Block of Neuronal Tetrodotoxin-Resistant Na  Currents by Stereoisomers of Piperidine Local Anesthetics Michael E. Bra ¨u, PD Dr. med.*, Pierre Branitzki†, Andrea Olschewski, Dr. med.*, Werner Vogel, Prof. Dr. rer. nat.†, and Gunter Hempelmann, Prof. Dr. med., Dr. h.c.* Departments of *Anesthesiology and Intensive Care Medicine and †Physiology, Justus-Liebig-University, Giessen, Germany Tetrodotoxin (TTX)-sensitive Na + channels in the pe- ripheral nervous system are the major targets for local anesthetics. In the peripheral nociceptive system, a Na + channel subtype resistant to TTX and with distinct elec- trophysiological 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 in- creased activation threshold compared with TTX- sensitive Na + currents and may have different pharma- cological properties. We studied the effects of stereoisomers of piperidine local anesthetics on neuro- nal 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, ropiva- caine, 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 rela- tionships. Potencies for tonic and for use-dependent block increased with rising lipid solubilities of the drugs. Stereoselective action was not observed. We con- clude that block of TTX-resistant Na + currents may lead to blockade of TTX-resistant action potentials in nociceptive fibers and consequently may be responsi- ble for pain suppression during local anesthesia. (Anesth Analg 2000;91:1499 –1505) P iperidine local anesthetics, such as mepivacaine, ropivacaine, and bupivacaine are widely used in clinical practice. These amide-linked drugs share a common basic structure, differing only in the length of the alkyl chain attached to the tertiary amine in molecule, and because of a chiral carbon in the piper- idine ring, they exist as stereoisomers or enantiomers (Fig. 1). Despite similar nerve blocking potencies, the S(-)-forms of ropivacaine and bupivacaine have dis- tinct advantages over the R(+)-forms or the racemic mixtures. This is mainly because of the decreased cardiovascular and central nervous system side effects of the S(-)-enantiomers (1) resulting in an increased therapeutic index. Because of these advantages, ropi- vacaine has only been introduced into clinical practice as the S(-)-enantiomer, and bupivacaine, used as the racemic mixture of both enantiomers, will soon be available in the S(-)-form known as levobupivacaine. The local anesthetic action of these drugs is achieved by Na + channel blockade in the peripheral nervous system. Na + channels are integral membrane proteins re- sponsible for the initiation of action potentials in many excitable tissues. In the peripheral nervous system, expeditious opening of voltage-gated Na + channels combined with the passive electrical properties of my- elinated axons allow high conduction velocities as necessary for adequate interaction of the individual with its environment. In the peripheral nociceptive system, a distinct Na + channel subtype resistant to the classical neurotoxin tetrodotoxin (TTX) is found, which is to some extent involved in action potential conduction along the axon (2) and in impulse initia- tion in peripheral nerve endings of nociceptors (3). Compound action potentials in C-fibers are partly resistant to TTX, but depend on extracellular Na + ions. This was demonstrated by using various prepa- rations of different species including human sural nerves (2) and demonstrates the important role of TTX-resistant Na + channels in conduction of nocicep- tive impulses. It further underlines the importance of blocking these channels during local anesthesia, which Supported, in part, by the Deutsche Forschungsgemeinschaft, Grant Vo188/13 to WV and by the Fo ¨ rderkreis Ana ¨sthesie e.V. Giessen Accepted for publication August 2, 2000. Address correspondence and reprint requests to Michael E. Bra ¨u, PD Dr. med, Abteilung Anaesthesiologie und Operative Intensiv- medizin Justus-Liebig-Universita ¨ t, Rudolf-Buchheim-Str. 7, D-35385 Giessen, Germany. Address e-mail to meb@anesthesiology.de. ©2000 by the International Anesthesia Research Society 0003-2999/00 Anesth Analg 2000;91:1499–1505 1499