The Second‐Generation Antipsychotic Perospirone Inhibits Voltage‐Gated K ⁺ Channels in Coronary Arterial Smooth Muscle Cells

Perospirone is a second-generation antipsychotic classified as a serotonin-dopamine antagonist that is primarily used to treat schizophrenia and bipolar disorder. While its therapeutic effects have been attributed to D₂ and 5-HT_2A receptor antagonism and partial 5-HT_1A agonism, its potential interactions with ion channels remain unexplored. In this study, we investigated the effects of perospirone on vascular voltage-gated K⁺ (Kv) channels in freshly isolated rabbit coronary arterial smooth muscle cells. Perospirone inhibited vascular Kv channels in a concentration-dependent manner, with a half-maximal inhibitory concentration (IC₅₀) of 20.54 ± 2.89 μM and a Hill coefficient of 0.92 ± 0.07. Perospirone did not change the activation or inactivation kinetics and did not exhibit use-dependent inhibition, suggesting that the interaction between the drug and the channels did not affect the voltage sensors or conformational states of the channels. Pretreatment with the Kv2.1 inhibitor guangxitoxin or the Kv7 inhibitor linopirdine did not change the extent of the perospirone-induced Kv current inhibition, whereas pretreatment with the Kv1.5 inhibitor DPO-1 partially attenuated the inhibitory effect of perospirone on Kv currents. These findings demonstrate that perospirone inhibits vascular Kv1.5 subtype channels in a concentration-dependent but use-independent manner. This previously unrecognized off-target effect suggests that perospirone can affect vascular function, highlighting its potential cardiovascular implications in clinical settings.