к阿片受体在抗缺血再灌注大鼠心律失常中的作用及机制
|
摘要
阿片肽和阿片受体在体内分布广泛,人们已经认识到其在中枢镇痛、心血管功能调节等方面都具有十分重要的作用。实验已经证明在心肌细胞膜和血管壁上存在大量的阿片受体,心脏亦可自身合成内源性阿片肽,提示阿片肽系统对心血管系统有自分泌调节作用。在体、离体的研究都发现阿片受体的激活具有抗缺血/再灌注性心律失常的作用,然而心肌缺血后心脏阿片受体系统如何变化,迄今尚无报道,对阿片肽和阿片受体的进一步研究将为临床应用阿片类物质治疗缺血性心律失常奠定理论基础。
目的:
(1)研究在缺血/再灌注不同时间点,大鼠心脏组织中κ阿片受体基因和蛋白质水平的表达。
(2)给予κ阿片受体的选择性激动剂U50,488H和选择性阻断剂nor-BNI,研究κ阿片受体在抗缺血/再灌注大鼠心律失常中的作用。
(3)采用Gi/o蛋白抑制剂、ATP敏感钾通道阻断剂、蛋白激酶C选择性抑制剂和酪氨酸激酶抑制剂,初步探讨κ阿片受体抗缺血/再灌注性心律失常可能涉及的细胞信号通路。
方法:
(1)实验采用健康雄性SPRAGUE-DAWLEY大鼠(体质量220～300 g),按随机原则分组,根据不同实验要求给予相应的处理。建立在体的大鼠冠状动脉缺血/再灌注动物模型,记录各项心功能指标,并在实验结束时分部位留取心肌组织。
(2)运用RT-PCR技术检测在缺血/再灌注的不同时间点,大鼠心肌组织中κ阿片受体mRNA的表达水平。
(3)运用WESTERN BLOT技术检测在缺血/再灌注的不同时间点,大鼠心肌组织中κ阿片受体蛋白质的表达水平。
结果:1.缺血/再灌注不同时间点κ阿片受体基因水平和蛋白水平表达的变化情况
在再灌注即刻、再灌注60 min、再灌注180 min时κ阿片受体mRNA表达量明显高于正常组和假手术组(P<0.01),而再灌注360 min时κ阿片受体mRNA表达恢复到正常水平;在再灌注即刻、再灌注60 min、再灌注180 min和再灌注360 minκ阿片受体蛋白质的表达量明显高于正常组和假手术组(P<0.05)。
2.к阿片受体介导的抗心律失常作用
对照组在观察期间内仅偶尔出现室性早搏,未发生室性心动过速和室颤。I/R组大鼠在心肌缺血时,心电图ST段明显抬高,可出现室性早搏、室性心动过速和室颤等心律失常;在再灌注即刻,又出现较为严重的室性心动过速和室颤,此后随着再灌注时间的延长,大鼠心电图ST段明显恢复,心肌缺血改善,心律失常的发生减少。U50,488H+I/R组大鼠在心肌缺血/再灌注期间,也可出现室性早搏、室性心动过速和室颤等心律失常,不过与I/R组相比,其持续时间明显缩短,发生率亦明显降低,心律失常的评分明显减少(P<0.01)。为进一步证实U50,488H的抗心律失常作用是否由к阿片受体所介导,在U50,488H+I/R组基础上,提前15 min给予大鼠选择性к阿片受体阻断剂nor-BNI,结果发现U50,488H的抗心律失常作用可被nor-BNI完全阻断(P<0.01);而nor-BNI本身对心肌缺血/再灌注所致心律失常没有影响(P>0.05)。
3. Gi/o、PKC、KATP和TK阻断剂对к阿片受体抗心律失常作用的影响
与I/R组相比,U50,488H+I/R组大鼠心律失常评分明显下降,若分别不同时间提前给予Gi/o蛋白抑制剂Pertussis toxin、KATP通道阻断剂glibenclamide和PKC的选择性抑制剂chelerythrine后,U50,488H的抗心律失常作用可以被显著减弱或完全阻断(P<0.05);而提前给予TK的抑制剂genistein对U50,488H的抗心律失常作用无明显影响(P>0.05)。
结论:1.本研究首次发现心肌缺血/再灌注可导致心脏κ阿片受体的基因和蛋白质水平的明显上调,该反应有利于内源性阿片肽抗缺血/再灌注性心律失常作用的发挥,可能是心脏自我保护作用的一种代偿机制。
2.心肌缺血/再灌注时,外源性к阿片受体激动剂U50,488H通过激动к阿片受体介导了明确的抗缺血/再灌注性心律失常的作用,该作用的细胞信号途径可能涉及Gi/o、PKC和KATP等分子。
Endogenous opioid peptides (EOPs) and opioid receptors, which widely exist in diverse systems, play important roles in central analgesia as well as in the regulation of cardiovascular functions. Opioid receptors are found rich on the membrane of cardiac myocytes and in blood vessel wall,at the mean time, heart itself is found capable of producing EOPs, which suggests that opioid peptides act on the cardiovascular system. Our study showed that activation ofк-opioid receptor during myocardial ischemia and reperfusion in rats induced an anti-arrhythmic effect in vivo, as well as in vitro. However, it is not clear so far whether there is alters in the opioid receptor system under the condition of myocardial ischemia. Further study of EOPs and opioid receptors would hopefully build the theoretical foundation of treating arrhythmia induced by coronary artery ischemia with opioid in clinic.
1. Objectives:
(1) To observe the expression ofк-opioid receptor in myocardial ischemia and reperfusion in rats.
(2) We use U50,488H (a selectiveк-opioid receptor agonist) and nor-BNI (a selectiveк-opioid receptor antagonist) to investigate the anti-arrhythmic effect ofк-opioid receptor during myocardial ischemia and reperfusion in rats.
(3) To investigate the possible signal pathway involved in the anti-arrhythmic effect ofк-opioid receptor during myocardial ischemia and reperfusion by using pertussis toxin (a Gi/o protein inhibitor), glibenclamide (an ATP-sensitive potassium channel blocker), chelerythrine (a selective PKC inhibitor) and genistein (a Tyrosine kinase inhibitor).
2. Methods:
(1) Male Sprague-Dawley rats weighing 220～300 g were used for all experiments. The rats were randomly divided into different groups according to experiment protocol. Parameters of heart function were recorded during the myocardial ischemia and reperfusion injuries, and the tissue of heart was kept for afterwards analysis.
(2) The RT-PCR technique was used to investigate the content ofк-opioid receptor mRNA in rat at different time point during ischemia and reperfusion.
(3) The WESTERN BLOT technique was used to investigate the density ofк-opioid receptor protein in rat at different time point during ischemia and reperfusion.
3. Results:
(1) The changes ofк-opioid receptor gene and protein at the different time during ischemia and reperfusion:
①compared with control group, the content ofк-opioid receptor mRNA was increased significantly at 0 min, 60 min and 180 min during reperfusion (P<0.01), and was decreased to the normal level at 360 min.
②compared with control group, the density ofк-opioid receptor protein was increased significantly at 0 min, 60 min, 180 min and 360 min during reperfusion (P<0.05).
