PMID: 9658202Jul 11, 1998Paper

Structural determinants of potency and stereoselective block of hKv1.5 channels induced by local anesthetics

Molecular Pharmacology
M LongobardoC Valenzuela

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 a KD value of 32 +/- 1 microM [i.e., 2.5-fold more potent than (S)-(-)-ropivacaine]. (R)-(+)-Ropivacaine block also was voltage dependent, with a fractional electrical distance (delta) of 0.156 +/- 0.003 (n = 14) referred to the inner surface. Both (S)-(-)- and (R)-(+)-mepivacaine blocked hKv1.5 channels, with KD values of 286.8 +/- 34.1 and 379.0 +/- 56.0 microM, respectively [i.e., block was not stereoselective (p > 0.05)]. (S)-(-)-Mepivacaine an...Continue Reading

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Citations

May 12, 2000·British Journal of Pharmacology·M LongobardoC Valenzuela
Jan 24, 2002·The Journal of Pharmacology and Experimental Therapeutics·David GodreauStéphane N Hatem
Sep 20, 2011·Paediatric Anaesthesia·Jean-Xavier Mazoit
Jun 8, 2012·Chirality·Carmen ValenzuelaTeresa González
Jun 20, 2014·British Journal of Pharmacology·A MacíasC Valenzuela
Feb 23, 2019·Frontiers in Molecular Neuroscience·Diego A PerazaCarmen Valenzuela
Mar 26, 2003·Anesthesia and Analgesia·James C Crews, Theodore E Rothman
Dec 6, 2002·British Journal of Pharmacology·Teresa GonzálezCarmen Valenzuela
Sep 12, 2008·Current Opinion in Anaesthesiology·Wolfgang Zink, Bernhard M Graf
Jun 29, 2001·The Journal of General Physiology·M W BrockW F Gilly
Jun 12, 2012·European Journal of Pharmacology·Nobutaka KariyaJean-Xavier Mazoit
Apr 6, 2021·British Journal of Pharmacology·Aytug K KiperNiels Decher
Jan 19, 2007·Journal of Medicinal Chemistry·Iana VazzanaFabio Sparatore

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