Enhancing effects of salicylate on quinidine-induced block of human wild type and LQT3 related mutant cardiac Na+ channels.
It is unknown whether salicylate enhances the action of antiarrhythmic agents on human Na+ channels with state dependency and tissue specificity. We therefore investigated effects of salicylate on quinidine-induced block of human cardiac and skeletal muscle Na+ channels. Human cardiac wild-type (hH1), LQT3-related mutant (ΔKPQ), and skeletal muscle (hSkM1) Na+ channel α subunits were expressed in COS7 cells. Effects of salicylate on quinidine-induced tonic and use-dependent block of Na+ channel currents were examined by the whole-cell patch-clamp technique. Salicylate enhanced the quinidine-induced tonic and use-dependent block of both hH1 and hSkM1 currents at a holding potential (HP) of -100 mV but not at -140 mV. Salicylate decreased the IC50 value for the quinidine-induced tonic block of hH1 at an HP of -100 mV, and produced a negative shift in the steady-state inactivation curve of hH1 in the presence of quinidine. According to the modulated receptor theory, it is probable that salicylate decreases the dissociation constant for quinidine binding to inactivated-state channels. Furthermore, salicylate significantly enhanced the quinidine-induced tonic and use-dependent block of the peak and steady-state ΔKPQ channel currents. The results suggest that salicylate enhances quinidine-induced block of Na+ channels via increasing the affinity of quinidine to inactivated state channels.
Division of Regenerative Medicine and Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Science, Japan.
Tadashi
T
Urashima
Yasutaka
Y
Kurata
Junichiro
J
Miake
Masaru
M
Kato
Kazuyoshi
K
Ogura
Akio
A
Yano
Masamitsu
M
Adachi
Yasunori
Y
Tanaka
Kensaku
K
Yamada
Toshihiro
T
Hamada
Einosuke
E
Mizuta
Masanari
M
Kuwabara
Masahiko
M
Kato
Yasutaka
Y
Yamamoto
Kazuhide
K
Ogino
Akio
A
Yoshida
Yasuaki
Y
Shirayoshi
Ichiro
I
Hisatome
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006321:Heart / Q000187:drug effects; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel; D011485:Protein Binding; D011802:Quinidine / Q000378:metabolism / Q000494:pharmacology*; D012459:Salicylates / Q000494:pharmacology*; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism*
D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D012459:Salicylates; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D011802:Quinidine