(2) Anti-arrhythmic effects induced byк-opioid receptor activation: Few ventricular premature contractions were observed in the rats control group. After left anterior descending coronary artery (LAD) occlusion, ventricular premature contractions, ventricular tachycardia and ventricular fibrillation were examined by electrocardiogram. In the course of reperfusion, much more ventricular arrhythmia appeared especially at the immediate time of reperfusion. Finally, the incidence of ventricular arrhythmia was reduced with the development of reperfusion. With the pretreatment of U50,488H, the endurances of ventricular arrhythmia in the rats of U50,488H+ischemia/reperfusion (U50,488H+I/R) group were significantly shortened, and the incidence of ventricular arrhythmia was reduced as well as the arrhythmia score (P<0.01). With the pretreatment of nor-BNI for 15 min in U50,488H+I/R group, the anti-arrhythmic effect of U50,488H was completely blocked (P<0.01). But it had no effect on the arrhythmia induced by ischemia and reperfusion in I/R group (P>0.05).
(3) The influence of inhibitors of Gi/o protein, PKC and Tyrosine kinase, ATP-sensitive potassium channel blocker on the anti arrhythmic effect ofк-opioid receptor activation: Pretreated with pertussis toxin, glibenclamide and chelerythrine respectively, the anti-arrhythmic effects induced by U50,488H during myocardial ischemia and reperfusion were significantly attenuated or even were completely blocked (P<0.05). The anti-arrhythmic effects of U50,488H were not significantly affected by pretreatment with genistein(P>0.05).
4. Conclusions
(1) Our study finds that the increasing expression ofк-opioid receptor is induced by the myocardial ischemia and reperfusion for the first time. And it is helpful for the EOPs to act the anti-arrhythmia effect during myocardial ischemia and reperfusion. This may be a compensational mechanism of heart’s self-protection.
(2) U50,488H exerts an anti-arrhythmic effect through activatingк-opioid receptor in the rats with myocardial ischemia and reperfusion. The signal pathway may be correlated with Gi/o, PKC and KATP channel.
目的:
(1)研究在缺血/再灌注不同时间点,大鼠心脏组织中κ阿片受体基因和蛋白质水平的表达。
(2)给予κ阿片受体的选择性激动剂U50,488H和选择性阻断剂nor-BNI,研究κ阿片受体在抗缺血/再灌注大鼠心律失常中的作用。
(3)采用Gi/o蛋白抑制剂、ATP敏感钾通道阻断剂、蛋白激酶C选择性抑制剂和酪氨酸激酶抑制剂,初步探讨κ阿片受体抗缺血/再灌注性心律失常可能涉及的细胞信号通路。
方法:
(1)实验采用健康雄性SPRAGUE-DAWLEY大鼠(体质量220～300 g),按随机原则分组,根据不同实验要求给予相应的处理。建立在体的大鼠冠状动脉缺血/再灌注动物模型,记录各项心功能指标,并在实验结束时分部位留取心肌组织。
(2)运用RT-PCR技术检测在缺血/再灌注的不同时间点,大鼠心肌组织中κ阿片受体mRNA的表达水平。
(3)运用WESTERN BLOT技术检测在缺血/再灌注的不同时间点,大鼠心肌组织中κ阿片受体蛋白质的表达水平。
结果:1.缺血/再灌注不同时间点κ阿片受体基因水平和蛋白水平表达的变化情况
在再灌注即刻、再灌注60 min、再灌注180 min时κ阿片受体mRNA表达量明显高于正常组和假手术组(P<0.01),而再灌注360 min时κ阿片受体mRNA表达恢复到正常水平;在再灌注即刻、再灌注60 min、再灌注180 min和再灌注360 minκ阿片受体蛋白质的表达量明显高于正常组和假手术组(P<0.05)。
2.к阿片受体介导的抗心律失常作用
对照组在观察期间内仅偶尔出现室性早搏,未发生室性心动过速和室颤。I/R组大鼠在心肌缺血时,心电图ST段明显抬高,可出现室性早搏、室性心动过速和室颤等心律失常;在再灌注即刻,又出现较为严重的室性心动过速和室颤,此后随着再灌注时间的延长,大鼠心电图ST段明显恢复,心肌缺血改善,心律失常的发生减少。U50,488H+I/R组大鼠在心肌缺血/再灌注期间,也可出现室性早搏、室性心动过速和室颤等心律失常,不过与I/R组相比,其持续时间明显缩短,发生率亦明显降低,心律失常的评分明显减少(P<0.01)。为进一步证实U50,488H的抗心律失常作用是否由к阿片受体所介导,在U50,488H+I/R组基础上,提前15 min给予大鼠选择性к阿片受体阻断剂nor-BNI,结果发现U50,488H的抗心律失常作用可被nor-BNI完全阻断(P<0.01);而nor-BNI本身对心肌缺血/再灌注所致心律失常没有影响(P>0.05)。
3. Gi/o、PKC、KATP和TK阻断剂对к阿片受体抗心律失常作用的影响
与I/R组相比,U50,488H+I/R组大鼠心律失常评分明显下降,若分别不同时间提前给予Gi/o蛋白抑制剂Pertussis toxin、KATP通道阻断剂glibenclamide和PKC的选择性抑制剂chelerythrine后,U50,488H的抗心律失常作用可以被显著减弱或完全阻断(P<0.05);而提前给予TK的抑制剂genistein对U50,488H的抗心律失常作用无明显影响(P>0.05)。
结论:1.本研究首次发现心肌缺血/再灌注可导致心脏κ阿片受体的基因和蛋白质水平的明显上调,该反应有利于内源性阿片肽抗缺血/再灌注性心律失常作用的发挥,可能是心脏自我保护作用的一种代偿机制。
2.心肌缺血/再灌注时,外源性к阿片受体激动剂U50,488H通过激动к阿片受体介导了明确的抗缺血/再灌注性心律失常的作用,该作用的细胞信号途径可能涉及Gi/o、PKC和KATP等分子。
Endogenous opioid peptides (EOPs) and opioid receptors, which widely exist in diverse systems, play important roles in central analgesia as well as in the regulation of cardiovascular functions. Opioid receptors are found rich on the membrane of cardiac myocytes and in blood vessel wall,at the mean time, heart itself is found capable of producing EOPs, which suggests that opioid peptides act on the cardiovascular system. Our study showed that activation ofк-opioid receptor during myocardial ischemia and reperfusion in rats induced an anti-arrhythmic effect in vivo, as well as in vitro. However, it is not clear so far whether there is alters in the opioid receptor system under the condition of myocardial ischemia. Further study of EOPs and opioid receptors would hopefully build the theoretical foundation of treating arrhythmia induced by coronary artery ischemia with opioid in clinic.
1. Objectives:
(1) To observe the expression ofк-opioid receptor in myocardial ischemia and reperfusion in rats.
(2) We use U50,488H (a selectiveк-opioid receptor agonist) and nor-BNI (a selectiveк-opioid receptor antagonist) to investigate the anti-arrhythmic effect ofк-opioid receptor during myocardial ischemia and reperfusion in rats.
(3) To investigate the possible signal pathway involved in the anti-arrhythmic effect ofк-opioid receptor during myocardial ischemia and reperfusion by using pertussis toxin (a Gi/o protein inhibitor), glibenclamide (an ATP-sensitive potassium channel blocker), chelerythrine (a selective PKC inhibitor) and genistein (a Tyrosine kinase inhibitor).
2. Methods:
(1) Male Sprague-Dawley rats weighing 220～300 g were used for all experiments. The rats were randomly divided into different groups according to experiment protocol. Parameters of heart function were recorded during the myocardial ischemia and reperfusion injuries, and the tissue of heart was kept for afterwards analysis.
(2) The RT-PCR technique was used to investigate the content ofк-opioid receptor mRNA in rat at different time point during ischemia and reperfusion.
(3) The WESTERN BLOT technique was used to investigate the density ofк-opioid receptor protein in rat at different time point during ischemia and reperfusion.
