Electrophysiological Characterization of MK886-Mediated Suppression of Voltage-Gated K+ Currents in Rabbit Coronary Artery Smooth Muscle Cells

초록

MK886 is a selective inhibitor of 5-lipoxygenase-activating protein that suppresses leukotriene synthesis and improves vascular reactivity in rabbit models of endotoxic shock. However, its direct effects on vascular voltage-gated K+ (Kv) channels remain unclear. In this study, we used the whole-cell patch-clamp technique to investigate the electrophysiological actions of MK886 on Kv currents in rabbit coronary artery smooth muscle cells. MK886 inhibited Kv currents in a concentration-dependent manner, with an IC50 of 0.51 +/- 0.23 mu M and a Hill coefficient of 0.9 +/- 0.14 (n = 8). While steady-state activation was not significantly affected, MK886 induced a pronounced leftward shift in the steady-state inactivation curve, implying preferential binding to the inactivated state of the channel. Consistent with this interpretation, it produced use-dependent inhibition during repetitive depolarizing pulses at 1 and 2 Hz and significantly slowed recovery from inactivation. Pharmacological dissection using subtype-selective Kv channel inhibitors revealed that the MK886-induced inhibition was reduced in the presence of DPO-1, stromatoxin-1, and linopirdine compared with MK886 alone. The reduction was more pronounced under DPO-1 and stromatoxin-1 conditions, suggesting that Kv1.5- and Kv2.1-related components may contribute to MK886-induced Kv current inhibition, with possible involvement of Kv7-related components to a lesser extent. In conclusion, MK886 directly suppresses rabbit coronary artery Kv currents in a concentration- and state-dependent manner by modulating inactivation gating, with substantial involvement of Kv1.5- and Kv2.1-related channel components and possible contribution of Kv7-related components.

키워드