Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have revealed the importance of fish-derived peptide hormones to human endocrinology. These peptides include melanin-concentrating hormone (MCH), urocortins (human urotensin-I), and urotensin-II. MCH, a hypothalamic peptide, is a potent stimulator on appetite. Urocortins, e.g. urocortin 1 and urocortin 3 (stresscopin), are endogenous ligands for the corticotropin-releasing factor (CRF) receptors, particularly CRF type 2 receptor, that mediates a vasodilator action, a positive inotropic action and a central appetite-inhibiting action. These actions mediated by CRF type 2 receptor may ameliorate the stress response. Human urotensin-II is a potent vasoconstrictor peptide, while it acts as a vasodilator on some arteries. Human urotensin-II is expressed in various types of cells and tissues, including cardiovascular tissues, as well as many types of tumor cells. Thus, these fish-derived peptides appear to play important roles in human physiology, such as appetite regulation, stress response and cardiovascular regulation, and also in diseases, for example, obesity, cardiovascular diseases and tumors. Development of antagonists/agonists against the receptors for these peptides may open new strategies for the treatment of various diseases, including obesity-related diseases, hypertension, heart failure and malignant tumors.
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PMID:Translational medicine in fish-derived peptides: from fish endocrinology to human physiology and diseases. 1500 3

The pronounced pharmacodynamic effects of human urotensin-II (U-II), a 'somatostatin-like' cyclic undecapeptide, are mediated via the G protein-coupled receptor UT (formerly known as GPR14). Emerging clinical studies implicate U-II in the etiology of several cardiorenal and metabolic disease states in humans. Although the specific pathogenic role(s) of U-II remain to be clearly defined, existing data warrant further clinical investigation. The therapeutic development of specific U-II/UT inhibitors will assist in establishing a causative role for U-II in the progression and/or maintenance of hypertension, heart failure, renal tubular disease and diabetes.
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PMID:Urotensin-II as a novel therapeutic target in the clinical management of cardiorenal disease. 1508 93

The identification of a human homolog of urotensin-II (U-II) and a novel, specific G-protein-coupled receptor by Ames et al. in 1999 changed the perception that the U-II isopeptide family was an esoteric collection of 'somatostatin-like neuropeptides' present only in the nervous systems of an eclectic array of aquatic invertebrates, fish and amphibians. In this article, we review recent developments in the pharmacology of human U-II, focusing on the actions of this peptide in the mammalian cardiorenal system. The putative role of U-II in the etiology of hypertension, heart failure, renal dysfunction and diabetes is discussed, as are novel U-II receptor antagonists.
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PMID:From 'gills to pills': urotensin-II as a regulator of mammalian cardiorenal function. 1510 93

Aortae taken from spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats aged 4, 8 and 16 weeks were prepared as rings and used to measure the effects of five vasoconstrictors. The endothelium was removed in order to measure selectively the contractile responses induced by potassium chloride (KCl), phenylephrine (PHE), angiotensin-II (Ang II), endothelin-1 (ET-1) and human urotensin-II (U-II). These responses were assumed to derive from the activation of specific receptors (namely alpha1, AT1, ETA and UT-II) or from depolarization of the smooth muscle fibers by KCl. Specific antagonists prazosin, losartan, BQ-123 and [Orn8]-UII were used at various concentrations for a pharmacological characterization of these latter receptor systems. The primary purpose of the study was to explore mechanisms or factors that may intervene in the development and maintenance of high blood pressure in SHR. Results indicate that isolated aortae of SHR and WKY contain contractile sites (receptors) whose pharmacological profiles (pEC50 for agonists, pA2 for antagonists) are very similar to those of other biological systems and should be considered as typical for the alpha1, AT1, ETA and UT-II receptor types. Aortae taken from SHR 4 (non hypertensive), 8 and 16 weeks old (hypertensive) responded to the vasoconstrictors with reduced maximal contractions compared to those of age-matched WKY. These unexpected reduced responses of aortae, observed with the five vasoconstrictors, may be attributed to a non specific lesions. Maximal contraction of aortae from SHR increased from 4 to 16 weeks for KCI, PHE and U-II, decreased for Ang II, and remained stable for ET-1. There was also an age-dependent increase of maximal contraction induced by U-II in WKY. It is suggested that aortae from SHR undergo early remodelling that leads to reduced contractility in vitro and possibly to vessel rigidity in vivo. The factors involved in this process appear to be of genetic origin since they are present before hypertension: they may contribute to modify aortic compliance and perhaps vascular resistance in hypertensive animals and thus being the cause and not the consequence of high blood pressure.
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PMID:Contractile responses of aortae from WKY and SHR to vasoconstrictors. 1555 54

