Centre de Résonance Magnétique des Systèmes Biologiques, Université Bordeaux, France.
Biochem J. 2012 Jun 1;444(2):315-21. doi: 10.1042/BJ20112011.
Bupivacaine is a widely used anaesthetic injected locally in clinical practice for short-term neurotransmission blockade. However, persistent side effects on mitochondrial integrity have been demonstrated in muscle parts surrounding the injection site. We use the precise language of metabolic control analysis in the present study to describe in vivo consequences of bupivacaine injection on muscle energetics during contraction. We define a model system of muscle energy metabolism in rats with a sciatic nerve catheter that consists of two modules of reactions, ATP/PCr (phosphocreatine) supply and ATP/PCr demand, linked by the common intermediate PCr detected in vivo by (31)P-MRS (magnetic resonance spectroscopy). Measured system variables were [PCr] (intermediate) and contraction (flux). We first applied regulation analysis to quantify acute effects of bupivacaine. After bupivacaine injection, contraction decreased by 15.7% and, concomitantly, [PCr] increased by 11.2%. The regulation analysis quantified that demand was in fact directly inhibited by bupivacaine (-21.3%), causing an increase in PCr. This increase in PCr indirectly reduced mitochondrial activity (-22.4%). Globally, the decrease in contractions was almost fully explained by inhibition of demand (-17.0%) without significant effect through energy supply. Finally we applied elasticity analysis to quantify chronic effects of bupivacaine iterative injections. The absence of a difference in elasticities obtained in treated rats when compared with healthy control rats clearly shows the absence of dysfunction in energetic control of muscle contraction energetics. The present study constitutes the first and direct evidence that bupivacaine myotoxicity is compromised by other factors during contraction in vivo, and illustrates the interest of modular approaches to appreciate simple rules governing bioenergetic systems when affected by drugs.
布比卡因是一种广泛应用于临床的局部麻醉剂，用于短期神经传递阻断。然而，在注射部位周围的肌肉部位已经证明了对线粒体完整性的持续副作用。在本研究中，我们使用代谢控制分析的精确语言来描述布比卡因注射对肌肉收缩过程中能量代谢的体内影响。我们使用大鼠坐骨神经导管建立了一个肌肉能量代谢模型系统，该系统由两个反应模块组成，即 ATP/PCr（磷酸肌酸）供应和 ATP/PCr 需求，由体内通过（31）P-MRS（磁共振光谱）检测到的共同中间产物 PCr 连接。测量的系统变量是[PCr]（中间产物）和收缩（通量）。我们首先应用调节分析来量化布比卡因的急性作用。布比卡因注射后，收缩减少了 15.7%，同时[PCr]增加了 11.2%。调节分析量化了需求实际上直接受到布比卡因的抑制（-21.3%），导致 PCr 增加。这种 PCr 的增加间接降低了线粒体活性（-22.4%）。总的来说，收缩的减少几乎完全可以通过需求的抑制来解释（-17.0%），而通过能量供应没有显著影响。最后，我们应用弹性分析来量化布比卡因反复注射的慢性作用。与健康对照组相比，治疗组大鼠的弹性差异没有差异，这清楚地表明肌肉收缩能量代谢的能量控制没有功能障碍。本研究首次直接证明，在体内收缩过程中，布比卡因的肌毒性受到其他因素的影响，并且说明了模块化方法在评估受药物影响的生物能系统的简单规则时的重要性。
