BackgroundThe local anesthetic bupivacaine exists in two stereoisomeric forms, R(+)‐ and S(−)‐bupivacaine. Because of its lower cardiac and central nervous system toxicity, attempts were made recently to introduce S(−)‐bupivacaine into clinical anesthesia. We investigated stereoselective actions of R(+)‐ and S(−)‐bupivacaine toward two local anesthetic‐sensitive ion channels in peripheral nerve, the Na+and the flicker K+channel.MethodsIn patch‐clamp experiments on enzymatically demyelinated peripheral amphibian nerve fibers, Na+and flicker K+channels were investigated in outside‐out patches. Half‐maximum inhibiting concentrations (IC50) were determined. For the flicker K+channel, simultaneous block by R(+)‐bupivacaine and S(−)‐bupivacaine was analyzed for competition and association (k1) and dissociation rate constants (k−1) were determined.ResultsBoth channels were reversibly blocked by R(+)‐ and S(−)‐bupivacaine. The IC50values (±SEM) for tonic Na+channel block were 29 ± 3 &mgr;M and 44 ± 3 &mgr;M, respectively. IC50values for flicker K+channel block were 0.15 ± 0.02 &mgr;M and 11 ± 1 &mgr;M, respectively, resulting in a high stereopotency ratio (±) of 73. Simultaneously applied enantiomers competed for a single binding site. Rate constants k1and k−1were 0.83 ± 0.13 × 106M−1· s−1and 0.13 ± 0.03 s−1, respectively, for R(+)‐bupivacaine and 1.90 ± 0.20 × 106M−1· s−1and 8.3 ± 1.0 s−1, respectively, for S(−)‐bupivacaine.ConclusionsBupivacaine block of Na+channels shows no salient stereoselectivity. Block of flicker K+channels has the highest stereoselectivity ratio of bupivacaine action known so far. This stereoselectivity derives predominantly from a difference in k−1, suggesting a tight fit between R(+)‐bupivacaine and the binding site. The flicker K+channel may play an important role in yet unknown toxic mechanisms of R(+)‐bupivacaine.