Inhibition of voltage-dependent K+ channels by iloperidone in coronary arterial smooth muscle cells.
J Appl Toxicol
; 40(9): 1297-1305, 2020 09.
Article
en En
| MEDLINE
| ID: mdl-32285496
ABSTRACT
Iloperidone, a second-generation atypical antipsychotic drug, is widely used in the treatment of schizophrenia. However, the side-effects of iloperidone on vascular K+ channels remain to be determined. Therefore, we explored the effect of iloperidone on voltage-dependent K+ (Kv) channels in rabbit coronary arterial smooth muscle cells using the whole-cell patch-clamp technique. Iloperidone inhibited vascular Kv channels in a concentration-dependent manner with a half-maximal inhibitory concentration (IC50 ) of 2.11 ± 0.5 µM and a Hill coefficient of 0.68 ± 0.03. Iloperidone had no effect on the steady-state inactivation kinetics. However, it shifted the steady-state activation curve to the right, indicating that iloperidone inhibited Kv channels by influencing the voltage sensors. Application of 20 repetitive depolarizing pulses (1 and 2 Hz) progressively increased the inhibition of the Kv current in the presence of iloperidone. Furthermore, iloperidone increased the recovery time constant from Kv channel inactivation, suggesting that iloperidone-induced inhibition of Kv channels is use (state)-dependent. Pretreatment with a Kv1.5 inhibitor (diphenyl phosphine oxide 1 [DPO-1]) inhibited the Kv current to a level similar to that with iloperidone alone. However, pretreatment with a Kv2.1 or Kv7.X inhibitor (guangxitoxin or linopirdine) did not affect the inhibitory effect of iloperidone on Kv channels. Therefore, iloperidone directly inhibits Kv channels in a concentration- and use (state)-dependent manner independently of its antagonism of serotonin and dopamine receptors. Furthermore, the primary target of iloperidone is the Kv1.5 subtype.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Piperidinas
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Antipsicóticos
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Vasos Coronarios
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Miocitos del Músculo Liso
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Canales Aniónicos Dependientes del Voltaje
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Isoxazoles
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Potenciales de la Membrana
Idioma:
En
Revista:
J Appl Toxicol
Año:
2020
Tipo del documento:
Article
País de afiliación:
Corea del Sur