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ET System (et + system)

Distribution by Scientific Domains

Medical Sciences	100%

Selected Abstracts

The science of endothelin-1 and endothelin receptor antagonists in the management of pulmonary arterial hypertension: current understanding and future studies

EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2009
N. J. Davie
Abstract Pathological vascular remodelling is a key contributor to the symptomatology of pulmonary arterial hypertension (PAH), and reversing this process may offer the best hope for improving this debilitating condition. The vascular remodelling process is believed to be due to endothelial cell dysfunction and to involve altered production of endothelial cell-derived vasoactive mediators. The observation that circulating plasma levels of the vasoactive peptide endothelin (ET)-1 are raised in patients with PAH, and that ET-1 production is increased in the pulmonary tissue of affected individuals, makes it a particularly interesting target for a therapeutic intervention in PAH. Clinical trials with ET receptor antagonists (ETRAs) show that they provide symptomatic benefit in patients with PAH, thereby proving the clinical relevance of the ET system as a therapeutic target. In this paper, we review the role of ET-1 together with the available data on the roles of the specific ET receptors and ETRAs in PAH. In particular, we discuss the possible role of ET receptor selectivity in the vascular remodelling process in PAH and whether selective ETA or nonselective ETA/ETB blockade offers the greatest potential to improve symptoms and alter the clinical course of the disease. [source]

Endothelin receptor selectivity in chronic kidney disease: rationale and review of recent evidence

EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2009
W. Neuhofer
Abstract Endothelin (ET) is a potent vasoconstrictory peptide with proinflammatory and profibrotic properties that exerts its biological effects through two pharmacologically distinct receptor subtypes, namely ETA and ETB. In addition to its substantial contribution to normal renal function, a large body of evidence suggests that derangement of the renal ET system is involved in the initiation and progression of chronic kidney disease (CKD) in diabetes, hypertension and glomerulonephritis. Thus, the use of ET receptor antagonists (ERAs) may offer potential novel treatment strategies in CKD. Recent literature on the role of the renal ET system in the healthy kidney was reviewed. In addition, an unbiased PubMed search was performed for studies published during the last 5 years that addressed the effects of ERAs in CKD. A particular objective was to extract information regarding whether selective or nonselective ERAs may have therapeutic potential in humans. ET-1 acts primarily as an autocrine or paracrine factor in the kidney. In normal physiology, ET-1 promotes diuresis and natriuresis by local production and action through ETB receptors in the renal medulla. In pathology, ET-1 mediates vasoconstriction, mesangial-cell proliferation, extracellular matrix production and inflammation, effects that are primarily conveyed by ETA receptors. Results obtained in animal models and in humans with the use of ERAs in CKD are encouraging; nevertheless, it is still under debate which receptor subtype should be targeted. According to most studies, selective inhibition of ETA receptors appears superior compared with nonselective ERAs because this approach does not interfere with the natriuretic, antihypertensive and ET clearance effects of ETB receptors. Although preliminary data in humans are promising, the potential role of ERAs in patients with CKD and the question of which receptor subtype should be targeted can only be clarified in randomized clinical trials. [source]

Hypercholesterolaemia induces early renal lesions characterized by upregulation of MMP-9 and iNOS and ETAR: alleviated by a dual endothelin receptor antagonist CPU0213 and simvastatin

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 6 2009
Lu Luo
Abstract Objectives We aimed to investigate hypercholesterolaemia-induced early renal lesions which result in abnormal expression of endothelin A receptor (ETAR), induced nitric oxide synthase (iNOS) and matrix metalloproteinase 9 (MMP-9). We hypothesized that this is due to an upregulated endothelin (ET) pathway consequent to hypercholesterolaemia and that CPU0213, a dual ET antagonist, could mitigate these changes. Methods Rats were randomly divided into four groups: (1), control; (2), high-fat diet for 60 days (HFD); HFD rats medicated in the last 15 days with either (3) CPU0213 (30 mg/kg daily, s.c.) or (4) simvastatin (4 mg/kg daily, p.o.). Key findings Body weight, serum triglycerides, total cholesterol and low-density-lipoprotein cholesterol were significantly increased, whereas high-density lipoprotein cholesterol decreased in the HFD group, relative to normal. Meanwhile, these changes were associated with upregulation of mRNA and protein of ETAR, iNOS and MMP-9 in the kidney. The lipid-lowering effect of simvastatin was predominant, lessening abnormal expression of these molecules in the kidney dramatically. Interestingly, CPU0213 significantly normalized expression of mRNA and protein of ETAR, iNOS and MMP-9, comparable with simvastatin, leaving no changes in hyperlipidaemia. Conclusions CPU0213 relieves renal lesions by blunting hypercholesterolaemia caused by the upregulated ET system, iNOS and MMP-9 in the kidney. This indicates that CPU0213 is promising in treating patients with end stage renal disease. [source]

