Urotensin ll (U-II) antagonist binds to urotensin receptor and is involved in the regulation of cardiovascular homeostasis and pathology.

Behm DJ et al.,in 2002 showed inhibition of the urotensin receptor binding/function and also potentiated endothelin-1 induced contraction in the rat isolated aorta by a novel U-II receptor antagonist 1. Luisa G et al., (2009) investigated the expression of U-II and U-II receptor in adrenocortical and adrenomedullary tumors and the functional effects of urotensin II receptor activation. The expression of U-II and U-II receptor was measured by real time RT-PCR in aldosterone-producing adenoma (n=22) and pheochromocytoma (n=10), using histologically normal adrenocortical (n=6) and normal adrenomedullary (n=5) tissue as control. U-II peptide and U-II receptor protein were investigated with immunohistochemistry and immunoblotting. To identify U-II  related and U-II receptor-related pathways, a whole transcriptome analysis was used. The adrenocortical effects of U-II receptor activation were also assessed by U-II infusion with/without the U-II receptor antagonist palosuran in rats. U-II was more expressed in pheochromocytoma than in aldosterone-producing adenoma tissue; the opposite was seen for the U-II receptor expression. U-II receptor activation in vivo in rats enhanced (by 182 ± 9%; P < 0.007) the adrenocortical expression of immunoreactive aldosterone synthase 2.

Structural Characteristics
The vasoactive cyclic 11-amino acid peptide U-II has recently been discovered as the endogenous ligand of the orphan G-protein-coupled receptor GPR14. As U-II might be involved in the regulation of cardiovascular homeostasis and pathology, a nonpeptidic GPR14/U-II antagonist is of considerable basic and therapeutic interest. Authors have performed structure−activity relationship studies on U-II by investigating 25 peptide analogues to mobilize intracellular calcium in GPR14-transfected CHO cells, demonstrating that only the side chains of the residues Trp-7, Lys-8, and Tyr-9 are required for receptor recognition and activation. The solution structure of U-II derived by nuclear magnetic resonance has served as a structural template for a three-dimensional three point pharmacophore query for the virtual screening of the Aventis compound repository for nonpeptidic U-II receptor antagonists. Highly active lead compounds of six different scaffold classes could be identified, antagonizing the biological activity of U-II in vitro. The most potent compound identified by the virtual screening approach, 1-(3-carbamimidoyl-benzyl)-4-methyl-1H-indole-2-carboxylic acid (naphthalen-1-ylmethyl)amide, reveals an IC50 of 400 nM in a functional fluorometric imaging plate reader assay and constitutes a promising lead 3

Mode of Action
U-II the most potent mammalian vasoconstrictor identified, and its receptor, UT, exhibits increased expression in cardiac tissue and plasma in congestive heart failure (CHF) patients. Cardiomyocyte hypertrophy is primarily responsible for increased myocardial mass associated with cardiac injury. Neurohumoral factors such as angiotensin-II, endothelin-1, catecholamines, and inflammatory cytokines are thought to mediate this response. U-II shares similar biological activities with other hypertrophic Gq-coupled receptor ligands such as angiotensin-II and endothelin-1, but a role for U-II in cardiomyocyte hypertrophy has not been characterized. The hypothesis of the current study was that U-II, acting through its Gq-coupled receptor UT plays a hypertrophic role in cardiac hypertrophic remodeling. Adenoviral upregulation of the UT receptor unmasked U-II-induced hypertrophy in H9c2 cardiomyocytes, with a threshold response of 202±8 binding sites/cell. U-II was equally as efficacious as phenylephrine in inducing hypertrophy, measured by a reporter assay (EC50 0.7±0.2 nM) and [3H]-leucine incorporation (EC50 150±40 nM). A competitive peptidic UT receptor antagonist, BIM-23127, inhibited U-II-induced hypertrophy (KB 34±6 nM). U-II did not affect cell proliferation or apoptosis, indicating that U-II is more hypertrophic than apoptotic or hyperplastic in cardiomyocytes. U-II (10 nM) stimulated interleukin-6 release in UT-expressing cardiomyocytes (4.6-fold at 6 h). Finally, in a rat heart failure model, cardiac ventricular mRNA expression of U-II, UT receptor, interleukin-6, and interleukin-1- is increased time-dependently following myocardial injury. These results indicate that U-II might play a role in cardiac remodeling associated with CHF by stimulation of cardiomyocyte hypertrophy via UT, and through upregulation of inflammatory cytokines. As such, UT antagonism may represent a novel therapeutic target for the clinical management of heart failure 4.


Cardiovascular actions of U-II are complex and include direct effects on the vasculature, systemic hemodynamic effects and effects on the myocardium, including actions on contractility, myocyte hypertrophy and extracellular matrix deposition 5.

Plasma levels of urotensin have been found to be elevated in patients with chronic heart failure, diabetes mellitus and chronic renal disease.

Progression of these disease states, elevations in plasma level raise the possibility that U-II might be involved in the pathogenesis and/or progression of chronic renal disease states.

Highly selective U-II antagonists have been developed, which should help to definitively clarify the role of urotensin II in these and other conditions 5.

U-II is a putative mediator of the effects of the adrenal medulla and pheochromocytoma on the adrenocortical zona glomerulosa. This pathophysiological link might account for the reported causal relationship between pheochromocytoma and primary aldosteronism 2.


1.       Behm DJ, Herold CL, Ohlstein EH, Knight SD, Dhanak D, Douglas SA (2002). 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., 137(4):449-458.

2.       Giuliani L, Lenzini L, Antonello M, Aldighieri E, Belloni AS, Fassina A, Gomez-Sanchez C, Rossi GP  (2009). Expression and functional role of urotensin-II and its receptor in the adrenal cortex and medulla: novel insights for the pathophysiology of primary aldosteronism. J Clin Endocrinol Metab., 94(2):684-690.

3.       Flohr S, Kurz M, Kostenis E, Brkovich A, Fournier A, Klabunde T (2002). 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., 45 (9):1799–1805.

4.       Johns DG, Ao Z, Naselsky D, Herold CL, Maniscalco K, Sarov-Blat L, Steplewski K, Aiyar N, Douglas SA (2004). Urotensin-II-mediated cardiomyocyte hypertrophy: effect of receptor antagonism and role of inflammatory mediators. Naunyn-Schmiedeberg's Archives of Pharmacology, 370(4):238-250.

5.       Russell FD (2004). Emerging roles of urotensin-II in cardiovascular disease. Pharmacol Ther., 103(3):223-243.

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