Membrane Protein Physiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
J Cardiovasc Pharmacol. 2011 Jun;57(6):672-81. doi: 10.1097/FJC.0b013e318217943d.
Atrial fibrillation (AF) is associated with increased morbidity and is in addition the most prevalent cardiac arrhythmia. Compounds used in pharmacological treatment has traditionally been divided into Na(+) channel inhibitors, β-blockers, K(+) channel inhibitors, and Ca(2+) channel inhibitors, whereas newer multichannel blockers such as amiodarone and ranolazine have been introduced later. This study was devoted to the evaluation of an acute pacing-induced in vivo model of AF in rats. Antiarrhythmic effects of well-known compounds such as lidocaine, dofetilide, and ranolazine were confirmed in this model. In addition, antiarrhythmic effects of different inhibitors of Ca(2+)-activated small conductance K(+) (SK) channels were demonstrated. Intravenous application of 5 mg/kg of the negative SK channel modulator NS8593 reduced AF duration by 64.5%, and the lowest significantly effective dose was 1.5 mg/kg. A dose-effect relationship was established based on 6 different dose groups. Furthermore, it was demonstrated that the antiarrhythmic effect of NS8593 and other tested drugs was associated with an increase in atrial effective refractory period. The functional role of SK channels was confirmed by 2 other SK channel inhibitors, UCL1684 and apamin, thereby confirming the hypothesis that these channels might constitute a new promising target for antiarrhythmic treatment.
心房颤动（AF）与发病率增加有关，此外，它是最常见的心律失常。药理学治疗中使用的化合物传统上分为钠（Na+）通道抑制剂、β-受体阻滞剂、钾（K+）通道抑制剂和钙（Ca2+）通道抑制剂，而后来又引入了新型多通道阻滞剂，如胺碘酮和雷诺嗪。本研究致力于评估大鼠体内急性起搏诱导的 AF 模型。在该模型中证实了利多卡因、多非利特和雷诺嗪等知名化合物的抗心律失常作用。此外，还证明了不同钙激活小电导钾（SK）通道抑制剂的抗心律失常作用。静脉注射 5mg/kg 的负 SK 通道调节剂 NS8593 可使 AF 持续时间减少 64.5%，最低有效剂量为 1.5mg/kg。基于 6 个不同剂量组建立了剂量-效应关系。此外，还证明了 NS8593 和其他测试药物的抗心律失常作用与心房有效不应期的增加有关。通过另外两种 SK 通道抑制剂 UCL1684 和蜂毒肽证实了 SK 通道的功能作用，从而证实了这些通道可能成为抗心律失常治疗的新的有前途的靶标这一假说。
