Activation of Peripheral Delta Opioid Receptors Increases Cardiac Tolerance to Arrhythmogenic Effect of Ischemia/Reperfusion
Activation of Peripheral Delta Opioid Receptors Increases Cardiac Tolerance to Arrhythmogenic Effect of Ischemia/Reperfusion
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DOI：
10.1111/acem.12286
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发表时间：
2014-01-01
影响因子：
4.4
通讯作者：
Pei, Jian-Ming
中科院分区：
文献类型：
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作者：
Maslov, Leonid N.;Oeltgen, Peter R.;Pei, Jian-Ming
目的探讨外周、(1)、(2)和痛觉肽类阿片受体激动剂在大鼠心肌耐受缺血/再灌注致心律失常作用中的作用。方法经麻醉的雄性开胸Wistar大鼠左冠状动脉闭塞45min (1a期10min， 2b期35min)，再灌注2h（实验1），缺血10min，再灌注10min（实验2）。在实验1中，生理盐水或载体对照和小鼠特异性阿片类物质dermorphin-H （Derm-H）和([d-Ala2, N-Me-Phe4， Gly-ol5]脑啡肽（DAMAGO）；δ -1特异性阿片类药物d- pen2,5脑啡肽（DPDPE）；nociceptin;并在缺血前15min输注δ -2特异性阿片类药物deltorphin-II （Delt-II）、Delt-Dvariant （Delt-Dvar）和deltorphin-E （Delt-E）。实验2在缺血前15min灌注DPDPE、Delt-D、Delt-Dvar和Delt-E。在缺血前25min输注通用阿片受体拮抗剂纳曲酮、外周作用拮抗剂甲氧基纳洛酮、选择性(1)拮抗剂7-苄基马来酸纳曲酮和特异性(2)拮抗剂甲磺酸纳曲酮。结果在实验1中，与对照组相比，所有剂量的阿片类药物Derm-H和DAMGO、DPDPE和nociceptin预处理在缺血45分钟内均未降低缺血性心律失常的发生率。(2)阿片类药物Delt-II （0.12mg/kg）、Delt-Dvar （0.3mg/kg）和Delt-E （0.18mg/kg）在150nmol/kg剂量下均表现出与生理盐水或对照相比显著的抗心律失常作用。19只接受Delt-II治疗的动物中，有9只在缺血前10分钟（1a期）对致心律失常的影响具有耐受性，19只中有11只在随后的35分钟缺血（1b期）中无室性心律失常。在1a期，Delt-II还将室性早搏和室性心动过速的发生率降低了近一半。Delt-II不影响心室颤动（VF）的发生率。Delt-Dvar和Delt-E预处理完全阻断了1b期VF的发生。Delt-E还减少了50%的室性早搏，并且在缺血1b期室性心动过速的发生率降低了两倍以上。对长期缺血后再灌注致心律失常的作用，δ -2阿片类药物的耐受性均未增强。在实验2中，缺血10min再灌注10min后，与对照组相比，0.12mg/kg的Delt-II降低了室性早搏和室性心动过速的发生率，完全阻断了10min再灌注后VF的发生率。Delt-Dvar和Delt-E无影响，再灌注10min后DPDPE无影响。在缺血10min和再灌注10min时，δ - ii的抗心律失常作用被外周作用阿片受体抑制剂甲氧基纳洛酮和选择性δ -2阿片受体抑制剂甲磺酸纳曲本完全阻断，而不被选择性δ -1抑制剂7-苄基马来酸纳曲酮阻断。单独使用拮抗剂对心律失常无影响。结论δ - ii、δ - dvar和δ - e激活外周δ -2阿片受体可增强心肌对缺血致心律失常的耐受性。(C) 2013年由急诊医学学会发表目的：目的：研究阿片类受体激动剂对急性心肌缺血再灌注患者心脏耐受的调节作用(1),(2)。方法：1)实验1:45分钟阻断冠状动脉（f1a期10min， f2b期35min）， 2小时再灌注；2)实验2：缺血10分钟再灌注10分钟。在实验1,15分钟后，血氧障碍，使用perfundio suero salino或medio de los阿片类药物特异性Dermorfina-H (Derm-H), y ([D-Ala2, N-Me-Phe4, Gly-ol5] enceefalina (DAMAGO)；el阿片特异性(1)d - pen2,5encefalina (DPDPE)；nociceptina;(2) Deltorfina-II (Delt-II), Delt-Dvar (Delt-Dvar), Delt-E （Delt-E）。在实验2中，15分钟后，血液充血，使用ddppe， Delt-D, Delt-Dvar, Delt-E。perfudieron, 25 min de la isquemia, el antagonista del receptor opiaceo universal（纳曲舒纳），el antagonista que actua a nivel periferico（纳曲舒纳），el antagonista selective (1) 7- benzilidio（纳曲舒纳），el antagonista maletrexona（纳曲舒纳），el antagonista specific (2) naltriben mesilato。结果在实验1中，阿片类药物对皮肤- h - DAMGO、ddppe的治疗效果较好，在缺血45分钟内，与对照组相比，无明显减少妊娠和不良血氧血症的发生率。两种阿片类药物(2)Delt-II （0.12 mg/kg）、Delt-Dvar （0.3 mg/kg）和Delt-E （0.18 mg/kg）均具有显著的抗炎作用，剂量为150nmol/kg，与盐对照和中等剂量对照比较。新发现的19只动物的Delt-II耐受性对脑室炎（SAV）的影响分别为10分钟缺血期（fase 1a）和11分钟缺血期（fase 1b）。Delt-II tambien对早产儿心室收缩率（CVP）、室性心动过速（TV）持续时间、室性心动过速（TV）和室性心动过速的影响。δ -ⅱ对心室纤颤（FV）发生率无影响。采用Delt-Dvar和Delt-E块式完井进行El处理，可降低FV的发生率。Delt-E - tambien将CVP降低到50%以上，而在血氧不足的情况下，tvp的发生率增加了一倍。无大剂量阿片类药物耐受性差(2)对缺血再灌注心肌梗死的影响明显，缺血时间较长。实验2：缺血10分钟再灌注10分钟，与对照组相比，Delt-II （0.12 mg/kg）可降低CVP发生率，可降低缺血10分钟再灌注10分钟后的FV发生率。Delt-Dvar和Delt-E无诱导作用，两组ddppe再灌注时间为10分钟。抗炎药物Delt-II持续时间损失10分钟缺血后10分钟再灌注后完全阻断药物抑制药物受体阿片类药物抑制药物受体阿片类药物受体阿片类药物-2选择性美甲氧基钠，选择性7-苄基纳曲舒纳。两种拮抗剂对急性心肌梗死无明显影响。结论la受体受体的激活(2)对外周血差δ - ii、δ - dvar和δ - e受体的耐受性影响心肌缺血的发生。
