Urantide对心肌缺血及再灌注损伤的保护作用及作用机制
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摘要
UrotensinⅡ(UⅡ)是一种生长激素样神经环肽,目前已发现该活性肽广泛存在于哺乳动物脊髓、脑组织及心血管组织中,是一种十分重要的内源性血管活性物质。1998年首次从人体中克隆出人urotensinⅡ(human UⅡ, hUⅡ),1999年发现了hUⅡ的特异性受体——UT受体。基础研究显示hUⅡ具有强烈的血管收缩作用,作用强度较ET-1高1-2个数量级,是迄今已知的最强的血管收缩剂。临床研究也提示hUⅡ及其UT受体可能为心血管药物作用的一个新的靶点。
Urantide是在UⅡ基础上衍生的肽类UT受体拮抗剂。Urantide与多种动物的重组UT受体均具有相当高的亲和力。在离体血管实验中,urantide表现为一强有力的纯UT受体竞争性拮抗剂。鉴于hUⅡ有很强的收缩冠状动脉,可减少心肌血流的作用,我们推测urantide对心肌缺血缺氧损伤可能有保护作用,但迄今未见urantide用于心肌缺血的报道。因此,本文从以下几个方面对urantide进行研究,以观察urantide对心肌缺血损伤的影响并探讨其作用机制。
第一部分Urantide对实验性心肌缺血的保护作用及机制
1、Urantide对异丙肾上腺素(Isoproterenol,Iso)诱发小鼠急性心肌缺血性损伤的保护作用
皮下注射Iso可导致小鼠出现急性心肌缺血,并产生典型的缺血心电图改变。在异丙肾上腺素(Iso)诱发小鼠急性心肌损伤模型上,urantide在3～30μg·kg-1范围内可明显抑制sc Iso致ST段的抬高;10、30μg·kg-1 urantide可显著降低小鼠血清及心肌匀浆中LDH活性和MDA含量,明显升高NOS活性和NO含量,同时减轻sc Iso诱导的心肌病理损伤。
2、Urantide对垂体后叶素(Pit)诱发小鼠急性心肌缺血性损伤的保护作用
在舌下静脉注射垂体后叶素(Pit)诱发小鼠心肌损伤模型上,结果显示:urantide在3～30μg·kg-1范围内可明显抑制iv Pit致ST段及T波的抬高;30μg·kg-1 urantide可显著降低小鼠血清及心肌线粒体中LDH活性和MDA含量,明显升高SOD活性;10μg·kg-1 urantide也能显著降低小鼠心肌线粒体中MDA含量,同时减轻iv Pit诱导的心肌病理损伤。
3、Urantide对冠脉结扎(LAD)致大鼠急性心肌缺血的保护作用及机制
在大鼠冠状动脉左前降支结扎和松开致心肌局部缺血再灌注损伤的模型上,urantide (10, 30μg·kg-1)对再灌注30min及1h时ECG中ST段及T波的抬高有明显的抑制作用;urantide (10, 30μg·kg-1)各组能显著降低梗死区与缺血危险区的比值(IS/AAR),同时能不同程度地降低血清中LDH活性和MDA含量,升高NOS活性和NO含量。HE染色和电镜结果表明10、30μg·kg-1 urantide可显著减轻I/R诱导的心肌细胞和亚细胞水平的损伤。在western blotting实验中,10、30μg·kg-1 urantide能显著增加eNOS、p-ERK的蛋白表达;明显降低iNOS、p-JNK的蛋白表达。
第二部分Urantide对缺氧复氧心肌细胞的保护作用及机制
在乳鼠原代心肌细胞缺氧再复氧模型中,研究了urantide预处理对A/R诱导心肌细胞损伤的保护作用及其作用机制。实验结果表明:urantide在10-6～10-9 mol·L-1浓度范围内能显著降低细胞培养上清液中cTnI含量、CK活性的增高和细胞内钙离子浓度的上升;10-6和10-7 mol·L-1的urantide能同时降低培养上清中LDH活性和MDA含量。MTT染色提示10-6和10-7 mol·L-1的urantide能明显增加细胞存活率;流式细胞仪、台盼兰排斥实验及Hochest荧光染色结果显示urantide在10-6～10-9 mol·L-1浓度范围内能显著抑制A/R后心肌细胞凋亡率的升高。
结论: Urantide对心肌缺血及缺血再灌注损伤具有明显的保护作用,其机制可能与减轻细胞膜脂质过氧化、增加NO的生成、抗凋亡、减轻钙超载等有关。
UrotensinⅡ(U-Ⅱ)is an 11 amino acid cyclic peptide which was first isolated from the fish spinal cord, and recently cloned in several mammalian species, including humans. Ames (1999) found the specific human receptor of urotensinⅡ, now referred to as UT receptor. Many studies have shown that U-Ⅱmay play an important role in cardiovascular regulation. As we know now, U-Ⅱis the most potent vasoconstrictor and is even more potent than endothelin-1 (ET-1). Growing evidence suggests that the U-Ⅱ/UT system may be a novel therapeutic target for cardiovascular disease.
