修回日期: 2010-08-10
接受日期: 2010-08-17
在线出版日期: 2010-11-08
尾加压素Ⅱ(urotensin Ⅱ, UⅡ)是一种生长抑素样环肽, 是目前发现的最强的缩血管物质, 其生物学作用多样, 与多种疾病密切相关. 越来越多的研究发现UⅡ及其受体(urotensin Ⅱreceptor, UT)系统与肝硬化门脉高压症密切相关, 本研究就UⅡ/UT系统在肝硬化门脉高压症中的研究进展作一总结.
引文著录: 刘殿刚, 王宇. UⅡ/UT系统在肝硬化门脉高压症中的研究进展. 世界华人消化杂志 2010; 18(31): 3332-3337
Revised: August 10, 2010
Accepted: August 17, 2010
Published online: November 8, 2010
Urotensin II (UII), a vasoactive peptide with structural similarity to somatostatin, is the most potent vasoconstrictor known in systemic resistance vessels and has multiple biological effects related to a variety of human diseases. Numerous studies have found that UII and its receptor (UT) play an important role in the pathogenesis of portal hypertension. This paper reviews the recent advances in understanding the role of the UII/UT system in the pathogenesis of portal hypertension.
- Citation: Liu DG, Wang Y. Advances in understanding the role of the UII/UT system in the pathogenesis of portal hypertension. Shijie Huaren Xiaohua Zazhi 2010; 18(31): 3332-3337
- URL: https://www.wjgnet.com/1009-3079/full/v18/i31/3332.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v18.i31.3332
肝硬化门脉高压症形成的机制主要是肝内阻力增加和门脉血流量增多. 肝内阻力增加是始动因素, 其原因主要分机械性和动力性因素, 机械性因素是不可逆的, 而动力性因素是可逆的[1,2]. 血管活性物质可以解除或是减弱这种可逆性的因素[3]. 尾加压素Ⅱ(urotensinⅡ, UⅡ)是有效的血管活性物质, 在肝硬化门脉高压症病理生理改变中起重要作用[4]. UⅡ需与其受体(urotensin Ⅱ receptor, UT)结合才能发挥各种生物学作用[5]. 近来研究发现UⅡ/UT系统参与肝硬化门脉高压症的发病并可能成为新的潜在的治疗靶点[6].
UⅡ最早是1985年自硬骨鱼的脊髓尾部神经分泌系统分离出来的一种生长抑素样环肽, 属于神经肽范围, 是迄今发现的体内最强缩血管活性物质[7]. 人类UⅡ由11个氨基酸组成, 相对分子质量为1 388, 编码UⅡ的基因位于1p36, 有5个外显子[8]. 1999年Ames等首次报道人体内一种孤儿G蛋白偶联受体14(G protein coupled receptor, GPR14)是UⅡ的特异性受体, 后更名为UT. UⅡ与UT结合后导致细胞内钙离子浓度升高, 引起多种生物学作用[9-11]. UⅡ/UT主要分布于心血管和神经系统[12,13], 随着研究深入, 还发现其分布广泛、生物学活性多样, 他能够作用于多系统、多器官, 发挥多种生物学效应[14].
UⅡ的生物学作用多样, 与心血管疾病[15-18]、糖尿病[19,20]、肾脏疾病[18,21,22]等多种疾病密切相关. 最近研究发现其在肝硬化门脉高压症中起重要作用. UⅡ参与肝硬化门脉高压症的生物学作用主要包括血管活性作用、丝裂原活性及纤维化作用, 其中血管活性性质研究最多, 资料最充分. 近年来其丝裂原活性及纤维化作用越来越受到人们重视.
1.2.1 血管活性功能: UⅡ的血管活性作用分为收缩血管作用及舒张血管作用, 由GPR14介导, 经Rho-A/Rho-kinase途径激活平滑肌细胞导致血管收缩[23,24], 经内皮型一氧化氮合酶(endothelial constitutive NO synthase, eNOS)信号通路激活内皮细胞导致血管舒张[11]. UⅡ的血管活性作用因种属、解剖位置、血管大小不同, 其生理作用可出现相反的结果, 其机制仍待进一步研究. 如UⅡ可引起全身阻力血管收缩, 其缩血管作用为内皮素的10余倍[5], 而UⅡ对大鼠肠系膜血管、人腹部阻力血管是舒张作用[25,26]. UⅡ可引起啮齿类动物大静脉收缩, 而对人肺静脉是舒张作用[26]. 离子渗透方法发现UⅡ可引起健康人血管舒张, 而引起高血压和慢性心衰患者血管收缩. 这种差异可能与上述患者内皮细胞损伤, 不能产生舒张血管的物质有关[27]. 肝硬化门脉高压患者肝窦内皮细胞受损, 窦周系统不能产生舒张血管物质一氧化氮(nitric oxide, NO)导致窦周阻力增加, 而肝硬化时肝内阻力的增加主要来源于肝窦[28-31].
