Xu Y Q, Pickoff A S, Clarkson C W
Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112.
Circ Res. 1991 Sep;69(3):644-56. doi: 10.1161/01.res.69.3.644.
The voltage-dependent properties of the voltage-activated sodium channel were studied in neonatal (1-2-day-old) and adult rat ventricular cardiac myocytes using the whole-cell variation of the patch-clamp technique (16 degrees C, [Na]i = 15 mM, [Na]o = 25 mM). The voltage dependence of the sodium conductance-membrane potential relation was similar in both neonatal and adult myocytes except for a difference in slope; the adult sodium conductance-membrane potential relation was slightly more steep. Neonatal cells also differed from adult cells by demonstrating a more negative voltage midpoint of their sodium availability curve, a slower rate of recovery from inactivation at hyperpolarized potentials, and a greater extent of slow inactivation development compared with adult cells. Phenytoin (40 microM) reduced the sodium current in a tonic and use-dependent manner in both adult and neonatal myocytes. However, phenytoin (40 microM) produced significantly more tonic block at negative holding potentials (e.g., -140 mV) in neonatal myocytes (22 +/- 5% [mean +/- SEM], n = 14) than in adult myocytes (10 +/- 2%, n = 11) (p less than 0.05). The amplitudes of use-dependent block obtained during trains of 1-second pulses to -20 mV were also significantly greater in neonatal myocytes than in adult myocytes when the diastolic interval was varied over a range of 0.1-1.5 seconds (p less than 0.05). Definition of the time courses of block development at -20 mV indicated that phenytoin had a slightly higher affinity for inactivated sodium channels in neonatal cells. In addition, the time constant of recovery from use-dependent block by phenytoin was found to be significantly longer in neonatal cells than in adult cells at membrane potentials between -160 and -100 mV (p less than 0.001). The marked differences in phenytoin effect on cardiac sodium channels in neonatal versus adult rat cardiac myocytes suggest that there may be significant developmental changes in the sodium channel blocking effects of class I antiarrhythmic drugs in cardiac tissue.
利用膜片钳技术的全细胞记录模式（16℃，[Na]i = 15 mM，[Na]o = 25 mM），研究了新生（1 - 2日龄）和成年大鼠心室肌细胞中电压门控钠通道的电压依赖性特性。新生和成年心肌细胞中钠电导-膜电位关系的电压依赖性相似，但斜率不同；成年的钠电导-膜电位关系稍陡。新生细胞与成年细胞的不同之处还在于，其钠通道可用率曲线的电压中点更负，在超极化电位下从失活状态恢复的速率较慢，且与成年细胞相比，缓慢失活的发展程度更大。苯妥英（40 μM）以强直和使用依赖性方式降低成年和新生心肌细胞中的钠电流。然而，苯妥英（40 μM）在新生心肌细胞（22±5% [平均值±标准误]，n = 14）中负性钳制电位（如 - 140 mV）时产生的强直阻滞明显多于成年心肌细胞（10±2%，n = 11）（p < 0.05）。当舒张期在0.1 - 1.5秒范围内变化时，在一系列1秒脉冲至 - 20 mV期间获得的使用依赖性阻滞幅度在新生心肌细胞中也明显大于成年心肌细胞（p < 0.05）。对 - 20 mV时阻滞发展时间进程的定义表明，苯妥英对新生细胞中失活钠通道的亲和力略高。此外，发现在 - 160至 - 100 mV的膜电位下，苯妥英引起的使用依赖性阻滞恢复的时间常数在新生细胞中明显长于成年细胞（p < 0.001）。苯妥英对新生与成年大鼠心肌细胞中心脏钠通道的作用存在显著差异，这表明I类抗心律失常药物在心脏组织中对钠通道的阻滞作用可能存在显著的发育变化。
