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Molecular Pharmacology

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Research ArticleArticle

Mechanism of Modification, by Lidocaine, of Fast and Slow Recovery from Inactivation of Voltage-Gated Na+ Channels

Vaibhavkumar S. Gawali, Peter Lukacs, Rene Cervenka, Xaver Koenig, Lena Rubi, Karlheinz Hilber, Walter Sandtner and Hannes Todt
Molecular Pharmacology November 2015, 88 (5) 866-879; DOI: https://doi.org/10.1124/mol.115.099580
Vaibhavkumar S. Gawali
Center for Physiology and Pharmacology, Department of Neurophysiology and Neuropharmacology (V.S.G., P.L., R.C., X.K., L.R., K.H., H.T.) and Center for Physiology and Pharmacology (W.S.), Medical University of Vienna, Vienna, Austria
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Peter Lukacs
Center for Physiology and Pharmacology, Department of Neurophysiology and Neuropharmacology (V.S.G., P.L., R.C., X.K., L.R., K.H., H.T.) and Center for Physiology and Pharmacology (W.S.), Medical University of Vienna, Vienna, Austria
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Rene Cervenka
Center for Physiology and Pharmacology, Department of Neurophysiology and Neuropharmacology (V.S.G., P.L., R.C., X.K., L.R., K.H., H.T.) and Center for Physiology and Pharmacology (W.S.), Medical University of Vienna, Vienna, Austria
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Xaver Koenig
Center for Physiology and Pharmacology, Department of Neurophysiology and Neuropharmacology (V.S.G., P.L., R.C., X.K., L.R., K.H., H.T.) and Center for Physiology and Pharmacology (W.S.), Medical University of Vienna, Vienna, Austria
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Lena Rubi
Center for Physiology and Pharmacology, Department of Neurophysiology and Neuropharmacology (V.S.G., P.L., R.C., X.K., L.R., K.H., H.T.) and Center for Physiology and Pharmacology (W.S.), Medical University of Vienna, Vienna, Austria
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Karlheinz Hilber
Center for Physiology and Pharmacology, Department of Neurophysiology and Neuropharmacology (V.S.G., P.L., R.C., X.K., L.R., K.H., H.T.) and Center for Physiology and Pharmacology (W.S.), Medical University of Vienna, Vienna, Austria
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Walter Sandtner
Center for Physiology and Pharmacology, Department of Neurophysiology and Neuropharmacology (V.S.G., P.L., R.C., X.K., L.R., K.H., H.T.) and Center for Physiology and Pharmacology (W.S.), Medical University of Vienna, Vienna, Austria
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Hannes Todt
Center for Physiology and Pharmacology, Department of Neurophysiology and Neuropharmacology (V.S.G., P.L., R.C., X.K., L.R., K.H., H.T.) and Center for Physiology and Pharmacology (W.S.), Medical University of Vienna, Vienna, Austria
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Abstract

The clinically important suppression of high-frequency discharges of excitable cells by local anesthetics (LA) is largely determined by drug-induced prolongation of the time course of repriming (recovery from inactivation) of voltage-gated Na+ channels. This prolongation may result from periodic drug-binding to a high-affinity binding site during the action potentials and subsequent slow dissociation from the site between action potentials (“dissociation hypothesis”). For many drugs it has been suggested that the fast inactivated state represents the high-affinity binding state. Alternatively, LAs may bind with high affinity to a native slow-inactivated state, thereby accelerating the development of this state during action potentials (“stabilization hypothesis”). In this case, slow recovery between action potentials occurs from enhanced native slow inactivation. To test these two hypotheses we produced serial cysteine mutations of domain IV segment 6 in rNav1.4 that resulted in constructs with varying propensities to enter fast- and slow-inactivated states. We tested the effect of the LA lidocaine on the time course of recovery from short and long depolarizing prepulses, which, under drug-free conditions, recruited mainly fast- and slow-inactivated states, respectively. Among the tested constructs the mutation-induced changes in native slow recovery induced by long depolarizations were not correlated with the respective lidocaine-induced slow recovery after short depolarizations. On the other hand, for long depolarizations the mutation-induced alterations in native slow recovery were significantly correlated with the kinetics of lidocaine-induced slow recovery. These results favor the “dissociation hypothesis” for short depolarizations but the “stabilization hypothesis” for long depolarizations.

Footnotes

    • Received April 17, 2015.
    • Accepted September 9, 2015.
  • This study was funded by the Austrian Science Fund FWF [Grants P210006-B11 and W1232-B11].

  • dx.doi.org/10.1124/mol.115.099580.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 88 (5)
Molecular Pharmacology
Vol. 88, Issue 5
1 Nov 2015
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Research ArticleArticle

Lidocaine Modifies Fast and Slow Repriming of Nav Channels

Vaibhavkumar S. Gawali, Peter Lukacs, Rene Cervenka, Xaver Koenig, Lena Rubi, Karlheinz Hilber, Walter Sandtner and Hannes Todt
Molecular Pharmacology November 1, 2015, 88 (5) 866-879; DOI: https://doi.org/10.1124/mol.115.099580

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Research ArticleArticle

Lidocaine Modifies Fast and Slow Repriming of Nav Channels

Vaibhavkumar S. Gawali, Peter Lukacs, Rene Cervenka, Xaver Koenig, Lena Rubi, Karlheinz Hilber, Walter Sandtner and Hannes Todt
Molecular Pharmacology November 1, 2015, 88 (5) 866-879; DOI: https://doi.org/10.1124/mol.115.099580
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