1.2.2 促增殖及促纤维化作用: 随着对UⅡ丝裂原活性及纤维化活性的深入研究, 发现UⅡ是一种内源性丝裂原. 有研究报道UⅡ可引起血管平滑肌细胞和内皮细胞增殖分化, 加速巨噬细胞泡沫细胞的形成, 刺激心肌细胞肥大, 并上调转化生长因子β(transforming growth factor beta, TGFβ)表达而诱导心肌成纤维细胞分泌胶原[32-34]. 我们前期结果发现肝星状细胞表达UT, UⅡ可以促进肝星状细胞增殖, 促进肝星状细胞Ⅰ、Ⅲ型胶原的合成以及Ⅰ、Ⅲ型胶原和金属蛋白酶抑制物-1(tissue inhibitor of metalloproteinase 1, TIMP-1)mRNA表达. 提示UⅡ可直接促进肝星状细胞增殖, 促进胶原合成, 抑制胶原降解而加速肝脏纤维化[35].
UⅡ参与心力衰竭、高血压、糖尿病、肾脏衰竭等多种疾病的发生发展[41-43]. 近来研究发现UⅡ与肝硬化门脉高压症有一定关系[6,44-47].
最初研究UⅡ与肝硬化门脉高压症的关系是从临床资料开始的. Heller等[45]研究发现肝硬化患者血浆UⅡ水平明显高于健康对照组, 与门脉压力呈正相关. 肝静脉UⅡ水平明显高于门静脉, 提示肝硬化时UⅡ来源于肝细胞. Kemp等[48]发现血浆UⅡ水平在肝硬化患者明显升高, 且血浆UⅡ升高的程度与门脉压力及疾病严重程度成正比(Child-Pugh分级). UⅡ基线的水平可以预测肝硬化并发症的发生, 如难治性腹水及患者的存活率.
近期研究发现对正常SD大鼠经微量泵持续注入UⅡ评估其对肝纤维化及门脉高压的作用, 研究分为正常组, UⅡ低剂量组, UⅡ高剂量组. 结果发现UⅡ可以剂量依赖性的增加门脉压力, UⅡ还可以促进肝脏羟脯氨酸、I型胶原及纤维化细胞因子, TGFβ1、结缔组织生长因子(connective tissue growth factor, CTGF)等的表达, 提示UⅡ通过调节内脏血管和体循环的血管舒缩, 而介导了肝硬化门脉高压时血流动力学的失调, 此外UⅡ还可以诱导纤维化细胞因子分泌而促进肝纤维化[49]. 肝星状细胞在肝纤维化过程中起重要作用, 他的活化决定肝纤维化的形成、发展与转归, 是肝纤维化的关键环节[50,51]. UⅡ是一种内源性丝裂原, 具有促增殖作用. 我们研究发现UⅡ可以促进肝星状细胞增殖, 增加胶原合成, 抑制胶原降解, 促进细胞外基质沉积, 而发挥促纤维化作用[35].
上述资料提示UⅡ在肝硬化门脉高压症患者升高, UⅡ还可以通过其血管活性作用、丝裂原活性、纤维化作用加速肝硬化门脉高压血流动力学的失调并促进肝纤维化进程而参与肝硬化门脉高压的病理生理学改变.
