Abstract
Urotensin II, an 11-amino acid peptide, has been found to be the most potent vasoconstrictor yet described, in certain vascular beds. Discovery of its endogenous receptor (UII-R) has ignited considerable interest in this system’s role in disease states associated with increased vascular tone (eg, systemic hypertension). Urotensin II was shown to have direct effects on the heart in addition to effects on vascular tone. In human systemic hypertension, increased plasma levels of urotensin II were noted, with a weak but significant correlation to absolute blood pressure levels. Furthermore, hypertensive patients demonstrate net vasoconstrictor responsiveness in skin microcirculation compared to normal controls. Highly selective UII-R antagonists have been developed based on the known structure of UII-R. Early preclinical and clinical studies report potential beneficial effects in renal disease, heart failure, and diabetes, although effects on blood pressure have been equivocal.
Similar content being viewed by others
References and Recommended Reading
Bern H, Pearson D, Larson B, Nishioka R: Complete amino acid sequence of urotensin I, a hypotensive and corticotropin-releasing neuropeptide from Catostomus. Recent Prog Horm Res 1985, 41:533–552.
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 the mouse and monkey. Br J Pharmacol 2002, 136:9–22.
Coulouarn Y, Jegou S, Tostivint H, et al.: Cloning, sequence analysis and tissue distribution of the mouse and rat urotensin II precursors. FEBS Lett 1999, 457:28–32.
Pearson D, Shively J, Clark B, et al.: Urotensin II: a somatostatin-like peptide in the caudal neurosectretory system of fishes. Proc Natl Acad Sci U S A 1980, 77:5021–5024.
Krum H, Kompa A, Hannan R, Thomas W: Emerging role of the urotensin II system in cardiovascular disease. Heart Drug 2003, 3:153–158.
Carotenuto A, Grieco P, Campiglia P, et al.: Unraveling the active confirmation of urotensin II. J Med Chem 2004, 47:1652–1661.
Bern H, Pearson D, Larson B, Nishioka R: Neurohormones from fish tails: the caudal neurosecretory system. I. “Urophysiology” and the caudal neurosecretory system of fishes. Recent Prog Hormone Res 1995, 41:533–552.
Douglas S, Dhanak D, Johns D: From ‘gills to pills’: urotensin-II as a regulator of mammalian cardiorenal function. Trends Pharmacol Sci 2004, 25:76–85.
Flohr S, Kurtz M, Kostenis E, et al.: 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, 45:1799–1805.
Wilson S, Bergsma D, Chambers J, et al.: Orphan G-protein-coupled receptors: the next generation of drug targets?. Br J Pharmacol 1998, 125:1387–1392.
Liu Q, Pong SS, Zeng Z, et al.: Identification of urotensin II as the endogenous ligand for the orphan G-protein-coupled receptor GPR14. Biochem Biophys Res Commun 1999, 266:174–178.
Maguire J, Davenport A. Is urotensin II the new endothelin?. Br J Pharmacol 2002, 137:579–588.
Sauzeau V, Mellionnec E, Bertoglio J, et al.: Human urotensin II induced contraction and arterial smooth muscle cell proliferation are mediated by RhoA and Rho-Kinase. Circ Res 2001, 88:1102–1104.
Mori M, Sugo T, Abe M, et al.: Urotensin II is the endogenous ligand of a G-protein-coupled orphan receptor, SENR (GPR14). Biochem Biophys Res Comm 1999, 265:123–129.
Totsune K, Takahashi K, Arihara Z, et al.: Role of urotensin II in patients on dialysis. Lancet 2001, 358:810–811.
Ames RS, Sarau HM, Chambers JK, et al.: Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14. Nature 1999, 401:282–286.
Behm D, Harrison S, Ao Z, et al.: Deletion of the UT receptor gene results in the selective loss of urotensin II contractile activity in the aortae isolated from UT receptor knockout mice. Br J Pharmacol 2003, 139:464–472.
Stirrat A, Gallagher M, Douglas S, et al.: Potent vasodilatory responses to human urotensin II in human pulmonary and abdominal resistance arteries. Am J Physiol Heart Circ Physiol 2001, 280:H925–H928.
Hillier C, Berry C, Petrie M, et al.: Effects of urotensin II in human arteries and veins of varying calibre. Circulation 2001, 103:1378–1381.
Maguire J, Kuc R, Davenport A: Orphan-receptor ligand human urotensin II: receptor localization in human tissues and comparison of vasconstrictor responses with endothelin-1. Br J Pharmacol 2000, 131:441–446.
Russell F, Molenaar P, O’Brien D: Cardiostimulant effects of urotenin II in human heart in vitro. Br J Pharmacol 2001, 132:5–9.
Douglas S, Sulpizio A, Piercy V, et al.: 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, 131:1262–1274.
Gardiner S, March J, Kemp P, et al.: Depressor and regionally selective vasodilator effects of human and rat urotensin II in conscious rats. Br J Pharmacol 2001, 132:1625–1629.
Lin Y, Tsuchihashi T, Matsumura K, et al.: Central cardiovascular action of urotensin II in conscious rats. J Hypertens 2003, 21:159–165.
