Comparison of kinetic properties of quinidine and dofetilide block of HERG channels.
Comparison of kinetic properties of quinidine and dofetilide block of HERG channels.
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DOI：
10.1016/j.ejphar.2004.04.015
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发表时间：
2004-06
影响因子：
5
通讯作者：
K. Tsujimae;Shingo Suzuki;M. Yamada;Y. Kurachi
中科院分区：
文献类型：
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作者：
K. Tsujimae;Shingo Suzuki;M. Yamada;Y. Kurachi
许多药物抑制人类乙醚-a-go-go相关基因(HERG)电流，延长心脏动作电位时程。我们研究了在非洲爪哇卵母细胞中表达的HERG通道奎尼丁阻滞剂的动力学特性，并与III类抗心律失常药多非利特的阻滞剂进行了比较。这两种药物均以使用依赖和频率无关的方式抑制Herg电流。然而，潜在的机制是不同的。在稳态下，奎尼丁阻滞剂具有电压和时间依赖性。在膜电位为正值时，阻断起效非常快。因此，奎尼丁主要通过这种快速的阻断动力学引起频率无关的阻断。相反，多非利特在稳态下以电压和时间无关的方式阻断HERG电流，这是因为在负电位下的解锁非常缓慢，这也导致了频率无关的阻断。因此，奎尼丁和多非利特可能通过不同的阻断和解阻动力学机制引起动作电位时程的逆频率依赖性延长。
Many drugs inhibit human ether-a-go-go related gene (HERG) current and prolong cardiac action potential duration. We examined the kinetic properties of quinidine block of HERG channels expressed in Xenopus oocytes in comparison with those of the block by a class III antiarrhythmic dofetilide. Both of the drugs inhibited HERG currents in a use-dependent and frequency-independent manner. However, the underlying mechanisms were different. Under the steady state, quinidine block was voltage- and time-dependent. At positive membrane potentials, the onset of block was very fast. Thus, quinidine caused frequency-independent block mainly through this fast blocking kinetic. In contrast, dofetilide blocked HERG currents in a voltage- and time-independent manner under the steady state because of very slow unblocking at negative potentials, which also caused frequency-independent block. Therefore, quinidine and dofetilide might cause the reverse frequency-dependent prolongation of action potential duration through distinct mechanisms with regard to blocking and unblocking kinetics.