尾加压素Ⅱ对心脏的作用研究
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摘要
尾加压素Ⅱ是最早从鱼的尾垂体分离出来的一种多肽,最近哺乳动物包括人的尾加压素Ⅱ已经被克隆出来。研究表明,尾加压素Ⅱ在心血管系统有重要作用,它曾被认为是最强的缩血管物质之一。对于不同种属的动物,静脉注射尾加压素Ⅱ产生的心血管反应有很大的差异,甚至对于同一种属的动物,报道也并不一致。尾加压素Ⅱ能增加人右心房肌的收缩力,但对左心室心肌的直接作用还有待阐明。尾加压素Ⅱ受体GPR14分布比较广泛,包括心血管组织,中枢和内分泌组织等。人们通过RT-PCR和配体受体结合实验证实GPR14在心血管的表达,但对于GPR14蛋白在心脏的表达以及它在心脏中分布的具体的细胞类型还缺乏直接的证据。另外,尾加压素Ⅱ可能会介导心肌细胞的肥大,在一些慢性缺氧或充血性心衰情况,尾加压素Ⅱ和其受体出现上调,推测尾加压素Ⅱ可能参与心血管的重构过程。一氧化氮具有舒张血管,保护心肌的作用。它参与尾加压素Ⅱ对心血管作用的调节。硫化氢是最近受到关注的具有生物活性的气体小分子,能抑制心肌收缩,舒张血管。但它是否参与尾加压素Ⅱ对心血管的作用,还需要进一步的研究。
我们主要通过免疫组化和免疫荧光双标的方法观察GPR14在心脏中的表达,结果表明,GPR14主要表达于正常大鼠左心室的心肌细胞上,在心脏的其他部分包括心房,右心室和主动脉瓣膜没有观察到GPR14蛋白的阳性表达;在心脏中其他的细胞包括冠脉血管的内皮和平滑肌细胞上未见GPR14的表达。我们利用Western blot和逆转录—聚合酶链的方法进一步证实GPR14蛋白和基因确实表达在左心室。我们又通过免疫组化的方法观察GPR14蛋白在大鼠心梗后3天和2周梗塞区边缘的表达,结果表明,与假手术组相比,GPR14在表达的量和表达的细胞类型上,均没有出现明显的变化。在房间隔缺损病人的右心房,我们观察到GPR14受体的表达,主要在靠近心外膜的心肌组织;而在右心耳,GPR14蛋白的表达与血管分布有关。
为了从功能学上进一步证实尾加压素Ⅱ受体确实表达在左心室的心肌上,我们观察了尾加压素Ⅱ对左室乳头肌的作用,结果提示,尾加压素增加左室乳头肌的收缩强度,但并不改变其他的收缩参数,包括收缩舒张速率,收缩潜伏期,达到最大收缩张力的时间以及舒张到一半的时间。我们还观察了给麻醉大鼠静脉注射尾加压素Ⅱ引起的心血管效应,主要引起左室收缩压,股动脉收缩压和舒张压,心率的下降;心肌收缩力(dp/dt)和心肌舒张能力(-dp/dt)的减弱;左室舒张压的升高:提示尾加压素Ⅱ可能对心脏具有抑制作用。我们推测在整体实验中,尾加压素Ⅱ可能通过调节其他物质如一氧化氮和硫化氢等气体小分子
Urotensin II, a cyclic neuropeptide initially isolated from the urophysis of teleost fish, has recently been cloned in several mammalian species including human. Recently it has been shown to play a role via its receptor GPR14 in the cardiovascular system of the mammalian. It has been recognized as one of most potent vasoconstrictors identified to date. Systemic administration of human urotensin II induced various cardiovascular responses in different species. A stimulant effect of urotensin II in isolated human right atrial trabeculae had been reported. While little is known about its putative direct effect on the left ventricle. GPR14 is widely expressed in many tissues such as cardiovascular tissues, central nervous system and endocrine tissues. GPR14 has been observed in the rat heart by ligand binding assay and reverse transcripticn-polymerase chain reaction. However, the cellular distribution of the GPR14 protein remains to be further clarified. Moreover, urotensin II has been suggested to be a mediator of cardiomyocyte hypertrophy. Both It and its receptor have been shown to be up-regulated in the heart in chronic hypoxia and congestive heart failure, suggesting a possible role of urotensin II in cardiac remodeling. Nitric oxide (NO) has been recognized as an important regulator in the cardiovascular system. NO induces blood vessel relaxation and inotropic effects in the myocardium. Urotensin II has been reported to induce cardiovascular effects via the NOS(nitric oxide synthase) /NO system. Hydrogen sulfide (H2S) is new biological gas molecule endogenously generated from cysteine in a reaction catalysed by cystathionine P -synthase(CBS) and/or cystathionine- Y -lyase. It has recently been discovered play an important role in the cardiovascular system. The role of H_2S in urotensin II effects remains to be explored.In the present study, we investigated the cellular distribution of GPR14 protein in rat heart by using immunohistochemistry and confocal microscopic immunofluorescence double staining with antipeptide polyclonal antibodies against GPR14 and cell type markers for myocytes and endothelial cells. In paraffin-embedded heart sections, positive immunohistochemical staining was observed in the left ventricle but not in the right ventricule, atria and aortic valve. Immunofluorescence double staining revealed the cardiac myocyte as the only cell type expressing GPR14 protein in frozen heart sections as well as in isolated cardiac myocytes. There was no visible signal for GPR14 in intramyocardial coronary arteries
