O-20137 A novel volume-regulated anion channel inhibitor, YM-255693, prevents ischemia-induced arrhythmia in rats

The aim of this study is to evaluate a contribution of the volume-regulated anion channel (VRAC) to ischemia-induced arrhythmia. YM-255693, an isothiazol derivative, inhibited VRAC in hypotonic stimulus-induced taurine efflux assay in HeLa cells (IC50=0. 83μM) more potently than often-used VRAC bloc...

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Bibliographic Details
Published in:Journal of Pharmacological Sciences 2004, Vol.94 (suppl.1), p.108-108
Main Authors: Hiroshi Shibata, Tomo-oki Satoh, Tohru Ugawa, Hiroko Yanai-Inamura, Noriyuki Masuda, Wataru Uchida, Keiji Miyata
Format: Article
Language:Japanese
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Summary:The aim of this study is to evaluate a contribution of the volume-regulated anion channel (VRAC) to ischemia-induced arrhythmia. YM-255693, an isothiazol derivative, inhibited VRAC in hypotonic stimulus-induced taurine efflux assay in HeLa cells (IC50=0. 83μM) more potently than often-used VRAC blocker, DIDS or NPPB. In contrast, YM-255693 weakly inhibited Ca2+-activated and cAMP-activated Cl- channel in HTC cells (IC50=5. 9μM) and T84 cells (40% at 30μM), respectively. VRAC is reported to be involved in control of membrane potential in the ischemic condition in cardiac myocytes. YM-255693 was, therefore, tested in ischemia-induced arrhythmia models in vitro and in vivo. YM-255693 prevented coronary artery (LAD) ligation-induced ventricular arrhythmias in Langendorff-perfused rat hearts. Moreover, YM-255693 at 30mg/kg i. v. inhibited LAD ligation-induced ventricular arrhythmias in anesthetized rats. Our data suggest that VRAC contributes to the occurrence of ventricular arrhythmias, and that VRAC inhibitors such as YM-255693 constitute a new class of antiarrhythmic agents.
ISSN:1347-8613