ヒト心筋Kv1.5チャネルに及ぼすnisoldipineの抑制機構

抄録

Human Kv1.5 (hKv1.5) channels conduct the ultra-rapid delayed rectifier potassium current (I_Kur) that is highly expressed in atria but scarcely in ventricle. hKv1.5 mediates action potential repolarization of human atrial myocytes and blockade of this channel has been expected to prolong the action potential duration (APD) and thereby reduce the occurrence of reentrant-based arrhythmias such as atrial fibrillation (AF). The aim of this study was to investigate the effect of nisoldipine a Ca²⁺ channel blocker used widely for the treatment of variety of cardiovascular disorders on hKv1.5 currents heterologously expressed in CHO cells. Nisoldipine, rapidly and reversibly inhibited hKv1.5 current in a concentration-dependent manner with an IC₅₀ of 3.0 μM. The block of hKv1.5 progressed with time during depolarizing voltage with a more rapid block at higher concentrations. Block increased rapidly between -40 mV and +10 mV, coincident with channel opening and suggested an open channel block mechanism. Nisoldipine markedly shifted the voltage dependence of channel opening to more hyperpolarizing potentials. In addition, mutations of T480A (near to pore helix) and I508A (located in S6 segment) significantly reduced the block action (with an IC₅₀ of 16.1 μM for T480A). The present results suggest that (i) nisoldipine inhibits hKv1.5 currents at relatively low concentration as an open channel blocker and (ii) the binding sites for the block are probably related to threonine 480 and isoleucine 508. [J Physiol Sci. 2008;58 Suppl:S75]