脂质乳剂通过抑制布比卡因诱导的蛋白激酶C（PKC）和CPI-17去磷酸化，抑制毒性剂量布比卡因诱导的血管舒张，但对毒性剂量甲哌卡因诱导的血管舒张无影响。
Lipid emulsion inhibits vasodilation induced by a toxic dose of bupivacaine by suppressing bupivacaine-induced PKC and CPI-17 dephosphorylation but has no effect on vasodilation induced by a toxic dose of mepivacaine.
作者信息
Cho Hyunhoo, Ok Seong Ho, Kwon Seong Chun, Lee Soo Hee, Baik Jiseok, Kang Sebin, Oh Jiah, Sohn Ju-Tae
机构信息
Department of Anesthesiology and Pain Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Korea.
Department of Physiology, Institute for Clinical and Translational Research, Catholic Kwangdong University College of Medicine, Gangneung, Korea.
出版信息
Korean J Pain. 2016 Oct;29(4):229-238. doi: 10.3344/kjp.2016.29.4.229. Epub 2016 Sep 29.
BACKGROUND
The goal of this study was to investigate the effect of lipid emulsion on vasodilation caused by toxic doses of bupivacaine and mepivacaine during contraction induced by a protein kinase C (PKC) activator, phorbol 12,13-dibutyrate (PDBu), in an isolated endothelium-denuded rat aorta.
METHODS
The effects of lipid emulsion on the dose-response curves induced by bupivacaine or mepivacaine in an isolated aorta precontracted with PDBu were assessed. In addition, the effects of bupivacaine on the increased intracellular calcium concentration ([Ca]) and contraction induced by PDBu were investigated using fura-2 loaded aortic strips. Further, the effects of bupivacaine, the PKC inhibitor GF109203X and lipid emulsion, alone or in combination, on PDBu-induced PKC and phosphorylation-dependent inhibitory protein of myosin phosphatase (CPI-17) phosphorylation in rat aortic vascular smooth muscle cells (VSMCs) was examined by western blotting.
RESULTS
Lipid emulsion attenuated the vasodilation induced by bupivacaine, whereas it had no effect on that induced by mepivacaine. Lipid emulsion had no effect on PDBu-induced contraction. The magnitude of bupivacaine-induced vasodilation was higher than that of the bupivacaine-induced decrease in [Ca]. PDBu promoted PKC and CPI-17 phosphorylation in aortic VSMCs. Bupivacaine and GF109203X attenuated PDBu-induced PKC and CPI-17 phosphorylation, whereas lipid emulsion attenuated bupivacaine-mediated inhibition of PDBu-induced PKC and CPI-17 phosphorylation.
CONCLUSIONS
These results suggest that lipid emulsion attenuates the vasodilation induced by a toxic dose of bupivacaine via inhibition of bupivacaine-induced PKC and CPI-17 dephosphorylation. This lipid emulsion-mediated inhibition of vasodilation may be partly associated with the lipid solubility of local anesthetics.
背景
本研究的目的是在蛋白激酶C（PKC）激活剂佛波醇12,13 - 二丁酸酯（PDBu）诱导收缩的情况下，研究脂质乳剂对毒性剂量的布比卡因和甲哌卡因在离体去内皮大鼠主动脉中引起的血管舒张的影响。
方法
评估脂质乳剂对用PDBu预收缩的离体主动脉中布比卡因或甲哌卡因诱导的剂量 - 反应曲线的影响。此外，使用负载fura - 2的主动脉条研究布比卡因对PDBu诱导的细胞内钙浓度（[Ca]）升高和收缩的影响。进一步，通过蛋白质印迹法检测布比卡因、PKC抑制剂GF109203X和脂质乳剂单独或联合对PDBu诱导的大鼠主动脉血管平滑肌细胞（VSMCs）中PKC和肌球蛋白磷酸酶磷酸化依赖性抑制蛋白（CPI - 17）磷酸化的影响。
结果
脂质乳剂减弱了布比卡因诱导的血管舒张，而对甲哌卡因诱导的血管舒张没有影响。脂质乳剂对PDBu诱导的收缩没有影响。布比卡因诱导的血管舒张幅度高于布比卡因诱导的[Ca]降低幅度。PDBu促进主动脉VSMCs中PKC和CPI - 17磷酸化。布比卡因和GF109203X减弱了PDBu诱导的PKC和CPI - 17磷酸化，而脂质乳剂减弱了布比卡因介导的对PDBu诱导的PKC和CPI - 17磷酸化的抑制。
结论
这些结果表明，脂质乳剂通过抑制布比卡因诱导的PKC和CPI - 17去磷酸化来减弱毒性剂量的布比卡因诱导的血管舒张。这种脂质乳剂介导的血管舒张抑制可能部分与局部麻醉药的脂溶性有关。
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