Structure–Activity Relationships of Human Urotensin II and Related Analogues on Rat Aortic Ring Contraction

Labarrère, Patricia; Chatenet, David; Leprince, Jérôme; Marionneau, Céline; Loirand, Gervaise; Tonon, Marie‐Christine; Dubessy, Christophe; Scalbert, Elizabeth; Pfeiffer, Bruno; Renard, Pierre; Calas, Bernard; Pacaud, Pierre; Vaudry, Hubert

doi:10.1080/1475636031000093507

Cited by 80 publications

(103 citation statements)

References 44 publications

(104 reference statements)

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“…5-20 ng/kg per min directly into the renal artery (Zhang et al 2003), which potentially exposed the kidney to supraphysiological doses of the hormone. The heterologous nature of the peptides used in these studies is unlikely to have had a significant impact on the outcome, as the UTSR is unable to distinguish between UTS from a number of species, including humans and rats (Labarrere et al 2003).…”

Section: Discussionmentioning

confidence: 99%

Renal haemodynamic and tubular actions of urotensin II in the rat

Abdel-Razik¹,

Forty²,

Balment³

et al. 2008

Journal of Endocrinology

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Urotensin II (UTS) is a potent vasoactive peptide that was originally identified in teleost fish. Mammalian orthologues of UTS and its receptor (UTSR) have been described in several species, including humans and rats. We have shown previously that bolus injections of UTS caused a decrease in urine flow and sodium excretion rates in parallel with marked reductions in renal blood flow (RBF) and glomerular filtration rate (GFR). The aim of this study was to determine the effect of UTS infusion at a dose that has minimal impact upon renal haemodynamics in order to identify a potential direct tubular action of UTS. Infusion of rat UTS (rUTS) at 0 . 6 pmol/min per 100 g body weight in male Sprague-Dawley rats, which had no effect on RBF and caused a 30% reduction in GFR, resulted in a significant increase in the fractional excretion of sodium (vehicle 2 . 3G0 . 6 versus rUTS 0 . 6 pmol 4 . 5G0 . 6%, P!0 . 05) and potassium. At the higher dose of 6 pmol/min per 100 g body weight, haemodynamic effects dominated the response. rUTS induced a marked reduction in RBF and GFR (vehicle 1 . 03G 0 . 06 versus rUTS 6 pmol 0 . 31G0 . 05 ml/min per 100 g body weight, P!0 . 05) resulting in an anti-diuresis and antinatriuresis, but no change in fractional excretion of sodium or potassium. Uts2d and Uts2r mRNA expression were greater in the renal medulla compared with the cortex. Together, these data support an inhibitory action of Uts2d on renal tubule sodium and potassium reabsorption in the rat, in addition to its previously described renal haemodynamic effects.

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Section: Discussionmentioning

confidence: 99%

Renal haemodynamic and tubular actions of urotensin II in the rat

Abdel-Razik¹,

Forty²,

Balment³

et al. 2008

Journal of Endocrinology

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“…The importance of the cyclic hexapeptide sequence in UII has already been suggested from its conservation across species and further confirmed in elegant experiments. For example, the octapeptide hUII (4 -11), which contains the cyclic hexapeptide sequence, has been demonstrated as the minimum active fragment necessary for high-affinity binding to the UT receptor (67). In fact, the potency of UII (4 -11) (EC 50 ϭ 2.7) was shown to be four times greater than that of the complete molecule (EC 50 ϭ 11.9), indicating that the COOH-terminal region is largely responsible for biological activity (67).…”

