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Inhibition of cardiomyocyte automaticity by electrotonic application of inward rectifier current from Kir2.1 expressing cells

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Abstract

A biological pacemaker might be created by generation of a cellular construct consisting of cardiac cells that display spontaneous membrane depolarization, and that are electrotonically coupled to surrounding myocardial cells by means of gap junctions. Depending on the frequency of the spontaneously beating cells, frequency regulation might be required. We hypothesized that application of Kir2.1 expressing non-cardiac cells, which provide I K1 to spontaneously active neonatal cardiomyocytes (NCMs) by electrotonic coupling in such a cellular construct, would generate an opportunity for pacemaker frequency control. Non-cardiac Kir2.1 expressing cells were co-cultured with spontaneously active rat NCMs. Electrotonic coupling between the two cell types resulted in hyperpolarization of the cardiomyocyte membrane potential and silencing of spontaneous activity. Either blocking of gap-junctional communication by halothane or inhibition of I K1 by BaCl2 restored the original membrane potential and spontaneous activity of the NCMs. Our results demonstrate the power of electrotonic coupling for the application of specific ion currents into an engineered cellular construct such as a biological pacemaker.

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Acknowledgments

We thank Anatoli Lopatin for sharing Kir2.1-GFP expression construct and Henk Rozemuller for FACS sorting of the HEK-KWGF cells. This study is supported by the Technology Foundation (STW program DPTE, grant #MKG5942, MvdH and grant UGT.6746, TvV), the Netherlands Heart Foundation (grant 2003B073, TdB) and the Netherlands Organization for Scientific Research (NWO, grant 916.36.012, TvV). FP6 (Framework Program LSHB-CT-2004-502988) of the European Committee (BK).

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Authors and Affiliations

  1. Department of Medical Physiology, Heart Lung Center Utrecht, University Medical Center Utrecht, Yalelaan 50, 3584, Utrecht, The Netherlands

    Teun P. de Boer, Toon A. B. van Veen, Marien J. C. Houtman, John A. Jansen, Marc A. Vos & Marcel A. G. van der Heyden

  2. Experimental and Molecular Cardiology Group, Academic Medical Center, Amsterdam, The Netherlands

    Shirley C. M. van Amersfoorth

  3. Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands

    Pieter A. Doevendans

  4. Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands

    Teun P. de Boer, Shirley C. M. van Amersfoorth & Marcel A. G. van der Heyden

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  1. Teun P. de Boer
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  2. Toon A. B. van Veen
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  8. Marcel A. G. van der Heyden
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Correspondence to Marcel A. G. van der Heyden.

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de Boer, T.P., van Veen, T.A.B., Houtman, M.J.C. et al. Inhibition of cardiomyocyte automaticity by electrotonic application of inward rectifier current from Kir2.1 expressing cells. Med Bio Eng Comput 44, 537–542 (2006). https://doi.org/10.1007/s11517-006-0059-8

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