我们主要通过免疫组化和免疫荧光双标的方法观察GPR14在心脏中的表达,结果表明,GPR14主要表达于正常大鼠左心室的心肌细胞上,在心脏的其他部分包括心房,右心室和主动脉瓣膜没有观察到GPR14蛋白的阳性表达;在心脏中其他的细胞包括冠脉血管的内皮和平滑肌细胞上未见GPR14的表达。我们利用Western blot和逆转录—聚合酶链的方法进一步证实GPR14蛋白和基因确实表达在左心室。我们又通过免疫组化的方法观察GPR14蛋白在大鼠心梗后3天和2周梗塞区边缘的表达,结果表明,与假手术组相比,GPR14在表达的量和表达的细胞类型上,均没有出现明显的变化。在房间隔缺损病人的右心房,我们观察到GPR14受体的表达,主要在靠近心外膜的心肌组织;而在右心耳,GPR14蛋白的表达与血管分布有关。
为了从功能学上进一步证实尾加压素Ⅱ受体确实表达在左心室的心肌上,我们观察了尾加压素Ⅱ对左室乳头肌的作用,结果提示,尾加压素增加左室乳头肌的收缩强度,但并不改变其他的收缩参数,包括收缩舒张速率,收缩潜伏期,达到最大收缩张力的时间以及舒张到一半的时间。我们还观察了给麻醉大鼠静脉注射尾加压素Ⅱ引起的心血管效应,主要引起左室收缩压,股动脉收缩压和舒张压,心率的下降;心肌收缩力(dp/dt)和心肌舒张能力(-dp/dt)的减弱;左室舒张压的升高:提示尾加压素Ⅱ可能对心脏具有抑制作用。我们推测在整体实验中,尾加压素Ⅱ可能通过调节其他物质如一氧化氮和硫化氢等气体小分子
Urotensin II, a cyclic neuropeptide initially isolated from the urophysis of teleost fish, has recently been cloned in several mammalian species including human. Recently it has been shown to play a role via its receptor GPR14 in the cardiovascular system of the mammalian. It has been recognized as one of most potent vasoconstrictors identified to date. Systemic administration of human urotensin II induced various cardiovascular responses in different species. A stimulant effect of urotensin II in isolated human right atrial trabeculae had been reported. While little is known about its putative direct effect on the left ventricle. GPR14 is widely expressed in many tissues such as cardiovascular tissues, central nervous system and endocrine tissues. GPR14 has been observed in the rat heart by ligand binding assay and reverse transcripticn-polymerase chain reaction. However, the cellular distribution of the GPR14 protein remains to be further clarified. Moreover, urotensin II has been suggested to be a mediator of cardiomyocyte hypertrophy. Both It and its receptor have been shown to be up-regulated in the heart in chronic hypoxia and congestive heart failure, suggesting a possible role of urotensin II in cardiac remodeling. Nitric oxide (NO) has been recognized as an important regulator in the cardiovascular system. NO induces blood vessel relaxation and inotropic effects in the myocardium. Urotensin II has been reported to induce cardiovascular effects via the NOS(nitric oxide synthase) /NO system. Hydrogen sulfide (H2S) is new biological gas molecule endogenously generated from cysteine in a reaction catalysed by cystathionine P -synthase(CBS) and/or cystathionine- Y -lyase. It has recently been discovered play an important role in the cardiovascular system. The role of H_2S in urotensin II effects remains to be explored.In the present study, we investigated the cellular distribution of GPR14 protein in rat heart by using immunohistochemistry and confocal microscopic immunofluorescence double staining with antipeptide polyclonal antibodies against GPR14 and cell type markers for myocytes and endothelial cells. In paraffin-embedded heart sections, positive immunohistochemical staining was observed in the left ventricle but not in the right ventricule, atria and aortic valve. Immunofluorescence double staining revealed the cardiac myocyte as the only cell type expressing GPR14 protein in frozen heart sections as well as in isolated cardiac myocytes. There was no visible signal for GPR14 in intramyocardial coronary arteries
引文
1. Bern HA, Pearson D, Larson BA, Nishioka RS. Neurohormones from fish tails: the caudal neurosecretory system. "Urophysiology" and the caudal neurosecretory system of fishes. Recent Prog Horm Res, 1985, 41: 533-552.
2. Coulouarn Y. Lihrmann I, Jegou S, Anouar Y, Tostivint H, Beauvillain JC. Conlon JM, Bern HA, Vaudry H. 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. Proc Natl Acad Sci U S A ,1998, 95(26): 15803-15808.
3. Gibson A, Wallace P, Bern HA. Cardiovascular effects of urotensin Ⅱ in anesthetized and pithed rats. Gen Comp Endocrinol, 1986, 64(3): 435-439.