Urantide is derived from hU-Ⅱ, whose structure is [Pen5, DTrp7, Orn8]hU-Ⅱ(4–11). The present results of many studies show that urantide is actually the most potent UT receptor antagonist at rat UT receptors, being 50- to 100-fold more potent than any other compound described thus far. At the same time, urantide is a high selective and competitive antagonist in the rat isolated aorta bioassay: one of the most reliable and responsive bioassays for studying hU-Ⅱ-mediated effects. It is worth noting that urantide also shows a comparable high affinity for human UT receptors . As a potent vasoconstrictor, U-Ⅱcould also constrict coronary artery, therefore decreased myocardial blood flow. We presumed that urantide, as a UT receptor antagonist, probably could antagonize this effect, thus play a protective role on myocardial ischemia. So we designed the following experiments.
Part I The protective effects of urantide on experimental myocardial ischemia model
1、Protective effect of urantide on acute myocardial ischemia injury induced by isoproterenol in mice
Acute myocardial ischemia episodes and typical ischemia ECG developed after subcutaneous injection (sc) of Iso. The results revealed that urantide in the range of 3～30μg·kg-1 iv markedly inhibited Iso-induced raise of the ST segment of ECG;10 and 30μg·kg-1 significantly reduced the increases of MDA content and LDH activity in myocardial supertant and blood serum,remarkably raised the activity of NOS and the content of NO.Urantide (10 and 30μg·kg-1) also significantly ameliorated myocardial ischemic injury.
2、Protective effect of urantide on myocardial ischemia induced by pituitrin in mice
To explore the protective effects of urantide on experimental acute myocardial ischemia induced by pituitrin (Pit) in mice, 6 IU·kg-1 Pit was given through intraveneous injection. Results demonstrated the administration of urantide 3～30μg·kg-1 markedly inhibited Pit-induced raise of the ST and T segment of ECG;30μg·kg-1 significantly reduced the increases of MDA content and LDH activity in myocardial mitochondria and blood serum,remarkably raised the activity of SOD. 10μg·kg-1 urantide could also reduced the increases of MDA content. At the same time, urantide (10 and 30μg·kg-1) significantly ameliorated myocardial ischemic injury.
3、The effects and mechanism of urantide on myocardial infarction induced by ligating left anterior descending coronary artery in rats
After ligating left anterior descending coronary artery in rats, MDA content and LDH activity in blood serum increased significantly, while NO content and NOS activity decreased sharply. Urantide (10, 30μg/kg) markedly inhibited the elevation of MDA content and LDH activity, and inhibited the decline of NO content and NOS activity, at the same time decreased I/R-induced IS/AAR. With the intravenous administration of urantide, the morphological injury induced by I/R was highly improved. Except for this, urantide (10, 30μg/kg) up-regulated the expression of p-ERK and eNOS protein, but down-regulated the I/R induced expression of iNOS and p-JNK.
