Ca2+/calmodulin-dependent protein kinase inhibition suppresses post-ischemic arrhythmogenesis and mediates sinus bradycardic recovery in reperfusion

Background: Ca2+/calmodulin-dependent protein kinase (CaMKII) activation is known to be associated with conditions where the incidence of arrhythmias is increased, and where cardiomyocyte Ca2+-overload occurs. The goal of this study was to determine whether CaMKII inhibition in the intact heart may be linked to the suppression of ventricular arrhythmias occurring during reperfusion after an ischemic insult. Methods: Non-paced male rat hearts (n=8-11) were treated with a CaMKII inhibitor (KN93, 2.5 mu mol/L) 10 min prior to global ischemia (20 min) and for the initial 10 min of reperfusion. Cardiac mechanical and arrhythmic responses were evaluated under constant pressure perfusion conditions and myocyte damage assessed by measurement of coronary effluent lactate dehydrogenase (LDH). Results: Under basal conditions, KN93 increased coronary flow (41 +/- 8% increase, p<0.05) and was negatively inotropic (29 +/- 7% decrease, p<0.05), but did not affect heart rate. Ischemic contracture was significantly diminished in KN93-treated hearts (onset, min: 11.48 +/- 0.50 vs 16.27 +/- 1.23, p<0.05). CaMKII inhibition in early reperfusion almost completely abolished the incidence of ventricular tachycardia/fibrillation in reperfusion (11/11 control vs 1/8 KN93). In the absence of ventricular arrhythmias, heart rate was substantially reduced (% basal; 100 +/- 3% vs 46 > 8%, p<0.05) throughout reperfusion. Left ventricular developed pressure was initially low in KN93 hearts post-ischemia, but recovered to control levels by the end of 60 min reperfusion (68 +/- 5% vs 56 +/- 5%, p=ns). LDH was significantly reduced in KN93-treated hearts. Conclusion: Although CaMKII inhibition diminishes contractile performance of the intact heart in the initial post-ischemic period, it provides crucial benefits through protection against potentially lethal reperfusion-induced arrhythmias and cardiomyocyte sarcolemmal rupture. (C) 2011 Elsevier Ireland Ltd. All rights reserved.