4. Gibson A. Complex effects of Gillichthys urotensin Ⅱ on rat aortic strips. Br J Pharmacol. 1987, 91 (1): 205-212.
5. Douglas SA, Sulpizio AC, Piercy V, Sarau HM, Ames RS, Aiyar NV. Ohlstein EH. Willette RN. Differential vasoconstrictor activity of human urotensin-Ⅱ in vascular tissue isolated from the rat. mouse, dog, pig, marmoset and cynomolgus monkey. Br J Pharmacol, 2000, 131(7): 1262-1274.
6. Ames RS, Sarau HM, Chambers JK, Willette RN, Aiyar NV, Romanic AM, Louden CS, Foley JJ, Sauermelch CF, Coatney RW, Ao Z, Disa J, Holmes SD, Stadel JM, Martin JD. Liu WS, Glover GI, Wilson S, McNulty DE, Ellis CE, Elshourbagy NA, Shabon U, Trill JJ, Hay DW, Ohlstein EH, Bergsma DJ. Douglas SA. Human urotensin-Ⅱ is a potent vasoconstrictor and agonist for the orphan receptor GPR 14. Nature, 1999, 401: 282-286.
7. MacLean MR, Alexander D, Stirrat A, Gallagher M, Douglas SA, Ohlstein EH, Morecroft I, Polland K. Contractile responses to human urotensin-Ⅱ in rat and human pulmonary arteries: effect of endothelial factors and chronic hypoxia in the rat. Br J Pharmacol. 2000, 130(2): 201-204.
8. Douglas SA, Ohlstein EH. Human urotensin-Ⅱ, the most potent mammalian vasoconstrictor identified to date, as a therapeutic target for the management of cardiovascular disease. Trends Cardiovasc Med, 2000, 10(6): 229-237.
9. 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(8): 1865-1870.
10. 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(8): 1625-1629.
11. 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(2): H925-H928.
12. Hassan GS, Chouiali F, Saito T, Hu F, Douglas SA, Ao Z. Willette RN, Ohlstein EH, Giaid A. Effect of human urotensin- II infusion on hemodynamics and cardiac function. Can J Physiol Pharmacol ,2003, 81(2): 125-128.
13. Gray GA, Jones MR. Sharif I. Human urotensin II increases coronary perfusion pressure in the isolated rat heart: potentiation by nitric oxide synthase and cyclooxygenase inhibition. Life Sci ,2001, 69(2): 175-180.
14. Katano Y, Ishihata A, Aita T, Ogaki T, Horie T. Vasodilator effect of urotensin II, one of the most potent vasoconstricting factors, on rat coronary arteries. Eur J Pharmacol. 2000 Aug 18; 402(1-2):R5-7.
15. Li L, Yuan WJ, Su DF.Effects of rat urotensin II on coronary flow and myocardial eNOS protein expression in isolated rat heart. Acta Pharmacol Sin. 2004 Nov; 25(11): 1444-9.
16. Russell FD, Molenaar P, O'Brien DM. Cardiostimulant effects of urotensin-II in human heart in vitro. Br J Pharmacol ,2001, 132(1): 5-9.
17. Russell FD. Emerging roles of urotensin-II in cardiovascular disease. Pharmacol Then 2004,103(3):223-43.
18. Liu Q, Pong SS, Zeng Z, Zhang Q, Howard AD, Williams DL Jr, Davidoff M, Wang R, Austin CP. McDonald TP, Bai C, George SR, Evans JF, Caskey CT. Identification of urotensin II as the endogenous ligand for the orphan G-protein-coupled receptor GPR14. Biochem Biophys Res Commun .1999, 266(1): 174-178.
19. Mori M, Sugo T, Abe M. Shimomura Y, Kurihara M. Kitada C, Kikuchi K. Shintani Y, Kurokawa T, Onda H, Nishimura O, Fujino M. Urotensin II is the endogenous ligand of a G-protein-coupled orphan receptor (GPR14). Biochem Biophys Res Commun ,1999,265(1): 123-129.
20. Tzanidis A, Hannan RD, Thomas WG, Onan D, Autelitano DJ, See F, Kelly DJ, Gilbert RE, Krum H. Direct actions of urotensin II on the heart. Implications for cardiac ftbrosis and hypertrophy. Circ Res ,2003, 93(3): 246-253.
21. Matsushita M, Shichiri M, Imai T, Iwashina M, Tanaka H, Takasu N, Hirata Y. Co-expression of urotensin Ⅱ and its receptor (GPR14) in human cardiovascular and renal tissues. J Hypertens. 2001 ,19(12):2185-90.
22. Conlon JM, Yano K, Waugh D, Hazon N. Distribution and molecular forms of urotensin Ⅱ and its role in cardiovascular regulation in vertebrates. J Exp Zool ,1996, 275(2-3): 226-238.
23. Douglas SA, Tayara L, Ohlstein EH, Halawa N, Giaid A. Congestive heart failure and expression of myocardial urotensin Ⅱ. Lancet ,2002, 359(9322): 1990-1997.
24. Zhang Y, Li J, Cao J, Chen J, Yang J, Zhang Z, Du J, Tang C. Effect of chronic hypoxia on contents of urotensin Ⅱ and its functional receptors in rat myocardium. Heart Vessels ,2002, 16(2): 64-68.
25. Zou Y, Nagai R, Yamazaki T. Urotensin II induces hypertrophic responses in cultured cardiomyocytes from neonatal rats. FEBS Lett, 2001,508(1): 57-60.
