Johns J A, Anno T, Bennett P B, Snyders D J, Hondeghem L M
Department of Medicine, Vanderbilt University Medical School, Nashville, Tennessee, TN 37232.
J Cardiovasc Pharmacol. 1989 Jun;13(6):826-35. doi: 10.1097/00005344-198906000-00004.
O-demethyl encainide (ODE) is a metabolite of encainide with potent antiarrhythmic effects. We studied block of sodium channels by ODE in isolated guinea pig ventricular myocytes, using both direct measurement of whole cell sodium current and Vmax. Specifically, we examined whether block by ODE was use-dependent, whether ODE blocked activated or inactivated channels, and whether ODE's effect depended on membrane potential. At cold temperatures (15-20 degrees C), ODE was a potent blocker of activated cardiac sodium channels, with little or no effect on inactivated channels. At these temperatures, there was no detectable diastolic recovery from block. Repeated depolarizations produced use-dependent unblocking, which increased as the holding potential was made more negative. At warmer temperatures, use-dependent unblocking was increased, the availability curve of sodium channels for use-dependent unblocking was less shifted toward negative potentials, and diastolic recovery from block became detectable, albeit slow (tau approximately 25 s). Our findings demonstrate that electrophysiologic effects of agents such as ODE may be both quantitatively and qualitatively different at cold temperatures than at normal body temperature. One should be cautious about extrapolating electrophysiologic data obtained at cold temperatures to clinical situations.
O-去甲基恩卡胺（ODE）是恩卡胺的一种代谢产物，具有强大的抗心律失常作用。我们在分离的豚鼠心室肌细胞中研究了ODE对钠通道的阻断作用，采用了全细胞钠电流和Vmax的直接测量方法。具体而言，我们研究了ODE的阻断是否具有使用依赖性，ODE是阻断激活的还是失活的通道，以及ODE的作用是否依赖于膜电位。在低温（15 - 20摄氏度）下，ODE是激活的心脏钠通道的强效阻断剂，对失活通道几乎没有影响。在这些温度下，未检测到阻断后的舒张期恢复。重复去极化产生使用依赖性的解阻断，随着静息电位变得更负，这种解阻断增加。在较高温度下，使用依赖性解阻断增加，钠通道用于使用依赖性解阻断的可用性曲线向负电位的偏移较小，并且阻断后的舒张期恢复变得可检测到，尽管很慢（时间常数约为25秒）。我们的研究结果表明，像ODE这样的药物的电生理效应在低温下与正常体温下可能在数量和质量上都有所不同。在将低温下获得的电生理数据外推到临床情况时应谨慎。
