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Contribution of ion currents to beat-to-beat variability of action potential duration in canine ventricular myocytes

  • Ion channels, receptors and transporters
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Abstract

Although beat-to-beat variability (short-term variability, SV) of action potential duration (APD) is considered as a predictor of imminent cardiac arrhythmias, the underlying mechanisms are still not clear. In the present study, therefore, we aimed to determine the role of the major cardiac ion currents, APD, stimulation frequency, and changes in the intracellular Ca2+ concentration ([Ca2+]i) on the magnitude of SV. Action potentials were recorded from isolated canine ventricular cardiomyocytes using conventional microelectrode techniques. SV was an exponential function of APD, when APD was modified by current injections. Drug effects were characterized as relative SV changes by comparing the drug-induced changes in SV to those in APD according to the exponential function obtained with current pulses. Relative SV was increased by dofetilide, HMR 1556, nisoldipine, and veratridine, while it was reduced by BAY K8644, tetrodotoxin, lidocaine, and isoproterenol. Relative SV was also increased by increasing the stimulation frequency and [Ca2+]i. In summary, relative SV is decreased by ion currents involved in the negative feedback regulation of APD (I Ca, I Ks, and I Kr), while it is increased by I Na and I to. We conclude that drug-induced effects on SV should be evaluated in relation with the concomitant changes in APD. Since relative SV was decreased by ion currents playing critical role in the negative feedback regulation of APD, blockade of these currents, or the beta-adrenergic pathway, may carry also some additional proarrhythmic risk in addition to their well-known antiarrhythmic action.

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Acknowledgments

Financial support was provided by grants from the Hungarian Scientific Research Fund (OTKA-K100151, OTKA-K109736, OTKA-K101196, OTKA-PD101171, and OTKA-NK104331). Further support was obtained from the Hungarian Government and the European Community (TAMOP-4.2.2.A-11/1/KONV-2012-0045 and TAMOP-4.2.2/B-10/1-2010-0024 research projects). Research of KK and HB was supported by the European Union and the State of Hungary, co-financed by the European Social Fund in the framework of TÁMOP-4.2.4.A/2-11/1-2012-0001 “National Excellence Program.” The authors thank Miss Éva Sági for her excellent technical assistance.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Physiology, Faculty of Medicine, University of Debrecen, 4012, Nagyerdei krt 98, Debrecen, Hungary

    Norbert Szentandrássy, Kornél Kistamás, Bence Hegyi, Balázs Horváth, Ferenc Ruzsnavszky, Krisztina Váczi, János Magyar, Tamás Bányász & Péter P. Nánási

  2. Department of Dental Physiology and Pharmacology, Faculty of Dentistry, University of Debrecen, Debrecen, Hungary

    Norbert Szentandrássy & Péter P. Nánási

  3. Division of Sport Physiology, Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

    János Magyar

  4. Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary

    András Varró

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  1. Norbert Szentandrássy
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Correspondence to Péter P. Nánási.

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Szentandrássy, N., Kistamás, K., Hegyi, B. et al. Contribution of ion currents to beat-to-beat variability of action potential duration in canine ventricular myocytes. Pflugers Arch - Eur J Physiol 467, 1431–1443 (2015). https://doi.org/10.1007/s00424-014-1581-4

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