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Effects of SEA0400 and KB-R7943 on Na+/Ca2+ exchange current and L-type Ca2+ current in canine ventricular cardiomyocytes

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Abstract

SEA0400 and KB-R7943 are compounds synthesised to block transsarcolemmal Na+/Ca2+ exchange current (INa/Ca); however, they Have also been shown to inhibit L-type Ca2+ current (ICa). The potential value of these compounds depends critically on their relative selectivity for INa/Ca over ICa. In the present work, therefore, the concentration-dependent effects of SEA0400 and KB-R7943 on INa/Ca and ICa were studied and compared in canine ventricular cardiomyocytes using the whole-cell configuration of the patch clamp technique. SEA0400 and KB-R7943 decreased INa/Ca in a concentration-dependent manner, having EC50 values of 111±43 nM and 3.35±0.82 μM, when suppressing inward currents, while the respective EC50 values were estimated at 108±18 nM and 4.74±0.69 μM in the case of outward current block. SEA0400 and KB-R7943 also blocked ICa, having comparable EC50 values (3.6 μM and 3.2 μM, respectively). At higher concentrations (10 μM) both drugs accelerated inactivation of ICa, retarded recovery from inactivation and shifted the voltage dependence of inactivation towards more negative voltages. The voltage dependence of activation was slightly modified by SEA0400, but not by KB-R7943. Based on the relatively good selectivity of submicromolar concentrations of SEA0400—but not KB-R7943—for INa/Ca over ICa, SEA0400 appears to be a suitable tool to study the role of INa/Ca in Ca2+ handling in canine cardiac cells. At concentrations higher than 1 μM, however, ICa is progressively suppressed by the compound.

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Acknowledgements

This work was supported by grants from the Hungarian Research Fund (OTKA-T037334, OTKA-T037332, OTKA-T 043182, OTKA T-035018, OTKA T-037520 and OTKA T-048698), the Hungarian Ministry of Health (ETT-06031/2003, ETT-572/2003 and ETT 188/2003) and the Hungarian Ministry of Education (Bio-37 KPI), by National Research and Development Programs (NKFP-1A/0011/2002, NKFP-1A/008/2004) and by the János Bolyai Research Scholarship (for L.V.).

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Authors and Affiliations

  1. Department of Physiology, University Medical School of Debrecen, P.O. Box 22, 4012, Debrecen, Hungary

    Péter Birinyi, Tamás Bányász, Balázs Horváth, Norbert Szentandrássy, János Magyar & Péter P. Nánási

  2. Department of Pharmacology and Pharmacotherapy, Albert Szent-Györgyi Medical and Pharmaceutical Center, University of Szeged, P.O. Box 427, 6701, Szeged, Hungary

    Károly Acsai, András Tóth, László Virág & András Varró

  3. Institute of Pharmaceutical Chemistry, Albert Szent-Györgyi Medical and Pharmaceutical Center, University of Szeged, P.O. Box 121, 6701, Szeged, Hungary

    Ferenc Fülöp

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  1. Péter Birinyi
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  2. Károly Acsai
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  3. Tamás Bányász
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  5. Balázs Horváth
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  6. László Virág
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  7. Norbert Szentandrássy
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  8. János Magyar
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  10. Ferenc Fülöp
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  11. Péter P. Nánási
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Correspondence to Péter P. Nánási.

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Birinyi, P., Acsai, K., Bányász, T. et al. Effects of SEA0400 and KB-R7943 on Na+/Ca2+ exchange current and L-type Ca2+ current in canine ventricular cardiomyocytes. Naunyn Schmied Arch Pharmacol 372, 63–70 (2005). https://doi.org/10.1007/s00210-005-1079-x

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  • DOI: https://doi.org/10.1007/s00210-005-1079-x

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