Duloxetine inhibits voltage-dependent K plus channels in rabbit coronary arterial smooth muscle: Electrophysiological evidence and mechanistic insights

초록

Duloxetine, a serotonin-norepinephrine reuptake inhibitor, has been associated with increased blood pressure and other vascular side effects. However, the mechanisms underlying these effects remain poorly understood. Voltage-dependent K+ (Kv) channels are key regulators of membrane potential and vascular tone in arterial smooth muscle cells. Therefore, we examined the effects of duloxetine on Kv channels in rabbit coronary arterial smooth muscle cells using the whole-cell patch-clamp technique. Duloxetine inhibited arterial Kv currents in a concentration-dependent manner, with an IC50 of 4.95 +/- 0.15 mu M and a Hill coefficient of 1.13 +/- 0.03. Although duloxetine did not significantly alter the steady-state activation curve, it shifted the inactivation curve toward more negative potentials. These results suggest that duloxetine inhibits Kv channels by affecting their inactivation voltage sensor domain. The inhibitory action of duloxetine on Kv channels also occurred in a use (state)-dependent manner, as evidenced by a gradual reduction in current amplitude during repetitive stimulation and a prolonged recovery time from inactivation. Duloxetine-mediated inhibition of Kv channels was more closely associated with the Kv1.5 and Kv2.1 subtypes than with Kv7. Based on these findings, we conclude that duloxetine inhibits arterial Kv channels in a concentration-and use (state)-dependent manner by modulating voltage-dependent inactivation gating.

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