ObjectivesThe objective of this study was to investigate the role of peripheral , (1), (2), and nociceptin opioid receptors agonists in the regulation of cardiac tolerance to the arrhythmogenic effect of ischemia/reperfusion in rats.MethodsAnesthetized open-chest male Wistar rats were subjected to either 45minutes of left coronary artery occlusion (phase 1a 10minutes and phase 2b 35minutes) and 2hours of reperfusion in Experiment 1 or 10minutes of ischemia and 10minutes of reperfusion in Experiment 2. In Experiment 1, saline or vehicle controls and the mu-specific opioids dermorphin-H (Derm-H) and ([d-Ala2, N-Me-Phe4, Gly-ol5] enkephalin (DAMAGO); the delta-1-specific opioid d-Pen2,5enkephalin (DPDPE); nociceptin; and the delta-2-specific opioids deltorphin-II (Delt-II), Delt-Dvariant (Delt-Dvar), and deltorphin-E (Delt-E) were infused 15minutes prior to ischemia. In Experiment 2, DPDPE, Delt-D, Delt-Dvar, and Delt-E were infused at 15minutes prior to ischemia. The universal opioid receptor antagonist naltrexone, the peripherally acting antagonist naloxone methiodide, the selective (1) antagonist 7-benzylidene naltrexone maleate, and the specific (2) antagonist naltriben mesylate were infused 25minutes prior to ischemia.ResultsIn Experiment 1, pretreatment with the opioids Derm-H and DAMGO, DPDPE, and nociceptin at all doses tested did not reduce the incidence of ischemia-induced arrhythmias compared to controls during 45minutes of ischemia. The (2) opioids Delt-II (0.12mg/kg), Delt-Dvar (0.3mg/kg), and Delt-E (0.18mg/kg) all demonstrated significant antiarrhythmic effects at the 150nmol/kg dose compared to saline or vehicle controls. Nine of 19 animals treated with Delt-II were tolerant without ventricular arrhythmias to the arrhythmogenic effect of ischemia during the first 10minutes of ischemia (phase 1a) and 11 of 19 were without ventricular arrhythmias during the following 35minutes of ischemia (phase 1b). Delt-II also decreased the incidence of premature ventricular contractions and ventricular tachycardia by almost half during phase 1a. Delt-II did not affect the incidence of ventricular fibrillation (VF). Pretreatment with Delt-Dvar and Delt-E completely blocked the incidence of VF in phase 1b. Delt-E also decreased premature ventricular contractions by 50%, and the incidence of ventricular tachycardia decreased over twofold in phase 1b of ischemia. There was no enhanced tolerance by any of the delta-2 opioids to the arrhythmogenic effect of reperfusion after long-term ischemia. In Experiment 2, after 10minutes of ischemia and 10minutes of reperfusion, Delt-II (0.12mg/kg) reduced the incidence of premature ventricular contractions and ventricular tachycardia compared to controls, and completely blocked the incidence of VF following 10minutes of reperfusion. Delt-Dvar and Delt-E were without effect, as was DPDPE following 10minutes of reperfusion. The antiarrhythmic effect of Delt-II during 10minutes of ischemia and 10minutes of reperfusion was completely blocked by the peripherally acting opioid receptor inhibitor naloxone methiodide and the selective delta-2 opioid receptor inhibitor naltriben mesylate, but not by the selective delta-1 inhibitor 7-benzylidene naltrexone maleate. The antagonists alone had no effect on arrhythmogenesis.ConclusionsPeripheral delta-2 opioid receptor activation by Delt-II, Delt-Dvar, and Delt-E enhanced cardiac tolerance to the arrhythmogenic effects of ischemia. (C) 2013 by the Society for Academic Emergency MedicineResumenObjetivosEl objetivo de este estudio fue investigar el papel de los receptores agonistas opiaceos perifericos , (1), (2) y nociceptina en la regulacion de la tolerancia cardiaca al efecto arritmogenico de la isquemia-reperfusion en las ratas.MetodologiaRatas Wistar machos anestesiadas para la apertura del torax fueron sometidas a: 1) experimento 1: 45 minutos de oclusion de la arteria coronaria izquierda (fase 1a 10min y fase 2b 35min), y 2 horas de reperfusion; o 2) experimento 2: 10 minutos de isquemia y 10 minutos de reperfusion. En el Experimento 1, 15 minutos antes de la isquemia, se perfundio suero salino o medio de los controles y los opioides especificos Dermorfina-H (Derm-H), y ([D-Ala2, N-Me-Phe4, Gly-ol5] encefalina (DAMAGO); el opiode especifico (1) D-Pen2,5encefalina (DPDPE); nociceptina; y los opioides especificos (2) Deltorfina-II (Delt-II), Delt-varianteD (Delt-Dvar), y Deltorfina-E (Delt-E). En el Experimento 2, 15 minutos antes de la isquemia, se perfundio DPDPE, Delt-D, Delt-Dvar, y Delt-E. Se perfudieron, 25 minutos antes de la isquemia, el antagonista del receptor opiaceo universal (naltrexona), naloxona metiodida (antagonista que actua a nivel periferico), el antagonista selectivo (1) 7-benzilideno naltrexona maleato y el antagonista especifico (2) naltriben mesilato.ResultadosEn el Experimento 1, el tratamiento previo con los opioides Derm-H y DAMGO, DPDPE, asi como nociceptina a cualquier dosis probada, no redujo la incidencia de arritmias inducidas por isquemia en comparacion con los controles durante 45 minutos de isquemia. Los opioides (2) Delt-II (0,12mg/kg), Delt-Dvar (0,3mg/kg) y Delt-E (0,18mg/kg) demostraron todos efectos antiarritmicos significativos a la dosis de 150nmol/kg en comparacion con salino o medio de los controles. Nueve de los 19 animales tratados con Delt-II toleraron sin arritmias ventriculares (SAV) el efecto arritmogenico de la isquemia durante los primeros 10 minutos de isquemia (fase 1a) y 11 de 19 SAV durante los siguientes 35 minutos de isquemia (fase 1b). Delt-II tambien disminuyo la incidencia de contracciones ventriculares prematuras (CVP) y taquicardia ventricular (TV) durante casi la mitad de la fase 1a. Delt-II no afecto a la incidencia de fibrilacion ventricular (FV). El tratamiento previo con Delt-Dvar y Delt-E bloqueo completamente la incidencia de FV en la fase 1b. Delt-E tambien disminuyo las CVP un 50%, y la incidencia de TV se redujo mas del doble en la fase 1b de isquemia. No hubo mayor tolerancia por ninguno de los opioides (2) para el impacto arritmogenico de la reperfusion tras el largo tiempo de isquemia. En el Experimento 2, tras 10 minutos de isquemia y 10 minutos de reperfusion, Delt-II (0,12mg/kg) redujo la incidencia de CVP y TV comparado con los controles, y bloqueo completamente la incidencia de FV a los 10 minutos de la reperfusion. Delt-Dvar y Delt-E no tuvieron efecto, como lo tuvo DPDPE a los 10 minutos de la reperfusion. El efecto antiarritmico de Delt-II durante los 10 minutos de isquemia y 10 minutos de reperfusion fue completamente bloqueado por el inhibidor del receptor opiaceo de accion periferica naloxona metiodida y el inhibidor del receptor opiaceo delta-2 selectivo naltriben mesilato, pero no por el inhibidor (1) selectivo 7-benzylidene naltrexona maleato. Los antagonistas aislados no tienen efectos en la arritmogenesis.ConclusionesLa activacion del receptor opiaceo (2) periferico por Delt-II, Delt-Dvar y Delt-E aumento la tolerancia cardiaca al impacto arritmogenico de la isquemia.