From the Department of Anesthesiology and Perioperative Medicine, Division of Molecular Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California.
Anesthesiology. 2018 Jul;129(1):154-162. doi: 10.1097/ALN.0000000000002195.
We have previously shown that intralipid (lipid emulsion) protects the heart against ischemia/reperfusion injury and bupivacaine-induced cardiotoxicity. However, the precise underlying mechanisms are not fully understood. Here we explored the hypothesis that free fatty acid receptor-1 or G-protein-coupled receptor 40 is expressed in the heart and that cardioprotective effects of lipid emulsion are mediated through G-protein-coupled receptor 40 in two animal models of ischemia/reperfusion injury and bupivacaine-induced cardiotoxicity.
Langendorff-perfused male mouse hearts were subjected to ischemia/reperfusion with lipid emulsion alone (1%) or with G-protein-coupled receptor 40 antagonist (GW1100, 10 µM). Additionally, cardiotoxicity was achieved in male rats with bupivacaine bolus (10 mg/kg, IV) followed by lipid emulsion alone (20%, 5 ml/kg bolus, and 0.5 ml · kg · min maintenance, IV) or with GW1100 pretreatment (2.5 mg/kg, IV).
G-protein-coupled receptor 40 is expressed in rodent hearts. GW1100 abolished lipid emulsion-induced cardioprotection against ischemia/reperfusion in mice because rate pressure product and left ventricular developed pressure were lower than lipid emulsion alone (rate pressure product: 2,186 ± 1,783 [n = 7] vs. 11,607 ± 4,347 [n = 8]; left ventricular developed pressure: 22.6 ± 10.4 vs. 63.8 ± 20; P < 0.0001). Lipid emulsion + GW1100 also demonstrated reduced LV dP/dtmax and LV dP/dtmin (dP/dtmax = 749 ± 386 vs. 2,098 ± 792, P < 0.001; dP/dtmin = -443 ± 262 vs. -1,447 ± 546, P < 0.001). In bupivacaine-induced cardiotoxicity rat model, GW1100 pretreatment had no significant effect on heart rate (HR) and ejection fraction after 30 min (HR: 302 ± 17 vs. 312 ± 38; ejection fraction: 69 ± 3% vs. 73 ± 4%). GW1100 pretreatment, however, prevented lipid-rescue, with no recovery after 10 min. In the control group, lipid emulsion improved HR (215 ± 16 at 10 min) and fully rescued left ventricle function at 10 min (ejection fraction = 67 ± 8%, fractional shortening = 38 ± 6%).
G-protein-coupled receptor 40 is expressed in the rodent heart and is involved in cardioprotection mediated by lipid emulsion against ischemia/reperfusion injury and bupivacaine-induced cardiotoxicity.
我们之前已经表明，脂肪乳（脂质乳剂）可以保护心脏免受缺血/再灌注损伤和布比卡因引起的心脏毒性。然而，确切的潜在机制尚不完全清楚。在这里，我们假设游离脂肪酸受体-1 或 G 蛋白偶联受体 40 在心脏中表达，并且脂质乳剂的心脏保护作用是通过 G 蛋白偶联受体 40 在两种缺血/再灌注损伤和布比卡因引起的心脏毒性的动物模型中介导的。
用单独的脂肪乳（1%）或 G 蛋白偶联受体 40 拮抗剂（GW1100，10 μM）对 Langendorff 灌注的雄性小鼠心脏进行缺血/再灌注。此外，在雄性大鼠中用布比卡因（10mg/kg，IV）进行心脏毒性实验，然后单独用脂肪乳（20%，5ml/kg 推注，0.5ml·kg·min 维持，IV）或用 GW1100 预处理（2.5mg/kg，IV）。
G 蛋白偶联受体 40 在啮齿动物心脏中表达。GW1100 消除了脂肪乳对缺血/再灌注引起的心脏保护作用，因为心率血压乘积和左心室发展压低于单独使用脂肪乳（心率血压乘积：2186±1783[n=7] vs. 11607±4347[n=8]；左心室发展压：22.6±10.4 vs. 63.8±20；P<0.0001）。脂质乳剂+GW1100 还显示 LV dP/dtmax 和 LV dP/dtmin 降低（dP/dtmax=749±386 vs. 2098±792，P<0.001；dP/dtmin=-443±262 vs. -1447±546，P<0.001）。在布比卡因引起的心脏毒性大鼠模型中，GW1100 预处理对 30 分钟后的心率（HR）和射血分数没有显著影响（HR：302±17 vs. 312±38；射血分数：69±3% vs. 73±4%）。然而，GW1100 预处理预防了脂质挽救，10 分钟后没有恢复。在对照组中，脂肪乳剂改善了 HR（10 分钟时 215±16），并在 10 分钟时完全挽救了左心室功能（射血分数=67±8%，缩短分数=38±6%）。
G 蛋白偶联受体 40 在啮齿动物心脏中表达，并参与脂肪乳剂介导的缺血/再灌注损伤和布比卡因引起的心脏毒性的心脏保护作用。
