Lurasidone is a second-generation antipsychotic drug used to treat schizophrenia, mania, and bipolar disorder. The drug is an antagonist of the 5-HT2A and D2 receptors. No effect of lurasidone on the voltage-gated K+ (Kv) channels has yet been identified. Here, we show that lurasidone inhibits the vascular Kv channels of rabbit coronary arterial smooth muscle cells in a dose-dependent manner with an IC50 of 1.88 ± 0.21 μM and a Hill coefficient of 0.98 ± 0.09. Although lurasidone (3 μM) did not affect the activation kinetics, the drug negatively shifted the inactivation curve, suggesting that the drug interacted with the voltage sensors of Kv channels. Application of 1 or 2 Hz train steps in the presence of lurasidone significantly increased Kv current inhibition. The recovery time after channel inactivation increased in the presence of lurasidone. These results suggest that the inhibitory action of lurasidone is use (state)-dependent. Pretreatment with a Kv 1.5 subtype inhibitor effectively reduced the inhibitory effect of lurasidone. However, the inhibitory effect on Kv channels did not markedly change after pretreatment with a Kv 2.1 or a Kv7 subtype inhibitor. In summary, lurasidone inhibits vascular Kv channels (primarily the Kv1.5 subtype) in a concentration- and use (state)-dependent manner by shifting the steady-state inactivation curve.
Keywords: Coronary arterial smooth muscle cell; Electrophysiology; Lurasidone; Voltage-gated K(+) channel.
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