Inhibitory effects of vesnarinone on cloned cardiac delayed rectifier K(+) channels expressed in a mammalian cell line.
Vesnarinone, a phosphodiesterase inhibitor, prolongs cardiac action potential duration by inhibiting the delayed rectifier K(+) current, I(K). We examined the effect of this agent on human ether-a-go-go related gene (HERG) and KvLQT1/minK K(+) channels heterologously expressed in human embryonic kidney 293T cells with the whole-cell patch-clamp technique. HERG channel current was inhibited by vesnarinone in a concentration-dependent manner, whereas KvLQT1/minK current was hardly affected by the drug. The inhibition of HERG current by vesnarinone became more prominent and faster as the membrane potential was more depolarized. The properties of inhibition could be described by a first order reaction between the drug and the channel that was apparently independent of HERG channel gating. Although the unbinding rate constant of the drug was constant, the apparent binding rate constant increased as the membrane was more depolarized and the drug concentration was raised. This model also could explain the fast recovery from the drug's effect at hyperpolarized potentials and its rate-dependent inhibition of HERG. Therefore, the effect of vesnarinone on the HERG-K(+) current could be adequately described by a simple kinetic model of drug-channel interaction.
Katayama
Y
Y
Department of Pharmacology II, Faculty of Medicine & Graduate School of Medicine, Osaka University, Osaka, Japan.
Fujita
A
A
Ohe
T
T
Findlay
I
I
Kurachi
Y
Y
D000200:Action Potentials / Q000187:drug effects; D027682:Cation Transport Proteins; D002460:Cell Line; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006321:Heart / Q000187:drug effects*; D006801:Humans; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011719:Pyrazines; D011804:Quinolines / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013997:Time Factors; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D010726:Phosphodiesterase Inhibitors; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011719:Pyrazines; D011804:Quinolines; D011994:Recombinant Proteins; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; C059983:potassium channel protein I(sk); C041667:vesnarinone