3. Results:
(1) The changes ofк-opioid receptor gene and protein at the different time during ischemia and reperfusion:
①compared with control group, the content ofк-opioid receptor mRNA was increased significantly at 0 min, 60 min and 180 min during reperfusion (P<0.01), and was decreased to the normal level at 360 min.
②compared with control group, the density ofк-opioid receptor protein was increased significantly at 0 min, 60 min, 180 min and 360 min during reperfusion (P<0.05).
(2) Anti-arrhythmic effects induced byк-opioid receptor activation: Few ventricular premature contractions were observed in the rats control group. After left anterior descending coronary artery (LAD) occlusion, ventricular premature contractions, ventricular tachycardia and ventricular fibrillation were examined by electrocardiogram. In the course of reperfusion, much more ventricular arrhythmia appeared especially at the immediate time of reperfusion. Finally, the incidence of ventricular arrhythmia was reduced with the development of reperfusion. With the pretreatment of U50,488H, the endurances of ventricular arrhythmia in the rats of U50,488H+ischemia/reperfusion (U50,488H+I/R) group were significantly shortened, and the incidence of ventricular arrhythmia was reduced as well as the arrhythmia score (P<0.01). With the pretreatment of nor-BNI for 15 min in U50,488H+I/R group, the anti-arrhythmic effect of U50,488H was completely blocked (P<0.01). But it had no effect on the arrhythmia induced by ischemia and reperfusion in I/R group (P>0.05).
(3) The influence of inhibitors of Gi/o protein, PKC and Tyrosine kinase, ATP-sensitive potassium channel blocker on the anti arrhythmic effect ofк-opioid receptor activation: Pretreated with pertussis toxin, glibenclamide and chelerythrine respectively, the anti-arrhythmic effects induced by U50,488H during myocardial ischemia and reperfusion were significantly attenuated or even were completely blocked (P<0.05). The anti-arrhythmic effects of U50,488H were not significantly affected by pretreatment with genistein(P>0.05).
4. Conclusions
(1) Our study finds that the increasing expression ofк-opioid receptor is induced by the myocardial ischemia and reperfusion for the first time. And it is helpful for the EOPs to act the anti-arrhythmia effect during myocardial ischemia and reperfusion. This may be a compensational mechanism of heart’s self-protection.
(2) U50,488H exerts an anti-arrhythmic effect through activatingк-opioid receptor in the rats with myocardial ischemia and reperfusion. The signal pathway may be correlated with Gi/o, PKC and KATP channel.
引文
[1] Pert, CB, Snyder, SH. Opiate receptor: demonstration innervous tissue[J]. Science, 1973; 179: 1011– 1014.
[2] Reinscheid RK, Nothacker HP, Bourson A, Ardati A, Henningsen RA, Bunzow JR, Grandy DK, Langen H, Monsma FJ Jr, Civelli O. Orphanin FQ: a neuropeptide that activates an opioidlike G protein-coupled receptor[J]. Science, 1995,2709(5237): 792-794.
[3] Meunier JC, Mollereau C, Toll L, Suaudeau C, Moisand C, Albinerie P,Butour JL,Guillemot JC,Ferrara P,Monsarrat B. Isolation and structure of the endogenous agonist of opioid receptor-like ROL1 receptor[J]. Nature, 1995,377(6549): 532-535.
[4] Zadina JE, Hackler L, Ge LJ, Kastin AJ. A potent and selective endogenous agonist for the mu-opiate receptor[J]. Nature, 1997, 386(6624): 499-502.
[5] Hughes J, Smith TW, Kosterlitz HW, Fothergill LA, Morgan BA, Morris HR. Identification of two related pentapeptides from the brain with potent opiate agonist activity[J]. Nature, 1975; 258: 577-580.
[6] Govoni S, Hanbauer I, Hexum TD, Yang HY, Kelly GD, Costa E.In vivo characterization of the mechanisms that secrete enkephalin-like immunoreactive peptides stored in dog adrenal medulla[J].Neuropharmacology, 1981; 30: 639-645.
[7] Weihe E, McKnight AT, Corbett AD, Kosterlitz HW. Proenkephain-and prodynorphin-derived opioid peptides in guinea- pig heart[J]. Neuropeptides, 1985; 5: 453-456.
[8] Howells RD, Kilpatrick DL, Bailey LC, Noe M, Udenfriend S. Proenkephain mRNA in rat heart[J]. Proc Natl ACAD Sci U S A, 1986; 83: 1960-1963.
[9] Ouellette M, Brakier GL. Increas in the relative abundance of preproenkephalin A messenger RNA in the ventricles of cardiomyopathic hamsters[J]. Biochim Biophys Res Commun, 1988; 155: 449-454.
[10] Lang RE, Hermann K, Dietz R, Gaida W, Ganten D, Kraft K, Unger T. Evidence for the presence of eproenkephalins in the heart[J]. Life Sci, 1983; 32(4): 399-406.
[11] 林树新,范谨之,王复周.动脉壁脑啡肽的含量、存在部位及作用途径[J].生理学报, 1989; 41(3): 241-243.
[12] Tai KK,Jin WQ,Chan TYK,Wong TM. Characterization of [H3]-U69593 binding sites in the rat heart by receptor binding studies[J]. J Mol Cell Cardiol,1991;23:1297-1302.
[13] Simonin F,Gaveriaux RC,Kieffer BL. Kappa opioid receptor in human: cDNA and genomic cloning chromosomal assignment,functional expression, pharmacology and expression pattern in the central nervous system[J]. Proc Natl Acad Sci USA,1995;92(15):7006-7010.
[14] Sheng JZ,Wong NS,Wang HX,Wong TM. Pertussis toxin, but not tyrosine kinase inhibitor, abolish effects of U50,488H on [Ca2+]i in myocytes[J]. Am J Physiol,1997;272:C560-C564.
[15] Gaveriaux RC, Peluso J, Kieffer BL. Detection of opioid receptor mRNA by RT-PCR reveals alterative splicing for the delta- and kappa- opioid receptors[J]. Brain Res Mol Brain Res, 1997; 48:298:304.
[16] Krumins SA, Faden AL, Feuerstein G. Opiate binding in rat hearts: modulation of binding after hemorrhagic shock[J]. Biochem Biophsy Res Comm, 1985; 127: 120-128.
[17] Caffrey JL, Gaugl JF, Jones CE. Local endogenous opiate activity in dog myocardium: receptor blockadewith naloxone[J]. Am J Physiol, 1985; 248: H382-388.
[18] Ventura C, Bastagli L, Bernardi P, Caldarera CM, Guarnieri C. Opioid receptors in rat cardiac sarcolemma: effect of phenylephrine and isoproterenol[J]. Biochim Biophys Acta, 1989; 987: 69-74.
[19] Tai KK, Jin WQ, Chan TYK, Wong TM. Characterization of [3H]-U69593 binding sites in the rat heart by receptor binding studies[J]. J Mol Cell Cardiol, 1991; 23: 1297-1302.
[20] Zimlichman R, Gefel D, Eliahou H, Matas Z, Rosen B, Gass S, Ela C, Eilam Y, Vogel Z, Barg J. Expression of opioid receptors during heart ontogeny in normotensive and hypertensive rats[J]. Circ, 1996; 93: 1020-1025.
[21] 林树新,范谨之,王复周.脑啡肽对离体动脉条收缩活动的影响及其机制分析[J].动物学报,1992; 38(2): 202-204.
[22] Pugsley MK,Penz WP,Walker MJ,Wong TM. Antiarrhythmic effects of U50,488H in rats subject to coronary artery occlusion[J]. Eur J Pharmacol,1992; 212:15-19.