关于UⅡ/UT分布的一系列研究表明, UⅡ只有和UT受体结合, 才能完成其生物学效应, 因此检测正常肝组织和肝硬化肝组织UⅡ/UT表达的变化, 能进一步阐明UⅡ在肝硬化门脉高压中的意义. Trebicka等[52]研究发现胆管结扎的肝硬化大鼠其肝脏表达UⅡ/UT较正常大鼠明显升高, 且UT在肝脏表达定位于动静脉及胆管的内皮细胞、库普弗细胞. 我们前期研究也发现肝硬化门脉高压患者肝脏UⅡ/UT基因水平较正常对照人群明显升高, 血UⅡ水平也显著升高且与肝脏UⅡ mRNA水平呈正相关. 此外, 肝脏UT蛋白表达也明显升高, 肝脏库普弗细胞、肝窦内皮细胞表达UT[6], 而这些细胞在肝硬化门脉高压中发挥重要作用, UⅡ/UT可能通过调节这些细胞而在肝硬化门脉高压中发挥重要作用. 但Leifeld等[53]研究肝硬化及暴发性肝炎患者中UⅡ/UT表达时, 发现UⅡ/UT的表达在肝硬化肝组织和正常肝组织表达没有明显差异, 这与Trebicka及我们的研究不一致, 这种差异的可能与以下因素有关: (1)所选择患者不同; (2)UⅡ是一自分泌和旁分泌物质[54,55], 推测UⅡ分泌后马上降解; (3)方法和敏感度不同, 我们分别用基因检测UⅡ/UT的表达, 免疫组织化学和免疫荧光双标方法检测UT的细胞定位, Western blot定量分析UT蛋白表达. (4)除了病因方面的不同, 我们选择的患者均证实具有门脉高压的存在.
总之, 目前研究提示肝硬化门脉高压时肝脏表达UⅡ/UT明显升高, 阻断UⅡ/UT的作用有望成为治疗肝硬化门脉高压症的新靶点.
研究特异性受体拮抗剂在理解UⅡ/UT的生理作用以及揭示其治疗潜力方面非常重要. 如同血管紧张素Ⅱ(angiotensinⅡ, AngⅡ)受体拮抗剂[2,56-58]和内皮素受体拮抗剂[31,59-63]能够用于门脉高压的治疗, 尾加压素受体拮抗剂不久将可能为这种疾病治疗的提供另一种选择[54].
2002年, Behm等[65,66]首先发现生长激素释放抑制因子(somatostatin, SST)拮抗剂SB-710411, 在离体的大鼠主动脉, 10 μmol/L的SB-710411能显著地抑制hUⅡ引起的收缩反应, 但却没有抑制AngⅡ、氯化钾、苯肾上腺素引起的收缩作用. 随后Patacchini等[67]又发现新的人类UⅡ受体拮抗剂, 命名为Urantide, 在离体的大鼠主动脉研究中发现, 其拮抗人类UⅡ的作用是其他任何化学物的50-100倍. 该拮抗剂能与人类UⅡ受体高选择性结合, 极低水平时可能产生激动效能. Palosuran(ACT-058362)[68]是一种新合成的非肽类UⅡ受体拮抗剂, 具有高度特异性, Clozel等证实其能以剂量依赖的方式抑制UⅡ引起的兔主动脉环收缩, 与人类UⅡ受体的结合能力明显高于兔UⅡ受体[69,70].
关于UT拮抗剂在肝硬化门脉高压症中的作用已成为国内外研究的热点. 研究发现UT拮抗剂SB-710411预防给药可以改善CCl4肝硬化大鼠模型的高动力循环状态, 降低肝硬化大鼠的肝纤维化评分、肝组织中羟脯氨酸含量、血肝纤维化指标透明质酸和层粘连蛋白水平, 下调大鼠肝脏的Ⅰ型胶原、Ⅲ型胶原以及TIMP-1 mRNA表达, 从而改善肝脏纤维化[35]. 提示UT拮抗剂SB-710411可以预防肝纤维化, 改善门脉高压的血流动力学紊乱, 可用于预防肝硬化门脉高压的发生发展. Trebicka等[52]研究Palosuran对胆管结扎肝硬化大鼠血流动力学的影响, 结果发现Palosuran可以增加内脏血管阻力, 降低门脉血流, 而降低门脉压力, 其机制与上调肠系膜血管RhoA/Rho-kinase, 增加Rho-kinase活性, 降低一氧化氮/环磷酸鸟苷(nitric oxide/cyclic guanosine monophosphate, NO/cGMP)信号通路, 导致血管收缩有关. 此外Palosuran可以增加胆管结扎肝硬化大鼠的肾小球率过滤, 促进水钠排泄. 有研究发现Urantide对心肌缺血具有保护作用[71], 但目前尚无Urantide与肝硬化门脉高压的研究报道.
