内源性孤啡肽通过调节β1肾上腺素能受体对大鼠缺血性心律失常的影响
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摘要
目的探讨内源性孤啡肽(N/OFQ)对大鼠缺血性心律失常的影响以及心肌细胞β1肾上腺素能受体(β1-AR)在其中的作用。方法采用结扎左冠状动脉前降支(冠脉)的方法制备大鼠急性心肌缺血模型。将60只大鼠按随机数字表法分为3组,即假手术组(Sham组)、冠脉结扎组(CAO组)和孤啡肽受体拮抗剂(UFP-101)预处理组(U+CAO组),每组20只。3组大鼠分别在冠脉结扎后15 min和1 h 2个时间点各处死10只大鼠。记录心电数据,采用的表达,RT-qPCR法检测β1-AR mRNA的表达。结果与Sham组比较,CAO组出现缺血性心律失常,且主要集中在冠脉结扎后15 min内,UFP-101预处理显著降低心律失常发生。15 min时:与Sham组比较,CAO组全细胞β1-AR、β1-AR mRNA表达下调,而细胞膜β1-AR上调(均P<0.05),U+CAO组全细胞β1-AR蛋白及其mRNA表达无统计学意义(均P>0.05),而细胞膜β1-AR下调(P<0.05);与CAO组比较,U+CAO组全细胞β1-AR蛋白及mRNA表达上调,而细胞膜β1-AR下调(P<0.05)。1 h时:与Sham组比较,CAO组和U+CAO组全细胞β1-AR蛋白及mRNA表达上调,而细胞膜β1-AR下调(均P<0.05)。结论内源性N/OFQ可上调心肌细胞膜β1-AR参与大鼠缺血性心律失常过程。
ObjectiveTo investigate the effect of nociceptin/orphanin FQ(N/OFQ) on ventricular arrhythmias inducedby acute myocardial ischemia, and the role of β1-adrenergic receptor(β1-AR) thereof.MethodsThe rat model of acutemyocardial ischemia was prepared by ligating the left anterior descending branch of the coronary artery. A total of 60 ratswere randomly divided into 3 groups, namely sham-operation group(Sham group), coronary artery occlusion group(CAOgroup) and the pretreatment of N/OFQ receptor antagonist(UFP-101) group(U+CAO group). Ten rats were sacrificed at 15 minutes, and another ten rats were sacrificed at 1 hour after CAO. Electrocardiographic data were recorded. The expressionsof β1-AR from myocardial cell membrane and whole cell were detected by Western blot assay. The expression of β1-ARmRNA was detected by RT-qPCR.ResultsCompared with Sham group, ischemic arrhythmias occurred in CAO group, andmainly occurred during 15 minutes after CAO. The pretreatment with UFP-101 can significantly decrease ischemicarrhythmias. At 15 min, compared with Sham group, the expressions of β1-AR and β1-AR mRNA in whole cell were down-regulated, and the membrane β1-AR was up-regulated(all P<0.05) in CAO group. Meanwhile, no significant differenceswere found in the expression of β1-AR and its mRNA in whole cell(all P>0.05). The expression of membrane β1-AR wasdown-regulated(P<0.05) in U+CAO group. Compared with the CAO group, the expressions of β1-AR and β1-AR mRNAin whole cell were up-regulated while the β1-AR in membrane was down-regulated(all P<0.05) in U+CAO group. At 1 h,compared with Sham group, the expressions of β1-AR and β1-AR mRNA in the whole cell were up-regulated, and themembrane β1-AR was down-regulated(all P<0.05) in CAO and U+CAO group.ConclusionEndogenous N/OFQ canregulate the expression of β1-AR in myocardial cell membrane and participate in the process of ischemic arrhythmia in rats.
