期刊
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
卷 457, 期 2, 页码 253-270出版社
SPRINGER HEIDELBERG
DOI: 10.1007/s00424-008-0508-3
关键词
Epac; cAMP; Calcium; Ventricular arrhythmia; Ryanodine receptor; CaMKII
类别
资金
- Medical Research Council
- Wellcome Trust
- British Heart Foundation
- Helen Kirkland Trust
- Papworth Hospital, UK
- Trinity College, Cambridge
- MRC
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 wildtype murine hearts perfused with the Epac activator 8-pCPT-2'-O-Me-cAMP (8-CPT, 1 mu M) 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 (Delta APD(90)) (11.1 +/- 2.6 versus 7.9 +/- 2.8 ms; n=10) or apicobasal 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 Ca2+ levels demonstrated abnormal Ca2+ 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 Ca2+ homeostasis. Epac-dependent effects were reduced by Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibition with 1 mu M KN-93. These findings associate VT in an intact cardiac preparation with altered cellular Ca2+ 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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