近来肝硬化门脉高压的治疗取得了重大进展, 但目前尚无有效的治疗肝硬化门脉高压的药物, 上述研究提示UT拮抗剂可以降低肝硬化门脉高压症的门脉压力, 降低纤维化指标, 并促进水钠排泄, 因而在肝硬化门脉高压症方面具有潜在治疗作用.
肝硬化门脉高压症时UⅡ/UT水平表达增加, UⅡ可加速肝硬化门脉高压血流动力学的失调并促进肝纤维化进程. 随着研究的深入, UT拮抗剂可能成为防治肝硬化门脉高压症的重要治疗工具, 尤其是Palosuran作为一种新合成的特异性高、与人类UT结合能力强的非肽类化合物, 理化特性稳定, 用药途径简单, 且已在二期临床用于治疗糖尿病、肾病, 安全性高, 可用来进一步研究UⅡ的生理病理特性, 并为肝硬化门脉高压症的药物治疗提供新的思路.
肝硬化门脉高压症形成的机制主要是肝内阻力增加和门脉血流量增多. 血管活性物质在其中发挥重要作用, 尾加压素Ⅱ是有效的血管活性物质, 在肝硬化门脉高压症病理生理改变中起重要作用.
王德盛, 副教授, 中国人民解放军第四军医大学西京医院肝胆外科
目前UⅡ/UT系统对门脉压力及纤维化程度的影响是研究的热点、重点, UⅡ/UT系统有望成为肝硬化门脉高压治疗的新靶点.
Heller等研究发现肝硬化患者血浆UⅡ水平明显高于健康对照组, 与门脉压力呈正相关. 肝静脉UⅡ水平明显高于门静脉, 提示肝硬化时UⅡ来源于肝细胞.
UⅡ/UT系统与肝硬化门脉高压的关系是国外研究的热点, 但国内文献报道较少, 且未有人进行详细总结. 本文对其研究进展进行详细总结, 并结合本实验室的研究成果, 对读者可以起到很好的参考作用.
UⅡ/UT与肝硬化门脉高压症密切相关, 在肝硬化门脉高压中发挥重要作用, UT拮抗剂可能成为防治肝硬化门脉高压症的重要治疗工具, 为肝硬化门脉高压症的药物治疗提供新的思路.
本文选题恰当, 新颖性较好, 具有一定的参考作用.
编辑 曹丽鸥 电编 何基才
| 1. | Cichoz-Lach H, Celiński K, Słomka M, Kasztelan-Szczerbińska B. Pathophysiology of portal hypertension. J Physiol Pharmacol. 2008;59 Suppl 2:231-238. [PubMed] |
| 2. | Bonis PA, Friedman SL, Kaplan MM. Is liver fibrosis reversible? N Engl J Med. 2001;344:452-454. [PubMed] [DOI] |
| 3. | Gatta A, Bolognesi M, Merkel C. Vasoactive factors and hemodynamic mechanisms in the pathophysiology of portal hypertension in cirrhosis. Mol Aspects Med. 2008;29:119-129. [PubMed] [DOI] |
| 4. | Newby DE, Jalan R. UROTENSIN II: BETTER THAN SOMATOSTATIN FOR PORTAL HYPERTENSION? Hepatology. 2000;31:1201-1202. [PubMed] [DOI] |
| 5. | Ames RS, Sarau HM, Chambers JK, Willette RN, Aiyar NV, Romanic AM, Louden CS, Foley JJ, Sauermelch CF, Coatney RW. Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14. Nature. 1999;401:282-286. [PubMed] [DOI] |
| 6. | Liu D, Chen J, Wang J, Zhang Z, Ma X, Jia J, Wang Y. Increased expression of urotensin II and GPR14 in patients with cirrhosis and portal hypertension. Int J Mol Med. 2010;25:845-851. [PubMed] |
| 7. | Bern HA, Pearson D, Larson BA, Nishioka RS. Neurohormones from fish tails: the caudal neurosecretory system. I. "Urophysiology" and the caudal neurosecretory system of fishes. Recent Prog Horm Res. 1985;41:533-552. [PubMed] |
| 8. | Ong KL, Lam KS, Cheung BM. Urotensin II: its function in health and its role in disease. Cardiovasc Drugs Ther. 2005;19:65-75. [PubMed] [DOI] |
| 9. | Gardiner SM, March JE, Kemp PA, Davenport AP, Bennett T. Depressor and regionally-selective vasodilator effects of human and rat urotensin II in conscious rats. Br J Pharmacol. 2001;132:1625-1629. [PubMed] [DOI] |
| 10. | Nothacker HP, Wang Z, McNeill AM, Saito Y, Merten S, O'Dowd B, Duckles SP, Civelli O. Identification of the natural ligand of an orphan G-protein-coupled receptor involved in the regulation of vasoconstriction. Nat Cell Biol. 1999;1:383-385. [PubMed] [DOI] |
| 11. | Gardiner SM, March JE, Kemp PA, Maguire JJ, Kuc RE, Davenport AP, Bennett T. Regional heterogeneity in the haemodynamic responses to urotensin II infusion in relation to UT receptor localisation. Br J Pharmacol. 2006;147:612-621. [PubMed] [DOI] |
| 12. | Kemp W, Roberts S, Krum H. Urotensin II: a vascular mediator in health and disease. Curr Vasc Pharmacol. 2005;3:159-168. [PubMed] [DOI] |
