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- Title
Nicorandil stimulates a Na/Ca exchanger by activating guanylate cyclase in guinea pig cardiac myocytes.
- Authors
Wei, Jiazhang; Watanabe, Yasuhide; Takeuchi, Kazuhiko; Yamashita, Kanna; Tashiro, Miyuki; Kita, Satomi; Iwamoto, Takahiro; Watanabe, Hiroshi; Kimura, Junko
- 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 exchange current ( I). In this study, we investigated the effect of nicorandil on the cardiac Na/Ca exchanger (NCX1). We used the whole-cell patch clamp technique and the Fura-2/AM (Ca indicator) method to investigate the effect of nicorandil on I in isolated guinea pig ventricular myocytes and CCL39 fibroblast cells transfected with dog heart NCX1. Nicorandil enhanced I in a concentration-dependent manner. The EC (half-maximum concentration for enhancement of the drug) values were 15.0 and 8.7 μM for the outward and inward components of I, respectively. 8-Bromoguanosine 3′,5′-cyclic monophosphate (8-Br-cGMP), a membrane-permeable analog of guanosine 3′,5′-cyclic monophosphate (cGMP), enhanced I. 1 H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a guanylate cyclase inhibitor (10 μM), completely abolished the nicorandil-induced I increase. Nicorandil increased I 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 exit via NCX1. This may partially contribute to the cardioprotection by nicorandil in addition to shortening action potential duration (APD) by activating KATP channels.
- Subjects
NICORANDIL; GUANYLATE cyclase; GUINEA pigs; MUSCLE cells; ANGINA pectoris treatment; MYOCARDIAL depressants
- Publication
Pflügers Archiv: European Journal of Physiology, 2016, Vol 468, Issue 4, p693
- ISSN
0031-6768
- Publication type
Article
- DOI
10.1007/s00424-015-1763-8