Referenced in: none

Automatically associated channels: Kv7.1

Title: Enhancing effects of salicylate on quinidine-induced block of human wild type and LQT3 related mutant cardiac Na+ channels.

Authors: Tadashi Urashima, Yasutaka Kurata, Junichiro Miake, Masaru Kato, Kazuyoshi Ogura, Akio Yano, Masamitsu Adachi, Yasunori Tanaka, Kensaku Yamada, Toshihiro Hamada, Einosuke Mizuta, Masanari Kuwabara, Masahiko Kato, Yasutaka Yamamoto, Kazuhide Ogino, Akio Yoshida, Yasuaki Shirayoshi, Ichiro Hisatome

Journal, date & volume: Biomed. Res., 2011 Oct , 32, 303-12

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/22033299

Abstract
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.