| 13. | Vaudry H, Do Rego JC, Le Mevel JC, Chatenet D, Tostivint H, Fournier A, Tonon MC, Pelletier G, Conlon JM, Leprince J. Urotensin II, from fish to human. Ann N Y Acad Sci. 2010;1200:53-66. [PubMed] [DOI] |
| 14. | Ross B, McKendy K, Giaid A. Role of urotensin II in health and disease. Am J Physiol Regul Integr Comp Physiol. 2010;298:R1156-R1172. [PubMed] [DOI] |
| 15. | Hirose T, Takahashi K, Mori N, Nakayama T, Kikuya M, Ohkubo T, Kohzuki M, Totsune K, Imai Y. Increased expression of urotensin II, urotensin II-related peptide and urotensin II receptor mRNAs in the cardiovascular organs of hypertensive rats: comparison with endothelin-1. Peptides. 2009;30:1124-1129. [PubMed] |
| 16. | Leonard AD, Thompson JP, Hutchinson EL, Young SP, McDonald J, Swanevelder J, Lambert DG. Urotensin II receptor expression in human right atrium and aorta: effects of ischaemic heart disease. Br J Anaesth. 2009;102:477-484. [PubMed] [DOI] |
| 17. | Chen YH, Yandle TG, Richards AM, Palmer SC. Urotensin II immunoreactivity in the human circulation: evidence for widespread tissue release. Clin Chem. 2009;55:2040-2048. [PubMed] [DOI] |
| 18. | Hirose T, Mori N, Totsune K, Morimoto R, Maejima T, Kawamura T, Metoki H, Asayama K, Kikuya M, Ohkubo T. Gene expression of (pro)renin receptor is upregulated in hearts and kidneys of rats with congestive heart failure. Peptides. 2009;30:2316-2322. [PubMed] [DOI] |
| 19. | Tian L, Li C, Qi J, Fu P, Yu X, Li X, Cai L. Diabetes-induced upregulation of urotensin II and its receptor plays an important role in TGF-beta1-mediated renal fibrosis and dysfunction. Am J Physiol Endocrinol Metab. 2008;295:E1234-E1242. [PubMed] [DOI] |
| 20. | Dai HY, Guo XG, Ge ZM, Li ZH, Yu XJ, Tang MX, Zhang Y. Elevated expression of urotensin II and its receptor in diabetic cardiomyopathy. J Diabetes Complications. 2008;22:137-143. [PubMed] [DOI] |
| 21. | Takahashi K, Hirose T, Mori N, Morimoto R, Kohzuki M, Imai Y, Totsune K. The renin-angiotensin system, adrenomedullins and urotensin II in the kidney: possible renoprotection via the kidney peptide systems. Peptides. 2009;30:1575-1585. [PubMed] [DOI] |
| 22. | Mosenkis A, Kallem RR, Danoff TM, Aiyar N, Bazeley J, Townsend RR. Renal impairment, hypertension and plasma urotensin II. Nephrol Dial Transplant. 2011;26:609-614. [PubMed] |
| 23. | Watanabe T, Kanome T, Miyazaki A, Katagiri T. Human urotensin II as a link between hypertension and coronary artery disease. Hypertens Res. 2006;29:375-387. [PubMed] [DOI] |
| 24. | Zhu YC, Zhu YZ, Moore PK. The role of urotensin II in cardiovascular and renal physiology and diseases. Br J Pharmacol. 2006;148:884-901. [PubMed] [DOI] |
| 25. | Bottrill FE, Douglas SA, Hiley CR, White R. Human urotensin-II is an endothelium-dependent vasodilator in rat small arteries. Br J Pharmacol. 2000;130:1865-1870. [PubMed] [DOI] |
| 26. | Stirrat A, Gallagher M, Douglas SA, Ohlstein EH, Berry C, Kirk A, Richardson M, MacLean MR. Potent vasodilator responses to human urotensin-II in human pulmonary and abdominal resistance arteries. Am J Physiol Heart Circ Physiol. 2001;280:H925-H928. [PubMed] |
