Differential effects of bupivacaine and ropivacaine enantiomers on intracellular Ca 2+ regulation in murine skeletal muscle fibers

Abstract

Background: Increased intracellular Ca 2+ concentrations are considered to be a major pathomechanism in local anesthetic myotoxicity. Racemic bupivacaine and 5-ropivacaine cause Ca 2+ release from the sarcoplasmic reticulum of skeletal muscle fibers and simultaneously inhibit Ca 2+ reuptake. Examining the optical isomers of both agents, the authors investigated stereoselective effects on muscular Ca 2+ regulation to get a closer insight in subcellular mechanisms of local anesthetic myotoxicity. Methods: R- and S-enantiomers as well as racemic mixtures of both agents were tested in concentrations of 1, 5,10, and 15 mM. Saponin-skinned muscle fibers from the extensor digitorum longus muscle of BALB/c mice were examined according to a standardized procedure. For the assessment of effects on Ca 2+ uptake and release from the sarcoplasmic reticulum, agents were added to the loading solution and the release solution, respectively, and force and Ca 2+ transients were monitored. Results: The effects of S-enantiomers on both Ca 2+ release and reuptake were significantly more pronounced than those of racemic mixtures and R-enantiomers, respectively. In addition, the effects of racemates were markedly stronger than those of R-enantiomers. With regard to Ca 2+ release, the effects of bupivacaine isomers were more pronounced than the isomers of ropivacaine. Conclusions: These data show that stereoselectivity is involved in alterations of intracellular Ca2+ regulation by bupivacaine and ropivacaine. S-enantiomers seem to be more potent than R-enantiomers, with intermediate effects of racemic mixtures. In addition, lipophilicity also seems to determine the extent of Ca 2+ release by local anesthetics. © 2005 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.