心脏 μ-阿片受体参与慢性心力衰竭中阿片类药物诱导的心脏保护。
Cardiac μ-opioid receptor contributes to opioid-induced cardioprotection in chronic heart failure.
机构信息
Department of Anaesthesiology, The Second Hospital of Anhui Medical University, Hefei, China.
Department of Ultrasound, The Second Hospital of Anhui Medical University, Hefei, China.
出版信息
Br J Anaesth. 2018 Jul;121(1):26-37. doi: 10.1016/j.bja.2017.11.110. Epub 2018 Feb 2.
BACKGROUND
The therapeutic potential of cardiac μ-opioid receptors in ischaemia-reperfusion (I/R) injury during opioid-modulating diseases, such as heart failure, is unknown. We aimed to explore the changes of cardiac μ-opioid receptor expression during heart failure, and its role in opioid-induced cardioprotection.
METHODS
Rats received doxorubicin (DOX) or were subjected to coronary artery ligation to induce heart failure, or received normal saline (NS) as control. Hearts from NS or DOX rats were isolated and subjected to myocardial ischaemia and reperfusion in an in vitro perfusion system. The opioid [D-Ala,N-MePhe, Gly-ol]-enkephalin (DAMGO), with a high μ-opioid receptor specificity, morphine, and remifentanil were administrated before I/R with or without opioid receptor antagonists, or an extracellular signal-regulated kinase (ERK) inhibitor.
RESULTS
Cardiac μ-opioid receptor mRNA concentrations were 3.2 times elevated in DOX-treated rats compared with NS rats, while cardiac μ-opioid receptor protein concentrations showed 6.1- and 3.5-fold increases in DOX-treated and post-infarcted rats, respectively. DAMGO reduced I/R-caused infarct size, expressed as the ratio of area at risk, from 0.50 (0.04) to 0.25 (0.03) in failing rat hearts, but had no effect on infarct size in control hearts. DAMGO promoted phosphorylation of ERK and glycogen synthase kinase (GSK)-3β only in failing hearts. DAMGO-mediated cardioprotection was blocked by an ERK inhibitor. The μ-opioid receptor antagonist D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) prevented morphine- and remifentanil-induced cardioprotection and phosphorylation of ERK and GSK-3β in failing hearts. In contrast, δ- and κ-opioid receptor selective antagonists were less potent than CTOP in the failing hearts.
CONCLUSIONS
Cardiac μ-opioid receptors were substantially up-regulated during heart failure, which increased DAMGO-induced cardioprotection against I/R injury.
背景
在阿片类药物调节疾病（如心力衰竭）引起的缺血再灌注（I/R）损伤期间，心脏μ-阿片受体的治疗潜力尚不清楚。我们旨在探讨心力衰竭期间心脏μ-阿片受体表达的变化及其在阿片类药物诱导的心脏保护中的作用。
方法
大鼠接受多柔比星（DOX）或冠状动脉结扎以诱导心力衰竭，或接受生理盐水（NS）作为对照。来自 NS 或 DOX 大鼠的心脏在体外灌注系统中进行心肌缺血和再灌注。阿片类药物[D-Ala，N-MePhe，Gly-ol]-enkephalin（DAMGO），具有高μ-阿片受体特异性，吗啡和瑞芬太尼在 I/R 前与或不与阿片受体拮抗剂或细胞外信号调节激酶（ERK）抑制剂一起给药。
结果
与 NS 大鼠相比，DOX 处理的大鼠心脏μ-阿片受体 mRNA 浓度升高了 3.2 倍，而 DOX 处理和梗死后大鼠心脏μ-阿片受体蛋白浓度分别升高了 6.1 倍和 3.5 倍。DAMGO 降低了心力衰竭大鼠的 I/R 引起的梗死面积，从梗死面积与危险区的比值 0.50（0.04）降低至 0.25（0.03），但对对照心脏的梗死面积没有影响。DAMGO 仅在心力衰竭心脏中促进 ERK 和糖原合酶激酶（GSK）-3β的磷酸化。DAMGO 介导的心脏保护作用被 ERK 抑制剂阻断。μ-阿片受体拮抗剂 D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2（CTOP）阻止了吗啡和瑞芬太尼诱导的心力衰竭心脏中的心脏保护和 ERK 和 GSK-3β 的磷酸化。相比之下，与 CTOP 相比，δ-和 κ-阿片受体选择性拮抗剂在心力衰竭心脏中的作用较弱。
结论
心脏μ-阿片受体在心力衰竭期间大量上调，这增加了 DAMGO 诱导的对 I/R 损伤的心脏保护作用。
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