Impact of Classic Adrenal Secretagogues on mRNA Levels of Urotensin II and Its Receptor in Adrenal Gland of Rats.

Urotensin 2 (Uts2) is a biologically active peptide involved in the regulation of a variety of physiological and pathophysiological processes. In both the human and rat adrenal gland, the expressions of the Uts2 gene and its receptor (Uts2r) have been described. This paper focuses on the description of the hormonal control of the mRNA levels of urotensin II and its receptor in the adrenal gland of the rat, both in vitro and in vivo. The initial in vitro experiments were carried out on freshly isolated rat adrenocortical cells and their primary culture. The obtained results indicated a stimulating PKA-independent effect of ACTH on the Uts2 mRNA level in the tested cells, with no changes in the Uts2r transcript. Subsequent in vivo experiments showed that ACTH-induced adrenal growth was accompanied by an elevated level of the Uts2 mRNA, with unchanged expression of Uts2r. In the other types of in vivo gland growth studied, enucleation-induced adrenal regeneration and compensatory growth of the gland, the mRNA levels of the studied genes showed no significant differences. The only exception was hemiadrenalectomy, which led to a significant increase in Uts2 mRNA expression level 24 h after surgery. In 12-week-old rats of both sexes, gonadectomy led to a significant increase in the level of Uts2 mRNA in the adrenal gland, an effect that was prevented by sex hormones' replacement. No changes in Uts2r transcript levels were observed under these conditions. Thus, this study suggests that the regulation of Uts2 and Uts2r mRNA levels differs significantly in the rat adrenal gland. While Uts2 transcript levels appear to be mainly dependent on ACTH action, Uts2r mRNA levels are not under the control of this hormone.

An investigation of saliva and plasma levels of urotensin 2 in recently diagnosed type 2 diabetes mellitus patients on metformin treatment.

INTRODUCTION: Diabetes mellitus (DM) is a primary disease of the carbohydrate metabolism that is characterised by absolute or relative insulin deficiency, or insulin resistance. Although life expectancy is low for diabetic patients, the prognosis has been improved in recent decades. Metformin is an oral antidiabetic that reduces insulin resistance and plasma glucose levels by decreasing glucose production in the liver. It can be used as a standalone treatment or in combination with other antidiabetic medications or insulin. Urotensin 2 (U-II), which is one of the most effective known vasoconstrictor peptides, was observed to act as a vasoconstrictor in diseases such as hypertension and heart failure, and to induce vasodilation in healthy volunteers. Some studies have proposed that the activation of the U-II system could lead to metabolic syndrome. Certain studies have determined a link between DM and U-II. However, there exist no studies on the effects of U-II in recently diagnosed type 2 DM patients after metformin treatment. This study aims to investigate the plasma and saliva levels of U-II at diagnosis and after a three-month metformin treatment in recently diagnosed type 2 DM patients, and to compare these levels to those of healthy volunteers. MATERIAL AND METHODS: Our study compared 30 recently diagnosed type 2 DM patients to their states after three-month metformin treatment and 30 healthy volunteers. RESULTS: When compared with the control group, there was no significant increase in the plasma and saliva U-II levels of recently diagnosed type 2 DM patients. We determined a statistically significant increase in the plasma and saliva ureotensin-2 levels of recently diagnosed type 2 DM patients after a three-month metformin treatment (p < 0.05). CONCLUSIONS: It was concluded that the patients with type 2 DM have a multifactorial aetiopathogenesis and an increase in U-II levels after metformin treatment. Metformin has no known effect on the U-II metabolism; therefore, the findings need confirmation through more clinical and experimental studies with more participants.

Effect of the urotensin receptor antagonist palosuran in hypertensive patients with type 2 diabetic nephropathy.

The urotensin system has been hypothesized to play an important role in the pathophysiology of diabetic nephropathy. In this multicenter, randomized, double-blind, placebo-controlled, 2-period crossover study, the effects of the urotensin receptor antagonist palosuran on urinary albumin excretion and blood pressure in hypertensive patients with type 2 diabetic nephropathy treated with a single blocker of the renin-angiotensin-aldosterone system were assessed. Patients with 24-hour albuminuria >0.5 and <3.0 g, systolic blood pressure >135 and <170 mm Hg, and/or diastolic blood pressure >85 and <110 mm Hg received both palosuran 125 mg BID and placebo for 4 weeks each. Fifty-four patients (20% women; mean age: 61.6 years, blood pressure: 155/84 mm Hg, and albuminuria: 1016 mg per 24 hours) were included in the per-protocol analysis. Palosuran did not affect albuminuria, blood pressure, glomerular filtration rate, or renal plasma flow significantly. These results question whether urotensin receptor antagonism represents a new treatment strategy in this high-risk patient population.

