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Effects of tacrolimus on action potential configuration and transmembrane ion currents in canine ventricular cells

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Abstract

Tacrolimus is a commonly used immunosuppressive agent which causes cardiovascular complications, e.g., hypertension and hypertrophic cardiomyopathy. In spite of it, there is little information on the cellular cardiac effects of the immunosuppressive agent tacrolimus in larger mammals. In the present study, therefore, the concentration-dependent effects of tacrolimus on action potential morphology and the underlying ion currents were studied in canine ventricular cardiomyocytes. Standard microelectrode, conventional whole cell patch clamp, and action potential voltage clamp techniques were applied in myocytes enzymatically dispersed from canine ventricular myocardium. Tacrolimus (3–30 μM) caused a concentration-dependent reduction of maximum velocity of depolarization and repolarization, action potential amplitude, phase-1 repolarization, action potential duration, and plateau potential, while no significant change in the resting membrane potential was observed. Conventional voltage clamp experiments revealed that tacrolimus concentrations ≥3 μM blocked a variety of ion currents, including ICa, Ito, IK1, IKr, and IKs. Similar results were obtained under action potential voltage clamp conditions. These effects of tacrolimus developed rapidly and were fully reversible upon washout. The blockade of inward currents with the concomitant shortening of action potential duration in canine myocytes is the opposite of those observed previously with tacrolimus in small rodents. It is concluded that although tacrolimus blocks several ion channels at higher concentrations, there is no risk of direct interaction with cardiac ion channels when applying tacrolimus in therapeutic concentrations.

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Acknowledgments

Financial support was provided by grants from the Hungarian Scientific Research Fund (OTKA-K100151, OTKA101196, OTKA-PD101171). Further support was obtained from the Hungarian Government (CNK-77855, TAMOP-4.2.1/B-09/1/KONV-2010-007 and TAMOP-4.2.2.A-11/1/KONV-2012-0045 research projects).

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Authors and Affiliations

  1. Department of Physiology, Medical and Health Science Center, University of Debrecen, H-4012, Debrecen, P.O. Box 22, Hungary

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

  2. Department of Surgery, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary

    László Szabó

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  1. László Szabó
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  2. Norbert Szentandrássy
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  3. Kornél Kistamás
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  11. Péter P. Nánási
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Correspondence to Péter P. Nánási.

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Szabó, L., Szentandrássy, N., Kistamás, K. et al. Effects of tacrolimus on action potential configuration and transmembrane ion currents in canine ventricular cells. Naunyn-Schmiedeberg's Arch Pharmacol 386, 239–246 (2013). https://doi.org/10.1007/s00210-012-0823-2

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  • DOI: https://doi.org/10.1007/s00210-012-0823-2

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