title: Nicorandil stimulates a Na⁺/Ca²⁺ exchanger by activating guanylate cyclase in guinea pig cardiac myocytes.
abstract: Nicorandil, a hybrid of an ATP-sensitive K(+) (KATP) channel opener and a nitrate generator, is used clinically for the treatment of angina pectoris. This agent has been reported to exert antiarrhythmic actions by abolishing both triggered activity and spontaneous automaticity in an in vitro study. It is well known that delayed afterdepolarizations (DADs) are caused by the Na(+)/Ca(2+) exchange current (I NCX). In this study, we investigated the effect of nicorandil on the cardiac Na(+)/Ca(2+) exchanger (NCX1). We used the whole-cell patch clamp technique and the Fura-2/AM (Ca(2+) indicator) method to investigate the effect of nicorandil on I NCX in isolated guinea pig ventricular myocytes and CCL39 fibroblast cells transfected with dog heart NCX1. Nicorandil enhanced I NCX in a concentration-dependent manner. The EC50 (half-maximum concentration for enhancement of the drug) values were 15.0 and 8.7 μM for the outward and inward components of I NCX, respectively. 8-Bromoguanosine 3',5'-cyclic monophosphate (8-Br-cGMP), a membrane-permeable analog of guanosine 3',5'-cyclic monophosphate (cGMP), enhanced I NCX. 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a guanylate cyclase inhibitor (10 μM), completely abolished the nicorandil-induced I NCX increase. Nicorandil increased I NCX in CCL39 cells expressing wild-type NCX1 but did not affect mutant NCX1 without a long intracellular loop between transmembrane segments (TMSs) 5 and 6. Nicorandil at 100 μM abolished DADs induced by electrical stimulation with ouabain. Nicorandil enhanced the function of NCX1 via guanylate cyclase and thus may accelerate Ca(2+) exit via NCX1. This may partially contribute to the cardioprotection by nicorandil in addition to shortening action potential duration (APD) by activating KATP channels.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, 431-3192, Japan.
authors.forename: Jiazhang
authors.initials: J
authors.lastname: Wei
authors.affiliation: Division of Pharmacological Science, Department of Health Science, Hamamatsu University School of Medicine, Hamamatsu, 431-3192, Japan. w-yasu@hama-med.ac.jp.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, 431-3192, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Takeuchi
authors.affiliation: Division of Pharmacological Science, Department of Health Science, Hamamatsu University School of Medicine, Hamamatsu, 431-3192, Japan.
authors.forename: Kanna
authors.initials: K
authors.lastname: Yamashita
authors.affiliation: Division of Pharmacological Science, Department of Health Science, Hamamatsu University School of Medicine, Hamamatsu, 431-3192, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Tashiro
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Fukuoka University, Fukuoka, 814-0180, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Kita
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Fukuoka University, Fukuoka, 814-0180, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Iwamoto
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, 431-3192, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Department of Pharmacology, Fukushima Medical University, Fukushima, 960-1295, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Kimura
mesh_terms: D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D006162:Guanylate Cyclase / Q000378:metabolism*; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D020108:Nicorandil / Q000494:pharmacology*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*
chemical_list: D000889:Anti-Arrhythmia Agents; D019831:Sodium-Calcium Exchanger; D020108:Nicorandil; D006162:Guanylate Cyclase; D002118:Calcium
keywords: Cardiac myocytes; Cyclic GMP; KATP channel opener; Na+/Ca2+ exchange current (I NCX); Nicorandil