Wilkinson I, Affolter J, de Haas S, et al.: High plasma concentrations of human urotensin II do not alter local or systemic hemodynamics in man. Cardiovasc Res 2002, 53:341–347.
Affolter J, Newby D, Wilkinson I, et al.: No effect on central or peripheral blood pressure or systemic urotensin II infusion in humans. Br J Clin Pharmacol 2002, 54:617–621.
Bohm F, Pernow J: Urotensin II evokes potent vasoconstriction in humans in vivo. Br J Pharmacol 2002, 135:25–27.
Douglas S: Human urotensin II as a novel cardiovascular target: ‘heart’ of the matter or simply a fishy ‘tail’?. Curr Opin Pharmacol 2003, 3:159–167.
Lim M, Honisett S, Sparkes C, et al.: Differential effect of urotensin II on vascular tone in normal subjects and patients with chronic heart failure. Circulation 2004, 109:1212–1214.
Abdelrahman A, Pang C: Involvement of the nitric oxide/L-arginine and sympathetic nervous systems on the vasodepressor action of human urotensin II in anesthetized rats. Life Sci 2002, 71:819–825.
Zhang A, Chen Y, Zhang D, et al.: Urotensin II is a nitric oxide-dependent vasodilator and natriuretic peptide in the rat kidney. Am J Physiol Renal Physiol 2003, 285:F792–F798.
Cheung B, Leung R, Bun Man Y, Wong L: Plasma concentration of urotensin II is raised in hypertension. J Hypertens 2004, 22:1341–1344.
Matsushita M, Shichiri M, Imai T, et al.: Co-expression of urotensin II and its receptor (GPR14) in human cardiovascular and renal tissue. J Hypertens 2001, 19:2185–2190.
Sondermeijer B, Kompa A, Komesaroff P, Krum H: Effect of exogenous urotensin-II on vascular tone in skin micro-circulation of patients with essential hypertension. Am J Hypertens 2005, 18:1195–1199.
Watanabe T, Pakala R, Katagiri T, Benedict C: Synergistc effect of urotensin II with serotonin on vascular smooth muscle cell proliferation. J Hypertens 2001, 19:2191–2196.
Russell F, Molenaar P: Cardiovascular actions of human urotensin II—considerations for hypertension. Naunyn Schmiedebergs Arch Pharmacol 2004, 369:274–280.
Totsune K, Takahashi K, Arihara Z, et al.: Role of urotensin II in patients on dialysis. Lancet 2001, 358:810–811.
Langham R, Kelly DJ, Gow RM, et al.: Increased expression of urotensin II and urotensin receptor in human diabetic nephropathy. Am J Kidney Dis 2004, 44:826–831.
Tzanidis A, Hannan RD, Thomas WG, et al.: Direct actions of urotensin II on the heart: implications for cardiac fibrosis and hypertrophy. Circ Res 2003, 93:246–253.
Ng L, Loke I, O’Brien R, et al.: Plasma urotensin in human systolic heart failure. Circulation 2002, 106:2877–2880.
Richards A, Nicholls M, Lainchbury J, et al.: Plasma urotensin II in heart failure. Lancet 2002, 360:545–546.
Russell F, Meyers D, Galbraith A, et al.: Elevated plasma levels of human urotensin II immunoreactivity in congestive heart failure. Am J Physiol Heart Circ Physiol 2003, 285:H1576–H1581.
Douglas S, Tayara L, Ohlstein E, et al.: Congestive heart failure and expression of myocardial urotensin II. Lancet 2002, 359:1990–1997.
Behm D, Herold C, Ohlstein E, et al.: Pharmacological characterisation of SB-7104011 (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.
Camarda V, Guerrini R, Kostenis E, et al.: A new ligand for the urotensin II receptor. Br J Pharmacol 2002, 137:311–314.
Herold C, Behm D, Buckles P, et al.: The neuromedin B receptor antagonist BIM-23127 is a potent antagonist at human and rat urotensin II receptors. Br J Pharmacol 2003, 139:203–207.
Clozel M, Binkert C, Birker-Robaczewska M, et al.: Pharmacology of the urotensin II receptor antagonist ACT-058362: first demonstration of a pathophysiological role of the urotensin system. J Pharmacol Exp Ther 2004, 311:204–212.
Sidharta PN, Wagner FD, Bohnemeier H, et al.: Pharmacodynamics and pharmacokinetics of the urotensin II receptor antagonist palosuran in macroalbuminuric, diabetic patients. Clin Pharmacol Ther 2006, 80:246–256.
Bousette N, Hu F, Ohlstein EH, et al.: Urotensin-II blockade with SB-611812 attenuates cardiac dysfunction in a rat model of coronary artery ligation. J Mol Cell Cardiol 2006, 41:285–295.
Palosuran in Clinical Development. Available at: http://www.actelion.com/uninet/www/www_main_p.nsf/Content/Other+Projects+in+Clinical+Development.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Krum, H., Kemp, W. Therapeutic potential of blockade of the Urotensin II system in systemic hypertension. Current Science Inc 9, 53–58 (2007). https://doi.org/10.1007/s11906-007-0010-x
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11906-007-0010-x