Part II The protective effects and mechanism of urantide on cultured neonatal rat cardiomyocytes with anoxia and reoxygenation
cultured neonatal rat cardiomyocytes, an anoxia/reoxygenation (A/R) model was established. Cellular injury was evaluated by measuring cell viability, the release of CK、LDH and MDA. The results showed that on the A/R model of myocardial cells, 10-6～10-9 mol·L-1 urantide could evidently inhibit the increases of cTnI content and CK activity, reduce the rise of intracellular Ca2+ concentration.10-6～10-7mol·L-1 urantide increased the viability of myocardial cells injured by A/R and cut down LDH activity and MDA content in the cell culture medium.The examination of flow cytometer method and Hochest 33258 staining also showed that urantide in range of 10-6～10-9 mol·L-1 had significant inhibitory effect on A/R-induced cardiomyocytes apoptosis.
Conclusions: Our findings indicate that urantide has a protective effect against myocardial ischemia or I/R injury in rats and mouse. The protective mechanism may related with anti-oxidation, inhibiting the cardiomyocytes apoptosis, lowing the cardiomyocytes calcium overload and augmenting the synthesis of NO.
Urantide是在UⅡ基础上衍生的肽类UT受体拮抗剂。Urantide与多种动物的重组UT受体均具有相当高的亲和力。在离体血管实验中,urantide表现为一强有力的纯UT受体竞争性拮抗剂。鉴于hUⅡ有很强的收缩冠状动脉,可减少心肌血流的作用,我们推测urantide对心肌缺血缺氧损伤可能有保护作用,但迄今未见urantide用于心肌缺血的报道。因此,本文从以下几个方面对urantide进行研究,以观察urantide对心肌缺血损伤的影响并探讨其作用机制。
第一部分Urantide对实验性心肌缺血的保护作用及机制
1、Urantide对异丙肾上腺素(Isoproterenol,Iso)诱发小鼠急性心肌缺血性损伤的保护作用
皮下注射Iso可导致小鼠出现急性心肌缺血,并产生典型的缺血心电图改变。在异丙肾上腺素(Iso)诱发小鼠急性心肌损伤模型上,urantide在3～30μg·kg-1范围内可明显抑制sc Iso致ST段的抬高;10、30μg·kg-1 urantide可显著降低小鼠血清及心肌匀浆中LDH活性和MDA含量,明显升高NOS活性和NO含量,同时减轻sc Iso诱导的心肌病理损伤。
2、Urantide对垂体后叶素(Pit)诱发小鼠急性心肌缺血性损伤的保护作用
在舌下静脉注射垂体后叶素(Pit)诱发小鼠心肌损伤模型上,结果显示:urantide在3～30μg·kg-1范围内可明显抑制iv Pit致ST段及T波的抬高;30μg·kg-1 urantide可显著降低小鼠血清及心肌线粒体中LDH活性和MDA含量,明显升高SOD活性;10μg·kg-1 urantide也能显著降低小鼠心肌线粒体中MDA含量,同时减轻iv Pit诱导的心肌病理损伤。
3、Urantide对冠脉结扎(LAD)致大鼠急性心肌缺血的保护作用及机制
在大鼠冠状动脉左前降支结扎和松开致心肌局部缺血再灌注损伤的模型上,urantide (10, 30μg·kg-1)对再灌注30min及1h时ECG中ST段及T波的抬高有明显的抑制作用;urantide (10, 30μg·kg-1)各组能显著降低梗死区与缺血危险区的比值(IS/AAR),同时能不同程度地降低血清中LDH活性和MDA含量,升高NOS活性和NO含量。HE染色和电镜结果表明10、30μg·kg-1 urantide可显著减轻I/R诱导的心肌细胞和亚细胞水平的损伤。在western blotting实验中,10、30μg·kg-1 urantide能显著增加eNOS、p-ERK的蛋白表达;明显降低iNOS、p-JNK的蛋白表达。
第二部分Urantide对缺氧复氧心肌细胞的保护作用及机制
在乳鼠原代心肌细胞缺氧再复氧模型中,研究了urantide预处理对A/R诱导心肌细胞损伤的保护作用及其作用机制。实验结果表明:urantide在10-6～10-9 mol·L-1浓度范围内能显著降低细胞培养上清液中cTnI含量、CK活性的增高和细胞内钙离子浓度的上升;10-6和10-7 mol·L-1的urantide能同时降低培养上清中LDH活性和MDA含量。MTT染色提示10-6和10-7 mol·L-1的urantide能明显增加细胞存活率;流式细胞仪、台盼兰排斥实验及Hochest荧光染色结果显示urantide在10-6～10-9 mol·L-1浓度范围内能显著抑制A/R后心肌细胞凋亡率的升高。
结论: Urantide对心肌缺血及缺血再灌注损伤具有明显的保护作用,其机制可能与减轻细胞膜脂质过氧化、增加NO的生成、抗凋亡、减轻钙超载等有关。
