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Background: The 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.

Methods: In 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.

Results: Both channels were reversibly blocked by R( )- and S(-)-bupivacaine. The IC50 values ( /-SEM) for tonic Na channel block were 29 /- 3 [mu]M and 44 /- 3 [mu]M, respectively. IC50 values for flicker K channel block were 0.15 /- 0.02 [mu]M and 11 /- 1 [mu]M, respectively, resulting in a high stereopotency ratio ( /-) of 73. Simultaneously applied enantiomers competed for a single binding site. Rate constants k1 and k-1 were 0.83 /- 0.13 x 106 M-1 [middle dot] s-1 and 0.13 /- 0.03 s-1, respectively, for R( )-bupivacaine and 1.90 /- 0.20 x 106 M-1 [middle dot] s-1 and 8.3 /- 1.0 s-1, respectively, for S(-)-bupivacaine.

Conclusions: Bupivacaine 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.

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