26. Croston GE, Olsson R, Currier EA, Burstein ES, Weiner D, Nash N, Severance D, Allenmark SG, Thunberg L, Ma JN, Mohell N, O'Dowd B, Brann MR, Hacksell U. Discovery of the first nonpeptide agonist of the GPR14/urotensin- Ⅱ receptor: 3-(4-chlorophenyl)-3-(2- (dimethylamino)ethyl)isochroman-1-one (AC-7954). J Med Chem ,2002, 45(23): 4950-4953.
27. Grieco P, Carotenuto A, Campiglia P, Zampelli E, Patacchini R, Maggi CA, Novellino E, Rovero P. A new, potent urotensin II receptor peptide agonist containing a Pen residue at the disulfide bridge. J Med Chem ,2002, 45(20): 4391-4394.
28. 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(4): 449-458.
29. Flohr S, Kurz M, Kostenis E, Brkovich A, Fournier A, Klabunde T. Identification 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 Med Chem ,2002, 45(9): 1799-1805.
30. Rossowski WJ, Cheng BL, Taylor JE, Datta R, Coy DH. Human urotensin Ⅱ -induced aorta ring contractions are mediated by protein kinase C, tyrosine kinases and Rho-kinase: inhibition by somatostatin receptor antagonists. Eur J Pharmacol, 2002, 438(3): 159-170.
31. Kumar A, Brar R, Wang P, Dee L, Skorupa G, Khadour F, Schulz R, Parrillo JE. Role of nitric oxide and cGMP in human septic serum-induced depression of cardiac myocyte contractility. Am J Physiol. 1999 Jan; 276(1 Pt 2): R265-76.
32. Finkel MS, Oddis CV. Jacob TD, Watkins SC, Hattler BG, Simmons RL. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science. 1992; 257(5068): 387-9.
33. Zhang AY, Chen YF, Zhang DX, Yi FX, Qi J, Andrade-Gordon P, de Garavilla L, Li PL, Zou AP. Urotensin Ⅱ is a nitric oxide-dependent vasodilator and natriuretic peptide in the rat kidney. Am J Physiol Renal Physiol. 2003 Oct; 285(4): F792-8.
34.李玲,袁文俊,潘秀颉,王伟忠,邱景伟,唐朝枢.尾加压素对新生大鼠心肌细胞一氧化氮合成的影响.生理学报.2002,54(4):307-310.
35. Zhao W, Zhang J, Lu Y, Wang R. The vasorelaxant effect of H(2)S as a novel endogenous gaseous K(ATP) channel opener. EMBO J. 2001, 20(21): 6008-16.
36. Geng B, Yang J, Qi Y, Zhao J. Pang Y, Du J, Tang C. H2S generated by heart in rat and its effects on cardiac function. Biochem Biophys Res Commun. 2004; 313(2): 362-8.
37. Swaroop M, Bradley K, Ohura T. Tahara T, Roper MD, Rosenberg LE, Kraus JP. Rat cystathionine beta-synthase. Gene organization and alternative splicing. J Biol Chem. 1992 Jun 5; 267(16):11455-61.
38. Stipanuk MH, Beck PW. Characterization of the enzymic capacity for cysteine desulphhydration in liver and kidney of the rat. Biochem J. 1982 15; 206(2): 267-77
39. Maguire JJ, Kuc RE, Davenport AP. Orphan-receptor ligand human urotensin Ⅱ: receptor localization in human tissues and comparison of vasoconstrictor responses with endothelin-1. Br J Pharmacol. 2000, 131 (3): 441-6.
40. Gardiner SM, March JE, Kemp PA, Bennett T. Bolus injection of human UⅡ in conscious rats evokes a biphasic haemodynamic response. Br J Pharmacol. 2004 Oct; 143(3): 422-30.
41. Zhu YZ, Wang ZJ. Zhu YC, Zhang L, Oakley RM, Chung CW, Lim KW, Lee HS, Ozoux ML, Linz W, Bohm M, Kostenis E. Urotensin Ⅱ causes fatal circulatory collapse in anesthesized monkeys in vivo: a "vasoconstrictor" with a unique
??hemodynamic profile. Am J Physiol Heart Circ Physiol. 2004 Mar;286(3):H830-6. Epub 2003 Nov 13.
42. Johns DG Ao Z. Naselsky D, Herold CL, Maniscalco K, Sarov-Blat L, Steplewski K, Aiyar N, Douglas SA. Urotensin-Ⅱ-mediated cardiomyocyte hypertrophy: effect of receptor antagonism and role of inflammatory mediators. Naunyn Schmiedebergs Arch Pharmacol. 2004 , 370(4):238-50.
43. Cheung BM, Leung R, Man YB, Wong LY. Plasma concentration of urotensin Ⅱ is raised in hypertension. J Hypertens. 2004. 22(7): 1341-4.
44. NgLL, Loke 1, O'Brien RJ, Squire IB, Davies JE. Plasma urotensin in human systolic heart failure.Circulation. 2002 , 106(23):2877-80.
45. Richards AM, Nicholls MG Lainchbury JG Fisher S, Yandle TG Plasma urotensin II in heart failure.Lancet. 2002 ,17;360(9332):545-6.
