Heavner J E, Shi B, Pitkänen M
Department of Anesthesiology, Texas Tech University Health Sciences Center, Lubbock 79430, USA.
Reg Anesth. 1996 May-Jun;21(3):243-8.
There is evidence that local anesthetic-induced seizures may be mediated by receptors for N-methyl-D-aspartate (NMDA) which activate production of nitric oxide (NO). The objective of this study was to determine the effects, if any, of inhibition of NO synthesis on the responses of the central nervous and cardiovascular systems to bupivacaine.
Sprague-Dawley rats were assigned to two groups. The lightly anesthetized (0.5% halothane, 70% nitrous oxide) and paralyzed (doxacurium) animals were given N omega-nitro-L-arginine methyl ester (L-NAME), a NO synthase inhibitor, 2 mg/kg/min (n = 6) or saline (n = 5) intravenously for 30 minutes. Then bupivacaine was administered intravenously (2 mg/kg/min) to both groups of animals until asystole. Arterial blood samples for bupivacaine concentration analysis (by high-pressure liquid chromatography) were taken during the stabilization period and during local anesthetic infusion. Student's t-test was used to determine significant differences (P < .05) between groups.
Average doses of bupivacaine that produced arrhythmias and asystole were remarkably lower in L-NAME-treated than in saline-treated rats (arrhythmia, 5.1 +/- 2.0 vs 15.8 +/- 3.8 mg/kg; asystole, 15.9 +/- 3.2 vs 27.8 +/- 6.1 mg/kg; both P < .05). The doses producing seizures and isoelectric electroencephalograms and the duration of seizures did not differ significantly between the two treatment groups. However, electroencephalographic epileptiform activity was less intense (lower amplitude, shorter duration of ictal activity) in the L-NAME-treated animals. Arterial plasma concentrations of bupivacaine 5 minutes after the start of bupivacaine infusion were significantly higher in the L-NAME than in the saline group (22.3 +/- 2.9 vs 12.8 +/- 1.5 micrograms/mL, P < .05).
These results suggest that NO synthase inhibition by L-NAME enhances the cardiac toxicity of bupivacaine, probably by a pharmacokinetic action, and reduces its central nervous system toxicity, probably by a pharmacodynamic action.
有证据表明局部麻醉药诱发的惊厥可能由N-甲基-D-天冬氨酸（NMDA）受体介导，该受体激活一氧化氮（NO）的生成。本研究的目的是确定抑制NO合成对中枢神经系统和心血管系统对布比卡因反应的影响（如果有）。
将Sprague-Dawley大鼠分为两组。轻度麻醉（0.5%氟烷，70%氧化亚氮）和麻痹（多沙库铵）的动物静脉注射NO合酶抑制剂Nω-硝基-L-精氨酸甲酯（L-NAME），剂量为2mg/kg/min（n = 6）或生理盐水（n = 5），持续30分钟。然后两组动物均静脉注射布比卡因（2mg/kg/min）直至心搏停止。在稳定期和局部麻醉药输注期间采集动脉血样本进行布比卡因浓度分析（采用高压液相色谱法）。采用Student t检验确定两组之间的显著差异（P <.05）。
L-NAME处理组大鼠发生心律失常和心搏停止的布比卡因平均剂量显著低于生理盐水处理组（心律失常：5.1±2.0 vs 15.8±3.8mg/kg；心搏停止：15.9±3.2 vs 27.8±6.1mg/kg；均P <.05）。两个治疗组之间产生惊厥和脑电图等电位的剂量以及惊厥持续时间无显著差异。然而，L-NAME处理组动物的脑电图癫痫样活动强度较低（振幅较低，发作期活动持续时间较短）。布比卡因输注开始5分钟后，L-NAME组动脉血浆布比卡因浓度显著高于生理盐水组（22.3±2.9 vs 12.8±1.5μg/mL，P <.05）。
这些结果表明，L-NAME抑制NO合酶可能通过药代动力学作用增强布比卡因的心脏毒性，并通过药效学作用降低其对中枢神经系统的毒性。
