Fatty-acid oxidation and calcium homeostasis are involved in the rescue of bupivacaine-induced cardiotoxicity by lipid emulsion in rats.
Fatty-acid oxidation and calcium homeostasis are involved in the rescue of bupivacaine-induced cardiotoxicity by lipid emulsion in rats.
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DOI：
10.1097/ccm.0b013e3182544f48
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发表时间：
2012-08
影响因子：
8.8
通讯作者：
Eghbali M
中科院分区：
文献类型：
--
作者：
Partownavid P;Umar S;Li J;Rahman S;Eghbali M
脂肪乳剂（LE）已被证明可有效地复苏布比卡因诱导的心脏骤停，但其作用机制尚不清楚。在这里，我们调查是否需要脂肪酸氧化的布比卡因诱导的心脏毒性的救援LE大鼠。我们还比较了LE复苏前后布比卡因诱导的心脏骤停中触发线粒体通透性转换孔（mPTP）开放的线粒体功能和钙阈值。前瞻性、随机、动物研究。大学研究实验室。成年雄性Sprague-Dawley大鼠用单剂量布比卡因（10 mg/kg，20秒，i. v.）20%LE（5 ml/kg推注，0.5ml/kg/min维持）并心脏按摩。CVT组大鼠分别单次静脉注射脂肪酸氧化抑制剂CVT（0.5、0.25、0.125、0.0625mg/kg）;在通过布比卡因过量诱导心搏停止前5分钟。测定心率（HR）、射血分数（EF）、短轴缩短率（FS）、心肌收缩末峰值（mPTP）开放阈值、氧耗量和膜电位。数值为平均值±SEM。布比卡因给药导致心搏停止。ILP输注后心功能逐渐改善，EF在5 min内完全恢复（EF=64±4%，FS=36± 3%，n=6），心率在10 min内增至239±9次/min（恢复71%，n=6）。LE仅能挽救低剂量CVT（0.0625 mg/kg）预处理的大鼠（10 min时HR=~181±11次/min，恢复56%; EF=50±1%; 5 min时FS=26±0.6%，n=3），但不能使高剂量CVT（0.5、0.25或0.125 mg/kg）预处理的大鼠复苏。与布比卡因过量给药后未接受ILP的组相比，从用20%LE复苏的大鼠中分离的心肌线粒体中响应于Ca 2+过载的钙保留能力显著更高（330±42 vs. 180±8.2 nmol/mg-线粒体蛋白，p<0.05，每组n=3）。布比卡因组输注LE复苏前后线粒体氧化速率和膜电位无明显变化。脂肪酸氧化是LE成功挽救布比卡因诱导的心脏毒性所必需的。这种拯救作用与线粒体渗透性转变孔开放的抑制有关。
Lipid Emulsion (LE) has been shown to be effective in resuscitating bupivacaine-induced cardiac arrest but its mechanism of action is not clear. Here we investigated whether fatty acid oxidation is required for rescue of bupivacaine induced cardiotoxicity by LE in rats. We also compared the mitochondrial function and calcium threshold for triggering of mitochondrial permeability transition pore (mPTP) opening in bupivacaine-induced cardiac arrest before and after resuscitation with LE. Prospective, randomized, animal study. University Research Laboratory. Adult male Sprague-Dawley rats. Asystole was achieved with a single dose of bupivacaine (10mg/kg over 20seconds, i.v.) and 20% LE infusion (5ml/kg bolus, and 0.5ml/kg/min maintenance) with cardiac massage started immediately. The rats in CVT group were pretreated with a single dose of fatty acid oxidation inhibitor CVT (0.5, 0.25, 0.125 or 0.0625mg/kg bolus i.v.) 5min prior to inducing asystole by bupivacaine overdose. Heart rate (HR), ejection fraction (EF), fractional shortening (FS), the threshold for opening of mPTP, oxygen consumption and membrane potential were measured. The values are Mean±SEM. Administration of bupivacaine resulted in asystole. ILP infusion improved the cardiac function gradually as the EF was fully recovered within 5min (EF=64±4% and FS=36±3%, n=6) and heart rate increased to 239±9 beats/min (71% recovery, n=6) within 10min. LE was only able to rescue rats pretreated with low dose of CVT (0.0625mg/kg) (HR=~181±11 beats/min at 10 min, recovery of 56%; EF=50±1%; FS=26±0.6% at 5min, n=3) but was unable to resuscitate rats pretreated with higher doses of CVT (0.5, 0.25 or 0.125mg/kg). The calcium retention capacity in response to Ca2+ overload was significantly higher in cardiac mitochondria isolated from rats resuscitated with 20% LE compared to the group that did not receive ILP after bupivacaine-overdose (330±42 vs. 180±8.2 nmol/mg-mitochondrial protein, p<0.05, n=3 in each group). The mitochondrial oxidative rate and membrane potential were similar in bupivacaine group before and after resuscitation with LE infusion. Fatty acid oxidation is required for successful rescue of bupivacaine induced cardiotoxicity by LE. This rescue action is associated with inhibition of mitochondrial permeability transition pore opening.