Lidocaine Prevents Oxidative Stress-Induced Endothelial Dysfunction of the Systemic Artery in Rats With Intermittent Periodontal Inflammation
Lidocaine Prevents Oxidative Stress-Induced Endothelial Dysfunction of the Systemic Artery in Rats With Intermittent Periodontal Inflammation
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DOI：
10.1213/ane.0000000000002102
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发表时间：
2017-06
影响因子：
5.7
通讯作者：
Takumi Saito;Yasuhiro Yamamoto;G. Feng;Y. Kazaoka;Y. Fujiwara;H. Kinoshita
中科院分区：
文献类型：
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作者：
Takumi Saito;Yasuhiro Yamamoto;G. Feng;Y. Kazaoka;Y. Fujiwara;H. Kinoshita
背景：牙周炎可导致体动脉内皮细胞功能障碍。然而，在痛苦的牙科手术中使用局麻药是否能缓解牙周炎症和系统内皮功能尚不清楚。本研究旨在探讨牙周注射利多卡因是否能预防脂多糖(LPS)引起的间歇性牙周炎大鼠氧化应激诱导的体动脉内皮功能障碍。方法：8~11周龄SD大鼠牙周注射脂多糖1500µg(内毒素组)。利多卡因(3 mg/kg)、内毒素+利多卡因(3 mg/kg)、内毒素+利多卡因(1.5 mg/kg)、内毒素+利多卡因(3 mg/kg，ip)组同时给予牙周注射利多卡因1.5 mg/kg、3 mg/kg或ip 3 mg/kg。对离体主动脉或下颌动脉进行组织病理学改变、等长力记录、活性氧和免疫印迹的评估。结果：对照组、内毒素组、内毒素+利多卡因(3 mg/kg)组和利多卡因(3 mg/kg)组的平均血压和心率差异无统计学意义。LPS抑制乙酰胆碱(ACh，10~(-9)~10~(-5)m o l/L)的松弛作用(ACh 3×10~(-8)m o l/L时降低29%，P=0.01)，这种松弛作用可被过氧化氢酶恢复。牙周利多卡因(1.5 mg/kg和3 mg/kg)可剂量依赖性地拮抗脂多糖所致的内皮功能障碍(ACh浓度为3×10-8m ol/kg时，差异分别为24.5%~31.1%，P=0.006或0.001)。IP注射利多卡因(3 mg/kg)可恢复ACh引起的大鼠血管扩张(ACh 3×10~(-8)m o l/L，P<0.01)。在脂多糖组，主动脉中的活性氧水平增加了一倍(P<；.001)，而这种增加可被聚乙二醇式过氧化氢酶、牙周利多卡因(3 mg/kg)或两者合用所消除。脂多糖诱导牙周组织中肿瘤坏死因子-α的蛋白表达增加4倍(P<；.001)，而利多卡因(3 mg/kg)联合给药部分降低了这一水平。应用利多卡因还降低了烟酰胺腺嘌呤二核苷酸磷酸氧化酶亚单位p47Phox的蛋白表达，该亚单位的蛋白表达被牙周脂多糖增强(增加5.6倍；P<；.001)。结论：利多卡因通过降低烟酰胺腺嘌呤二核苷酸磷酸氧化酶产生的活性氧和牙周肿瘤坏死因子水平来保护牙周炎大鼠的主动脉内皮功能。提示局部麻醉药在牙周病治疗中对体动脉内皮细胞功能有一定的改善作用。
BACKGROUND: Periodontal inflammation causes endothelial dysfunction of the systemic artery. However, it is unknown whether the use of local anesthetics during painful dental procedures alleviates periodontal inflammation and systemic endothelial function. This study was designed to examine whether the gingival or systemic injection of lidocaine prevents oxidative stress-induced endothelial dysfunction of the systemic artery in rats with intermittent periodontal inflammation caused by lipopolysaccharides (LPS). METHODS: Some rats received 1500 µg LPS injections to the gingiva during a week interval from the age of 8 to 11 weeks (LPS group). Lidocaine (3 mg/kg), LPS + lidocaine (3 mg/kg), LPS + lidocaine (1.5 mg/kg), and LPS + lidocaine (3 mg/kg, IP) groups simultaneously received gingival 1.5 or 3 mg/kg or IP 3 mg/kg injection of lidocaine on the same schedule as the gingival LPS. Isolated aortas or mandibles were subjected to the evaluation of histopathologic change, isometric force recording, reactive oxygen species, and Western immunoblotting. RESULTS: Mean blood pressure and heart rate did not differ among the control, LPS, LPS + lidocaine (3 mg/kg), and lidocaine (3 mg/kg) groups. LPS application reduced acetylcholine (ACh, 10–9 to 10–5 mol/L)-induced relaxation (29% difference at ACh 3 × 10–8 mol/L, P = .01), which was restored by catalase. Gingival lidocaine (1.5 and 3 mg/kg) dose dependently prevented the endothelial dysfunction caused by LPS application (24.5%–31.1% difference at ACh 3 × 10–8 mol/L, P = .006 or .001, respectively). Similar to the gingival application, the IP injection of lidocaine (3 mg/kg) restored the ACh-induced dilation of isolated aortas from rats with the LPS application (27.5% difference at ACh 3 × 10–8 mol/L, P < .001). Levels of reactive oxygen species were double in aortas from the LPS group (P < .001), whereas the increment was abolished by polyethylene glycol-catalase, gingival lidocaine (3 mg/kg), or the combination. The LPS induced a 4-fold increase in the protein expression of tumor necrosis factor- in the periodontal tissue (P < .001), whereas the lidocaine (3 mg/kg) coadministration partly reduced the levels. Lidocaine application also decreased the protein expression of the nicotinamide adenine dinucleotide phosphate oxidase subunit p47phox, which was enhanced by the gingival LPS (5.6-fold increase; P < .001). CONCLUSIONS: Lidocaine preserved the aortic endothelial function through a decrease in arterial reactive oxygen species produced by nicotinamide adenine dinucleotide phosphate oxidase and periodontal tumor necrosis factor- levels in rats with periodontal inflammation. These results suggest the beneficial effect of the gingival application of local anesthetics on the treatment of periodontal diseases on endothelial function of systemic arteries.