46. Dschietzig T, Bartsch C, Pregla R, Zurbrugg HR, Armbruster FP, Richter C. Laule M. Romeyke E, Neubert C, Voelter W, Baumann G Stangl K. Plasma levels and cardiovascular gene expression of urotensin-Ⅱ in human heart failure. Regul Pept. 2002 Dec 31;110(1):33-8.
47. Hazon N, Bjenning C, Conlon JM. Cardiovascular actions of dogfish urotensin Ⅱ in the dogfish Scyliorhinus canicula. Am J Physiol. 1993 , 265(3 Pt 2):R573-6.
48. Yano K, Hicks JW, Vaudry H, Conlon JM. Cardiovascular actions of frog urotensin Ⅱ in the frog, Rana catesbeiana.Gen Comp Endocrinol. 1995 ,97(1): 103-10.
49. Watson AM, Lambert GW. Smith KJ, May CN. Urotensin II acts centrally to increase epinephrine and ACTH release and cause potent inotropic and chronotropic actions. Hypertension. 2003,42(3):373-9.
50. Behm DJ. Doe CP, Johns DG Maniscalco K, Stankus GP. Wibberley A. Willette RN.Douglas SA. Urotensin-II: a novel systemic hypertensive factor in the cat. Naunyn Schmiedebergs Arch Pharmacol. 2004 , 369(3):274-80.
51. Affolter JT. Newby DE, Wilkinson IB, Winter MJ. Baiment RJ, Webb DJ. No effect on central or peripheral blood pressure of systemic urotensin II infusion in humans.Br J Clin Pharmacol. 2002 , 54(6):617-21.
52. Bohm F, Pernow J. Urotensin Ⅱ evokes potent vasoconstriction in humans in vivo.Br J Pharmacol. 2002 ,135(1):25-7.
53. Lin Y, Tsuchthashi T, Matsumura K, Abe I, Iida M. Central cardiovascular action of urotensin Ⅱ in conscious rats. J Hypertens. 2003 , 21(1): 159-65.
54. Kompa AR, Thomas WG See F, Tzanidis A, Hannan RD, Krum H. Cardiovascular role of urotensin Ⅱ: effect of chronic infusion in the rat. Peptides. 2004. 25(10): 1783-8.
55. Tasaki K, Hori M, Ozaki H, Karaki H, Wakabayashi I. Mechanism of human urotensin Ⅱ-induced contraction in rat aorta. J Pharmacol Sci. 2004, 94(4):376-83.
56. Itoh H, McMaster D, Lederis K. Functional receptors for fish neuropeptide urotensin Ⅱ in major rat arteries. Eur J Pharmacol. 1988 , 27;149(l-2):61-6.
57. Behm DJ, Harrison SM, Ao Z, Maniscalco K, Pickering SJ, Grau EV, Woods TN,Coatney RW, Doe CP, Willette RN, Johns DG Douglas SA. Deletion of the UT receptor gene results in the selective loss of urotensin-II contractile activity in aortae isolated from UT receptor knockout micc.Br J Pharmacol. 2003,139(2):464-72
58. Camarda V, Guerrini R, Kostenis E, Rizzi A. Calo G Hattenberger A,Zucchini M, Salvadori S, Regoli D. A new Iigand for the urotensin II receptor.Br J Pharmacol. 2002, 137(3):311-4.
59. Herold CL, Behm DJ, Buckley PT, Foley JJ, Wixted WE. Sarau HM. Douglas SA. The neuromedin B receptor antagonist. BIM-23127, is a potent antagonist at human and rat urotensin-II receptors. Br J Pharmacol. 2003 ,139(2):203-7.
60. 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(7): 1155-8.
61. Camarda V, Song W. Marzola E, Spagnol M, Guerrini R, Salvadori S, Regoli D, Thompson JP, Rowbotham DJ, Behm DJ, Douglas SA, Calo' G Lambert DG Urantide mimics urotensin-II induced calcium release in cells expressing recombinant UT receptors. Eur J Pharmacol. 2004 , 13;498(l-3):83-6.
62. Zhao W. Zhang J, Lu Y, Wang R. The vasorelaxant effect of H(2)S as a novel endogenous gaseous K(ATP) channel opener. EMBO J. 2001 .20(21):6008-16.
63. Hosoki R. Matsuki N, Kimura H. The possible role of hydrogen sulfide as an endogenous smooth muscle relaxant in synergy with nitric oxide. Biochem Biophys Res Commun. 1997 ,28;237(3):527-31
64. Geng B. Yang J, Qi Y, Zhao J, Pang Y, Du J, Tang C. H2S generated by heart in rat and its effects on cardiac function. Biochem Biophys Res Commun. 2004. 313(2):362-8.
65. Yan H, Du J, Tang C. The possible role of hydrogen sulfide on the pathogenesis
2. Coulouarn Y. Lihrmann I, Jegou S, Anouar Y, Tostivint H, Beauvillain JC. Conlon JM, Bern HA, Vaudry H. 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. Proc Natl Acad Sci U S A ,1998, 95(26): 15803-15808.