UrotensinⅡ(U-Ⅱ)is an 11 amino acid cyclic peptide which was first isolated from the fish spinal cord, and recently cloned in several mammalian species, including humans. Ames (1999) found the specific human receptor of urotensinⅡ, now referred to as UT receptor. Many studies have shown that U-Ⅱmay play an important role in cardiovascular regulation. As we know now, U-Ⅱis the most potent vasoconstrictor and is even more potent than endothelin-1 (ET-1). Growing evidence suggests that the U-Ⅱ/UT system may be a novel therapeutic target for cardiovascular disease.
Urantide is derived from hU-Ⅱ, whose structure is [Pen5, DTrp7, Orn8]hU-Ⅱ(4–11). The present results of many studies show that urantide is actually the most potent UT receptor antagonist at rat UT receptors, being 50- to 100-fold more potent than any other compound described thus far. At the same time, urantide is a high selective and competitive antagonist in the rat isolated aorta bioassay: one of the most reliable and responsive bioassays for studying hU-Ⅱ-mediated effects. It is worth noting that urantide also shows a comparable high affinity for human UT receptors . As a potent vasoconstrictor, U-Ⅱcould also constrict coronary artery, therefore decreased myocardial blood flow. We presumed that urantide, as a UT receptor antagonist, probably could antagonize this effect, thus play a protective role on myocardial ischemia. So we designed the following experiments.
Part I The protective effects of urantide on experimental myocardial ischemia model
1、Protective effect of urantide on acute myocardial ischemia injury induced by isoproterenol in mice
Acute myocardial ischemia episodes and typical ischemia ECG developed after subcutaneous injection (sc) of Iso. The results revealed that urantide in the range of 3～30μg·kg-1 iv markedly inhibited Iso-induced raise of the ST segment of ECG;10 and 30μg·kg-1 significantly reduced the increases of MDA content and LDH activity in myocardial supertant and blood serum,remarkably raised the activity of NOS and the content of NO.Urantide (10 and 30μg·kg-1) also significantly ameliorated myocardial ischemic injury.
2、Protective effect of urantide on myocardial ischemia induced by pituitrin in mice
To explore the protective effects of urantide on experimental acute myocardial ischemia induced by pituitrin (Pit) in mice, 6 IU·kg-1 Pit was given through intraveneous injection. Results demonstrated the administration of urantide 3～30μg·kg-1 markedly inhibited Pit-induced raise of the ST and T segment of ECG;30μg·kg-1 significantly reduced the increases of MDA content and LDH activity in myocardial mitochondria and blood serum,remarkably raised the activity of SOD. 10μg·kg-1 urantide could also reduced the increases of MDA content. At the same time, urantide (10 and 30μg·kg-1) significantly ameliorated myocardial ischemic injury.