Section: Uii-ut Interactionmentioning

confidence: 99%

Role of urotensin II in health and disease

Ross

McKendy

Giaid

2010

American Journal of Physiology-Regulatory, Integrative and Comp

126

107

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Urotensin II (UII) is an 11 amino acid cyclic peptide originally isolated from the goby fish. The amino acid sequence of UII is exceptionally conserved across most vertebrate taxa, sharing structural similarity to somatostatin. UII binds to a class of G protein-coupled receptor known as GPR14 or the urotensin receptor (UT). UII and its receptor, UT, are widely expressed throughout the cardiovascular, pulmonary, central nervous, renal, and metabolic systems. UII is generally agreed to be the most potent endogenous vasoconstrictor discovered to date. Its physiological mechanisms are similar in some ways to other potent mediators, such as endothelin-1. For example, both compounds elicit a strong vascular smooth muscle-dependent vasoconstriction via Ca 2ϩ release. UII also exerts a wide range of actions in other systems, such as proliferation of vascular smooth muscle cells, fibroblasts, and cancer cells. It also 1) enhances foam cell formation, chemotaxis of inflammatory cells, and inotropic and hypertrophic effects on heart muscle; 2) inhibits insulin release, modulates glomerular filtration, and release of catecholamines; and 3) may help regulate food intake and the sleep cycle. Elevated plasma levels of UII and increased levels of UII and UT expression have been demonstrated in numerous diseased conditions, including hypertension, atherosclerosis, heart failure, pulmonary hypertension, diabetes, renal failure, and the metabolic syndrome. Indeed, some of these reports suggest that UII is a marker of disease activity. As such, the UT receptor is emerging as a promising target for therapeutic intervention. Here, a concise review is given on the vast physiologic and pathologic roles of UII.UT receptor; somatostatin; human; experimental animals; autocrine/paracrine UROTENSIN II (UII) was initially isolated from the urophysis of the goby fish (Gillichthys mirabilis) (97). The peptide was subsequently isolated from the white sucker (Catostomus commersoni) and the carp (Cyprinus carpio). Although there were variations in the amino acid sequence near the amino terminus, in both species the UII molecule retained the COOH-terminal cyclic sequence: -Cys

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“…Rat UII ( pQHGTAPECFWKYCI), ]UII (4 -11), and [Ala 8 ]UII(4 -11) were synthesized (0.25-mmol scale) by the solid phase methodology on FmocIle-PEG-PS, Fmoc-Val-PEG-PS, and Fmoc-Ala-PEG-PS respectively, using a Pioneer Perseptice Biosystems peptide synthesizer (Applera-France, Courtaboeuf, France) and the standard Fmoc procedure as previously described (10). The synthetic peptides were purified by reversed-phase HPLC on a 2.2 £ 25-cm Vydac 218TP1022 C18 column (Alltech, Templemars, France), using a linear gradient (10 -50% over 50 min) of acetonitrile/trifluoroacetic acid (TFA) (99.9:0.1, v/v) at a flow rate of 10 ml/min.…”

Section: Peptidesmentioning

confidence: 99%

“…In order to gain insight into the structureactivity relationships of UII in pancreatic beta cells, we have also studied the effects of two UII analogs that have previously been found to have either high or no contractile activity in a rat aortic ring assay (10). In addition, given that a number of insulinostatic peptides -somatostatin, amilin, galanin, pancreastatin -are present in pancreatic tissue (31), we have searched for the possible occurrence of UII in rat pancreatic extracts.…”

Section: Introductionmentioning

confidence: 99%

Urotensin-II is present in pancreatic extracts and inhibits insulin release in the perfused rat pancreas

Silvestre

Egido

Hernández

et al. 2004

European Journal of Endocrinology

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Objective: Previous work from our laboratory has demonstrated that frog urotensin-II (UII), at a high concentration, inhibits glucose-induced insulin release in the rat pancreas. We have investigated the effect of rat UII and two structural analogs on insulin secretion and searched for the presence of UII-immunoreactivity in rat pancreatic extracts. Methods: The study was performed in the perfused rat pancreas. UII as well as its analogs were synthesized by solid phase methodology. Pancreatic extracts were analyzed for UII by reversed-phase HPLC combined with a sensitive UII RIA. Results: Infusion of synthetic rat UII inhibited glucose-induced insulin release in a dose-dependent manner (IC 50 : 0.12 nmol/l). UII (1 nmol/l) also inhibited the insulin responses induced by carbachol, glucagon-like peptide-1, and a calcium channel agonist (BAY K 8644). The inhibitory effect of UII was mimicked by the potent G protein-coupled receptor (GPR14) agonist [3-iodo-Tyr 6 ]UII(4 -11). In contrast, [Ala 8 ]UII(4 -11), a UII analog devoid of contractile activity on rat aortic rings, did not affect glucose-induced insulin secretion. Analysis of rat pancreatic extracts revealed the presence of an immunoreactive peptide exhibiting the same retention time as synthetic rat UII.Conclusions: Our results demonstrate that UII is a potent insulinostatic peptide. The observation that UII is actually present in the pancreas suggests that this peptide may play a physiological role in the control of insulin secretion. Concerning the two UII analogs tested, only ]UII(4 -11), reportedly possessing GPR14-mediated contractile activity, mimics the insulinostatic effect of UII. This finding would support the view that UII acts on the pancreatic beta cell through the GPR14 receptor.European Journal of Endocrinology 151 803-809

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Structure–Activity Relationships of Human Urotensin II and Related Analogues on Rat Aortic Ring Contraction

Cited by 80 publications

References 44 publications

Renal haemodynamic and tubular actions of urotensin II in the rat

Renal haemodynamic and tubular actions of urotensin II in the rat

Role of urotensin II in health and disease

Urotensin-II is present in pancreatic extracts and inhibits insulin release in the perfused rat pancreas

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