3. Gibson A, Wallace P, Bern HA. Cardiovascular effects of urotensin Ⅱ in anesthetized and pithed rats. Gen Comp Endocrinol, 1986, 64(3): 435-439.
4. Gibson A. Complex effects of Gillichthys urotensin Ⅱ on rat aortic strips. Br J Pharmacol. 1987, 91 (1): 205-212.
5. Douglas SA, Sulpizio AC, Piercy V, Sarau HM, Ames RS, Aiyar NV. Ohlstein EH. Willette RN. Differential vasoconstrictor activity of human urotensin-Ⅱ in vascular tissue isolated from the rat. mouse, dog, pig, marmoset and cynomolgus monkey. Br J Pharmacol, 2000, 131(7): 1262-1274.
6. Ames RS, Sarau HM, Chambers JK, Willette RN, Aiyar NV, Romanic AM, Louden CS, Foley JJ, Sauermelch CF, Coatney RW, Ao Z, Disa J, Holmes SD, Stadel JM, Martin JD. Liu WS, Glover GI, Wilson S, McNulty DE, Ellis CE, Elshourbagy NA, Shabon U, Trill JJ, Hay DW, Ohlstein EH, Bergsma DJ. Douglas SA. Human urotensin-Ⅱ is a potent vasoconstrictor and agonist for the orphan receptor GPR 14. Nature, 1999, 401: 282-286.
7. MacLean MR, Alexander D, Stirrat A, Gallagher M, Douglas SA, Ohlstein EH, Morecroft I, Polland K. Contractile responses to human urotensin-Ⅱ in rat and human pulmonary arteries: effect of endothelial factors and chronic hypoxia in the rat. Br J Pharmacol. 2000, 130(2): 201-204.
8. Douglas SA, Ohlstein EH. Human urotensin-Ⅱ, the most potent mammalian vasoconstrictor identified to date, as a therapeutic target for the management of cardiovascular disease. Trends Cardiovasc Med, 2000, 10(6): 229-237.
9. 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(8): 1865-1870.
10. 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(8): 1625-1629.
11. 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(2): H925-H928.
12. Hassan GS, Chouiali F, Saito T, Hu F, Douglas SA, Ao Z. Willette RN, Ohlstein EH, Giaid A. Effect of human urotensin- II infusion on hemodynamics and cardiac function. Can J Physiol Pharmacol ,2003, 81(2): 125-128.
13. Gray GA, Jones MR. Sharif I. Human urotensin II increases coronary perfusion pressure in the isolated rat heart: potentiation by nitric oxide synthase and cyclooxygenase inhibition. Life Sci ,2001, 69(2): 175-180.
14. Katano Y, Ishihata A, Aita T, Ogaki T, Horie T. Vasodilator effect of urotensin II, one of the most potent vasoconstricting factors, on rat coronary arteries. Eur J Pharmacol. 2000 Aug 18; 402(1-2):R5-7.
15. Li L, Yuan WJ, Su DF.Effects of rat urotensin II on coronary flow and myocardial eNOS protein expression in isolated rat heart. Acta Pharmacol Sin. 2004 Nov; 25(11): 1444-9.
16. Russell FD, Molenaar P, O'Brien DM. Cardiostimulant effects of urotensin-II in human heart in vitro. Br J Pharmacol ,2001, 132(1): 5-9.
17. Russell FD. Emerging roles of urotensin-II in cardiovascular disease. Pharmacol Then 2004,103(3):223-43.
18. Liu Q, Pong SS, Zeng Z, Zhang Q, Howard AD, Williams DL Jr, Davidoff M, Wang R, Austin CP. McDonald TP, Bai C, George SR, Evans JF, Caskey CT. Identification of urotensin II as the endogenous ligand for the orphan G-protein-coupled receptor GPR14. Biochem Biophys Res Commun .1999, 266(1): 174-178.
19. Mori M, Sugo T, Abe M. Shimomura Y, Kurihara M. Kitada C, Kikuchi K. Shintani Y, Kurokawa T, Onda H, Nishimura O, Fujino M. Urotensin II is the endogenous ligand of a G-protein-coupled orphan receptor (GPR14). Biochem Biophys Res Commun ,1999,265(1): 123-129.
20. Tzanidis A, Hannan RD, Thomas WG, Onan D, Autelitano DJ, See F, Kelly DJ, Gilbert RE, Krum H. Direct actions of urotensin II on the heart. Implications for cardiac ftbrosis and hypertrophy. Circ Res ,2003, 93(3): 246-253.
21. Matsushita M, Shichiri M, Imai T, Iwashina M, Tanaka H, Takasu N, Hirata Y. Co-expression of urotensin Ⅱ and its receptor (GPR14) in human cardiovascular and renal tissues. J Hypertens. 2001 ,19(12):2185-90.
22. Conlon JM, Yano K, Waugh D, Hazon N. Distribution and molecular forms of urotensin Ⅱ and its role in cardiovascular regulation in vertebrates. J Exp Zool ,1996, 275(2-3): 226-238.
23. Douglas SA, Tayara L, Ohlstein EH, Halawa N, Giaid A. Congestive heart failure and expression of myocardial urotensin Ⅱ. Lancet ,2002, 359(9322): 1990-1997.