ObjectiveTo investigate the effect of nociceptin/orphanin FQ(N/OFQ) on ventricular arrhythmias inducedby acute myocardial ischemia, and the role of β1-adrenergic receptor(β1-AR) thereof.MethodsThe rat model of acutemyocardial ischemia was prepared by ligating the left anterior descending branch of the coronary artery. A total of 60 ratswere randomly divided into 3 groups, namely sham-operation group(Sham group), coronary artery occlusion group(CAOgroup) and the pretreatment of N/OFQ receptor antagonist(UFP-101) group(U+CAO group). Ten rats were sacrificed at 15 minutes, and another ten rats were sacrificed at 1 hour after CAO. Electrocardiographic data were recorded. The expressionsof β1-AR from myocardial cell membrane and whole cell were detected by Western blot assay. The expression of β1-ARmRNA was detected by RT-qPCR.ResultsCompared with Sham group, ischemic arrhythmias occurred in CAO group, andmainly occurred during 15 minutes after CAO. The pretreatment with UFP-101 can significantly decrease ischemicarrhythmias. At 15 min, compared with Sham group, the expressions of β1-AR and β1-AR mRNA in whole cell were down-regulated, and the membrane β1-AR was up-regulated(all P<0.05) in CAO group. Meanwhile, no significant differenceswere found in the expression of β1-AR and its mRNA in whole cell(all P>0.05). The expression of membrane β1-AR wasdown-regulated(P<0.05) in U+CAO group. Compared with the CAO group, the expressions of β1-AR and β1-AR mRNAin whole cell were up-regulated while the β1-AR in membrane was down-regulated(all P<0.05) in U+CAO group. At 1 h,compared with Sham group, the expressions of β1-AR and β1-AR mRNA in the whole cell were up-regulated, and themembrane β1-AR was down-regulated(all P<0.05) in CAO and U+CAO group.ConclusionEndogenous N/OFQ canregulate the expression of β1-AR in myocardial cell membrane and participate in the process of ischemic arrhythmia in rats.
引文
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[14]张秦风,巩书文,李虹,等.中叶素在糖尿病合并冠心病中的作用[J].中国动脉硬化杂志,2018,26(4):424-428.Zhang QF,Gong SW,Li H,et al.The role of intermedin in diabetes combined with coronary heart disease[J].Chinese Journal of Arteriosclerosis,2018,26(4):424-428.doi:10.3969/j.issn.1007-3949.2018.04.018.
[15]王玥,岳维,李兔平,等.心肌降钙素基因相关肽基因转导对糖尿病大鼠心肌缺血/再灌注损伤的保护作用[J].国际麻醉学与复苏杂志,2018,39(6):521-526.Wang Y,Yue W,Li TP,et al.Protective effect of myocardial calcitonin gene-related peptide gene transduction on myocardial ischemia/reperfusion injury in diabetic rats[J].International Journal of Anesthesiology and Resuscitation,2018,39(6):521-526.doi:10.3760/cma.j.issn.1673-4378.2018.06.001.
[16]Sun T,Guo Z,Liu CJ,et al.Preservation of CGRP in myocardium attenuates development of cardiac dysfunction in diabetic rats[J].Int J Cardiol,2016,220:226-234.doi:10.1016/j.ijcard.2016.06.092.
[17]Wang LL,Guo Z,Han Y,et al.Implication of substance P in myocardial contractile function during ischemia in rats[J].Regul Pept,2011,167(2/3):185-191.doi:10.1016/j.regpep.2011.01.001.
[18]Wang LL,Han Y,Guo Z,et al.Esmolol activates endogenous neurokinin activity inhibiting infarction-induced arrhythmias in rats:novel mechanisms of anti-arrhythmia[J].Regul Pept,2013,186:116-122.doi:10.1016/j.regpep.2013.08.004.
[2]Fukui Y,Nozawa T,Ihori H,et al.Nicorandil attenuates ischemiareperfusion injury via inhibition of norepinephrine release from cardiac sympathetic nerve terminals[J].Int Heart J,2017,58(5):787-793.doi:10.1536/ihj.16-391.
[3]Gyires K,Feher A.Stress,neuropeptides and gastric mucosa[J].Curr Pharm Des,2017,23(27):3928-3940.doi:10.2174/1381612823666161118144216.
[4]Guo Z,Yao TP,Wang JP,et al.Acute myocardial ischemia upregulates nociceptin/orphanin FQ in dorsal root ganglion and spinal cord of rats[J].Neurosci Lett,2008,433(3):274-278.doi:10.1016/j.neulet.2008.01.042.
