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

@entity35 @entity63 @entity5649 @entity14374 @entity880 @entity2224 @entity141 @entity943
BACKGROUND: @entity141 /calmodulin-dependent protein kinase (CaMKII) activation is known to be associated with conditions where the incidence of @entity943 is increased, and where cardiomyocyte @entity141 -overload occurs. The goal of this study was to determine whether CaMKII inhibition in the intact heart may be linked to the suppression of @entity943 occurring during reperfusion after an ischemic insult. METHODS: Non-paced male @entity35 hearts (n = 8-11) were treated with a CaMKII inhibitor ( @entity14374 , 2.5  mol/L) 10 min prior to global @entity63 (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 @entity880 dehydrogenase (LDH). RESULTS: Under basal conditions, @entity14374 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. @entity5649 was significantly diminished in @entity14374 -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 @entity2224 in reperfusion (11/11 control vs 1/8 @entity14374 ). In the absence of @entity943 , heart rate was substantially reduced (% basal; 100    3% vs 46    8%, p<0.05) throughout reperfusion. Left ventricular developed pressure was initially low in @entity14374 hearts post- @entity63 , but recovered to control levels by the end of 60 min reperfusion (68    5% vs 56    5%, p = ns). LDH was significantly reduced in @entity14374 -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 @entity943 and cardiomyocyte sarcolemmal rupture.
