Inhibition by a novel anti-arrhythmic agent, NIP-142, of cloned human cardiac K+ channel Kv1.5 current.
NIP-142 was shown to prolong atrial effective refractory period and to terminate atrial fibrillation and flutter in in vivo canine models. To obtain information on its antiarrhythmic action, we examined the effect of NIP-142 on cloned human cardiac K+ channel Kv1.5 (hKv1.5) currents stably expressed in a human cell line using whole-cell voltage clamp methods. NIP-142 inhibited the hKv1.5 current in a concentration-dependent and voltage-independent manner. The inhibition was larger at the end of depolarizing pulse than at the outward current peak. The IC50 for inhibition of the steady-state phase was 4.75 microM. A cross-over phenomenon was observed when current traces in the absence and presence of NIP-142 were superimposed. Inhibition of hKv1.5 current by NIP-142 was frequency-independent; changing the depolarizing pulse frequencies (0.1, 0.2, 1 Hz) and little effect on the degree of inhibition. NIP-142 decreased the maximal peak amplitude of kHv1.5 current at the first command pulse after 3 min rest in the presence of the drug. These results suggest that NIP-142 has inhibitory effects on the hKv 1.5 current through interaction with both open and closed states of the channel, which may underlie its antiarrhythmic activity in the atria.
Matsuda
T
T
Department of Pharmacology, Toho University School of Pharmaceutical Sciences, Funabashi, Chiba, Japan.
Masumiya
H
H
Tanaka
N
N
Yamashita
T
T
Tsuruzoe
N
N
Tanaka
Y
Y
Tanaka
H
H
Shigenoba
K
K
D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D002460:Cell Line; D003001:Cloning, Molecular; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020128:Inhibitory Concentration 50; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology
D000889:Anti-Arrhythmia Agents; D001578:Benzopyrans; C427584:NIP142; D026902:Potassium Channel Blockers; D015221:Potassium Channels