title: A Comparative Analysis of Bupivacaine and Ropivacaine Effects on Human Cardiac SCN5A Channels.
abstract: BACKGROUND
  Intoxication with local anesthetics may induce cardiac arrhythmias by interaction with ion channels. Ropivacaine has been introduced into clinical anesthesia as a safer alternative to bupivacaine, which is associated with a relatively high risk of cardiac arrhythmias. Diverging safety profiles may result from differences in the mode of interaction with cardiac Na(+) channels. We conducted this study to test this hypothesis and to provide experimental basis for the ongoing discussion regarding the cardiotoxic profiles of these local anesthetics.
  
  
  METHODS
  The influence of bupivacaine and ropivacaine on the electrophysiological properties of Na(+) channels was investigated in human embryonic kidney-293 cells stably transfected with SCN5A channels cloned from the human heart using the patch-clamp technique in the outside-out configuration.
  
  
  RESULTS
  Open-channel block of SCN5A channels was concentration dependent, with bupivacaine being approximately 4.5-fold more potent than ropivacaine (IC50 = 69.5 ± 8.2 μM vs IC50 = 322.2 ± 29.9 μM). Both drugs influenced the voltage dependency of channel activation and steady-state inactivation by shifting the membrane potential of half-maximal activation/inactivation toward somewhat more negative membrane potentials. In their inactivated state, SCN5A channels were slightly more sensitive toward bupivacaine than toward ropivacaine (IC50 = 2.18 ± 0.16 μM vs IC50 = 2.73 ± 0.27 μM). Blockade of inactivated channels developed in a concentration-dependent manner, with comparable time constants for both drugs, whereas recovery from block was approximately 2-fold faster for ropivacaine than for bupivacaine.
  
  
  CONCLUSIONS
  Human cardiac Na(+) channels show state-dependent inhibition by ropivacaine, and the mode of interaction is comparable to that of bupivacaine. Therefore, modest differences in cardiotoxicity between these local anesthetic drugs are compatible with subtle differences in their interaction with human cardiac Na(+) channels.
authors.affiliation: From the *Department of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, DZHK (German Centre for Cardiovascular Research)-Hamburg/Kiel/Luebeck, Hamburg, Germany; †Department of Anesthesiology, German Armed Forces Hospital Hamburg, Academic Hospital of University Medical Center Hamburg-Eppendorf, Hamburg, Germany; and ‡Department of Anaesthesiology, Bogenhausen Hospital, Academic Hospital of Technische Universitaet Muenchen, Munich, Germany.
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Schwoerer
authors.forename: Hanno
authors.initials: H
authors.lastname: Scheel
authors.forename: Patrick
authors.initials: P
authors.lastname: Friederich
mesh_terms: D000577:Amides / Q000633:toxicity*; D000779:Anesthetics, Local / Q000633:toxicity*; D002045:Bupivacaine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D008564:Membrane Potentials; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000077212:Ropivacaine; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection
chemical_list: D000577:Amides; D000779:Anesthetics, Local; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D026941:Sodium Channel Blockers; D000077212:Ropivacaine; D002045:Bupivacaine