Department of Anesthesiology, University Hospital Maastricht, The Netherlands.
Reg Anesth Pain Med. 2013 Jan-Feb;38(1):9-15. doi: 10.1097/AAP.0b013e31827a3cbe.
Local anesthetics (LAs) are widely known for inhibition of voltage-gated sodium channels underlying their antiarrhythmic and antinociceptive effects. However, LAs have significant immunomodulatory properties and were shown to affect human neutrophil functions independent of sodium-channel blockade. Previous studies suggest a highly selective interaction between LAs and the α-subunit of G protein-coupled receptors of the Gq/G11 family as underlying mechanism. Providing a detailed structure function analysis, this study aimed to determine the active parts within the LA molecule responsible for the effects on human neutrophil priming.
Human neutrophils were incubated with structurally different LAs for 60 minutes, followed by priming and activation using either platelet-activating factor or lysophosphatidic acid and N-formyl-methionyl-L-leucyl-L-phenylalanine. Superoxide anion generation was determined, using the cytochrome c reduction assay.
Differences in priming inhibition of human neutrophils between LAs were smaller than expected, although significant. Ester-linked LAs blocked priming responses more effectively than did amide LAs. Furthermore, the inhibitory potency of LAs on priming decreased with an increase of their respective octanol-buffer coefficient, and inhibition did not correlate with sodium-channel-blocking potency. Charge was not crucially required for priming inhibition, yet it played a role in effect size.
Local anesthetics significantly attenuated Gαq-protein-mediated neutrophil priming. The most potent inhibition was achieved by ester compounds, inversely correlated with their octanol-buffer coefficient, and enhanced by permanent charges within the LA molecule. No correlation to their potency of blocking sodium channels was found.
局部麻醉剂（LA）因其对电压门控钠离子通道的抑制作用而具有抗心律失常和镇痛作用。然而，LA 具有显著的免疫调节特性，并被证明可独立于钠离子通道阻断作用影响人中性粒细胞的功能。先前的研究表明，LA 与 G 蛋白偶联受体的α亚单位之间存在高度选择性相互作用，这是其作用机制的基础。本研究旨在通过详细的结构功能分析，确定 LA 分子中负责影响人中性粒细胞初始激活的活性部分。
将人中性粒细胞与结构不同的 LA 孵育 60 分钟，然后用血小板激活因子或溶血磷脂酸和 N-甲酰基-甲硫氨酸-亮氨酸-苯丙氨酸进行初始激活和激活。使用细胞色素 c 还原测定法测定超氧化物阴离子的产生。
尽管差异有统计学意义，但 LA 对人中性粒细胞初始激活的抑制作用差异较小。酯类 LA 比酰胺类 LA 更有效地阻断初始激活反应。此外，LA 对初始激活的抑制作用随着其各自的辛醇-缓冲系数的增加而降低，抑制作用与钠离子通道阻断作用无关。电荷对于初始激活的抑制并非至关重要，但对作用大小有影响。
局部麻醉剂显著减弱了 Gαq 蛋白介导的中性粒细胞初始激活。最有效的抑制作用是由酯类化合物实现的，与它们的辛醇-缓冲系数呈负相关，并通过 LA 分子中的永久电荷增强。未发现与阻断钠离子通道的作用有关。
