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Antiarrhythmic activity of a new spiro-cyclic benzopyran activator of the cardiac mitochondrial ATP dependent potassium channels

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Abstract

‘Compound A’ (4ı-(N-(4-acetamidobenzyl))-2,2-dimethyl-2,3-dihydro-5ıH-spiro[chromene-4,2ı-[1,4]oxazinan]-5ı-one) is a new spiro-cyclic benzopyran activator of the mitochondrial ATP-dependent potassium channels (mitoKATP). We researched the effect of compound A on ischemia/reperfusion (I/R)-induced ventricular arrhythmias. We also tested the hypothesis that the application of the activation of mitoKATP in combination with the inhibition of sarcolemmal ATP-dependent potassium channels (sarcKATP) may produce a stronger antiarrhythmic effect. In anesthetized rats, myocardial ischemia was performed by ligating the left main coronary artery followed by reperfusion. At a dose of 10 mg/kg, compound A significantly decreased arrhythmia scores and the total length of arrhythmias, whereas this was found to be ineffective at a dose of 3 mg/kg. Pre-treatment with 5-HD, a selective mitoKATP blocker, abolished the antiarrhythmic effect of compound A. Both diazoxide, a selective mitoKATP opener and HMR 1098, a selective sarcKATP blocker, significantly decreased the total length of arrhythmias. However, the combination of neither diazoxide nor compound A with HMR 1098 showed no additional therapeutic benefit. These results reveal that compound A may have a dose-dependent antiarrythmic effect, which is more pronounced than the antiarrhythmic effect of diazoxide. The antiarrhythmic effect of compound A may possibly depend on mitoKATP activation.

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Acknowledgments

The authors disclose receipt of the following financial support for the research of this article (The Scientific and Technological Research Council of Turkey: SBAG-111S123). We gratefully acknowledge to Sanofi-Aventis Pharma, Frankfurt am Main/Deutchland, for the generous gift of HMR 1098.

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Authors and Affiliations

  1. Department of Biology, Faculty of Art and Sciences, Bülent Ecevit University, Zonguldak, Turkey

    Ersöz Gonca & Faruk Darıcı

  2. Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126, Pisa, Italy

    Simona Rapposelli & Maria Digiacomo

  3. Department of Pharmacology, Faculty of Medicine, Harran University, Şanliurfa, Turkey

    Zehra Yılmaz

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  1. Ersöz Gonca
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  2. Simona Rapposelli
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  5. Zehra Yılmaz
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Correspondence to Ersöz Gonca.

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Gonca, E., Rapposelli, S., Darıcı, F. et al. Antiarrhythmic activity of a new spiro-cyclic benzopyran activator of the cardiac mitochondrial ATP dependent potassium channels. Arch. Pharm. Res. 39, 1212–1222 (2016). https://doi.org/10.1007/s12272-016-0779-8

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