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

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

    Research output: Contribution to journalArticlepeer-review

    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 I(Ca), I(to), I(K1), I(Kr), and I(Ks). 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.

    Original languageEnglish
    Pages (from-to)239-46
    Number of pages8
    JournalNaunyn-Schmiedeberg's archives of pharmacology
    Volume386
    Issue number3
    DOIs
    Publication statusPublished - Mar 2013

    Keywords

    • Action Potentials
    • Animals
    • Cell Membrane
    • Dogs
    • Dose-Response Relationship, Drug
    • Female
    • Heart Ventricles
    • Immunosuppressive Agents
    • Ion Channels
    • Ion Transport
    • Male
    • Myocytes, Cardiac
    • Patch-Clamp Techniques
    • Tacrolimus

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