18600344

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2

The recently described exchange protein directly activated by cAMP (Epac) has been implicated in distinct protein kinase A-independent cellular signalling pathways. We investigated the role of Epac activation in adrenergically mediated ventricular arrhythmogenesis. In contrast to observations in control conditions (n = 20), monophasic action potentials recorded in 2 of 10 intrinsically beating and 5 of 20 extrinsically paced Langendorff-perfused wild-type murine hearts perfused with the Epac activator 8-pCPT-2'-O-Me-cAMP (8-CPT, 1 microM) showed spontaneous triggered activity. Three of 20 such extrinsically paced hearts showed spontaneous ventricular tachycardia (VT). Programmed electrical stimulation provoked VT in 10 of 20 similarly treated hearts (P < 0.001; n = 20). However, there were no statistically significant accompanying changes (P > 0.05) in left ventricular epicardial (40.7 +/- 1.2 versus 44.0 +/- 1.7 ms; n = 10) or endocardial action potential durations (APD(90); 51.8 +/- 2.3 versus 51.9 +/- 2.2 ms; n = 10), transmural (DeltaAPD(90)) (11.1 +/- 2.6 versus 7.9 +/- 2.8 ms; n = 10) or apico-basal repolarisation gradients, ventricular effective refractory periods (29.1 +/- 1.7 versus 31.2 +/- 2.4 ms in control and 8-CPT-treated hearts, respectively; n = 10) and APD(90) restitution characteristics. Nevertheless, fluorescence imaging of cytosolic Ca(2+) levels demonstrated abnormal Ca(2+) homeostasis in paced and resting isolated ventricular myocytes. Epac activation using isoproterenol in the presence of H-89 was also arrhythmogenic and similarly altered cellular Ca(2+) homeostasis. Epac-dependent effects were reduced by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) inhibition with 1 microM KN-93. These findings associate VT in an intact cardiac preparation with altered cellular Ca(2+) homeostasis and Epac activation for the first time, in the absence of altered repolarisation gradients previously implicated in reentrant arrhythmias through a mechanism dependent on CaMKII activity.

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MEDLINE

0031-6768

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253-70

pubmed-meshheading:18600344-Action Potentials, pubmed-meshheading:18600344-Adrenergic beta-Agonists, pubmed-meshheading:18600344-Animals, pubmed-meshheading:18600344-Benzylamines, pubmed-meshheading:18600344-Calcium Signaling, pubmed-meshheading:18600344-Calcium-Calmodulin-Dependent Protein Kinase Type 2, pubmed-meshheading:18600344-Cardiac Pacing, Artificial, pubmed-meshheading:18600344-Cyclic AMP, pubmed-meshheading:18600344-Female, pubmed-meshheading:18600344-Guanine Nucleotide Exchange Factors, pubmed-meshheading:18600344-Heart Ventricles, pubmed-meshheading:18600344-Homeostasis, pubmed-meshheading:18600344-Isoproterenol, pubmed-meshheading:18600344-Isoquinolines, pubmed-meshheading:18600344-Male, pubmed-meshheading:18600344-Mice, pubmed-meshheading:18600344-Models, Cardiovascular, pubmed-meshheading:18600344-Myocytes, Cardiac, pubmed-meshheading:18600344-Perfusion, pubmed-meshheading:18600344-Protein Kinase Inhibitors, pubmed-meshheading:18600344-Refractory Period, Electrophysiological, pubmed-meshheading:18600344-Sulfonamides, pubmed-meshheading:18600344-Tachycardia, Ventricular, pubmed-meshheading:18600344-Time Factors

Epac activation, altered calcium homeostasis and ventricular arrhythmogenesis in the murine heart.

Journal Article, In Vitro, Research Support, Non-U.S. Gov't