The effects of urotensin II and urantide on forearm blood flow and systemic haemodynamics in humans.

AIMS: (i) To compare the effects of intra-arterial administration of urotensin II in patients with CVD with healthy volunteers, and (ii) to study the haemodynamic effects of intra-arterial infusion of the urotensin II receptor antagonist, urantide. METHODS: Ten healthy volunteers and 10 patients with CVD received a dose-ramped brachial artery infusion of urotensin II. A further six healthy male volunteers received a prolonged urotensin II infusion and 11 healthy male volunteers received a dose-ramped infusion of urantide. Forearm blood flow (FBF) was measured every 20 min and blood pressure and heart rate were assessed every 20 min. RESULTS: In healthy volunteers and patients with CVD, intra-arterial infusion of urotensin II had no effect on FBF ratio. A dose-ramped infusion of urantide similarly had no effect on FBF ratio. During dose-ramped infusions of urotensin II and urantide, systolic and mean arterial blood pressure increased significantly. In healthy volunteers, urotensin II and urantide, respectively, increased systolic blood pressure from 133 +/- 6 to 137 +/- 5 mmHg (P < 0.01) and from 113 +/- 4 to 120 +/- 4 mmHg (P < 0.01). In patients with CVD, heart rate also significantly increased during dose-ramped infusion of urotensin II from 59 +/- 3 to 62 +/- 4 bpm (P < 0.05). CONCLUSIONS: We have shown no in vivo effect of urotensin II or urantide on human forearm resistance vessels. Previous discrepancies do not seem to relate to either the age or CVD status of subjects. Changes in systemic cardiovascular haemodynamics during the dose-ramped infusion studies are unlikely to be caused by urotensin II receptor modulation.

Palosuran inhibits binding to primate UT receptors in cell membranes but demonstrates differential activity in intact cells and vascular tissues.

BACKGROUND AND PURPOSE: The recent development of the UT ligand palosuran (1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea sulphate salt) has led to the proposition that urotensin-II (U-II) plays a significant pathological role in acute and chronic renal injury in the rat. EXPERIMENTAL APPROACH: In the present study, the pharmacological properties of palosuran were investigated further using a series of radioligand binding and functional bioassays. KEY RESULTS: Palosuran functioned as a 'primate-selective' UT ligand in recombinant cell membranes (monkey and human UT K(i) values of 4 +/- 1 and 5 +/- 1 nM), lacking appreciable affinity at other mammalian UT isoforms (rodent and feline K(i) values >1 microM). Paradoxically, however, palosuran lost significant (10- to 54-fold) affinity for native and recombinant human UT when radioligand binding was performed in intact cells (K(i) values of 50 +/- 3 and 276 +/- 67 nM). In accordance, palosuran also exhibited diminished activity in hUT (human urotensin-II receptor)-CHO (Chinese hamster ovary) cells (IC50 323 +/- 67 nM) and isolated arteries (K(b)>10 microM in rat aorta; K(b)>8.5 microM in cat arteries; K(b)>1.6 microM in monkey arteries; K(b) 2.2 +/- 0.6 microM in hUT transgenic mouse aorta). Relative to recombinant binding K(i) values, palosuran was subjected to a 392- to 690-fold reduction in functional activity in monkey isolated arteries. Such phenomena were peculiar to palosuran and were not apparent with an alternative chemotype, SB-657510 (2-bromo-N-[4-chloro-3-((R)-1-methyl-pyrrolidin-3-yloxy)-phenyl]-4,5-dimethoxybenzenesulphonamide HCl). CONCLUSIONS AND IMPLICATIONS: Collectively, such findings suggest that caution should be taken when interpreting data generated using palosuran. The loss of UT affinity/activity observed in intact cells and tissues cf. membranes offers a potential explanation for the disappointing clinical efficacy reported with palosuran in diabetic nephropathy patients. As such, the (patho)physiological significance of U-II in diabetic renal dysfunction remains uncertain.

Therapeutic potential of blockade of the urotensin II system in systemic hypertension.

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.