Corresponding distributions of increased endothelin-B receptor expression and increased endothelin-1 expression in the aorta of apolipoprotein E-deficient mice with advanced atherosclerosis

PATHOLOGY INTERNATIONAL, Issue 12 2000
Tsutomu Kobayashi
Endothelin (ET)-1 causes proliferation of vascular smooth muscle cells (VSMC). Although it has been reported that stimulation of ETB receptors as well as ETA receptors promote proliferation of VSMC, the precise distribution of each receptor subtype in atherosclerotic vessels is unknown. Previous studies demonstrated that apolipoprotein E (apoE)-deficient mice have hypercholesterolaemia and develop severe atherosclerosis. To investigate the pathophysiological roles of vascular ET system in atherosclerosis, we examined preproET-1 messenger ribonucleic acid expression in the aorta of apoE-deficient mice, and performed immunohistochemical staining for ET-1 and each ET receptor subtype (ETA and ETB receptors) in the atherosclerotic lesions of these mice. The level of preproET-1 mRNA in the aorta was significantly higher in the apoE-deficient mice than in the control mice. Strong ET-1 staining was observed in the macrophage-foam cells, intimal and medial VSMC in the atherosclerotic lesions of the apoE-deficient mice. In addition, in the atherosclerotic lesions, strong ETB receptor staining was observed in the macrophage-foam cells, intimal and medial VSMC, which distribution corresponded closely to that of ET-1. ETA receptor staining was observed in the medial VSMC of both groups, but not in the macrophage-foam cells of the apoE-deficient mice. ETA receptor staining in the medial VSMC was stronger in the apoE-deficient mice than in the control mice. These results suggest that the vascular ET system, including ET-1 and ET receptors, is activated in the atherosclerotic lesions of apoE-deficient mice. Since the distribution of strong ETB receptor staining corresponded closely to that of ET-1, it is suggested that the ET system, mediated by ETB receptors, has an important role in the pathophysiology of the atherosclerotic lesions of apoE-deficient mice. [source]

UPREGULATED ENDOTHELIN SYSTEM IN DIABETIC VASCULAR DYSFUNCTION AND EARLY RETINOPATHY IS REVERSED BY CPU0213 AND TOTAL TRITERPENE ACIDS FROM FRUCTUS CORNI

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 12 2007
Wei Su
SUMMARY 1The aims of the present study were to examine whether: (i) upregulation of the endothelin (ET) pathway is involved in impairment of vascular relaxation and early retinopathy in diabetic rats; and (ii) vascular and retinal abnormalities respond to the total triterpene acid (TTA) isolated from Fructus Corni compared with responses to the novel endothelin receptor antagonist CPU0213 and aminoguanidine (AMG), a special antagonist for advanced glycation end-products (AGE) and inducible nitric oxide synthase (iNOS). 2Male Sprague-Dawley rats were randomized into five groups, namely a normal control and four diabetic groups, which included an untreated diabetic group and groups treated with AMG (100 mg/kg, i.g.), CPU0213 (30 mg/kg, s.c.) or TTA (50 mg/kg, i.g.). Diabetes was induced by single injection of streptozotocin (60 mg/kg, i.p.) on the 1st day. The mRNA expression of prepro-endothelin-1 (ppET-1), endothelin-converting enzyme (ECE) and iNOS in the thoracic aorta and mRNA for ETA receptors and iNOS in the retina were detected by reverse transcription,polymerase chain reaction. Vasorelaxation to acetylcholine (ACh) and functional assessment of nitric oxide (NO) bioavailability was determined in the thoracic aorta. 3We observed upregulated mRNA expression of iNOS, ppET-1 and ECE in the thoracic aorta and upregulated mRNA for the ETA receptor and iNOS in the retina in the untreated diabetic group. Vasodilatation mediated by ACh and NO bioavailability were markedly reduced in the thoracic aorta compared with the normal control group. These abnormalities were essentially reversed by TTA, CPU0213 or AMG, with the exception with that AMG did not modify vasodilatation to ACh. 4These data suggest that upregulation of gene transcription of the ET system mediates depressed vasorelaxation, NO bioavailability and changes in iNOS and ETA receptors that reflect early retinopathy in diabetic rats. Total triterpene acid, in terms of pharmacological properties resembling the endothelin receptor antagonist CPU0213, is effective in normalizing expression of the ET system and iNOS in early diabetic retinopathy and vasculaopathy. [source]