Blockade of Voltage-Gated K+ Channels in Rabbit Coronary Arterial Smooth Muscle Cells by the Antipsychotic Drug Zotepine.

Zotepine is a second-generation antipsychotic that demonstrates significant efficacy in antagonizing D₂ and 5-HT_2A receptors. Although clinical investigations have shown that administering zotepine is associated with an increased prevalence of hyperglycemia and a heightened risk of cardiovascular disease, the side effects of zotepine on voltage-gated K⁺ (Kv) channels have not been established. Zotepine suppressed the vascular Kv channels in rabbit coronary arterial smooth muscle cells in a concentration-dependent manner, with an IC₅₀ of 5.3 ± 0.4 μM and a Hill coefficient of 1.6 ± 0.2. The decay rate of inactivation was significantly accelerated by zotepine. Applying zotepine (10 μM) shifted the steady-state inactivation curve in a negative direction. Applying train pulses at 1 and 2 Hz resulted in a progressive increase in blockage of the Kv currents by zotepine. Furthermore, zotepine prolonged the recovery time from inactivation. Although pretreatment with the Kv2.1 subtype inhibitor stromatoxin-1 and the Kv7 subtype inhibitor linopirdine did not change the degree of zotepine-induced inhibition of Kv currents, pretreatment with the Kv1.5 channel inhibitor DPO-1 decreased the inhibitory effects of zotepine on Kv currents. Zotepine also induced membrane depolarization. These results indicate that zotepine inhibits Kv currents (mainly Kv1.5 subtype) in dose-, time-, and use (state)-dependent manners by changing the steady-state inactivation curve.