Urotensin-II (U-II), acting through its G-protein-coupled receptor, UT, is a possible contributor to hypertension. Variable functional responses to U-II, both within and between species studied to date, complicate the characterization of UT antagonists. In the cat, however, U-II causes systemic hypertension and constricts arterial segments isolated from several vascular beds. The purpose of this study was to clone and pharmacologically characterize cat recombinant UT to determine whether this system represents a model for characterizing UT antagonists. Cloned cat UT displayed 74% identity to primate UT, and 77% identity to rodent UT. [(125)I] hU-II bound in a saturable manner to a single site on recombinant cat UT with high affinity (K(D) 288+/-13pM) and high density (B(max) 747+/-66fmol/mg protein). U-II isopeptides displayed equipotent, high affinity binding to cat UT (K(i) 1.8-5.3nM). Cat UT was coupled to intracellular [Ca(2+)] release (EC(50) 0.6+/-0.2nM) and total inositol phosphate (IP) formation (EC(50) 0.4+/-0.1nM). Protein kinase C activation desensitized cat, but not human, UT-mediated IP formation. UT mRNA expression was detected in cat blood vessels, trachea, lung, and kidney, where the medulla (K(D) 815+/-34) and cortex and (K(D) 316+/-39pM) displayed high affinity binding for human U-II (hU-II). The cat urotensin-II receptor represents a suitable in vitro model to examine the role of the U-II/UT system in the etiology of hypertension, assisting in the evaluation of the UT antagonists to help treat cardiovascular disease.
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PMID:Cloning and pharmacological characterization of the cat urotensin-II receptor (UT). 1576 43

The vascular system is rich in G-protein-coupled receptors (GPCRs), particularly Class 1 GPCRs, which are activated by an eclectic range of chemical entities including peptides. These chemical messengers can function in blood vessels as directly acting vasoconstrictors, directly acting vasodilators or indirectly acting vasodilators. During the past ten years >50 receptors previously designated as 'orphan receptors' have been paired with their cognate ligands. New transmitter systems are emerging with some displaying potent activity in the vascular system, including the vasoconstrictors apelin, motilin, neuromedin U, sphingosine-1-phosphate and urotensin-II, and the vasodilators ghrelin and nociceptin. All Class 2 GPCRs are activated by peptides. Those displaying vasoactivity all function as directly acting vasodilators and include adrenomedullin and the emerging urocortin transmitters. Hypertension can persist despite treatment with combinations of blood-pressure-lowering drugs. Thus, it is likely that further as yet undiscovered transmitter systems will provide new targets for novel therapies or diagnosis.
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PMID:Regulation of vascular reactivity by established and emerging GPCRs. 1605 40

Urotensin-II (U-II) receptors are widely distributed in the central nervous system. Intracerebroventricular (i.c.v.) injection of U-II causes hypertension and bradycardia and stimulates prolactin and thyrotropin secretion. However, the behavioral effects of centrally administered U-II have received little attention. In the present study, we tested the effects of i.c.v. injections of U-II on behavioral, metabolic, and endocrine responses in mice. Administration of graded doses of U-II (1-10,000 ng/mouse) provoked: (1) a dose-dependent reduction in the number of head dips in the hole-board test; (2) a dose-dependent reduction in the number of entries in the white chamber in the black-and-white compartment test, and in the number of entries in the central platform and open arms in the plus-maze test; and (3) a dose-dependent increase in the duration of immobility in the forced-swimming test and tail suspension test. Intracerebroventricular injection of U-II also caused an increase in: food intake at doses of 100 and 1,000 ng/mouse, water intake at doses of 100-10,000 ng/mouse, and horizontal locomotion activity at a dose of 10,000 ng/mouse. Whatever was the dose, the central administration of U-II had no effect on body temperature, nociception, apomorphine-induced penile erection and climbing behavior, and stress-induced plasma corticosterone level. Taken together, the present study demonstrates that the central injection of U-II at doses of 1-10,000 ng/mouse induces anxiogenic- and depressant-like effects in mouse. These data suggest that U-II may be involved in some aspects of psychiatric disorders.
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PMID:Behavioral effects of urotensin-II centrally administered in mice. 1616 Aug 78