3、The effects and mechanism of urantide on myocardial infarction induced by ligating left anterior descending coronary artery in rats
After ligating left anterior descending coronary artery in rats, MDA content and LDH activity in blood serum increased significantly, while NO content and NOS activity decreased sharply. Urantide (10, 30μg/kg) markedly inhibited the elevation of MDA content and LDH activity, and inhibited the decline of NO content and NOS activity, at the same time decreased I/R-induced IS/AAR. With the intravenous administration of urantide, the morphological injury induced by I/R was highly improved. Except for this, urantide (10, 30μg/kg) up-regulated the expression of p-ERK and eNOS protein, but down-regulated the I/R induced expression of iNOS and p-JNK.
Part II The protective effects and mechanism of urantide on cultured neonatal rat cardiomyocytes with anoxia and reoxygenation
cultured neonatal rat cardiomyocytes, an anoxia/reoxygenation (A/R) model was established. Cellular injury was evaluated by measuring cell viability, the release of CK、LDH and MDA. The results showed that on the A/R model of myocardial cells, 10-6～10-9 mol·L-1 urantide could evidently inhibit the increases of cTnI content and CK activity, reduce the rise of intracellular Ca2+ concentration.10-6～10-7mol·L-1 urantide increased the viability of myocardial cells injured by A/R and cut down LDH activity and MDA content in the cell culture medium.The examination of flow cytometer method and Hochest 33258 staining also showed that urantide in range of 10-6～10-9 mol·L-1 had significant inhibitory effect on A/R-induced cardiomyocytes apoptosis.
Conclusions: Our findings indicate that urantide has a protective effect against myocardial ischemia or I/R injury in rats and mouse. The protective mechanism may related with anti-oxidation, inhibiting the cardiomyocytes apoptosis, lowing the cardiomyocytes calcium overload and augmenting the synthesis of NO.
引文
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35、Simpson P, Savion S. Differentiation of rat myocytes in single cell cultures withand without proliferating on myocardial cells: Cross-striations,ultrastucture and chronotrpic response to isoproterenlol [ J ]. Circ Res, 1982, 50 (1):101 - 116.
36、McGee MP, Kreger A, Leake ES,et al. Toxicity of staphylococcal alpha toxin for rabbit alveolar macrophages. [J] Infect Immun 1998;39(1):439-444.
37、Li Q,Shang ZL,Yin JX, et al. Effect of agmatine on intracellular free calcium concentration in isolated rat ventricular myocytes. [J] Acta Physiologica Sinica. 2002;54(6):467-472
38、Schwartz SM. Cell death and the casoase cascade. Circulation [J],1998,97:227-229
39、Braunwald E,Stone FM ,Bindit t DG,et al. Myocardial Reperfusion: A double edged sward. [J] J Clin lnvest,1985;76:1713
40、郭智涛,汗波,石灵春,等.原代乳腺癌细胞对β-榄香烯体外敏感性研究. [J]中国肿瘤临床,2003;30:8-9
41、Ferrieres G, Calzolan C,Mani J C,et al. Human cardiac troponin I precise identification of antigenic epitopes and prediction of secondary structure [J]. Clin Chem,1998,44(3):487-493
42、郝捍东综述病毒性心肌炎的诊断及治疗问题探讨[J].国外医学心血管疾病分册,2000,27(1):31
