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Hydrogen peroxide modulates the Kv1.5 channel expressed in a mammalian cell line

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Abstract

Reactive oxygen species have been implicated in different types of cardiac arrhythmias including human atrial fibrillation. Kv1.5, the presumed molecular correlate of IKur, is an important determinant of human atrial repolarization. The aim of this study was to assess the effects of H2O2, at pathophysiologically relevant concentrations (20–1,000 μM), on Kv1.5 expressed in Chinese hamster ovary cell line. Kv1.5 cDNA in pcDNA3 expression vector and CD8, a surface marker protein, were cotransfected in cells by calcium phosphate precipitation. Kv1.5 activation kinetics were significantly accelerated while the activation curve was negatively shifted by 10 mV (V1/2 changed from −9.3 to −19.0 mV) in the presence of 100 μM H2O2. The shift in Kv1.5 peak current I-V curve was voltage-dependent, the current amplitude being increased for voltages <+20 mV but decreased for high depolarizing voltages. The rapid activation time constant obtained from a bi-exponential fitting was decreased from 16.1±3.4 ms to 8.8±1.5 ms for a −20 mV depolarization (n=9; P=0.01) and from 4.3±2.1 ms to 2.3±0.4 ms when cells were depolarized to +20 mV (P<0.05). Kv1.5 steady-state inactivation was not modified by H2O2. Intracellular application of SOD or catalase reduced the H2O2 induced shift of activation I-V curve and SOD significantly decreased Kv1.5 amplitude at +40 mV (n=9; P<0.05). In conclusion, H2O2 increased Kv1.5 current amplitude at voltages corresponding to the action potential repolarization phase and accelerated Kv1.5 channel opening. These changes can reduce the action potential duration, leading to a shortening of the atrial effective refractory period. H2O2-induced changes in Kv1.5 properties could thus be involved in initiation or perpetuation of AF.

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Acknowledgements

This work was supported by the Canadian Institute for Health Research (MT 12883 and MOP 64383) and the Heart and Stroke Foundation of Canada.

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Authors and Affiliations

  1. Quebec Heart Institute, Laval Hospital, 2725 Chemin Ste-Foy, Sainte-Foy, Quebec, G1V 4G5, Canada

    David Caouette, Christiane Dongmo, Jocelyn Bérubé, Dominique Fournier & Pascal Daleau

  2. Faculty of Pharmacy and Medicine, Laval University, Laval Hospital, Research Center, 2725 Chemin Ste-Foy, Sainte-Foy, Quebec, G1V 4G5, Canada

    Pascal Daleau

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  1. David Caouette
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  2. Christiane Dongmo
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  3. Jocelyn Bérubé
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  4. Dominique Fournier
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  5. Pascal Daleau
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Correspondence to Pascal Daleau.

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David Caouette and Christiane Dongmo contributed equally to this article

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Caouette, D., Dongmo, C., Bérubé, J. et al. Hydrogen peroxide modulates the Kv1.5 channel expressed in a mammalian cell line. Naunyn-Schmiedeberg's Arch Pharmacol 368, 479–486 (2003). https://doi.org/10.1007/s00210-003-0834-0

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  • DOI: https://doi.org/10.1007/s00210-003-0834-0

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