We studied single nucleotide polymorphisms (SNPs) and haplotypes in the urotensin-II (UTS2) and urotensin-II receptor gene (UTS2R) in Hong Kong Chinese (224 hypertensive and 306 normotensive unrelated subjects) and their relation to hypertension and the metabolic syndrome. For UTS2, the GGT haplotype (-605G, 143G and 3836T) was associated with higher plasma level of U-II and insulin, and higher homeostasis model assessment of insulin resistance index and beta-cell function. For UTS2R, the AC haplotype (-11640A and -8515C) was associated with higher 2 h plasma glucose after a 75 g oral glucose load. Therefore, U-II and its receptor may play a role in insulin resistance.
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PMID:Haplotypes in the urotensin II gene and urotensin II receptor gene are associated with insulin resistance and impaired glucose tolerance. 1659 76

Human urotensin-II (U-II) is the most potent vasoactive peptide identified to date, and may be involved in hypertension and atherosclerosis. We investigated the effects of the interactions between U-II or other vasoactive agents and mildly oxidized low-density lipoprotein (mox-LDL) or hydrogen peroxide (H2O2) on the induction of vascular smooth muscle cell (VSMC) proliferation. Growth-arrested rabbit VSMCs were incubated with vasoactive agents (U-II, endothelin-1, angiotensin-II, serotonin, or thromboxane-A2) in the presence or absence of mox-LDL or H2O2. [3H]Thymidine incorporation into DNA was measured as an index of VSMC proliferation. On interaction with mox-LDL or H2O2, U-II induced the greatest increase in [3H]thymidine incorporation among these vasoactive agents. A low concentration of U-II (10 nmol/l) enhanced the potential mitogenic effect of low concentrations of mox-LDL (120 to 337%) and H2O2 (177 to 226%). U-II at 50 nmol/l showed the maximal mitogenic effect (161%), which was abolished by G protein inactivator (GDP-beta-S), c-Src tyrosine kinase inhibitor (radicicol), protein kinase C (PKC) inhibitor (Ro31-8220), extracellular signal-regulated kinase (ERK) kinase inhibitor (PD98059), or Rho kinase inhibitor (Y27632). Mox-LDL at 5 microg/ml showed the maximal mitogenic effect (211%), which was inhibited by free radical scavenger (catalase), intracellular and extracellular antioxidants (N-acetylcysteine and probucol), nicotinamide adenine dinucleotide phosphate oxidase inhibitor (diphenylene iodonium), or c-Jun N-terminal kinase (JNK) inhibitor (SP600125). These results suggested that U-II acts in synergy with mox-LDL in inducing VSMC DNA synthesis at the highest rate among these vasoactive agents. Activation of the G protein/c-Src/PKC/ERK and Rho kinase pathways by U-II together with the redox-sensitive JNK pathway by mox-LDL may explain the synergistic interaction between these agents.
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PMID:Human urotensin-II potentiates the mitogenic effect of mildly oxidized low-density lipoprotein on vascular smooth muscle cells: comparison with other vasoactive agents and hydrogen peroxide. 1728 70

Salusin-alpha is a new bioactive peptide with mild hypotensive and bradycardic effects. Our recent study showed that salusin-alpha suppresses foam cell formation in human monocyte-derived macrophages by down-regulating acyl-CoA:cholesterol acyltransferase-1, contributing to its anti-atherosclerotic effect. To clarify the clinical implications of salusin-alpha in hypertension and its complications, we examined the relationship between serum salusin-alpha levels and carotid atherosclerosis in hypertensive patients. The intima-media thickness (IMT) and plaque score in the carotid artery, blood pressure, serum levels of salusin-alpha, and atherosclerotic parameters were determined in 70 patients with essential hypertension and in 20 normotensive controls. There were no significant differences in age, gender, body mass index, fasting plasma glucose level, or serum levels of high-sensitive C-reactive protein, high- or low-density lipoprotein (LDL) cholesterol, small dense LDL, triglycerides, lipoprotein(a), or insulin between the two groups. Serum salusin-alpha levels were significantly lower in hypertensive patients than in normotensive controls. The plasma urotensin-II level, maximal IMT, plaque score, systolic and diastolic blood pressure, and homeostasis model assessment for insulin resistance (HOMA-IR) were significantly greater in hypertensive patients than in normotensive controls. In all subjects, maximal IMT was significantly correlated with age, systolic blood pressure, LDL cholesterol, urotensin-II, salusin-alpha, and HOMA-IR. Forward stepwise multiple linear regression analysis revealed that salusin-alpha levels had a significantly independent and negative association with maximal IMT. Serum salusin-alpha levels were significantly lower in accordance with the severity of plaque score. Our results suggest that the decrease in serum salusin-alpha, an anti-atherogenic peptide, may be associated with carotid atherosclerosis in hypertensive patients.
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PMID:Serum salusin-alpha levels are decreased and correlated negatively with carotid atherosclerosis in essential hypertensive patients. 1849 65


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