Stereoselectivity of Bupivacaine in Local Anesthetic–sensitive Ion Channels of Peripheral Nerve

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Abstract

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 μM and 44 ± 3 μM, respectively. IC50 values for flicker K+ channel block were 0.15 ± 0.02 μM and 11 ± 1 μM, 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 × 106 M−1 · s−1 and 0.13 ± 0.03 s−1, respectively, for R(+)-bupivacaine and 1.90 ± 0.20 × 106 M−1 · 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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