Ren X L, Hoffman B F
Department of Pharmacology, Columbia University, College of Physicians and Surgeons, New York, New York 10032.
J Cardiovasc Electrophysiol. 1994 May;5(5):412-21. doi: 10.1111/j.1540-8167.1994.tb01180.x.
During the subacute phase of infarction in the canine heart, the subendocardial Purkinje fibers subtended by the infarct show depolarization greater than can be accounted for by the decrease in [K+]i, and generate abnormal action potentials and spontaneous rhythms due to abnormal automaticity. We have used pinacidil to hyperpolarize these fibers and evaluate the extent to which an increase in resting potential can normalize action potential generation.
Twenty-four hours after two-stage ligation of the canine left anterior descending coronary artery, preparations of subendocardial Purkinje fibers were studied in vitro by recording transmembrane potentials through standard microelectrodes and exposing the preparation to pinacidil and increases in [K+]o. Pinacidil increased resting potential to the estimated value of EK, abolished the abnormal automaticity, and restored action potentials of normal amplitude with normal values of Vmax. This effect often persisted after washout of pinacidil. Elevation of [K+]o from 4.0 to 20.0 mM slightly increased maximum diastolic potential, suggesting that the excess (over the change in EK) depolarization was caused by a decrease in gK1.
The ventricular arrhythmias seen during the subacute stage of infarction probably are caused by abnormal automaticity. Our findings support the conclusion that this abnormal automaticity arises in partially depolarized subendocardial Purkinje fibers. This loss of resting potential is due in large part to a decrease in gK1. Restoration of resting potential to the value of EK permits the Purkinje fibers to develop essentially normal action potentials. An agent capable of reversing the partial block of IK,1 thus might be an effective drug for some types of arrhythmias.
在犬类心脏梗死的亚急性期，梗死区域下方的心内膜下浦肯野纤维表现出的去极化程度大于因细胞内钾离子浓度降低所能解释的程度，并由于异常自律性产生异常动作电位和自发节律。我们使用吡那地尔使这些纤维超极化，并评估静息电位增加能在多大程度上使动作电位的产生恢复正常。
在犬左前降支冠状动脉进行两阶段结扎24小时后，通过标准微电极记录跨膜电位，并将标本暴露于吡那地尔和细胞外钾离子浓度升高的环境中，对心内膜下浦肯野纤维标本进行体外研究。吡那地尔将静息电位提高到估计的钾离子平衡电位值，消除了异常自律性，并恢复了具有正常最大上升速率值的正常幅度动作电位。在冲洗掉吡那地尔后，这种效应常常持续存在。将细胞外钾离子浓度从4.0 mM升高到20.0 mM会使最大舒张电位略有增加，这表明（超过钾离子平衡电位变化的）过度去极化是由内向整流钾电流通道电导降低所致。
梗死亚急性期出现的室性心律失常可能是由异常自律性引起的。我们的研究结果支持这样的结论，即这种异常自律性出现在部分去极化的心内膜下浦肯野纤维中。这种静息电位的丧失在很大程度上是由于内向整流钾电流通道电导降低所致。将静息电位恢复到钾离子平衡电位值可使浦肯野纤维产生基本正常的动作电位。因此，一种能够逆转内向整流钾电流通道部分阻滞的药物可能是治疗某些类型心律失常的有效药物。
