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Nicorandil stimulates a Na+/Ca2+ exchanger by activating guanylate cyclase in guinea pig cardiac myocytes

  • Muscle physiology
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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+/Ca2+ exchange current (I NCX). In this study, we investigated the effect of nicorandil on the cardiac Na+/Ca2+ exchanger (NCX1). We used the whole-cell patch clamp technique and the Fura-2/AM (Ca2+ 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 Ca2+ exit via NCX1. This may partially contribute to the cardioprotection by nicorandil in addition to shortening action potential duration (APD) by activating KATP channels.

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Abbreviations

APD:

Action potential duration

DADs:

Delayed afterdepolarizations

I NCX :

Na+/Ca2+ exchange current

I-V :

Current-voltage

KATP channel:

ATP-sensitive K+ channel

TMSs:

Transmembrane segments

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Acknowledgments

This research was supported by the Hamamatsu University School of Medicine Intramural Research Program.

Authors’ contributions

J-Z Wei, K Yamashita, M Tashiro, S Kita, T Iwamoto, and Y Watanabe performed the research (cell isolation: K Yamashita and Y Watanabe Y; patch clamp experiment: J-Z Wei, M Tashiro, and Y Watanabe Y; [Ca2+]i measurement: J-Z Wei and K Yamashita). K Takeuchi and Y Watanabe designed the research study. H Watanabe contributed an essential tool. J-Z Wei, K Yamashita, and Y Watanabe analysed the data. Y Watanabe and J Kimura wrote the paper.

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Authors and Affiliations

  1. Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, 431-3192, Japan

    Jiazhang Wei, Kazuhiko Takeuchi & Hiroshi Watanabe

  2. Division of Pharmacological Science, Department of Health Science, Hamamatsu University School of Medicine, Hamamatsu, 431-3192, Japan

    Yasuhide Watanabe, Kanna Yamashita & Miyuki Tashiro

  3. Department of Pharmacology, Faculty of Medicine, Fukuoka University, Fukuoka, 814-0180, Japan

    Satomi Kita & Takahiro Iwamoto

  4. Department of Pharmacology, Fukushima Medical University, Fukushima, 960-1295, Japan

    Junko Kimura

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  1. Jiazhang Wei
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  2. Yasuhide Watanabe
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  3. Kazuhiko Takeuchi
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Correspondence to Yasuhide Watanabe.

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Wei, J., Watanabe, Y., Takeuchi, K. et al. Nicorandil stimulates a Na+/Ca2+ exchanger by activating guanylate cyclase in guinea pig cardiac myocytes. Pflugers Arch - Eur J Physiol 468, 693–703 (2016). https://doi.org/10.1007/s00424-015-1763-8

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  • DOI: https://doi.org/10.1007/s00424-015-1763-8

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