43、Myocardial Infection Redefined——A Consensus Document of The Joint European Society of Cardiology/American College of Cardiology committee for the Redefinition of Myocardial Infarction [J]. J AmColl Cardiol,2000,36(3):959-969
44、Thomas NJ. Normal and abnonna1 consequences of apoptosis in the human heart [J]. Annu Rev Physiol, 1998,60:309- 325
45、Belmett MR. APoptosis in the cardiovascular system [J]. Heart,2002,87:480- 487
46、]Holleyman CR,Larson DF. Apoptosis in the ischemic reperfused myocardium. Perfusion [J],2001;16(6):491-502
47、]Gottlieb RA,Burleson K D,Kloner RA,et al. Reperfusion injury induces apoptosis in rabit cardiomyocytes. [J] Clin lnvest,1994,94(4):1621一1628
48、Fliss H,Gattinger D. Apoptosis in ischemic and reperfused rat myocardium. [J] Circ Res,1996,79(5):949-956
49、Fliss H. Accelerated apoptosis in reperfused myocardium:friend of Foe. [J] Basic Res Cardiol,1998;93(2)90
50、A.Freude B,Master TN,Robicsek F,et al. Apoptosis is initiated by Myocardial ischelnia and executed during reperfusion. [J] J Mol CellCardiol,2000,2:197-208
51、杨胜利,何作云,冯兵等,缺氧/复氧诱导培养人肥大心肌细胞凋亡模型的建立. [J]重庆医学,2004,33(l):4-6
52、Tzanidis A,Hannan RD,Thomas WG,et al. Direct actions of urotensin II on the heart. Lmplications for cardiac fibrosis and hypertrophy. [J] Circ Res.2003;93: 246-253
53、Opgaard OS,Nothacker H Ehlert FJ,et al. Human urotensin II mediates Vasoconstriction via in inositol phosphates. [J] Eur J Pharmacol.2000;406:265-271.
54、Coulouarn Y, Lihrmann I, Anouar Y,et al. Cloning of the cDNA encoding the urotensin II precursor in frog and human reveals intense expression of the urotensin II gene in motoneurons of the spinal cord [ J ]. Proc Natl Acad Sci U S A, 1998, 95 (26):15803 - 15808.
55、Gibson A. Complex effects of Gillichthys urtensin II on rat aortic strips [ J ]. Brit J Pharmacol, 1987, 91(1):205 - 212.
56、Rossowski WJ, ChengBeng L, Taylor E,et al. Human urotensin II-induced aorta ring contractions are mediated by protein kinase C,tyrosine kinases and Rho-kinase: Inhibition by somatostatin receptor antagonists[ J ]. Eur J Pharmacol, 2002, 438 (3): 159 - 170.
57、Bottrill, F.E., Douglas, S.A., Hiley, C.R., White, R. Human urotensin-II is an endothelium -dependent vasodilator in rat small arteries. [ J ] Br J Pharmacol., 2000, 130 (8):1865 -70
1、David P,Johne S,Brianr C,et al. Urotensin II: A somatostatin-like petide in the caudal neurosecretory system of fishes [ J ] . Proc NatlAcad Sci.1980,77:5-21
2、AMES RS, SARAU HM, CHAMBERS JK, et al. Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14 [ J ]. Nature, 1999, 401(6750): 282-286.
3、竺晓鸣,杜冠华. Progress in the study of biological activities of urotensinⅡ[ J ].中国药理学通报, 2006, 22 (6):651- 654.
4、Kemp W, Roberts S, Krum H. Urotensin II: a vascular mediator in health and disease [ J ]. Curr Vasc Pharmacol, 2005, 3 (2):159 - 168.
5、Bousette N, Giaid A. Urotensin-II and cardiovascular diseases [ J ]. Curr Hypertens Rep, 2006, 8 (6):479 - 483.
6、Ong KL, Lam KS, Cheung BM. Urotensin II: its function in health and its role in disease [ J ]. Cardiovasc Drugs Ther, 2005, 19 (1):65 - 75.
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32、Force T, Pombo CM, Avruch JA, Bonventre JV, Kyriakis JM. Stress-activated protein kinases in cardiovascular disease. [J] Circ Res. 1996;78:947–953.
