Differential Effects of Bupivacaine on Intracellular Ca2+ Regulation: Potential Mechanisms of Its Myotoxicity

• Published in: Anesthesiology (Philadelphia) 2002-09, Vol.97 (3), p.710-716
• Main Authors: Zink, Wolfgang, Graf, Bernhard M, Sinner, Barbara, Martin, Eike, Fink, Rainer H. A, Kunst, Gudrun
• Format: Article
• Language: English
• Subjects: Anesthetics, Local - pharmacology; Anesthetics, Local - toxicity; Animals; Biological and medical sciences; Bupivacaine - pharmacology; Bupivacaine - toxicity; Caffeine - pharmacology; Calcium - metabolism; Contractile Proteins - drug effects; Drug toxicity and drugs side effects treatment; In Vitro Techniques; Isometric Contraction - drug effects; Medical sciences; Mice; Mice, Inbred BALB C; Muscle Fibers, Skeletal - drug effects; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Pharmacology. Drug treatments; Phosphodiesterase Inhibitors - pharmacology; Sarcoplasmic Reticulum - drug effects; Sarcoplasmic Reticulum - metabolism; Toxicity: nervous system and muscle
• ISSN: 0003-3022; 1528-1175
• DOI: 10.1097/00000542-200209000-00026

BACKGROUNDBupivacaine produces skeletal muscle damage in clinical concentrations. It has been suggested that this may be caused by an increased intracellular level of [Ca]. Therefore, the aim of this study was to investigate direct intracellular effects of bupivacaine on Ca release from the sarcoplasmic reticulum (SR), on Ca uptake into the SR, and on Ca sensitivity of the contractile proteins. METHODSSaponin 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 Ca 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 versus free [Ca] was evaluated in the presence or absence of bupivacaine. RESULTSBupivacaine induces Ca release from the SR. In addition, the Ca 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 [Ca]-force relation toward lower [Ca]. CONCLUSIONSThese data reveal that bupivacaine does not only induce Ca release from the SR, but also inhibits Ca uptake by the SR, which is mainly regulated by SR Ca adenosine triphosphatase activity. It also has a Ca-sensitizing effect on the contractile proteins. These mechanisms result in increased intracellular [Ca] concentrations and may thus contribute to its pronounced skeletal muscle toxicity.