[23] Zhang WM, Wu S, Yu XC. Effects of U50,488H and bremazocine on [Ca2+]i and cAMP in naive and tolerant rat ventricular myocytes: evidence of kappaopioid receptor multiplicity in the heart[J]. J Mol Cell Cardiol, 1999; 31:355-362.
[24] Ventura C,Spurgeon H,Lakatta EG,Guarnieri C,Caporossi MC. кandδopioid receptor stimulation affects cardiac myocyte function and Ca2+ release from an intracellular pool in myocytes and neurons[J]. Circ Res, 1992; 70:66-81.
[25] Tai KK, Bian CF, Wong TM. кopioid receptor stimulation intracellular free calcium in isolated rat ventricular myocytes[J]. Life Sci, 1992; 51:909-913.
[26] Yu XC, Li HY, Wang HX. U50,488H inhibits effects of norepinephrine in rat cardiomyocytes-cross talk betweenкopioid receptor and β adrenoceptors[J]. J Mol Cell Cardiol, 1998; 30:405-413.
[27] Pepes S,Xiao RP, Hohl C. ‘Cross Talk ’ between opioid peptide and adrenergic receptor signaling in isolated rat heart[J]. Circ,1997;95:2122-2129.
[28] Yang SL,Xia Q, Shen YL, Zhou SY.Interaction between opioid receptor and adrenoceptor signaling in ischemia reperfusion of the isolated rat heart[J]. Zhejiang Da Xue Xue Bao Yi Xue Ban,2003;32(3):187-191.
[29] Lee AY。Stereospecific antiarrhythmic effects of naloxone against myocardial ischemia and reperfusion in dog[J]. Br J Pharmacol, 1992; 107(4): 1057.
[30] Wong TM , Lee AY. Chronic morphine treatment reduced the incidence of cardiac arrhythmiainduves by dynorphlin(1-13) or myocardial ischaemia and reperfusion[J]. Neurosci-Lett, 1987; 77(1): 61-65.
[31] Wong TM, Lee AY. Tai KK. Effects of drugs interacting with opioid receptors during normal perusion or ischaemia and reperfusion-an attmt to identify cardiac opioid receptor subtype(s) involved in arrhthmogenesis[J]. J Mol Cell Cardiol.1991; 22:1167-1175.
[32] Yu XC, Wang HX, Pei JM, Wong TM. Anti-arrhythmic effect ofκ-opioid receptor stimulation in the perfused rat heart: Involvement of a cAMP-dependent pathway[J]. J Mol Cell Cardiol.1999; 31:1809-1819.
[33] Ventura C, Pintus G. Opioid peptide gene expression in the primary hereditary cardiomyopathy of the Syrian hamster.Ⅲ: Autocrine stimulation of prodynorphin gene expression by dynorphin B[J]. J Biolchem, 1997; 272: 6699-6705.
[34] Baker CH, Sutton ET, Zhou Z, Reynolds DG. Reduced microvascular adrenergic receptor activity due to opioids in endoxin shock[J]. Circ Shock, 1990; 32 (2): 101-112.
[35] 杨 帆,林树新,袁祥鹏等.失血性休克大鼠动脉壁内脑啡肽含量的改变与意义[J].中国病理生理学杂志,1994; 10(7):705.
[36] Zastrow M. Opioid receptor regulation. [J]. Neuromolecular Med, 2004, 5(1):51-58.
[37] Wang X, Dergacheva O, Griffioen KJ, Huang ZG, Evans C, Gold A, Bouairi E, Mendelowitz D. Action of kappa and Delta opioid agonists on premotor cardiac vagal neurons in the nucleus ambiguu[J]. Neuroscience. 2004; 129(1):235-241.
[38] Keay KA, Crowfoot LJ, Floyd NS, Henderson LA, Christie MJ, Bandler R。Cardiovascular effects of microinjections of opioid agonists into the 'Depressor Region' of the ventrolateral periaqueductal gray region[J].Brain Res. 1997 Jul 11; 762(1-2):61-71.
[39] Maslov LN, Lishmanov IuB。[Antiarrhythmic properties of opioid receptor agonists[J]。Eksp Klin Farmakol. 2006 Jul-Aug;69(4):69-79.
[40] Wong TM, Shan J. Modulation of sympathetic actions on the heart by opioid receptor stimulation[J]. J Biomed Sci, 2001, 8(4):299-306.
[41] Farias M 3rd, Jackson KE, Yoshishige D, Caffrey JL. Cardiac enkephanlins interrupt vagal bradycardia via delta 2-opioid receptors in sino-atrial node[J]. Am J Physiol Heart Circ Physiol,2003,284(5):H1693-701.
[42] 胡德耀,开 丽,刘良明.阿片受体对失血性休克血管低反应性德调控作用[J].中国病理生理杂志,2001,17(11):1107.
[43] Bleasdale JE, Thakur NR, Gremban RS,Bundy GL,Fitzpatrick FA,Smith RJ,Bunting S. Selective inhibition of receptor-coupled phospholipase C-dependent processes in human platelets and polymorphonuclear neutrophils[J]. J. Pharmacol. Exp. Ther, 1990; 255: 750-768.
[44] Bian JS, Wang HX, Zhang WM, Wong TM. Effects of κ-opioid receptor stimulation in the heart and the involvement of protein kinase C[J]. Brit J Pharmacol, 1998; 124: 600-606.
[45] Protein kinase activation and myocardial ischemia and reperfusion injury[J]. Cardiaovasc Res, 2004; 61:427-436.
[46] Fryer RM, Hsu AK, Wang Y, Henry M, Eells J, Gross GJ. PKC-delta inhibition does not block preconditioning-induced preservation in mitochondrial ATP synthesis and infarct size reduction in rats[J]. Basic Res Cardiol, 2002;97(1):47-54.
[47] Fryer RM, Patel HH, Hsu AK, Gross GJ. Stress-activated protein kinase phosphorylation during cardioprotection in the ischemic myocardium[J]. Am J Physiol Heart Circ Physiol, 2001;281(3):H1184-1192.
[48] Mcpherson BC, Yao Z. Signal transduction of opioid induced cardioprotection in ischemia-reperfusion[J]. Anesthesiology, 2001;94(6):1082- 1088.
[49] Fryer RM, Wang Y, Hsu AK, Gross GJ. Essential activation of PKC-delta inopioid-initiated cardioprotection[J]. Am J Physiol Heart Circ Physiol, 2001; 280(3):H1346-1353.
[50] Fryer RM, Pratt PF, Hsu AK, Gross GJ. Differential activation of extracellular signal regulated kinase isoforms in preconditioning and opioid-induced cardioprotection[J]. J Pharmacol Exp Ther, 2001;296(2):642- 649.
[51] Miki T, Cohen MV, Downey JM. Opioid receptor contributes to ischemic preconditioning through protein kinase C activation in rabbits[J]. Mol Cell Biochem, 1998;186(1-2):3-12.
[52] Peart JN, Gross GJ. Exogenous activation of delta- and kappa-opioid receptors affords cardioprotection in isolated murine heart[J]. Basic Res Cardiol, 2004; 99(1):29-37.
[52] Baker CH, Sutton ET, Zhou Z. Reduced microvascular adrenergic receptor activity due to opioid in endoxin shock[J]. Circ Shock, 1990; 32(2):101.
[53] Lukitich J, Freinchling TD, O’connor KM, Kowey PR. The effect of beta-adrenergic blockade on vulnerability to ventricular fibrillation and inducibility of ventricular arrhythmia in short- and long-term feline infarction models[J]. Am Heart J, 1989;118(2):265-271.
