Differential effects of bupivacaine on intracellular Ca2+ regulation: potential mechanisms of its myotoxicity.
BACKGROUND
Bupivacaine produces skeletal muscle damage in clinical concentrations. It has been suggested that this may be caused by an increased intracellular level of [Ca2+]. Therefore, the aim of this study was to investigate direct intracellular effects of bupivacaine on Ca2+ release from the sarcoplasmic reticulum (SR), on Ca2+ uptake into the SR, and on Ca2+ sensitivity of the contractile proteins.


METHODS
Saponin skinned muscle fibers from the extensor digitorum longus muscle of BALB/c mice were examined according to a standardized procedure described previously. For the assessment of effects on Ca2+ uptake and release from the SR, bupivacaine was added to the loading solution and the release solution, respectively. Force transients and force decays were monitored, and the position of the curve relating relative isometric force free [Ca2+] was evaluated in the presence or absence of bupivacaine.


RESULTS
Bupivacaine induces Ca2+ release from the SR. In addition, the Ca2+ loading procedure is suppressed, resulting in smaller caffeine-induced force transients after loading in the presence of bupivacaine. The decay of caffeine-induced force transients is reduced by bupivacaine, and it also shifts [Ca2+]-force relation toward lower [Ca2+].


CONCLUSIONS
These data reveal that bupivacaine does not only induce Ca2+ release from the SR, but also inhibits Ca2+ uptake by the SR, which is mainly regulated by SR Ca2+ adenosine triphosphatase activity. It also has a Ca2+ -sensitizing effect on the contractile proteins. These mechanisms result in increased intracellular [Ca2+] concentrations and may thus contribute to its pronounced skeletal muscle toxicity.
Zink
Wolfgang
W
Department of Anesthesiology and the Institute of Physiology and Pathophysiology, University of Heidelberg, Germany.
Graf
Bernhard M
BM
Sinner
Barbara
B
Martin
Eike
E
Fink
Rainer H A
RH
Kunst
Gudrun
G
D000779:Anesthetics, Local / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D002045:Bupivacaine / Q000494:pharmacology* / Q000633:toxicity; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D003285:Contractile Proteins / Q000187:drug effects; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D018485:Muscle Fibers, Skeletal / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism
D000779:Anesthetics, Local; D003285:Contractile Proteins; D010726:Phosphodiesterase Inhibitors; D002110:Caffeine; D002118:Calcium; D002045:Bupivacaine