title: Block of neuronal tetrodotoxin-resistant Na+ currents by stereoisomers of piperidine local anesthetics.
abstract: Tetrodotoxin (TTX)-sensitive Na(+) channels in the peripheral nervous system are the major targets for local anesthetics. In the peripheral nociceptive system, a Na(+) channel subtype resistant to TTX and with distinct electrophysiological properties seems to be of importance for impulse generation and conduction. A current through TTX-resistant Na(+) channels displays slower activation and inactivation kinetics and has an increased activation threshold compared with TTX-sensitive Na(+) currents and may have different pharmacological properties. We studied the effects of stereoisomers of piperidine local anesthetics on neuronal TTX-resistant Na(+) currents recorded with the whole-cell configuration of the patch clamp method in enzymatically dissociated dorsal root ganglion neurons of adult rats. Stereoisomers of mepivacaine, ropivacaine, and bupivacaine reversibly inhibited TTX-resistant Na(+) currents in a concentration and use-dependent manner. All drugs accelerated time course of inactivation. Half-maximal blocking concentrations were determined from concentration-inhibition relationships. Potencies for tonic and for use-dependent block increased with rising lipid solubilities of the drugs. Stereoselective action was not observed. We conclude that block of TTX-resistant Na(+) currents may lead to blockade of TTX-resistant action potentials in nociceptive fibers and consequently may be responsible for pain suppression during local anesthesia.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Justus-Liebig-University, Giessen, Germany. meb@anesthesiology.de
authors.forename: M E
authors.initials: ME
authors.lastname: Bräu
authors.forename: P
authors.initials: P
authors.lastname: Branitzki
authors.forename: A
authors.initials: A
authors.lastname: Olschewski
authors.forename: W
authors.initials: W
authors.lastname: Vogel
authors.forename: G
authors.initials: G
authors.lastname: Hempelmann
mesh_terms: D000465:Algorithms; D000577:Amides / Q000494:pharmacology; D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D002045:Bupivacaine / Q000494:pharmacology; D002478:Cells, Cultured; D004351:Drug Resistance; D008619:Mepivacaine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D000077212:Ropivacaine; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000187:drug effects; D013237:Stereoisomerism; D013779:Tetrodotoxin / Q000494:pharmacology*
chemical_list: D000577:Amides; D000779:Anesthetics, Local; D010880:Piperidines; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013779:Tetrodotoxin; D000077212:Ropivacaine; D008619:Mepivacaine; D002045:Bupivacaine