| 27. | Shah V, Toruner M, Haddad F, Cadelina G, Papapetropoulos A, Choo K, Sessa WC, Groszmann RJ. Impaired endothelial nitric oxide synthase activity associated with enhanced caveolin binding in experimental cirrhosis in the rat. Gastroenterology. 1999;117:1222-1228. [PubMed] [DOI] |
| 28. | Lee JS, Semela D, Iredale J, Shah VH. Sinusoidal remodeling and angiogenesis: a new function for the liver-specific pericyte? Hepatology. 2007;45:817-825. [PubMed] [DOI] |
| 29. | Povero D, Busletta C, Novo E, di Bonzo LV, Cannito S, Paternostro C, Parola M. Liver fibrosis: a dynamic and potentially reversible process. Histol Histopathol. 2010;25:1075-1091. [PubMed] |
| 30. | Manning DS, Afdhal NH. Diagnosis and quantitation of fibrosis. Gastroenterology. 2008;134:1670-1681. [PubMed] [DOI] |
| 31. | Laleman W. Role of vasoactive substances and cellular effectors in the pathophysiology of cirrhotic portal hypertension: the past, the present and the future--Georges Brohée Lecture. Acta Gastroenterol Belg. 2009;72:9-16. [PubMed] |
| 32. | Zhang YG, Li YG, Liu BG, Wei RH, Wang DM, Tan XR, Bu DF, Pang YZ, Tang CS. Urotensin II accelerates cardiac fibrosis and hypertrophy of rats induced by isoproterenol. Acta Pharmacol Sin. 2007;28:36-43. [PubMed] |
| 33. | Watanabe T, Miyazaki A. New Frontiers in Lifestyle-Related Diseases. Roles of Vasoactive Agents in Macrophage Foam Cell Formation and Atherosclerosis. 1st Edition. Japan: Springer Japan 2008; 89-96. |
| 34. | Gruson D, Ginion A, Decroly N, Lause P, Vanoverschelde JL, Ketelslegers JM, Bertrand L, Thissen JP. Urotensin II induction of adult cardiomyocytes hypertrophy involves the Akt/GSK-3beta signaling pathway. Peptides. 2010;31:1326-1333. [PubMed] [DOI] |
| 35. | Liu DG, Wang J, Zhang ZT, Wang Y. The urotension II antagonist SB-710411 arrests fibrosis in CCL4cirrhotic rats. Mol Med Rep. 2009;2:953-961. |
| 36. | Douglas SA. Human urotensin-II as a novel cardiovascular target: 'heart' of the matter or simply a fishy 'tail'? Curr Opin Pharmacol. 2003;3:159-167. [PubMed] [DOI] |
| 37. | Matsumoto Y, Abe M, Watanabe T, Adachi Y, Yano T, Takahashi H, Sugo T, Mori M, Kitada C, Kurokawa T. Intracerebroventricular administration of urotensin II promotes anxiogenic-like behaviors in rodents. Neurosci Lett. 2004;358:99-102. [PubMed] [DOI] |
| 38. | Hunt BD, Ng LL, Lambert DG. A rat brain atlas of urotensin-II receptor expression and a review of central urotensin-II effects. Naunyn Schmiedebergs Arch Pharmacol. 2010;382:1-31. [PubMed] [DOI] |
| 39. | Suguro T, Watanabe T, Ban Y, Kodate S, Misaki A, Hirano T, Miyazaki A, Adachi M. Increased human urotensin II levels are correlated with carotid atherosclerosis in essential hypertension. Am J Hypertens. 2007;20:211-217. [PubMed] [DOI] |
| 40. | Bousette N, Patel L, Douglas SA, Ohlstein EH, Giaid A. Increased expression of urotensin II and its cognate receptor GPR14 in atherosclerotic lesions of the human aorta. Atherosclerosis. 2004;176:117-123. [PubMed] [DOI] |
| 41. | Kemp W, Roberts S, Krum H. Increased circulating urotensin II in cirrhosis: potential implications in liver disease. Peptides. 2008;29:868-872. [PubMed] [DOI] |