24. Zhang Y, Li J, Cao J, Chen J, Yang J, Zhang Z, Du J, Tang C. Effect of chronic hypoxia on contents of urotensin Ⅱ and its functional receptors in rat myocardium. Heart Vessels ,2002, 16(2): 64-68.
25. Zou Y, Nagai R, Yamazaki T. Urotensin II induces hypertrophic responses in cultured cardiomyocytes from neonatal rats. FEBS Lett, 2001,508(1): 57-60.
26. Croston GE, Olsson R, Currier EA, Burstein ES, Weiner D, Nash N, Severance D, Allenmark SG, Thunberg L, Ma JN, Mohell N, O'Dowd B, Brann MR, Hacksell U. Discovery of the first nonpeptide agonist of the GPR14/urotensin- Ⅱ receptor: 3-(4-chlorophenyl)-3-(2- (dimethylamino)ethyl)isochroman-1-one (AC-7954). J Med Chem ,2002, 45(23): 4950-4953.
27. Grieco P, Carotenuto A, Campiglia P, Zampelli E, Patacchini R, Maggi CA, Novellino E, Rovero P. A new, potent urotensin II receptor peptide agonist containing a Pen residue at the disulfide bridge. J Med Chem ,2002, 45(20): 4391-4394.
28. 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(4): 449-458.
29. Flohr S, Kurz M, Kostenis E, Brkovich A, Fournier A, Klabunde T. Identification 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 Med Chem ,2002, 45(9): 1799-1805.
30. Rossowski WJ, Cheng BL, Taylor JE, Datta R, Coy DH. Human urotensin Ⅱ -induced aorta ring contractions are mediated by protein kinase C, tyrosine kinases and Rho-kinase: inhibition by somatostatin receptor antagonists. Eur J Pharmacol, 2002, 438(3): 159-170.
31. Kumar A, Brar R, Wang P, Dee L, Skorupa G, Khadour F, Schulz R, Parrillo JE. Role of nitric oxide and cGMP in human septic serum-induced depression of cardiac myocyte contractility. Am J Physiol. 1999 Jan; 276(1 Pt 2): R265-76.
32. Finkel MS, Oddis CV. Jacob TD, Watkins SC, Hattler BG, Simmons RL. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science. 1992; 257(5068): 387-9.
33. Zhang AY, Chen YF, Zhang DX, Yi FX, Qi J, Andrade-Gordon P, de Garavilla L, Li PL, Zou AP. Urotensin Ⅱ is a nitric oxide-dependent vasodilator and natriuretic peptide in the rat kidney. Am J Physiol Renal Physiol. 2003 Oct; 285(4): F792-8.
34.李玲,袁文俊,潘秀颉,王伟忠,邱景伟,唐朝枢.尾加压素对新生大鼠心肌细胞一氧化氮合成的影响.生理学报.2002,54(4):307-310.
35. Zhao W, Zhang J, Lu Y, Wang R. The vasorelaxant effect of H(2)S as a novel endogenous gaseous K(ATP) channel opener. EMBO J. 2001, 20(21): 6008-16.
36. Geng B, Yang J, Qi Y, Zhao J. Pang Y, Du J, Tang C. H2S generated by heart in rat and its effects on cardiac function. Biochem Biophys Res Commun. 2004; 313(2): 362-8.
37. Swaroop M, Bradley K, Ohura T. Tahara T, Roper MD, Rosenberg LE, Kraus JP. Rat cystathionine beta-synthase. Gene organization and alternative splicing. J Biol Chem. 1992 Jun 5; 267(16):11455-61.
38. Stipanuk MH, Beck PW. Characterization of the enzymic capacity for cysteine desulphhydration in liver and kidney of the rat. Biochem J. 1982 15; 206(2): 267-77
39. Maguire JJ, Kuc RE, Davenport AP. Orphan-receptor ligand human urotensin Ⅱ: receptor localization in human tissues and comparison of vasoconstrictor responses with endothelin-1. Br J Pharmacol. 2000, 131 (3): 441-6.
40. Gardiner SM, March JE, Kemp PA, Bennett T. Bolus injection of human UⅡ in conscious rats evokes a biphasic haemodynamic response. Br J Pharmacol. 2004 Oct; 143(3): 422-30.
41. Zhu YZ, Wang ZJ. Zhu YC, Zhang L, Oakley RM, Chung CW, Lim KW, Lee HS, Ozoux ML, Linz W, Bohm M, Kostenis E. Urotensin Ⅱ causes fatal circulatory collapse in anesthesized monkeys in vivo: a "vasoconstrictor" with a unique
??hemodynamic profile. Am J Physiol Heart Circ Physiol. 2004 Mar;286(3):H830-6. Epub 2003 Nov 13.
42. Johns DG Ao Z. Naselsky D, Herold CL, Maniscalco K, Sarov-Blat L, Steplewski K, Aiyar N, Douglas SA. Urotensin-Ⅱ-mediated cardiomyocyte hypertrophy: effect of receptor antagonism and role of inflammatory mediators. Naunyn Schmiedebergs Arch Pharmacol. 2004 , 370(4):238-50.
43. Cheung BM, Leung R, Man YB, Wong LY. Plasma concentration of urotensin Ⅱ is raised in hypertension. J Hypertens. 2004. 22(7): 1341-4.
