Aydin Oezguer, Becker Ruediger, Kraft Patricia, Voss Frederik, Koch Martin, Kelemen Kamilla, Katus Hugo A, Bauer Alexander
Department of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
Europace. 2007 Nov;9(11):1094-8. doi: 10.1093/europace/eum160. Epub 2007 Aug 7.
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.
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.
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.
心律失常仍是西方国家主要的死亡原因。目前可用的抗心律失常药物存在疗效低和致心律失常作用的局限性。蛋白激酶C（PKC）信号通路在心律失常发生中的作用仍不清楚。本研究的目的是测试PKC刺激对全心电生理及其促心律失常/抗心律失常活性的影响。
在27个采用Langendorff灌注的兔心脏中测定左心室（LV）动作电位时程（APD 90%），分别使用单独的台氏液加PKC激动剂佛波醇-12-肉豆蔻酸酯-13-乙酸酯（PMA；100 nM）（9只兔）、单独使用维拉帕米（n = 6）、PMA与维拉帕米联合使用（0.25 mg/L，6只兔）或双吲哚马来酰胺（0.5 μM，n = 6）。进行间歇性程控额外刺激以诱发室性心律失常。单独给予PMA导致复极化显著缩短（APD 90%，157±8 vs. 128±5 ms，P<0.05）。9只动物中有7只可诱发非持续性室颤（VF）。灌注维拉帕米（156±6 vs. 169±4 ms，P>0.05）或PKC的选择性抑制剂双吲哚马来酰胺（136±4 vs. 146±4 ms，P>0.05）后，PMA诱导的复极化缩短可被抑制，且VF诱导失败。单独使用维拉帕米不影响APD，且不能诱发VF。
PKC的激活促进VF的诱导，这很可能是由于复极化缩短和显著的钙内流。这些发现表明PKC信号通路参与心律失常的发生。
