Jacobs E R, DeCoursey T E
Patch Clamp Center, Department of Medicine, Rush Medical Center, Chicago, Illinois.
J Pharmacol Exp Ther. 1990 Nov;255(2):459-72.
Block of inactivating delayed rectifier K+ currents was studied in rat alveolar epithelial cells in primary culture using the whole-cell configuration of the gigohm-seal voltage-clamp technique. Charybdotoxin was the only blocker studied which did not alter K+ current kinetics; it produced a simple block (K1 approximately 1 nM) which appeared to be independent of voltage or channel state (open, closed or inactivated). Tetraethylammonium slowed inactivation of K+ currents, consistent with the notion that blocked channels cannot inactivate. Verapamil and methoxyverapamil produced time-, voltage- and concentration-dependent "inactivation" or block of open channels during depolarizing pulses, with negligible block of closed channels at negative holding potentials. Capsaicin, chlorpromazine, phencyclidine, quinidine and tetrahydroaminoacridine both increased the rate of inactivation and decreased the peak K+ current. These characteristics suggest that both open and closed channels can be blocked, but that open channels are blocked preferentially. Nifedipine, like most other blockers, increased the rate of K+ current decay, but, unlike other blockers, resulted in two distinct kinetic components of current decay under some conditions. Because nifedipine is uncharged, the voltage and time-dependence of its block cannot be ascribed to a traditional ionic blockade mechanism. Mechanisms of K+ channel block are compared with block of Ca++ channels by calcium "antagonists" and block of Na+ channels by local anesthetics. Interactions between gating kinetics and K+ channel blockade seem to be the rule rather than the exception.
采用千兆欧封接电压钳技术的全细胞模式，对原代培养的大鼠肺泡上皮细胞中失活延迟整流钾电流的阻断进行了研究。大蝎毒素是所研究的唯一不改变钾电流动力学的阻断剂；它产生一种简单的阻断作用（K1约为1 nM），这种阻断似乎与电压或通道状态（开放、关闭或失活）无关。四乙铵减缓了钾电流的失活，这与被阻断的通道不能失活的观点一致。维拉帕米和甲氧维拉帕米在去极化脉冲期间产生时间、电压和浓度依赖性的“失活”或对开放通道的阻断，在负的钳制电位下对关闭通道的阻断可忽略不计。辣椒素、氯丙嗪、苯环利定、奎尼丁和四氢氨基吖啶既增加了失活速率，又降低了钾电流峰值。这些特性表明开放通道和关闭通道均可被阻断，但开放通道优先被阻断。硝苯地平与大多数其他阻断剂一样，增加了钾电流衰减速率，但与其他阻断剂不同的是，在某些条件下导致电流衰减出现两个不同的动力学成分。由于硝苯地平不带电荷，其阻断的电压和时间依赖性不能归因于传统的离子阻断机制。将钾通道阻断机制与钙“拮抗剂”对钙通道的阻断以及局部麻醉药对钠通道的阻断进行了比较。门控动力学与钾通道阻断之间的相互作用似乎是规律而非例外。
