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Molecular Pharmacology

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Research ArticleArticle

Structural Determinants of Potency and Stereoselective Block of hKv1.5 Channels Induced by Local Anesthetics

Mónica Longobardo, Eva Delpón, Ricardo Caballero, Juan Tamargo and Carmen Valenzuela
Molecular Pharmacology July 1998, 54 (1) 162-169; DOI: https://doi.org/10.1124/mol.54.1.162
Mónica Longobardo
Institute of Pharmacology and Toxicology, CSIC/UCM, School of Medicine. Universidad Complutense, Madrid, Spain
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Eva Delpón
Institute of Pharmacology and Toxicology, CSIC/UCM, School of Medicine. Universidad Complutense, Madrid, Spain
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Ricardo Caballero
Institute of Pharmacology and Toxicology, CSIC/UCM, School of Medicine. Universidad Complutense, Madrid, Spain
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Juan Tamargo
Institute of Pharmacology and Toxicology, CSIC/UCM, School of Medicine. Universidad Complutense, Madrid, Spain
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Carmen Valenzuela
Institute of Pharmacology and Toxicology, CSIC/UCM, School of Medicine. Universidad Complutense, Madrid, Spain
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Abstract

Block of hKv1.5 channels by bupivacaine is stereoselective, with (R)-(+)-bupivacaine being 7-fold more potent than (S)-(−)-bupivacaine. The study of the effects of chemically related enantiomers on these channels may help to elucidate the structural determinants of stereoselective hKv1.5 channels block by local anesthetics. In this study, we analyzed the effects of (R)-(+)-ropivacaine, (R)-(+)-mepivacaine, and (S)-(−)-mepivacaine on hKv1.5 channels stably expressed in Ltk− cells. (R)-(+)-Ropivacaine inhibited hKv1.5 current and induced a fast initial decline superimposed to the slow inactivation during the application of depolarizing pulses, which reached steady state at the end of 250-msec depolarizing pulses. The concentration-dependence block induced by (R)-(+)-ropivacaine yielded aK D value of 32 ± 1 μm [i.e., 2.5-fold more potent than (S)-(−)-ropivacaine]. (R)-(+)-Ropivacaine block also was voltage dependent, with a fractional electrical distance (δ) of 0.156 ± 0.003 (n = 14) referred to the inner surface. Both (S)-(−)- and (R)-(+)-mepivacaine blocked hKv1.5 channels, with K D values of 286.8 ± 34.1 and 379.0 ± 56.0 μm, respectively [i.e., block was not stereoselective (p > 0.05)]. (S)-(−)-Mepivacaine and (R)-(+)-mepivacaine block displayed no apparent time-dependence due to a very fast dissociation rate constant. However, block by mepivacaine enantiomers was voltage dependent, with δ values of 0.154 ± 0.015 and 0.160 ± 0.008 for the (S)-(−)- and (R)-(+)-enantiomers, respectively. We conclude that (1) (R)-(+)-ropivacaine and mepivacaine enantiomers block the open state of hKv1.5 channels and (2) the length of their alkyl substituent at position 1 determines the potency and the degree of stereoselectivity.

Footnotes

    • Received February 4, 1998.
    • Accepted March 30, 1998.
  • Send reprint requests to: Mónica Longobardo, B.S., Institute of Pharmacology and Toxicology, CSIC, School of Medicine, Universidad Complutense, 28040 Madrid, Spain. E-mail:carmenva{at}eucmax.sim.ucm.es

  • This work was support by Grants Fondo de Investigaciones Sanitarias 95/0318 (C.V.), Comisión Interministerial de Ciencia y Tecnología SAF96–0042 (J.T.), and SAF98–0058 (C.V.).

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 54 (1)
Molecular Pharmacology
Vol. 54, Issue 1
1 Jul 1998
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Research ArticleArticle

Structural Determinants of Potency and Stereoselective Block of hKv1.5 Channels Induced by Local Anesthetics

Mónica Longobardo, Eva Delpón, Ricardo Caballero, Juan Tamargo and Carmen Valenzuela
Molecular Pharmacology July 1, 1998, 54 (1) 162-169; DOI: https://doi.org/10.1124/mol.54.1.162

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Research ArticleArticle

Structural Determinants of Potency and Stereoselective Block of hKv1.5 Channels Induced by Local Anesthetics

Mónica Longobardo, Eva Delpón, Ricardo Caballero, Juan Tamargo and Carmen Valenzuela
Molecular Pharmacology July 1, 1998, 54 (1) 162-169; DOI: https://doi.org/10.1124/mol.54.1.162
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