33、Sugden PH, Clerk A. Regulation of the ERK subgroup of MAP kinase cascades through G protein-coupled receptors. [J] Cell Signal. 1997;9:337–351.
34、HaIaryI, Barbave F. In virto studies of single isolated beating heart cell [ J ]. Science, 1960,131:1674 - 1683.
35、Simpson P, Savion S. Differentiation of rat myocytes in single cell cultures withand without proliferating on myocardial cells: Cross-striations,ultrastucture and chronotrpic response to isoproterenlol [ J ]. Circ Res, 1982, 50 (1):101 - 116.
36、McGee MP, Kreger A, Leake ES,et al. Toxicity of staphylococcal alpha toxin for rabbit alveolar macrophages. [J] Infect Immun 1998;39(1):439-444.
37、Li Q,Shang ZL,Yin JX, et al. Effect of agmatine on intracellular free calcium concentration in isolated rat ventricular myocytes. [J] Acta Physiologica Sinica. 2002;54(6):467-472
38、Schwartz SM. Cell death and the casoase cascade. Circulation [J],1998,97:227-229
39、Braunwald E,Stone FM ,Bindit t DG,et al. Myocardial Reperfusion: A double edged sward. [J] J Clin lnvest,1985;76:1713
40、郭智涛,汗波,石灵春,等.原代乳腺癌细胞对β-榄香烯体外敏感性研究. [J]中国肿瘤临床,2003;30:8-9
41、Ferrieres G, Calzolan C,Mani J C,et al. Human cardiac troponin I precise identification of antigenic epitopes and prediction of secondary structure [J]. Clin Chem,1998,44(3):487-493
42、郝捍东综述病毒性心肌炎的诊断及治疗问题探讨[J].国外医学心血管疾病分册,2000,27(1):31
43、Myocardial Infection Redefined——A Consensus Document of The Joint European Society of Cardiology/American College of Cardiology committee for the Redefinition of Myocardial Infarction [J]. J AmColl Cardiol,2000,36(3):959-969
44、Thomas NJ. Normal and abnonna1 consequences of apoptosis in the human heart [J]. Annu Rev Physiol, 1998,60:309- 325
45、Belmett MR. APoptosis in the cardiovascular system [J]. Heart,2002,87:480- 487
46、]Holleyman CR,Larson DF. Apoptosis in the ischemic reperfused myocardium. Perfusion [J],2001;16(6):491-502
47、]Gottlieb RA,Burleson K D,Kloner RA,et al. Reperfusion injury induces apoptosis in rabit cardiomyocytes. [J] Clin lnvest,1994,94(4):1621一1628
48、Fliss H,Gattinger D. Apoptosis in ischemic and reperfused rat myocardium. [J] Circ Res,1996,79(5):949-956
49、Fliss H. Accelerated apoptosis in reperfused myocardium:friend of Foe. [J] Basic Res Cardiol,1998;93(2)90
50、A.Freude B,Master TN,Robicsek F,et al. Apoptosis is initiated by Myocardial ischelnia and executed during reperfusion. [J] J Mol CellCardiol,2000,2:197-208
51、杨胜利,何作云,冯兵等,缺氧/复氧诱导培养人肥大心肌细胞凋亡模型的建立. [J]重庆医学,2004,33(l):4-6
52、Tzanidis A,Hannan RD,Thomas WG,et al. Direct actions of urotensin II on the heart. Lmplications for cardiac fibrosis and hypertrophy. [J] Circ Res.2003;93: 246-253
53、Opgaard OS,Nothacker H Ehlert FJ,et al. Human urotensin II mediates Vasoconstriction via in inositol phosphates. [J] Eur J Pharmacol.2000;406:265-271.
54、Coulouarn Y, Lihrmann I, Anouar Y,et al. Cloning of the cDNA encoding the urotensin II precursor in frog and human reveals intense expression of the urotensin II gene in motoneurons of the spinal cord [ J ]. Proc Natl Acad Sci U S A, 1998, 95 (26):15803 - 15808.
