Novel, potent inhibitors of human Kv1.5 K+ channels and ultrarapidly activating delayed rectifier potassium current
Novel, potent inhibitors of human Kv1.5 K+ channels and ultrarapidly activating delayed rectifier potassium current
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DOI：
10.1124/jpet.106.101162
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发表时间：
2006-06-01
影响因子：
3.5
通讯作者：
Salata, Joseph J.
中科院分区：
文献类型：
--
作者：
Lagrutta, Armando;Wang, Jixin;Salata, Joseph J.
我们已经鉴定了一系列二苯基氧化膦（DPO）化合物，它们是克隆人类Kv1.5 （hKv1.5）通道的有效频率依赖性抑制剂。DPO在通道激活过程中以浓度依赖性的方式优先抑制hKv1.5在中国仓鼠卵巢细胞中的表达，并减缓尾电流的失活，符合开放通道阻断的主要机制。DPO与Kv1.5通道相互作用的不同动力学导致抑制的不同效价和频率依赖性，这些抑制对人类心房肌细胞中表达的hKv1.5电流和天然超快速激活延迟整流钾电流（I-Kur）具有可比性。在人心房肌细胞（I-Kur vs瞬时外向钾电流）和豚鼠心室肌细胞(I-Kur vs快速激活延迟整流钾电流（I-Kr），缓慢激活延迟整流钾电流（I-Ks）和内向整流钾电流（I-K1）中，DPO对其他心脏K+通道的选择性被证明是非洲蟾卵细胞中表达的Kv1.5通道比Kv3.1通道选择性高15倍。与选择性I-Kr阻滞剂的作用相反，DPO-1也延长了离体人心房肌细胞的动作电位，而不是心室肌细胞。DPO抑制hKv1.5和I-Kur的选择性和动力学以及由此产生的心房复极选择性延长可以为室上性心律失常的治疗提供有效的描述。
We have identified a series of diphenyl phosphine oxide (DPO) compounds that are potent frequency-dependent inhibitors of cloned human Kv1.5 (hKv1.5) channels. DPO inhibited hKv1.5 expressed in Chinese hamster ovary cells in a concentration-dependent manner preferentially during channel activation and slowed the deactivating tail current, consistent with a predominant open-channel blocking mechanism. Varying kinetics of DPO interaction with Kv1.5 channels resulted in differing potencies and frequency dependencies of inhibition that were comparable for both expressed hKv1.5 current and native ultrarapidly activating delayed rectifier potassium current (I-Kur) in human atrial myocytes. Selectivity of DPO versus other cardiac K+ channels was demonstrated in human atrial myocytes (I-Kur versus transient outward potassium current) and guinea pig ventricular myocytes [I-Kur versus rapidly activating delayed rectifier potassium current (I-Kr), slowly activating delayed rectifier potassium current (I-Ks) and inward rectifier potassium current (I-K1), and one compound (DPO-1) was shown to be 15-fold more selective for Kv1.5 versus Kv3.1 channels expressed in Xenopus oocytes. DPO-1 also prolonged action potentials of isolated human atrial but not ventricular myocytes, in contrast to the effect of a selective I-Kr blocker. The selectivity and kinetics of inhibition hKv1.5 and I-Kur by DPO and the resulting selective prolongation of atrial repolarization could provide an effective profile for treatment of supraventricular arrhythmias.