Rottlerin Increases Cardiac Contractile Performance and Coronary Perfusion Through BK Ca++ Channel Activation After Cold Cardioplegic Arrest in Isolated Hearts

BACKGROUND: Cardioplegia and cardiopulmonary bypass (CP/CPB) subjects myocardium to complex injurious stimuli that can result in cardiomyocyte and vascular contractile abnormalities. Rottlerin, originally identified as a delta-protein kinase C inhibitor, has a number of known additional effects that may be beneficial in the setting of CP/CPB. We tested the hypothesis that rottlerin mitigates deleterious effects associated with CP/CPB. METHODS AND RESULTS: Langendorff-perfused isolated rat hearts were subjected to 2 hours intermittent cold (10°C) CP (St Thomas II) followed by 30 minutes normothermic reperfusion. CP was delivered every 30 minutes for 1 minute. Hearts were treated with rottlerin 1 μmol/L (CP+R) (n=7) or without rottlerin (CP) (n=9), and the BK(Ca++) channel inhibitor paxilline 100 nmol/L was supplied in the CP. Hearts constantly perfused with KHB served as controls (n=6). Baseline parameters of cardiac function were similar between groups. CP resulted in reduced cardiac function (left ventricular diastolic pressure, 39 ± 3.8%; ± dP/dt, 32 ± 4.4%, -41 ± 5.1% decrease compared to baseline). Treatment with rottlerin 1 μmol/L significantly improved CP-induced cardiac function (left ventricular diastolic pressure, 20 ± 5.9%; ± dP/dt, 5.2 ± 4.5%, -11.6 ± 4.7% decrease versus baseline; P<0.05 CP+R versus CP). Rottlerin also caused a significant increase in coronary flow postreperfusion (CP, 34 ± 4.2% decrease from baseline; CP+R, 26 ± 9.6% increase over baseline; P=0.01). Independent of vascular effects, CP significantly decreased isolated myocyte contraction, which was restored by rottlerin treatment. The BK(Ca++) channel inhibitor greatly reduced the majority of beneficial effects associated with rottlerin. CONCLUSIONS: Rottlerin significantly improves cardiac performance after CP arrest through improved cardiomyocyte contraction and coronary perfusion.