[54] Cai JJ, Morgan DA, Haynes WG, Martins JB, Lee HC. Alpha 2-Adrenergic stimulation is protective against ischemia-reperfusion-induced ventricular arrhythmias in vivo[J]. Am J Physiol Heart Circ Physiol, 2002; 283(6):H2606-2611.
[55] Pugsley MK, Saint DA & Walker MJ. An electrophysiological basis for the antiarrhythmic actions of the kappa-opioid receptor agonist U-50,488H[J].Eur J Pharmacol. 1994 Aug 22; 261(3):303-309.
[56] Opie LH, Jennings. Reperfusion injury and its pharmacological modufication[J]. Circulation,1989;80:1049～1062.
[57].MaxwellSR, Lip GY. Reperfusion injury: a review of the pathphysiology, clinical manifestation and therapeutic options[J]. Int J cardiol, 1997;58(2): 95-102.
[58].David GD. Myocardial reperfusion injury: a new review[J]. Cardiaovasc Res, 2004; 61:363-364.
[59].Galinnanes M, Fowler AG. Role of clinical pathologies in myocardial injury following ischemia and reperfusion[J]. Cardiaovasc Res, 2004; 61:512- 521.
[60] Piper HM, Abdollah Y, Schafer C. The first minutes of reperfusion: a window of opportunity for cardioprotection[J]. Cardiaovasc Res, 2004; 61: 365-371.
[61] Hausenloy DJ, Yellon DM. New directions for protecting the heart against reperfusion injury: Targeting in reperfusion injury salvage kinase pathway[J].Cardiaovasc Res, 2004; 61:448-460.
[62] Napoli C, Pinto A, Cirino G. Pharmacological modulation, preclinical studies, and new clinical features of myocardial ischemic preconditioning[J]. Pharmacol Ther, 2000;88(3):311-331.
[63] Bolli R. The late phase of preconditioning[J]. Circ Res, 2000;87(11):972- 983.
[64] Schultz JE, Hsu AK, Gross GJ. Ischemic preconditioning in the intact rat heart is mediated by delta1- but not mu- or kappa-opioid receptors[J]. Circulation, 1998;97(13):1282-1289.
[65] Schultz JE, Hsu AK, Gross GJ. Ischemic preconditioning is mediated by a peripheral opioid receptor mechanism in the intact rat heart[J]. J Mol Cell Cardiol, 1997;29(5):1355-1362.
[66] Schultz JE, Hsu AK, Gross GJ. Morphine mimics the cardioprotective effect of ischemic preconditioning via a glibenclamide-sensitive mechanism in the rat heart[J]. Circ Res, 1996;78(6):1100-1104.
[67] Schultz JE, Rose E, Yao Z, Gross GJ. Evidence for involvement of opioid receptors in ischemic preconditioning in rat hearts[J]. Am J Physiol, 1995; 268(5 Pt 2):H2157-2161.
[68] Chatelain M, Fliss BN. Neutrophil accumulation experimental myocardial infarcts: relation with extent of injury and effect of reperfusion[J]. Circulation, 1987;75(5):1083～1090.
[69] Eefting F, Rensing B, Wigman J. Role of apoptosis in reperfusion injury[J]. Cardiaovasc Res, 2004; 61:414-426.
[70] Curtis M, Walker MJ. Quantification of arrhythmias using scoring systems: an examination of seven scores in a vivo model of regional myocardial ischemia[J]. Br J Pharmacol, 1988; 22(9):656-665.
[71] Suzuki S, Kato T, Kambe T, Sakamoto N, Sugiyama S, Ozawa T. An experimental study of release arrhythmia: Occlusion time-dependent changes in ventricular fibrillation threshold[J]. Am Heart J, 1979;98(6): 727- 731.
[72] Wu ZK, Iivainen T, Pehkonen E, Laurikka J, Tarkka MR. Ischemic preconditioning suppresses ventricular tachyarrhythmias after myocardial revascularization[J]. Circulation, 2002;106(24):3091-3096.
[73] Bolli R, Marban E. Molecular and cellular mechanisms of myocardial “stunning” [J]. Physical rev, 1999; 79(2):609-634.
[74] Billi R, Zhu Wx. Time -course and determinants of recovery of function after reversible ischemia in conscious dogs[J].Am J Physiol, 1988; 254:H102- H114.
[75] Hendrickson SC, Stlouis JD. Free fatty acid metabolism during myocardialischemic and reperfusion[J]. Mol Cell Biochem, 1997; 166 (1-2): 85-94.
[76] Dhalla NS Kurzel M. Status of myocardial antioxidant in ischemic- reperfusion injury[J]. Cardiovasc Res; 2000, 47(3):446-456.
[77] Bagchi D, Wetscher GJ, Bagchi M, Hinder PR, Perdikis G, Stohs SJ, Hinder RA, Das DK. Interrelationship between cellular calcium homeostasis and free radical generation in myocardial reperfusion injury[J]. Chem Biol Interact. 1997; 104(2-3): 65-85.
[78] Wallace KB, Eells JT, Madeira VM, Cortopassi G, Jones DP. Mitochondria-mediated cell injury[J]. Fundam Appl Toxicol. 1997; 38(1): 23-37.
[79] Shimizu S, Nomoto M, Naito S, Yamamoto T, Momose K. Stimulation of nitric oxide synthase during oxidative endothelial cell injury[J]. Biochem Pharmacol. 1998; 55(1): 77-83.
[80] Murry CH, Jennings RB, Reimer KA, Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium[J], Circulation, 1986,74(5) :1124-1136.
[81] Martin BJ,McClanahan TB,Van Wylen DG, Gallagher KP, Effects of ischemia, preconditioning, and adenosine deaminase inhibition on interstitial adenosine levels and infarct size[J].Basic Res Cardiol. 1997 Aug; 92(4):240-51. Erratum in: Basic Res Cardiol 1997 Dec; 92(6):435.
[82] Schultz JJ, Hsu AK, Gross GJ. Morphine mimics the cardioprotective effect of ischemic preconditioning via a glibenclamide-sensitive mechanism in the rat heart[J]. Circ Res, 1996; 78: 1100-1104.
[83] Schultz JJ, Hsu AK, Gross GJ. Ischemic preconditioning is mediated by a peripheral opioid receptor mechanism in the intact rat heart[J]. J Mol Cell Cardio, 1997; 29: 1355-1362.
[84] Schultz JJ, Hsu AK, Gross GJ. Ischemic preconditioning and morphine-induced cardioprotection involve the delta(δ)-opioid receptor in the intact rat heart[J]. J Mol Cell Cardiol, 1997; 29: 2187-2195.
[85] Miki T, Downey J. Opioid receptors participate in ischemic preconditioning in rabbits[J]. J Mol Cell Cardiol, 1996; 28: A187.
[86] Caffrey JL, Boluyt MO, Younes A, Barron BA, O'Neill L, Crow MT, Lakatta EG. Aging, cardiac proenkephalin mRNA and enkephalin peptides in the Fisher 344 rat[J]. J Mol Cell Cardiol, 1994; 26: 701-711.
[87] Wu S, Li HY, Wong TM. Cardioprotection of preconditioning by metabolicinhibition in the rat ventricular myocyte involvement of κ-opioid receptor[J]. Circ Res, 1999; 84: 1388-1395.
[88] Miyawaki H, Ashraf M. Ca2+ as a mediator of ischemic preconditioning[J]. Circ Res, 1997; 80: 790-799.
