Department of Anaesthesiology, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.
Br J Anaesth. 2014 Feb;112(2):370-9. doi: 10.1093/bja/aet299. Epub 2013 Sep 24.
Signalling of several G-protein-coupled receptors of the Gq/11 family is time-dependently inhibited by local anaesthetics (LAs). Since LA-induced modulation of muscarinic m1 and m3 receptor function may explain their beneficial effects in clinical practice, such as decreased postoperative cognitive dysfunction or less bronchoconstriction, we studied how prolonged exposure affects muscarinic signalling (Wang D, Wu X, Li J, Xiao F, Liu X, Meng M. The effect of lidocaine on early postoperative cognitive dysfunction after coronary artery bypass surgery. Anesth Analg 2002; 95: 1134-41; Groeben H, Silvanus MT, Beste M, Peters J. Combined lidocaine and salbutamol inhalation for airway anesthesia markedly protects against reflex bronchoconstriction. Chest 2000; 118: 509-15).
A two-electrode voltage clamp was used to assess the effects of lidocaine or its permanently charged analogue QX314 on recombinantly expressed m1 and m3 receptors in Xenopus oocytes. Antisense knock-down of functional Gαq-protein and inhibition of protein kinase C (PKC) served to define mechanisms and sites of action.
Lidocaine affected muscarinic signalling in a biphasic way: an initial decrease in methylcholine bromide-elicited m1 and m3 responses after 30 min, followed by a significant increase in muscarinic responses after 8 h. Intracellularly injected QX314 time-dependently inhibited muscarinic signalling, but had no effect in Gαq-depleted oocytes. PKC-antagonism enhanced m1 and m3 signalling, but completely abolished the LA-induced increase in muscarinic responses, unmasking an underlying time-dependent inhibition of m1 and m3 responses after 8 h.
Lidocaine modulates muscarinic m1 and m3 receptors in a time- and Gαq-dependent manner, but this is masked by enhanced PKC activity. The biphasic time course may be due to interactions of LAs with an extracellular receptor domain, modulated by PKC activity. Prolonged exposure to LAs may not benefit pulmonary function, but may positively affect postoperative cognitive function.
几种 Gq/11 家族的 G 蛋白偶联受体的信号会被局部麻醉剂（LA）随时间抑制。由于 LA 诱导的毒蕈碱 m1 和 m3 受体功能的调节可能解释了它们在临床实践中的有益作用，例如减少术后认知功能障碍或支气管痉挛较少，我们研究了长时间暴露如何影响毒蕈碱信号（Wang D、Wu X、Li J、Xiao F、Liu X、Meng M. 利多卡因对冠状动脉旁路手术后早期术后认知功能障碍的影响。麻醉分析 2002 年；95：1134-41；Groeben H、Silvanus MT、Beste M、Peters J. 利多卡因和沙丁胺醇联合吸入用于气道麻醉可显著防止反射性支气管痉挛。胸部 2000 年；118：509-15）。
使用双电极电压钳评估利多卡因或其永久带电类似物 QX314 对 Xenopus 卵母细胞中重组表达的 m1 和 m3 受体的影响。功能性 Gαq-蛋白的反义敲低和蛋白激酶 C（PKC）抑制用于定义作用机制和作用部位。
利多卡因以双相方式影响毒蕈碱信号：30 分钟后，甲基胆碱溴化物诱发的 m1 和 m3 反应最初减少，8 小时后毒蕈碱反应明显增加。细胞内注射 QX314 时间依赖性抑制毒蕈碱信号，但在 Gαq 耗尽的卵母细胞中没有作用。PKC 拮抗剂增强了 m1 和 m3 信号，但完全消除了 LA 诱导的毒蕈碱反应增加，揭示了 8 小时后 m1 和 m3 反应的潜在时间依赖性抑制。
利多卡因以时间和 Gαq 依赖的方式调节毒蕈碱 m1 和 m3 受体，但这被增强的 PKC 活性所掩盖。双相时间过程可能是由于 LA 与受 PKC 活性调节的细胞外受体结构域相互作用所致。长时间接触 LA 可能不会有益于肺功能，但可能会对术后认知功能产生积极影响。
