布比卡因诱导的心脏毒性中的胰岛素信号传导：恢复过程中的敏化作用及脂质乳剂的增强作用
Insulin Signaling in Bupivacaine-induced Cardiac Toxicity: Sensitization during Recovery and Potentiation by Lipid Emulsion.
作者信息
Fettiplace Michael R, Kowal Katarzyna, Ripper Richard, Young Alexandria, Lis Kinga, Rubinstein Israel, Bonini Marcelo, Minshall Richard, Weinberg Guy
机构信息
From the Department of Anesthesiology (M.R.F., K.K., R.R., A.Y., K.L., R.M., G.W.) and Department of Medicine (I.R., M.B.), and Neuroscience Program (M.R.F.), University of Illinois at Chicago, Chicago, Illinois; and Research and Development Service, Jesse Brown Veterans Affairs Medical Center (M.R.F., K.K., R.R., A.Y., K.L., I.R., G.W.), Chicago, Illinois.
出版信息
Anesthesiology. 2016 Feb;124(2):428-42. doi: 10.1097/ALN.0000000000000974.
BACKGROUND
The impact of local anesthetics on the regulation of glucose homeostasis by protein kinase B (Akt) and 5'-adenosine monophosphate-activated protein kinase (AMPK) is unclear but important because of the implications for both local anesthetic toxicity and its reversal by IV lipid emulsion (ILE).
METHODS
Sprague-Dawley rats received 10 mg/kg bupivacaine over 20 s followed by nothing or 10 ml/kg ILE (or ILE without bupivacaine). At key time points, heart and kidney were excised. Glycogen content and phosphorylation levels of Akt, p70 s6 kinase, s6, insulin receptor substrate-1, glycogen synthase kinase-3β, AMPK, acetyl-CoA carboxylase, and tuberous sclerosis 2 were quantified. Three animals received Wortmannin to irreversibly inhibit phosphoinositide-3-kinase (Pi3k) signaling. Isolated heart studies were conducted with bupivacaine and LY294002-a reversible Pi3K inhibitor.
RESULTS
Bupivacaine cardiotoxicity rapidly dephosphorylated Akt at S473 to 63 ± 5% of baseline and phosphorylated AMPK to 151 ± 19%. AMPK activation inhibited targets downstream of mammalian target of rapamycin complex 1 via tuberous sclerosis 2. Feedback dephosphorylation of IRS1 to 31 ± 8% of baseline sensitized Akt signaling in hearts resulting in hyperphosphorylation of Akt at T308 and glycogen synthase kinase-3β to 390 ± 64% and 293 ± 50% of baseline, respectively. Glycogen accumulated to 142 ± 7% of baseline. Irreversible inhibition of Pi3k upstream of Akt exacerbated bupivacaine cardiotoxicity, whereas pretreating with a reversible inhibitor delayed the onset of toxicity. ILE rapidly phosphorylated Akt at S473 and T308 to 150 ± 23% and 167 ± 10% of baseline, respectively, but did not interfere with AMPK or targets of mammalian target of rapamycin complex 1.
CONCLUSION
Glucose handling by Akt and AMPK is integral to recovery from bupivacaine cardiotoxicity and modulation of these pathways by ILE contributes to lipid resuscitation.
背景
局部麻醉药对蛋白激酶B（Akt）和5'-腺苷单磷酸激活蛋白激酶（AMPK）调节葡萄糖稳态的影响尚不清楚，但因其对局部麻醉药毒性及其静脉注射脂质乳剂（ILE）逆转作用的影响而显得重要。
方法
将Sprague-Dawley大鼠在20秒内给予10mg/kg布比卡因，随后不给予任何处理或给予10ml/kg ILE（或不含布比卡因的ILE）。在关键时间点，切除心脏和肾脏。对糖原含量以及Akt、p70 s6激酶、s6、胰岛素受体底物-1、糖原合酶激酶-3β、AMPK、乙酰辅酶A羧化酶和结节性硬化症2的磷酸化水平进行定量。三只动物接受渥曼青霉素以不可逆地抑制磷酸肌醇-3-激酶（Pi3k）信号传导。使用布比卡因和LY294002（一种可逆的Pi3K抑制剂）进行离体心脏研究。
结果
布比卡因心脏毒性迅速使S473位点的Akt去磷酸化至基线的63±5%，并使AMPK磷酸化至151±19%。AMPK激活通过结节性硬化症2抑制雷帕霉素复合物1哺乳动物靶点下游的靶点。IRS1反馈去磷酸化至基线的31±8%，使心脏中的Akt信号敏感化，导致T308位点的Akt过度磷酸化以及糖原合酶激酶-3β分别过度磷酸化至基线的390±64%和293±50%。糖原积累至基线的142±7%。在Akt上游不可逆地抑制Pi3k会加剧布比卡因心脏毒性，而用可逆抑制剂预处理可延迟毒性发作。ILE迅速使S473和T308位点的Akt磷酸化，分别达到基线的150±23%和167±10%，但不干扰AMPK或雷帕霉素复合物1哺乳动物靶点。
结论
Akt和AMPK对葡萄糖的处理对于从布比卡因心脏毒性中恢复至关重要，ILE对这些途径的调节有助于脂质复苏。
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