Europace Advance Access originally published online on August 7, 2007
Europace 2007 9(11):1094-1098; doi:10.1093/europace/eum160
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EXPERIMENTAL STUDIES
Effects of protein kinase C activation on cardiac repolarization and arrhythmogenesis in Langendorff-perfused rabbit hearts
Department of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany
Aims Cardiac arrhythmias are still a major cause of mortality in western countries. Currently available antiarrhythmic drugs are limited by a low efficacy and proarrhythmic effects. The role of the protein kinase C (PKC) signalling pathway in arrhythmogenesis is still unclear. The goal of the present study was to test the effects of PKC stimulation on whole heart electrophysiology and its pro-/antiarrhythmic activity.
Methods and results Left ventricular (LV) action potential duration (APD 90%) was determined in 27 Langendorff-perfused rabbit hearts, using Tyrode solution plus the PKC agonist phorbol-12-myristate-13-acetate (PMA; 100 nM) alone (nine rabbits), Verapamil alone (n = 6), or PMA in combination with Verapamil (0.25 mg/L, six rabbits), or bisindolylmaleimide (0.5 µM, n = 6). Intermittent programmed extra-stimulation was performed to induce ventricular arrhythmias. Administration of PMA alone led to a significant shortening of repolarization (APD 90%, 157 ± 8 vs. 128 ± 5 ms, P<0.05). Non-sustained ventricular fibrillation (VF) could be induced in seven out of nine animals. After perfusion of Verapamil (156 ± 6 vs. 169 ± 4 ms, P>0.05) or bisindolylmaleimide, a selective inhibitor of PKC (136 ± 4 vs. 146 ± 4 ms, P>0.05), PMA-induced shortening of repolarization could be inhibited, and induction of VF failed. Verapamil alone did not affect APD and VF could not be induced.
Conclusions Activation of PKC facilitates induction of VF, which is most likely due to a shortening of repolarization and a prominent calcium influx. These findings demonstrate involvement of the PKC-signalling pathway in arrhythmogenesis.
Key Words: Ventricular fibrillation, Protein kinase C, Verapamil, Repolarization, Monophasic action potentials, Arrhythmogenesis, Anti-arrhythmic drugs
* Corresponding author. Tel: 06221 5638672; fax: 06221 565514. E-mail address: alexander_bauer{at}med.uni-heidelberg.de
Oezguer Aydin and Ruediger Becker contributed equally to this work.
Manuscript submitted 21 May 2007. Accepted after revision 8 July 2007.