[89] Miki T, Cohen MV, Downey JM. Opioid receptor contributes to ischemic preconditionimg through protein kinase C activation in rabbits[J]. Mol Cel Bio, 1998; 186: 3-12.
[90] Zhou JJ, Pei JM, Wang GY, Wu S, Wang WP, Cho CH, Wong TM. Inducible HSP70 mediates delayed cardioprotection via U-50488H pretreatment in rat ventricular myocytes[J]. Am J Physiol Heart Circ Physiol, 2001; 281(1): H40-47.
[91] Maruyama R, Hatta E, Levi R. Norepinephrine release and ventricular fibrillation in myocardial ischemia/reperfusion: roles of angiotensin and bradykinin[J]. J Cardiovasc Pharmacol, 1999; 34(6):913-915.
[92]张鹏,朱运龙,王跃民,李明哲,毕辉,裴建明.к-阿片受体选择性激动剂U50,488H对大鼠心肌缺血/再灌注室性心律失常的影响[J].第四军医大学学报,2004,25(18):1648-1651.
[93] 姚青, 王跃民 , 张鹏,毕辉,裴建明.к-阿片受体介导的抗心律失常作用[J].心脏杂志 2004,16(2):109-112.
[94] 马赛,马骏雄,吕顺艳,王跃民,裴建明.阿片肽对心律失常的影响及机制[J].中国实用医学研究杂志 2005,4(2):174-177.
[2] Reinscheid RK, Nothacker HP, Bourson A, Ardati A, Henningsen RA, Bunzow JR, Grandy DK, Langen H, Monsma FJ Jr, Civelli O. Orphanin FQ: a neuropeptide that activates an opioidlike G protein-coupled receptor[J]. Science, 1995,2709(5237): 792-794.
[3] Meunier JC, Mollereau C, Toll L, Suaudeau C, Moisand C, Albinerie P,Butour JL,Guillemot JC,Ferrara P,Monsarrat B. Isolation and structure of the endogenous agonist of opioid receptor-like ROL1 receptor[J]. Nature, 1995,377(6549): 532-535.
[4] Zadina JE, Hackler L, Ge LJ, Kastin AJ. A potent and selective endogenous agonist for the mu-opiate receptor[J]. Nature, 1997, 386(6624): 499-502.
[5] Hughes J, Smith TW, Kosterlitz HW, Fothergill LA, Morgan BA, Morris HR. Identification of two related pentapeptides from the brain with potent opiate agonist activity[J]. Nature, 1975; 258: 577-580.
[6] Govoni S, Hanbauer I, Hexum TD, Yang HY, Kelly GD, Costa E.In vivo characterization of the mechanisms that secrete enkephalin-like immunoreactive peptides stored in dog adrenal medulla[J].Neuropharmacology, 1981; 30: 639-645.
[7] Weihe E, McKnight AT, Corbett AD, Kosterlitz HW. Proenkephain-and prodynorphin-derived opioid peptides in guinea- pig heart[J]. Neuropeptides, 1985; 5: 453-456.
[8] Howells RD, Kilpatrick DL, Bailey LC, Noe M, Udenfriend S. Proenkephain mRNA in rat heart[J]. Proc Natl ACAD Sci U S A, 1986; 83: 1960-1963.
[9] Ouellette M, Brakier GL. Increas in the relative abundance of preproenkephalin A messenger RNA in the ventricles of cardiomyopathic hamsters[J]. Biochim Biophys Res Commun, 1988; 155: 449-454.
[10] Lang RE, Hermann K, Dietz R, Gaida W, Ganten D, Kraft K, Unger T. Evidence for the presence of eproenkephalins in the heart[J]. Life Sci, 1983; 32(4): 399-406.
[11] 林树新,范谨之,王复周.动脉壁脑啡肽的含量、存在部位及作用途径[J].生理学报, 1989; 41(3): 241-243.
[12] Tai KK,Jin WQ,Chan TYK,Wong TM. Characterization of [H3]-U69593 binding sites in the rat heart by receptor binding studies[J]. J Mol Cell Cardiol,1991;23:1297-1302.
[13] Simonin F,Gaveriaux RC,Kieffer BL. Kappa opioid receptor in human: cDNA and genomic cloning chromosomal assignment,functional expression, pharmacology and expression pattern in the central nervous system[J]. Proc Natl Acad Sci USA,1995;92(15):7006-7010.
[14] Sheng JZ,Wong NS,Wang HX,Wong TM. Pertussis toxin, but not tyrosine kinase inhibitor, abolish effects of U50,488H on [Ca2+]i in myocytes[J]. Am J Physiol,1997;272:C560-C564.
[15] Gaveriaux RC, Peluso J, Kieffer BL. Detection of opioid receptor mRNA by RT-PCR reveals alterative splicing for the delta- and kappa- opioid receptors[J]. Brain Res Mol Brain Res, 1997; 48:298:304.
[16] Krumins SA, Faden AL, Feuerstein G. Opiate binding in rat hearts: modulation of binding after hemorrhagic shock[J]. Biochem Biophsy Res Comm, 1985; 127: 120-128.
[17] Caffrey JL, Gaugl JF, Jones CE. Local endogenous opiate activity in dog myocardium: receptor blockadewith naloxone[J]. Am J Physiol, 1985; 248: H382-388.
[18] Ventura C, Bastagli L, Bernardi P, Caldarera CM, Guarnieri C. Opioid receptors in rat cardiac sarcolemma: effect of phenylephrine and isoproterenol[J]. Biochim Biophys Acta, 1989; 987: 69-74.
[19] Tai KK, Jin WQ, Chan TYK, Wong TM. Characterization of [3H]-U69593 binding sites in the rat heart by receptor binding studies[J]. J Mol Cell Cardiol, 1991; 23: 1297-1302.
[20] Zimlichman R, Gefel D, Eliahou H, Matas Z, Rosen B, Gass S, Ela C, Eilam Y, Vogel Z, Barg J. Expression of opioid receptors during heart ontogeny in normotensive and hypertensive rats[J]. Circ, 1996; 93: 1020-1025.
[21] 林树新,范谨之,王复周.脑啡肽对离体动脉条收缩活动的影响及其机制分析[J].动物学报,1992; 38(2): 202-204.
[22] Pugsley MK,Penz WP,Walker MJ,Wong TM. Antiarrhythmic effects of U50,488H in rats subject to coronary artery occlusion[J]. Eur J Pharmacol,1992; 212:15-19.
[23] Zhang WM, Wu S, Yu XC. Effects of U50,488H and bremazocine on [Ca2+]i and cAMP in naive and tolerant rat ventricular myocytes: evidence of kappaopioid receptor multiplicity in the heart[J]. J Mol Cell Cardiol, 1999; 31:355-362.
[24] Ventura C,Spurgeon H,Lakatta EG,Guarnieri C,Caporossi MC. кandδopioid receptor stimulation affects cardiac myocyte function and Ca2+ release from an intracellular pool in myocytes and neurons[J]. Circ Res, 1992; 70:66-81.
[25] Tai KK, Bian CF, Wong TM. кopioid receptor stimulation intracellular free calcium in isolated rat ventricular myocytes[J]. Life Sci, 1992; 51:909-913.
[26] Yu XC, Li HY, Wang HX. U50,488H inhibits effects of norepinephrine in rat cardiomyocytes-cross talk betweenкopioid receptor and β adrenoceptors[J]. J Mol Cell Cardiol, 1998; 30:405-413.
[27] Pepes S,Xiao RP, Hohl C. ‘Cross Talk ’ between opioid peptide and adrenergic receptor signaling in isolated rat heart[J]. Circ,1997;95:2122-2129.