55、Gibson A. Complex effects of Gillichthys urtensin II on rat aortic strips [ J ]. Brit J Pharmacol, 1987, 91(1):205 - 212.
56、Rossowski WJ, ChengBeng L, Taylor E,et al. Human urotensin II-induced aorta ring contractions are mediated by protein kinase C,tyrosine kinases and Rho-kinase: Inhibition by somatostatin receptor antagonists[ J ]. Eur J Pharmacol, 2002, 438 (3): 159 - 170.
57、Bottrill, F.E., Douglas, S.A., Hiley, C.R., White, R. Human urotensin-II is an endothelium -dependent vasodilator in rat small arteries. [ J ] Br J Pharmacol., 2000, 130 (8):1865 -70
1、David P,Johne S,Brianr C,et al. Urotensin II: A somatostatin-like petide in the caudal neurosecretory system of fishes [ J ] . Proc NatlAcad Sci.1980,77:5-21
2、AMES RS, SARAU HM, CHAMBERS JK, et al. Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14 [ J ]. Nature, 1999, 401(6750): 282-286.
3、竺晓鸣,杜冠华. Progress in the study of biological activities of urotensinⅡ[ J ].中国药理学通报, 2006, 22 (6):651- 654.
4、Kemp W, Roberts S, Krum H. Urotensin II: a vascular mediator in health and disease [ J ]. Curr Vasc Pharmacol, 2005, 3 (2):159 - 168.
5、Bousette N, Giaid A. Urotensin-II and cardiovascular diseases [ J ]. Curr Hypertens Rep, 2006, 8 (6):479 - 483.
6、Ong KL, Lam KS, Cheung BM. Urotensin II: its function in health and its role in disease [ J ]. Cardiovasc Drugs Ther, 2005, 19 (1):65 - 75.
7、Colon JM, Yano K,Waugh D,et al. Distribution and molecular forms of urotensin II and its role in cardiovascular regulation in vertebrates. J Espl Zool,1996,275,226-238
8、Flohr S, Kurz M, Kostenis E, Brkovich A, Fournier A, Klabunde T. Identifi cation of nonpeptidic urotensin II receptor antagonists by virtual screening based on a pharmacophore model derived from structure-activity relationships and nuclear magnetic resonance studies on urotensin II. [ J ] J Med Chem , 2002, 45:1799–1805
9、Coulouarn Y,Lihrmann I,Jegou S,et al.Cloning of the cDNA encoding the urotensin II Precursor in frog and human reveals intense expression of the urotensin II gene in motoneurons of the spinal cord. [ J ] Proc Natl Acad Sci, 1998;95: 15803-15808.
10、Itoh H, McMaster D, Lederis K. Functional receptors for fish neuropeptide urotensin II in major rat arteries. [ J ] Eur J Pharmacol, 1998,149:61-66
11、Tat M, Ammar DA, Karpuj M, et al. A novel putative neuropeptide receptor expressed in neural tissue, including sensory epithelia. [ J ] Biochem Biophys Res Commun, 1995, 209(2):752-759.
12、Liu Q, Pong SS, Zeng Z, et al. Identification of urotensin II as the endogenous ligand for the orphan G-protein–coupled receptor GPR14. [ J ] Biochem Biophys Res Commun, 1999, 266:174–178.
13、Elshoubagy N, Douglas S, Shabon U, et al. Molecular and pharmacological characteristics of genes encoding urotensin II peptides and their cognate G-protein-coupled receptors from themouse and monkey. [ J ] Br J Pharmacol, 2002, 136:9–22.
14、Camarda V, Rizzi A, Calo G, et al. Effects of human urotensin II in isolated vessels of various species; comparison with other vasoactive agents. [ J ] Naunyn Schmiedebergs Arch Pharmacol, 2002;365:141–149.
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