RESUMO

The antimalarial drug mefloquine, is known to be a potassium channel blocker, although its mechanism of action has not being elucidated and its effects on the transient outward current (Ito) and the molecular correlate, the Kv4.3 channel has not being studied. Here, we describe the mefloquine-induced inhibition of the rat ventricular Ito and of CHO cells co-transfected with human Kv4.3 and its accessory subunit hKChIP2C by whole-cell voltage-clamp. Mefloquine inhibited rat Ito and hKv4.3+KChIP2C currents in a concentration-dependent manner with a limited voltage dependence and similar potencies (IC50=8.9µM and 10.5µM for cardiac myocytes and Kv4.3 channels, respectively). In addition, mefloquine did not affect the activation of either current but significantly modified the hKv4.3 steady-state inactivation and recovery from inactivation. The effects of this drug was compared with that of 4-aminopyridine (4-AP), a well-known potassium channel blocker and its binding site does not seem to overlap with that of 4-AP.

Assuntos

Potenciais de Ação/efeitos dos fármacos , Antimaláricos/toxicidade , Ativação do Canal Iônico/efeitos dos fármacos , Mefloquina/toxicidade , Miócitos Cardíacos/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/toxicidade , Canais de Potássio Shal/antagonistas & inibidores , 4-Aminopiridina/farmacologia , Animais , Antimaláricos/metabolismo , Sítios de Ligação , Células CHO , Cricetulus , Relação Dose-Resposta a Droga , Feminino , Proteínas Interatuantes com Canais de Kv/genética , Proteínas Interatuantes com Canais de Kv/metabolismo , Mefloquina/metabolismo , Simulação de Acoplamento Molecular , Miócitos Cardíacos/metabolismo , Potássio/metabolismo , Bloqueadores dos Canais de Potássio/metabolismo , Ligação Proteica , Ratos Wistar , Canais de Potássio Shal/genética , Canais de Potássio Shal/metabolismo , Fatores de Tempo , Transfecção