| 42. | McDonald J, Batuwangala M, Lambert DG. Role of urotensin II and its receptor in health and disease. J Anesth. 2007;21:378-389. [PubMed] [DOI] |
| 43. | Suguro T, Watanabe T, Kodate S, Xu G, Hirano T, Adachi M, Miyazaki A. Increased plasma urotensin-II levels are associated with diabetic retinopathy and carotid atherosclerosis in Type 2 diabetes. Clin Sci (Lond). 2008;115:327-334. [PubMed] [DOI] |
| 44. | Charles CJ, Rademaker MT, Richards AM, Yandle TG. Urotensin II: evidence for cardiac, hepatic and renal production. Peptides. 2005;26:2211-2214. [PubMed] [DOI] |
| 45. | Heller J, Schepke M, Neef M, Woitas R, Rabe C, Sauerbruch T. Increased urotensin II plasma levels in patients with cirrhosis and portal hypertension. J Hepatol. 2002;37:767-772. [PubMed] [DOI] |
| 46. | Kemp W, Roberts S, Komesaroff PA, Zomer E, Krum H. Urotensin II in chronic liver disease: in vivo effect on vascular tone. Scand J Gastroenterol. 2008;43:103-109. [PubMed] [DOI] |
| 47. | Hennenberg M, Trebicka J, Sauerbruch T, Heller J. Mechanisms of extrahepatic vasodilation in portal hypertension. Gut. 2008;57:1300-1314. [PubMed] |
| 48. | Kemp W, Krum H, Colman J, Bailey M, Yandle T, Richards M, Roberts S. Urotensin II: a novel vasoactive mediator linked to chronic liver disease and portal hypertension. Liver Int. 2007;27:1232-1239. [PubMed] |
| 49. | Kemp W, Kompa A, Phrommintikul A, Herath C, Zhiyuan J, Angus P, McLean C, Roberts S, Krum H. Urotensin II modulates hepatic fibrosis and portal hemodynamic alterations in rats. Am J Physiol Gastrointest Liver Physiol. 2009;297:G762-G767. [PubMed] [DOI] |
| 50. | Tacke F, Weiskirchen R. [Liver fibrosis - pathogenesis and novel therapeutic approaches]. Internist (Berl). 2010;51:21-29. [PubMed] [DOI] |
| 51. | Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;214:199-210. [PubMed] [DOI] |
| 52. | Trebicka J, Leifeld L, Hennenberg M, Biecker E, Eckhardt A, Fischer N, Pröbsting AS, Clemens C, Lammert F, Sauerbruch T. Hemodynamic effects of urotensin II and its specific receptor antagonist palosuran in cirrhotic rats. Hepatology. 2008;47:1264-1276. [PubMed] [DOI] |
| 53. | Leifeld L, Clemens C, Heller J, Trebicka J, Sauerbruch T, Spengler U. Expression of urotensin II and its receptor in human liver cirrhosis and fulminant hepatic failure. Dig Dis Sci. 2010;55:1458-1464. [PubMed] [DOI] |
| 54. | Matsushita M, Shichiri M, Fukai N, Ozawa N, Yoshimoto T, Takasu N, Hirata Y. Urotensin II is an autocrine/paracrine growth factor for the porcine renal epithelial cell line, LLCPK1. Endocrinology. 2003;144:1825-1831. [PubMed] [DOI] |
| 55. | Zhang Y, Li Y, Wei R, Wang Z, Bu D, Zhao J, Pang Y, Tang C. Urotensin II is an autocrine/paracrine growth factor for aortic adventitia of rat. Regul Pept. 2008;151:88-94. [PubMed] [DOI] |
| 56. | Wagatsuma Y, Naritaka Y, Shimakawa T, Kanako H, Keiichiro I, Shunichi S, Konno S, Katsube T, Ogawa K. Clinical usefulness of the angiotensin II receptor antagonist losartan in patients with portal hypertensive gastropathy. Hepatogastroenterology. 2006;53:171-174. [PubMed] |