[5]Shen MJ,Zipes DP.Role of the autonomic nervous system in modulating cardiac arrhythmias[J].Circ Res,2014,114(6):1004-1021.doi:10.1161/CIRCRESAHA.113.302549.
[6]Han Y,Guo Z,Wang LL,et al.Antagonism of endogenous nociceptin/orphanin FQ inhibits infarction-associated ventricular arrhythmias via PKC-dependent mechanism in rats[J].Br JPharmacol,2013,170(3):614-623.doi:10.1111/bph.12310.
[7]Miller LE,Hosick PA,Wrieden J,et al.Evaluation of arrhythmia scoring systems and exercise-induced cardioprotection[J].Med Sci Sports Exerc,2012,44(3):435-441.doi:10.1249/MSS.0b013e3182323f8b.
[8]Murphy SR,Wang L,Wang Z,et al.β-Adrenergic inhibition prevents action potential and calcium handling changes during regional myocardial ischemia[J].Front Physiol,2017,8:630.doi:10.3389/fphys.2017.00630.
[9]Maisel AS,Ransnas LA,Insel PA.Externalization of betaadrenergic receptors promoted by myocardial ischemia[J].Science,1985,230(4722):183-186.
[10]Hirschl MM,Wollmann CG,Erhart F,et al.Benefit of immediate beta-blocker therapy on mortality in patients with ST-segment elevation myocardial infarction[J].Crit Care Med,2013,41(6):1396-1404.doi:10.1097/CCM.0b013e31827caa64.
[11]任自文.心律失常的药物治疗[J].天津医药,2016,44(8):932-934.Ren ZW.The drug therapy of cardiac arrhythmias[J].Tianjin Med J,2016,44(8):932-934.doi:10.11958/20160573.
[12]Toll L,Bruchas MR,Calo′G,et al.Nociceptin/orphanin FQreceptor structure,signaling,ligands,functions,and interactions with opioid systems[J].Pharmacol Rev,2016,68(2):419-457.doi:10.1124/pr.114.009209.
[13]Di Diego JM,Antzelevitch C.Ischemic ventricular arrhythmias:experimental models and their clinical relevance[J].Heart Rhythm,2011,8(12):1963-1968.doi:10.1016/j.hrthm.2011.06.036.
[14]张秦风,巩书文,李虹,等.中叶素在糖尿病合并冠心病中的作用[J].中国动脉硬化杂志,2018,26(4):424-428.Zhang QF,Gong SW,Li H,et al.The role of intermedin in diabetes combined with coronary heart disease[J].Chinese Journal of Arteriosclerosis,2018,26(4):424-428.doi:10.3969/j.issn.1007-3949.2018.04.018.
[15]王玥,岳维,李兔平,等.心肌降钙素基因相关肽基因转导对糖尿病大鼠心肌缺血/再灌注损伤的保护作用[J].国际麻醉学与复苏杂志,2018,39(6):521-526.Wang Y,Yue W,Li TP,et al.Protective effect of myocardial calcitonin gene-related peptide gene transduction on myocardial ischemia/reperfusion injury in diabetic rats[J].International Journal of Anesthesiology and Resuscitation,2018,39(6):521-526.doi:10.3760/cma.j.issn.1673-4378.2018.06.001.
[16]Sun T,Guo Z,Liu CJ,et al.Preservation of CGRP in myocardium attenuates development of cardiac dysfunction in diabetic rats[J].Int J Cardiol,2016,220:226-234.doi:10.1016/j.ijcard.2016.06.092.
[17]Wang LL,Guo Z,Han Y,et al.Implication of substance P in myocardial contractile function during ischemia in rats[J].Regul Pept,2011,167(2/3):185-191.doi:10.1016/j.regpep.2011.01.001.
[18]Wang LL,Han Y,Guo Z,et al.Esmolol activates endogenous neurokinin activity inhibiting infarction-induced arrhythmias in rats:novel mechanisms of anti-arrhythmia[J].Regul Pept,2013,186:116-122.doi:10.1016/j.regpep.2013.08.004.