Effects of quinidine on the sodium current of guinea pig ventricular myocytes. Evidence for a drug-associated rested state with altered kinetics.
Effects of quinidine on the sodium current of guinea pig ventricular myocytes. Evidence for a drug-associated rested state with altered kinetics.
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DOI：
10.1161/01.res.66.2.565
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发表时间：
1990-02
影响因子：
20.1
通讯作者：
D. Snyders;L. Hondeghem
中科院分区：
文献类型：
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作者：
D. Snyders;L. Hondeghem
在豚鼠心肌细胞中，奎尼丁（20 μ M）在-120 mV时引起钠电流的强直阻滞减少不到10%，但快速脉冲串使其减少超过90%。使用依赖性阻滞的恢复具有时间和电压依赖性，并且总是缓慢的（-160 mV时tau = 34 +/- 10秒;-120 mV时tau = 90 +/- 35秒; n = 15，平均值+/- SD，p小于0.001，配对t检验）。然而，与重复激活相关的是，观察到从阻滞中恢复的快速成分：使用依赖性解除阻滞。超极化可增强钠通道的使用依赖性解除阻断作用，直至在-160 mV附近达到平台。与无药物钠通道的可利用性（h曲线）相比，使用依赖性解阻断的可利用性（h '曲线）的电压依赖性向更负的电位偏移约30 mV，斜率减小2.5倍。在-160 mV时，钠通道用于使用依赖性解除阻断的可用性的发展动力学是快速的（τ小于10 msec）。去极化至-120 mV降低了钠通道快速解除阻断的可用性，时间常数为191 +/- 46 msec（n = 14）。最后，通过频繁短暂去极化（激活）建立的阻滞在长时间失活期间下降。从这些结果中，我们得出结论，钠通道的时间和电压依赖性的可用性解锁是相当不同的可用性激活的无药物通道，休息药物相关的通道确实存在，和药物相关的通道不进行（或至少有一个大大降低电导）激活后，除非他们首先解锁。此外，激活和失活的渠道有不同的亲和力奎尼丁，因为奎尼丁可以占据通道受体，即使当“守卫”，我们的结果是不符合守卫受体假说，但可以解释的调制受体假说的框架内。
In guinea pig cardiac myocytes quinidine (20 microM) caused less than 10% tonic block reduction of the sodium current at -120 mV, but a fast pulse train reduced it more than 90%. Recovery from use-dependent block was time and voltage dependent, and was always slow (tau = 34 +/- 10 seconds at -160 mV; tau = 90 +/- 35 seconds at -120 mV; n = 15, mean +/- SD, p less than 0.001, paired t test). However, in association with repeated activation a fast component of recovery from block was observed: use-dependent unblocking. Availability of sodium channels for use-dependent unblocking was enhanced by hyperpolarization until a plateau was reached near -160 mV. Compared with the availability of drug-free sodium channels (h-curve), the voltage dependence of availability for use-dependent unblocking (h'-curve) was shifted by about 30 mV to more negative potentials, and its slope was reduced 2.5-fold. At -160 mV, the kinetics of development of availability of sodium channels for use-dependent unblocking were rapid (tau less than 10 msec). Depolarization to -120 mV reduced the availability of sodium channels for fast unblocking with a time constant of 191 +/- 46 msec (n = 14). Finally, block established by frequent brief depolarizations (activations) declined during prolonged inactivation. From these results we concluded that the time and voltage dependence of the availability of sodium channels for unblocking are considerably different from the availability for activation of drug-free channels, that rested drug-associated channels do exist, and that drug-associated channels do not conduct (or at least have a greatly reduced conductance) upon activation unless they first unblock. Furthermore, activated and inactivated channels have a different affinity for quinidine, and since quinidine can occupy the channel receptor even when "guarded," our results are incompatible with the guarded receptor hypothesis but can be explained within the framework of the modulated receptor hypothesis.