| 57. | Lubel JS, Herath CB, Burrell LM, Angus PW. Liver disease and the renin-angiotensin system: recent discoveries and clinical implications. J Gastroenterol Hepatol. 2008;23:1327-1338. [PubMed] [DOI] |
| 58. | Bataller R, Sancho-Bru P, Ginès P, Brenner DA. Liver fibrogenesis: a new role for the renin-angiotensin system. Antioxid Redox Signal. 2005;7:1346-1355. [PubMed] [DOI] |
| 59. | Reichen J, Lebrec D. The future treatment of portal hypertension. Best Pract Res Clin Gastroenterol. 2007;21:191-202. [PubMed] [DOI] |
| 61. | Urbanowicz W, Sogni P, Moreau R, Tazi KA, Barriere E, Poirel O, Martin A, Guimont MC, Cazals-Hatem D, Lebrec D. Tezosentan, an endothelin receptor antagonist, limits liver injury in endotoxin challenged cirrhotic rats. Gut. 2004;53:1844-1849. [PubMed] |
| 62. | Feng HQ, Weymouth ND, Rockey DC. Endothelin antagonism in portal hypertensive mice: implications for endothelin receptor-specific signaling in liver disease. Am J Physiol Gastrointest Liver Physiol. 2009;297:G27-G33. [PubMed] [DOI] |
| 63. | Debernardi-Venon W, Martini S, Biasi F, Vizio B, Termine A, Poli G, Brunello F, Alessandria C, Bonardi R, Saracco G. AT1 receptor antagonist Candesartan in selected cirrhotic patients: effect on portal pressure and liver fibrosis markers. J Hepatol. 2007;46:1026-1033. [PubMed] [DOI] |
| 64. | Krum H, Kemp W. Therapeutic potential of blockade of the urotensin II system in systemic hypertension. Curr Hypertens Rep. 2007;9:53-58. [PubMed] [DOI] |
| 65. | Behm DJ, Herold CL, Ohlstein EH, Knight SD, Dhanak D, Douglas SA. Pharmacological characterization of SB-710411 (Cpa-c[D-Cys-Pal-D-Trp-Lys-Val-Cys]-Cpa-amide), a novel peptidic urotensin-II receptor antagonist. Br J Pharmacol. 2002;137:449-458. [PubMed] [DOI] |
| 66. | Behm DJ, Ao Z, Camarda V, Aiyar NV, Johns DG, Douglas SA. Inhibitory effects of putative peptidic urotensin-II receptor antagonists on urotensin-II-induced contraction of cat isolated respiratory smooth muscle. Eur J Pharmacol. 2005;516:276-281. [PubMed] [DOI] |
| 67. | Patacchini R, Santicioli P, Giuliani S, Grieco P, Novellino E, Rovero P, Maggi CA. Urantide: an ultrapotent urotensin II antagonist peptide in the rat aorta. Br J Pharmacol. 2003;140:1155-1158. [PubMed] [DOI] |
| 68. | Carotenuto A, Grieco P, Rovero P, Novellino E. Urotensin-II receptor antagonists. Curr Med Chem. 2006;13:267-275. [PubMed] [DOI] |
| 69. | Clozel M, Binkert C, Birker-Robaczewska M, Boukhadra C, Ding SS, Fischli W, Hess P, Mathys B, Morrison K, Müller C. Pharmacology of the urotensin-II receptor antagonist palosuran (ACT-058362; 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea sulfate salt): first demonstration of a pathophysiological role of the urotensin System. J Pharmacol Exp Ther. 2004;311:204-212. [PubMed] [DOI] |
| 70. | Sidharta PN, van Giersbergen PL, Dingemanse J. Pharmacokinetics and pharmacodynamics of the urotensin-II receptor antagonist palosuran in healthy male subjects. J Clin Pharmacol. 2009;49:1168-1175. [PubMed] [DOI] |
| 71. | Yao H, Chen ZW. [Protective effect of urantide against myocardial ischemia injury]. Yaoxue Xuebao. 2008;43:150-156. [PubMed] |