[28] Yang SL,Xia Q, Shen YL, Zhou SY.Interaction between opioid receptor and adrenoceptor signaling in ischemia reperfusion of the isolated rat heart[J]. Zhejiang Da Xue Xue Bao Yi Xue Ban,2003;32(3):187-191.
[29] Lee AY。Stereospecific antiarrhythmic effects of naloxone against myocardial ischemia and reperfusion in dog[J]. Br J Pharmacol, 1992; 107(4): 1057.
[30] Wong TM , Lee AY. Chronic morphine treatment reduced the incidence of cardiac arrhythmiainduves by dynorphlin(1-13) or myocardial ischaemia and reperfusion[J]. Neurosci-Lett, 1987; 77(1): 61-65.
[31] Wong TM, Lee AY. Tai KK. Effects of drugs interacting with opioid receptors during normal perusion or ischaemia and reperfusion-an attmt to identify cardiac opioid receptor subtype(s) involved in arrhthmogenesis[J]. J Mol Cell Cardiol.1991; 22:1167-1175.
[32] Yu XC, Wang HX, Pei JM, Wong TM. Anti-arrhythmic effect ofκ-opioid receptor stimulation in the perfused rat heart: Involvement of a cAMP-dependent pathway[J]. J Mol Cell Cardiol.1999; 31:1809-1819.
[33] Ventura C, Pintus G. Opioid peptide gene expression in the primary hereditary cardiomyopathy of the Syrian hamster.Ⅲ: Autocrine stimulation of prodynorphin gene expression by dynorphin B[J]. J Biolchem, 1997; 272: 6699-6705.
[34] Baker CH, Sutton ET, Zhou Z, Reynolds DG. Reduced microvascular adrenergic receptor activity due to opioids in endoxin shock[J]. Circ Shock, 1990; 32 (2): 101-112.
[35] 杨 帆,林树新,袁祥鹏等.失血性休克大鼠动脉壁内脑啡肽含量的改变与意义[J].中国病理生理学杂志,1994; 10(7):705.
[36] Zastrow M. Opioid receptor regulation. [J]. Neuromolecular Med, 2004, 5(1):51-58.
[37] Wang X, Dergacheva O, Griffioen KJ, Huang ZG, Evans C, Gold A, Bouairi E, Mendelowitz D. Action of kappa and Delta opioid agonists on premotor cardiac vagal neurons in the nucleus ambiguu[J]. Neuroscience. 2004; 129(1):235-241.
[38] Keay KA, Crowfoot LJ, Floyd NS, Henderson LA, Christie MJ, Bandler R。Cardiovascular effects of microinjections of opioid agonists into the 'Depressor Region' of the ventrolateral periaqueductal gray region[J].Brain Res. 1997 Jul 11; 762(1-2):61-71.
[39] Maslov LN, Lishmanov IuB。[Antiarrhythmic properties of opioid receptor agonists[J]。Eksp Klin Farmakol. 2006 Jul-Aug;69(4):69-79.
[40] Wong TM, Shan J. Modulation of sympathetic actions on the heart by opioid receptor stimulation[J]. J Biomed Sci, 2001, 8(4):299-306.
[41] Farias M 3rd, Jackson KE, Yoshishige D, Caffrey JL. Cardiac enkephanlins interrupt vagal bradycardia via delta 2-opioid receptors in sino-atrial node[J]. Am J Physiol Heart Circ Physiol,2003,284(5):H1693-701.
[42] 胡德耀,开 丽,刘良明.阿片受体对失血性休克血管低反应性德调控作用[J].中国病理生理杂志,2001,17(11):1107.
[43] Bleasdale JE, Thakur NR, Gremban RS,Bundy GL,Fitzpatrick FA,Smith RJ,Bunting S. Selective inhibition of receptor-coupled phospholipase C-dependent processes in human platelets and polymorphonuclear neutrophils[J]. J. Pharmacol. Exp. Ther, 1990; 255: 750-768.
[44] Bian JS, Wang HX, Zhang WM, Wong TM. Effects of κ-opioid receptor stimulation in the heart and the involvement of protein kinase C[J]. Brit J Pharmacol, 1998; 124: 600-606.
[45] Protein kinase activation and myocardial ischemia and reperfusion injury[J]. Cardiaovasc Res, 2004; 61:427-436.
[46] Fryer RM, Hsu AK, Wang Y, Henry M, Eells J, Gross GJ. PKC-delta inhibition does not block preconditioning-induced preservation in mitochondrial ATP synthesis and infarct size reduction in rats[J]. Basic Res Cardiol, 2002;97(1):47-54.
[47] Fryer RM, Patel HH, Hsu AK, Gross GJ. Stress-activated protein kinase phosphorylation during cardioprotection in the ischemic myocardium[J]. Am J Physiol Heart Circ Physiol, 2001;281(3):H1184-1192.
[48] Mcpherson BC, Yao Z. Signal transduction of opioid induced cardioprotection in ischemia-reperfusion[J]. Anesthesiology, 2001;94(6):1082- 1088.
[49] Fryer RM, Wang Y, Hsu AK, Gross GJ. Essential activation of PKC-delta inopioid-initiated cardioprotection[J]. Am J Physiol Heart Circ Physiol, 2001; 280(3):H1346-1353.
[50] Fryer RM, Pratt PF, Hsu AK, Gross GJ. Differential activation of extracellular signal regulated kinase isoforms in preconditioning and opioid-induced cardioprotection[J]. J Pharmacol Exp Ther, 2001;296(2):642- 649.
[51] Miki T, Cohen MV, Downey JM. Opioid receptor contributes to ischemic preconditioning through protein kinase C activation in rabbits[J]. Mol Cell Biochem, 1998;186(1-2):3-12.
[52] Peart JN, Gross GJ. Exogenous activation of delta- and kappa-opioid receptors affords cardioprotection in isolated murine heart[J]. Basic Res Cardiol, 2004; 99(1):29-37.
[52] Baker CH, Sutton ET, Zhou Z. Reduced microvascular adrenergic receptor activity due to opioid in endoxin shock[J]. Circ Shock, 1990; 32(2):101.
[53] Lukitich J, Freinchling TD, O’connor KM, Kowey PR. The effect of beta-adrenergic blockade on vulnerability to ventricular fibrillation and inducibility of ventricular arrhythmia in short- and long-term feline infarction models[J]. Am Heart J, 1989;118(2):265-271.
[54] Cai JJ, Morgan DA, Haynes WG, Martins JB, Lee HC. Alpha 2-Adrenergic stimulation is protective against ischemia-reperfusion-induced ventricular arrhythmias in vivo[J]. Am J Physiol Heart Circ Physiol, 2002; 283(6):H2606-2611.
[55] Pugsley MK, Saint DA & Walker MJ. An electrophysiological basis for the antiarrhythmic actions of the kappa-opioid receptor agonist U-50,488H[J].Eur J Pharmacol. 1994 Aug 22; 261(3):303-309.
[56] Opie LH, Jennings. Reperfusion injury and its pharmacological modufication[J]. Circulation,1989;80:1049～1062.
[57].MaxwellSR, Lip GY. Reperfusion injury: a review of the pathphysiology, clinical manifestation and therapeutic options[J]. Int J cardiol, 1997;58(2): 95-102.
[58].David GD. Myocardial reperfusion injury: a new review[J]. Cardiaovasc Res, 2004; 61:363-364.
[59].Galinnanes M, Fowler AG. Role of clinical pathologies in myocardial injury following ischemia and reperfusion[J]. Cardiaovasc Res, 2004; 61:512- 521.
