Department of Physiology, University of Debrecen, Nagyerdei krt. 98. H-4012 Debrecen, Hungary.
Curr Med Chem. 2011;18(24):3597-606. doi: 10.2174/092986711796642355.
Class 3 antiarrhythmic agents exhibit reverse rate-dependent lengthening of the action potential duration (APD), i.e. changes in APD are greater at longer than at shorter cycle lengths. In spite of the several theories developed to explain this reverse rate-dependency, its mechanism has been clarified only recently. The aim of the present study is to elucidate the mechanisms responsible for reverse rate-dependency in mammalian ventricular myocardium. Action potentials were recorded using conventional sharp microelectrodes from human, canine, rabbit, guinea pig, and rat ventricular myocardium in a rate-dependent manner. Rate-dependent drug-effects of various origin were studied using agents known to lengthen or shorten action potentials allowing thus to determine the drug-induced changes in APD as a function of the cycle length. Both drug-induced lengthening and shortening of action potentials displayed reverse rate-dependency in human, canine, and guinea pig preparations, but not in rabbit and rat myocardium. Similar results were obtained when repolarization was modified by injection of inward or outward current pulses in isolated canine cardiomyocytes. In contrast to reverse rate-dependence, drug-induced changes in APD well correlated with baseline APD values (i.e. that measured before the superfusion of drug or injection of current) in all of the preparations studied. Since the net membrane current (I(net)), determined from the action potential waveform at the middle of the plateau, was inversely proportional to APD, and consequently to cycle length, it is concluded that that reverse rate-dependency may simply reflect the inverse relationship linking I(net) to APD. In summary, reverse rate-dependency is an intrinsic property of drug action in the hearts of species showing positive APD - cycle length relationship, including humans. This implies that development of a pure K(+) channel blocking agent without reverse rate-dependent effects is not likely to be successful.
III 类抗心律失常药物表现出反向的频率依赖性动作电位时程（APD）延长，即 APD 的变化在较长的心动周期比在较短的心动周期更为明显。尽管已经提出了几种理论来解释这种反向频率依赖性，但它的机制直到最近才得到阐明。本研究的目的是阐明哺乳动物心室心肌中反向频率依赖性的机制。使用传统的尖锐微电极，从人心、犬心、兔心、豚鼠心和鼠心以频率依赖性的方式记录动作电位。使用已知能延长或缩短动作电位的药物，研究各种来源的频率依赖性药物效应，从而可以确定药物诱导的 APD 变化作为心动周期的函数。在人心、犬心和豚鼠心肌中，药物诱导的动作电位延长和缩短都表现出反向频率依赖性，但在兔心和鼠心中则没有。在分离的犬心肌细胞中，通过注入内向或外向电流脉冲来改变复极化时，也得到了类似的结果。与反向频率依赖性相反，在所有研究的制剂中，药物诱导的 APD 变化与基线 APD 值（即在药物灌注或电流注射之前测量的 APD 值）很好地相关。由于从动作电位平台中部的动作电位波形确定的净膜电流（I（net））与 APD 成反比，并且与心动周期长度成反比，因此可以得出结论，反向频率依赖性可能简单地反映了将 I（net）与 APD 联系起来的反比关系。总之，反向频率依赖性是在具有正 APD-心动周期关系的物种（包括人类）心脏中药物作用的固有特性。这意味着开发一种没有反向频率依赖性的纯 K（+）通道阻断剂不太可能成功。
