respectively. Both adenos ine and aprikalim augmentation significantly improved myocyte function compared with cardioplegia-alone values (53.5 +/- 1.7, 57.6 +/- 2.0 v ersus 25.7 +/- 1.4 mu m/s, respectively, P<.05). Conclusions The uniqu e findings from the present study demonstrated that preconditioning pr ovides protective effects on myocyte contractile processes independent of nonmyocyte cell populations and that these effects are mediated in part through the activation of adenosine pathways or ATP-sensitive po tassium channels. Thus, preconditioning adjuvant to cardioplegia may p rovide a novel means of protecting myocardial function after cardiople gic arrest and rewarming.