Ionic mechanisms underlying overdrive suppression of sinoatrial node cells

当快速驱动时，窦房结起搏细胞的自发活动被一过性地抑制，这种现象被称为“过驱动抑制”。虽然已经提出了几种机制，但仍有许多问题需要澄清。最近，Boyett等人发现，在心室肌细胞中，刺激速度的增加导致L型钙电流(I_&lt；Ca&gt；)突然下降，然后缓慢下降。I&lt；Ca&gt；的缓慢下降被解释为I&lt；Ca&gt；的超慢电压依赖失活。本研究用全细胞钳技术研究了I&lt；Ca&Gt；失活对兔SA结节细胞超驱动抑制的作用。在电流钳制模式下，快速刺激(6.7赫兹)后，自发活动一过性抑制。在电压钳制模式下，当保持电位(HP)为-40 mV时，去极化频率从1赫兹增加到6.7赫兹，导致I&lt；Ca&gt；的急剧下降，随后又逐渐下降。当Hp为-80 mV时，脉搏频率的增加引起的I&t；Ca&Gt；下降幅度较小。当自发动作电位被-40 mV的高频脉冲串(6.7赫兹)打断时，在训练过程中I_t；Ca&gt；再次显著降低，并在训练后出现一过性的自发活动抑制。相反，由-80 mV的HP发出的高频脉冲的中断并没有引起I&lt；Ca&gt；的降低，而且训练后的自发活动也没有受到抑制。一系列高频脉冲对延迟整流钾电流和超极化激活电流均无影响。这些结果表明，SA节点中的过驱动抑制，至少部分是I_&lt；Ca&gt；的频率和电压依赖性失活的结果。

Spontaneous activity of sinoatrial (SA) node pacemaker cells are transiently suppressed when driven at a rapid rate, and this phenomenon is known as "overdrive suppression". Although several mechanisms have been proposed, much remains to be clarified. Recently Boyett et al.showed that in ventricular cells, an increase in the rate of stimulation led to an abrupt, followed by a slow, decrease in the L-type calcium current (I_<Ca>). The slow decrease in I_<Ca> was interpreted as an ultra-slow voltage-dependent inactivation of I_<ca>. In the present study, the contribution of inactivation of I_<Ca> to overdrive suppression was investigated in rabbit SA node cells by use of the whole-cell clamp technique. In the current-clamp mode, rapid stimulation (6.7Hz) was followed by a transient suppression of spontaneous activity. In the voltage-clamp mode, an increase in the rate of depolarization from 1 to 6.7 Hz from a holding potential (HP) of -40 mV resulted in an abrupt, followed by a progressive, decrease in I_<Ca>. With a HP of -80 mV,an increase in the pulse rate caused much less reduction of I_<Ca>. When spontaneous action potential was interrupted by a train of high-frequency pulses (6.7 Hz) from a HP of-40mV,there was again a marked decrease in I_<Ca> during the train, and after the train there was a transient suppression of spontaneous activity. In contrast, an interruption by high-frequency pulses from a HP of -80mV caused no decrease in I_<Ca>, and there was no suppression of spontaneous activity after the train. Neither delayd rectifier potassium current nor hyperpolarization-activated current was affected after a train of high-frequency pulses. These results suggest that overdrive suppression in the SA node is, in part at least, the result of a rate-and voltage-dependent inactivation of I_<Ca>.