44. NgLL, Loke 1, O'Brien RJ, Squire IB, Davies JE. Plasma urotensin in human systolic heart failure.Circulation. 2002 , 106(23):2877-80.
45. Richards AM, Nicholls MG Lainchbury JG Fisher S, Yandle TG Plasma urotensin II in heart failure.Lancet. 2002 ,17;360(9332):545-6.
46. Dschietzig T, Bartsch C, Pregla R, Zurbrugg HR, Armbruster FP, Richter C. Laule M. Romeyke E, Neubert C, Voelter W, Baumann G Stangl K. Plasma levels and cardiovascular gene expression of urotensin-Ⅱ in human heart failure. Regul Pept. 2002 Dec 31;110(1):33-8.
47. Hazon N, Bjenning C, Conlon JM. Cardiovascular actions of dogfish urotensin Ⅱ in the dogfish Scyliorhinus canicula. Am J Physiol. 1993 , 265(3 Pt 2):R573-6.
48. Yano K, Hicks JW, Vaudry H, Conlon JM. Cardiovascular actions of frog urotensin Ⅱ in the frog, Rana catesbeiana.Gen Comp Endocrinol. 1995 ,97(1): 103-10.
49. Watson AM, Lambert GW. Smith KJ, May CN. Urotensin II acts centrally to increase epinephrine and ACTH release and cause potent inotropic and chronotropic actions. Hypertension. 2003,42(3):373-9.
50. Behm DJ. Doe CP, Johns DG Maniscalco K, Stankus GP. Wibberley A. Willette RN.Douglas SA. Urotensin-II: a novel systemic hypertensive factor in the cat. Naunyn Schmiedebergs Arch Pharmacol. 2004 , 369(3):274-80.
51. Affolter JT. Newby DE, Wilkinson IB, Winter MJ. Baiment RJ, Webb DJ. No effect on central or peripheral blood pressure of systemic urotensin II infusion in humans.Br J Clin Pharmacol. 2002 , 54(6):617-21.
52. Bohm F, Pernow J. Urotensin Ⅱ evokes potent vasoconstriction in humans in vivo.Br J Pharmacol. 2002 ,135(1):25-7.
53. Lin Y, Tsuchthashi T, Matsumura K, Abe I, Iida M. Central cardiovascular action of urotensin Ⅱ in conscious rats. J Hypertens. 2003 , 21(1): 159-65.
54. Kompa AR, Thomas WG See F, Tzanidis A, Hannan RD, Krum H. Cardiovascular role of urotensin Ⅱ: effect of chronic infusion in the rat. Peptides. 2004. 25(10): 1783-8.
55. Tasaki K, Hori M, Ozaki H, Karaki H, Wakabayashi I. Mechanism of human urotensin Ⅱ-induced contraction in rat aorta. J Pharmacol Sci. 2004, 94(4):376-83.
56. Itoh H, McMaster D, Lederis K. Functional receptors for fish neuropeptide urotensin Ⅱ in major rat arteries. Eur J Pharmacol. 1988 , 27;149(l-2):61-6.
57. Behm DJ, Harrison SM, Ao Z, Maniscalco K, Pickering SJ, Grau EV, Woods TN,Coatney RW, Doe CP, Willette RN, Johns DG Douglas SA. Deletion of the UT receptor gene results in the selective loss of urotensin-II contractile activity in aortae isolated from UT receptor knockout micc.Br J Pharmacol. 2003,139(2):464-72
58. Camarda V, Guerrini R, Kostenis E, Rizzi A. Calo G Hattenberger A,Zucchini M, Salvadori S, Regoli D. A new Iigand for the urotensin II receptor.Br J Pharmacol. 2002, 137(3):311-4.
59. Herold CL, Behm DJ, Buckley PT, Foley JJ, Wixted WE. Sarau HM. Douglas SA. The neuromedin B receptor antagonist. BIM-23127, is a potent antagonist at human and rat urotensin-II receptors. Br J Pharmacol. 2003 ,139(2):203-7.
60. 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(7): 1155-8.
61. Camarda V, Song W. Marzola E, Spagnol M, Guerrini R, Salvadori S, Regoli D, Thompson JP, Rowbotham DJ, Behm DJ, Douglas SA, Calo' G Lambert DG Urantide mimics urotensin-II induced calcium release in cells expressing recombinant UT receptors. Eur J Pharmacol. 2004 , 13;498(l-3):83-6.
62. Zhao W. Zhang J, Lu Y, Wang R. The vasorelaxant effect of H(2)S as a novel endogenous gaseous K(ATP) channel opener. EMBO J. 2001 .20(21):6008-16.
63. Hosoki R. Matsuki N, Kimura H. The possible role of hydrogen sulfide as an endogenous smooth muscle relaxant in synergy with nitric oxide. Biochem Biophys Res Commun. 1997 ,28;237(3):527-31
64. Geng B. Yang J, Qi Y, Zhao J, Pang Y, Du J, Tang C. H2S generated by heart in rat and its effects on cardiac function. Biochem Biophys Res Commun. 2004. 313(2):362-8.
65. Yan H, Du J, Tang C. The possible role of hydrogen sulfide on the pathogenesis