[60] Piper HM, Abdollah Y, Schafer C. The first minutes of reperfusion: a window of opportunity for cardioprotection[J]. Cardiaovasc Res, 2004; 61: 365-371.
[61] Hausenloy DJ, Yellon DM. New directions for protecting the heart against reperfusion injury: Targeting in reperfusion injury salvage kinase pathway[J].Cardiaovasc Res, 2004; 61:448-460.
[62] Napoli C, Pinto A, Cirino G. Pharmacological modulation, preclinical studies, and new clinical features of myocardial ischemic preconditioning[J]. Pharmacol Ther, 2000;88(3):311-331.
[63] Bolli R. The late phase of preconditioning[J]. Circ Res, 2000;87(11):972- 983.
[64] Schultz JE, Hsu AK, Gross GJ. Ischemic preconditioning in the intact rat heart is mediated by delta1- but not mu- or kappa-opioid receptors[J]. Circulation, 1998;97(13):1282-1289.
[65] Schultz JE, Hsu AK, Gross GJ. Ischemic preconditioning is mediated by a peripheral opioid receptor mechanism in the intact rat heart[J]. J Mol Cell Cardiol, 1997;29(5):1355-1362.
[66] Schultz JE, Hsu AK, Gross GJ. Morphine mimics the cardioprotective effect of ischemic preconditioning via a glibenclamide-sensitive mechanism in the rat heart[J]. Circ Res, 1996;78(6):1100-1104.
[67] Schultz JE, Rose E, Yao Z, Gross GJ. Evidence for involvement of opioid receptors in ischemic preconditioning in rat hearts[J]. Am J Physiol, 1995; 268(5 Pt 2):H2157-2161.
[68] Chatelain M, Fliss BN. Neutrophil accumulation experimental myocardial infarcts: relation with extent of injury and effect of reperfusion[J]. Circulation, 1987;75(5):1083～1090.
[69] Eefting F, Rensing B, Wigman J. Role of apoptosis in reperfusion injury[J]. Cardiaovasc Res, 2004; 61:414-426.
[70] Curtis M, Walker MJ. Quantification of arrhythmias using scoring systems: an examination of seven scores in a vivo model of regional myocardial ischemia[J]. Br J Pharmacol, 1988; 22(9):656-665.
[71] Suzuki S, Kato T, Kambe T, Sakamoto N, Sugiyama S, Ozawa T. An experimental study of release arrhythmia: Occlusion time-dependent changes in ventricular fibrillation threshold[J]. Am Heart J, 1979;98(6): 727- 731.
[72] Wu ZK, Iivainen T, Pehkonen E, Laurikka J, Tarkka MR. Ischemic preconditioning suppresses ventricular tachyarrhythmias after myocardial revascularization[J]. Circulation, 2002;106(24):3091-3096.
[73] Bolli R, Marban E. Molecular and cellular mechanisms of myocardial “stunning” [J]. Physical rev, 1999; 79(2):609-634.
[74] Billi R, Zhu Wx. Time -course and determinants of recovery of function after reversible ischemia in conscious dogs[J].Am J Physiol, 1988; 254:H102- H114.
[75] Hendrickson SC, Stlouis JD. Free fatty acid metabolism during myocardialischemic and reperfusion[J]. Mol Cell Biochem, 1997; 166 (1-2): 85-94.
[76] Dhalla NS Kurzel M. Status of myocardial antioxidant in ischemic- reperfusion injury[J]. Cardiovasc Res; 2000, 47(3):446-456.
[77] Bagchi D, Wetscher GJ, Bagchi M, Hinder PR, Perdikis G, Stohs SJ, Hinder RA, Das DK. Interrelationship between cellular calcium homeostasis and free radical generation in myocardial reperfusion injury[J]. Chem Biol Interact. 1997; 104(2-3): 65-85.
[78] Wallace KB, Eells JT, Madeira VM, Cortopassi G, Jones DP. Mitochondria-mediated cell injury[J]. Fundam Appl Toxicol. 1997; 38(1): 23-37.
[79] Shimizu S, Nomoto M, Naito S, Yamamoto T, Momose K. Stimulation of nitric oxide synthase during oxidative endothelial cell injury[J]. Biochem Pharmacol. 1998; 55(1): 77-83.
[80] Murry CH, Jennings RB, Reimer KA, Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium[J], Circulation, 1986,74(5) :1124-1136.
[81] Martin BJ,McClanahan TB,Van Wylen DG, Gallagher KP, Effects of ischemia, preconditioning, and adenosine deaminase inhibition on interstitial adenosine levels and infarct size[J].Basic Res Cardiol. 1997 Aug; 92(4):240-51. Erratum in: Basic Res Cardiol 1997 Dec; 92(6):435.
[82] Schultz JJ, Hsu AK, Gross GJ. Morphine mimics the cardioprotective effect of ischemic preconditioning via a glibenclamide-sensitive mechanism in the rat heart[J]. Circ Res, 1996; 78: 1100-1104.
[83] Schultz JJ, Hsu AK, Gross GJ. Ischemic preconditioning is mediated by a peripheral opioid receptor mechanism in the intact rat heart[J]. J Mol Cell Cardio, 1997; 29: 1355-1362.
[84] Schultz JJ, Hsu AK, Gross GJ. Ischemic preconditioning and morphine-induced cardioprotection involve the delta(δ)-opioid receptor in the intact rat heart[J]. J Mol Cell Cardiol, 1997; 29: 2187-2195.
[85] Miki T, Downey J. Opioid receptors participate in ischemic preconditioning in rabbits[J]. J Mol Cell Cardiol, 1996; 28: A187.
[86] Caffrey JL, Boluyt MO, Younes A, Barron BA, O'Neill L, Crow MT, Lakatta EG. Aging, cardiac proenkephalin mRNA and enkephalin peptides in the Fisher 344 rat[J]. J Mol Cell Cardiol, 1994; 26: 701-711.
[87] Wu S, Li HY, Wong TM. Cardioprotection of preconditioning by metabolicinhibition in the rat ventricular myocyte involvement of κ-opioid receptor[J]. Circ Res, 1999; 84: 1388-1395.
[88] Miyawaki H, Ashraf M. Ca2+ as a mediator of ischemic preconditioning[J]. Circ Res, 1997; 80: 790-799.
[89] Miki T, Cohen MV, Downey JM. Opioid receptor contributes to ischemic preconditionimg through protein kinase C activation in rabbits[J]. Mol Cel Bio, 1998; 186: 3-12.
[90] Zhou JJ, Pei JM, Wang GY, Wu S, Wang WP, Cho CH, Wong TM. Inducible HSP70 mediates delayed cardioprotection via U-50488H pretreatment in rat ventricular myocytes[J]. Am J Physiol Heart Circ Physiol, 2001; 281(1): H40-47.
[91] Maruyama R, Hatta E, Levi R. Norepinephrine release and ventricular fibrillation in myocardial ischemia/reperfusion: roles of angiotensin and bradykinin[J]. J Cardiovasc Pharmacol, 1999; 34(6):913-915.
[92]张鹏,朱运龙,王跃民,李明哲,毕辉,裴建明.к-阿片受体选择性激动剂U50,488H对大鼠心肌缺血/再灌注室性心律失常的影响[J].第四军医大学学报,2004,25(18):1648-1651.
[93] 姚青, 王跃民 , 张鹏,毕辉,裴建明.к-阿片受体介导的抗心律失常作用[J].心脏杂志 2004,16(2):109-112.
[94] 马赛,马骏雄,吕顺艳,王跃民,裴建明.阿片肽对心律失常的影响及机制[J].中国实用医学研究杂志 2005,4(2):174-177.