Background

Dofetilide is a new class III antiarrhythmic agent with demonstrated efficacy in ventricular and atrial tachyarrhythmias. We investigated its class HI actions and their modulation by stimulation rate in rabbit atrial myocardium.

Methods and Results

Standard microelectrode techniques were used to record action potentials from rabbit atrial tissue at varying stimulation rates. Dofetilide produced a dose-dependent prolongation of action potential duration at concentrations from 1 nM to 1 μM at an interstimulus interval of 1000 ms. Action potential duration at 90% repolarization (action potential duration) was prolonged from 116 ± 11.7 ms in control solutions to 148 ± 13.9 ms at 1nM dofetilide and 186 ± 49.3 ms at 1 μM dofetilide (P < .05 for 1 nM vs control; P < .01 for 1 μM vs control). Reduction of interstimulus interval to 500 ms had no significant effect on action potential duration prolongation by dofetilide. At faster rates than this, and particularly at an interstimulus interval less than 330 ms, a marked “reverse rate dependence” of the class III effect was observed. Specifically, the high therapeutic concentration of 10 nM showed no effect on action potential duration at interstimulus interval of 250 ms or 200 ms, and even at a concentration of 30 nM, the small class III effect was no longer statistically significant at these rates.

Conclusion

Dofetilide prolongs action potential duration in rabbit atrial myocardium, but this effect is significantly attenuated at stimulation rates above 2 Hz.

中文翻译：

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多芬利特在兔心房心肌中的III类抗心律失常作用

背景

多非利特是一种新型的III类抗心律失常药，在心室和房性快速性心律失常中具有证明的功效。我们调查了其在兔心房心肌中的HI类作用及其受刺激率的调节作用。

方法与结果

使用标准的微电极技术，以不同的刺激率记录来自兔心房组织的动作电位。在浓度为1 nM到1μM的浓度下，多非利肽以1000 ms的刺激间隔产生剂量依赖性的动作电位持续时间延长。90％复极时的动作电位持续时间（动作电位持续时间）从对照溶液中的116±11.7 ms延长到1nM多美替利时的148±13.9 ms和1μM多美替利时的186±49.3 ms（与对照组相比，P <0.05 P <相对于对照，1μM为0.01。减少刺激间隔至500毫秒对多非利特对动作电位持续时间的延长没有明显影响。以比这快的速率，特别是在小于330 ms的刺激间隔时，观察到了III类效应的明显“反向速率依赖性”。具体而言，高治疗浓度10 nM在250 ms或200 ms的刺激间隔时对动作电位持续时间没有影响，即使在30 nM的浓度下，在这些速率下较小的III类作用也不再具有统计学意义。

结论

Dofetilide延长了兔心房心肌的动作电位持续时间，但是在2 Hz以上的刺激速率下，这种作用明显减弱。