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Asynchronous activation of calcium and potassium currents by isoproterenol in canine ventricular myocytes

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Abstract

Adrenergic activation of L-type Ca2+ and various K+ currents is a crucial mechanism of cardiac adaptation; however, it may carry a substantial proarrhythmic risk as well. The aim of the present work was to study the timing of activation of Ca2+ and K+ currents in isolated canine ventricular cells in response to exposure to isoproterenol (ISO). Whole cell configuration of the patch-clamp technique in either conventional voltage clamp or action potential voltage clamp modes were used to monitor I Ca, I Ks, and I Kr, while action potentials were recorded using sharp microelectrodes. ISO (10 nM) elevated the plateau potential and shortened action potential duration (APD) in subepicardial and mid-myocardial cells, which effects were associated with multifold enhancement of I Ca and I Ks and moderate stimulation of I Kr. The ISO-induced plateau shift and I Ca increase developed faster than the shortening of APD and stimulation of I Ks and I Kr. Blockade of β1-adrenoceptors (using 300 nM CGP-20712A) converted the ISO-induced shortening of APD to lengthening, decreased its latency, and reduced the plateau shift. In contrast, blockade of β2-adrenoceptors (by 50 nM ICI 118,551) augmented the APD-shortening effect and increased the latency of plateau shift without altering its magnitude. All effects of ISO were prevented by simultaneous blockade of both receptor types. Inhibition of phosphodiesterases decreased the differences observed in the turn on of the ISO-induced plateau shift and APD shortening. ISO-induced activation of I Ca is turned on faster than the stimulation of I Ks and I Kr in canine ventricular cells due to the involvement of different adrenergic pathways and compartmentalization.

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Acknowledgments

Financial support was provided by grants from the Hungarian Scientific Research Fund (OTKA-K100151, OTKA-K101196, OTKA-PD101171, and OTKA-NK104331). Further support was obtained from the Hungarian Government (TAMOP-4.2.2.A-11/1/KONV-2012-0045 and TAMOP-4.2.2/B-10/1-2010-0024 research projects). The authors thank Miss Éva Sági for her excellent technical assistance.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Physiology, Medical and Health Science Center, University of Debrecen, Debrecen, Nagyerdei krt 98, 4012, Hungary

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

  2. Department of Dental Physiology and Pharmacology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary

    Norbert Szentandrássy & Péter P. Nánási

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  1. Ferenc Ruzsnavszky
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  2. Bence Hegyi
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  3. Kornél Kistamás
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Correspondence to Péter P. Nánási.

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Ruzsnavszky, F., Hegyi, B., Kistamás, K. et al. Asynchronous activation of calcium and potassium currents by isoproterenol in canine ventricular myocytes. Naunyn-Schmiedeberg's Arch Pharmacol 387, 457–467 (2014). https://doi.org/10.1007/s00210-014-0964-6

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