Effects of protein kinase C activation on cardiac repolarization and arrhythmogenesis in Langendorff-perfused rabbit hearts.
OBJECTIVE
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.


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 microM, 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.
Department of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
Oezguer
O
Aydin
Ruediger
R
Becker
Patricia
P
Kraft
Frederik
F
Voss
Martin
M
Koch
Kamilla
K
Kelemen
Hugo A
HA
Katus
Alexander
A
Bauer
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D022062:Electrophysiologic Techniques, Cardiac; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011817:Rabbits; D015398:Signal Transduction / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D018754:Ventricular Dysfunction / Q000201:enzymology* / Q000209:etiology* / Q000503:physiopathology; D014693:Ventricular Fibrillation / Q000201:enzymology* / Q000209:etiology* / Q000503:physiopathology; D014700:Verapamil / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; C016658:phorbolol myristate acetate; D014700:Verapamil; D011493:Protein Kinase C; C088060:bisindolylmaleimide; D013755:Tetradecanoylphorbol Acetate