阿片受体在布比卡因诱导的心肌毒性的脂挽救中的作用。

Involvement of Opioid Receptors in the Lipid Rescue of Bupivacaine-Induced Cardiotoxicity.

机构信息

From the Department of Anesthesiology, University of California Los Angeles, Los Angeles, California.

出版信息

Anesth Analg. 2015 Aug;121(2):340-7. doi: 10.1213/ANE.0000000000000788.

DOI:10.1213/ANE.0000000000000788

PMID:25993392

Abstract

BACKGROUND

Lipid emulsion (LE) has been successfully used for resuscitation of local anesthetic cardiotoxicity caused by bupivacaine overdose. Opioid receptors have been shown to play a key role in cardio protection. We explored whether this rescue action of LE is mediated through opioid receptors.

METHODS

Asystole was induced by bupivacaine (10 mg/kg over 20 seconds, IV) in young male Sprague-Dawley rats, and resuscitation with LE (intralipid 20%; 5 mL/kg bolus and 0.5 mL/kg/min maintenance) was started immediately. The rats were pretreated 2 minutes before inducing asystole with nonselective opioid receptor antagonists such as naloxone and naloxone methiodide, as well as highly selective opioid receptor antagonists for subtype κ, δ, and µ or phosphate buffer solution as a control. Heart rates and ejection fractions were measured using echocardiography.

RESULTS

LE rescue of bupivacaine cardiotoxicity was prevented by high-dose (1 mg/kg) naloxone but not by lower doses of naloxone (1, 5, and 10 µg/kg), by naloxone methiodide (which does not cross the blood-brain barrier), and by a selective δ- and κ-opioid receptor antagonists at a higher (10 mg/kg) dose. Successful LE rescue was not affected by highly selective µ-opioid receptor antagonists. δ-Opioid receptor antagonist (10 mg/kg) pretreatment also resulted in reduced phosphorylation level of cardiac glycogen synthase kinase-3β in rats that were not resuscitated by LE compared with control.

CONCLUSIONS

Our data highlight the involvement of peripheral δ- and κ-opioid receptors in the rescue action of LE.

摘要

背景

脂肪乳（LE）已成功用于抢救布比卡因过量引起的局部麻醉药毒性引起的心脏毒性。阿片受体在心脏保护中起着关键作用。我们探讨了 LE 的这种抢救作用是否通过阿片受体介导。

方法

在年轻雄性 Sprague-Dawley 大鼠中，通过静脉注射（IV）布比卡因（10 mg/kg 超过 20 秒）诱导心搏停止，并立即开始使用 LE（Intralipid 20%；5 mL/kg 推注和 0.5 mL/kg/min 维持）复苏。在诱导心搏停止前 2 分钟，用纳洛酮和纳洛酮甲碘化物等非选择性阿片受体拮抗剂，以及对亚型 κ、δ 和 μ 具有高度选择性的阿片受体拮抗剂或磷酸盐缓冲液作为对照，预处理大鼠。使用超声心动图测量心率和射血分数。

结果

高剂量（1 mg/kg）纳洛酮而非低剂量（1、5 和 10 µg/kg）纳洛酮、纳洛酮甲碘化物（不能穿过血脑屏障）以及更高剂量（10 mg/kg）的选择性 δ-和 κ-阿片受体拮抗剂均可预防 LE 抢救布比卡因毒性。高选择性 μ-阿片受体拮抗剂不影响 LE 的成功抢救。与未用 LE 复苏的大鼠相比，预先用 δ-阿片受体拮抗剂（10 mg/kg）预处理还导致心脏糖原合酶激酶-3β的磷酸化水平降低，而 LE 未能复苏这些大鼠。