Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0035078 (renal failure)
 31,970 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This fifth international conference on ET serves to underline the rapid pace of development of our understanding of the very versatile ET system. On the one hand, the body uses ETs at several stages in embryonic development, in normal postnatal growth, and in cardiovascular homeostasis under healthy conditions. On the other hand, overwhelming evidence now exists that ET-1 plays important pathophysiological roles in conditions of decompensated vascular homeostasis. Indeed, in CHF this evidence is sufficient to justify the large-scale studies of morbidity and mortality needed to market ET antagonists as medicines. Other potentially important cardiovascular indications for ET antagonists are still emerging--including hypertension, stroke, subarachnoid haemorrhage and renal failure--and all are likely to be the subject of clinical trials over the next few years. As yet, there has been little work outside the cardiovascular and renal fields, but other areas, such as cancer treatment, may also prove promising. New molecules with increasing selectivity (ETA and ETB) continue to emerge and may be valuable. Inhibition of ECE-1 remains as an alternative approach and nonpeptide ECE inhibitors now exist. There appears to be a consensus that ETA blockade is beneficial in cardiovascular and renal disease. However, several strands of work presented at the meeting--the hypertensive salt-sensitive phenotype of rescued ETB knockout mice, the sustained and progressive hypertensive effects of ETB-selective antagonism in rats, ETB-mediated vasodilatation and natriuresis in dogs, and nitric oxide-dependent ETB-mediated vasodilatation in humans--all suggest that ETB-mediated vascular and renal responses may be protective. The development of selective ETA antagonists, therefore, now seems fully justified. In the future, direct comparisons in animal models, and patients, of ETA and ETA/B antagonists will be important in determining the value of additional ETB receptor blockade in individual diseases.
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PMID:Endothelin: new discoveries and rapid progress in the clinic. 950 92

Endothelin-1 (ET-1) is the most potent vasoconstrictor yet described. The active 21-amino-acid peptide is derived from the conversion of the inactive precursor "Big ET-1" by an enzyme called endothelin-converting enzyme. In addition to its potent action as a vasoconstrictor, endothelin promotes growth and proliferation of smooth muscle and myocardial hypertrophy. ET-1 levels are elevated in acute myocardial infarction (MI), atherosclerosis, renal failure, diabetes, pulmonary hypertension, and congestive heart failure (CHF). ET-1 levels correlate extremely well with the seriousness of the pathophysiologic condition. ET-1 levels at 72 h post MI accurately predict long-term survival. In patients with heart failure, ET-1 levels also predict long-term outcome, with the prognosis being severely compromised in patients with elevated ET-1 levels. Levels of plasma big ET-1 have been demonstrated to predict 1-year mortality and have been shown to be a better predictor of 1-year outcome than plasma atrial natriuretic peptide and norepinephrine, NYHA class, age, and echocardiographic left ventricular parameters. Although a small number of studies have reported beneficial effects of ACE inhibitors on ET-1 levels in animal models, most reports in humans have not found an effect of ACE inhibitors on ET-1 levels. Only one ACE inhibitor, fosinopril, has been shown to be effective in normalizing ET-1 levels in clinically relevant situations, such as the long-term study of patients with CHF. This observation may point to a superior role of fosinopril compared with other ACE inhibitors in CHF patients and may indicate beneficial effects of fosinopril beyond blood pressure control.
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PMID:Neurohormonal markers of clinical outcome in cardiovascular disease: is endothelin the best one? 973 39

The 21-amino acid peptide endothelin-1 (ET-1) is the predominant isoform of the endothelin peptide family, which includes ET-2, ET-3, and ET-4. It exerts various biological effects, including vasoconstriction and the stimulation of cell proliferation in tissues both within and outside of the cardiovascular system. ET-1 is synthesized by endothelin-converting enzymes (ECE), chymases, and non-ECE metalloproteases; it is regulated in an autocrine fashion in vascular and nonvascular cells. ET-1 acts through the activation of G(i)-protein-coupled receptors. ET(A) receptors mediate vasoconstriction and cell proliferation, whereas ET(B) receptors are important for the clearance of ET-1, endothelial cell survival, the release of nitric oxide and prostacyclin, and the inhibition of ECE-1. ET is activated in hypertension, atherosclerosis, restenosis, heart failure, idiopathic cardiomyopathy, and renal failure. Tissue concentrations more reliably reflect the activation of the ET system because increased vascular ET-1 levels occur in the absence of changes in plasma. Experimental studies using molecular and pharmacological inhibition of the ET system and the first clinical trials have demonstrated that ET-1 takes part in normal cardiovascular homeostasis. Thus, ET-1 plays a major role in the functional and structural changes observed in arterial and pulmonary hypertension, glomerulosclerosis, atherosclerosis, and heart failure, mainly through pressure-independent mechanisms. ET antagonists are promising new agents in the treatment of cardiovascular diseases.
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PMID:Endothelins and endothelin receptor antagonists: therapeutic considerations for a novel class of cardiovascular drugs. 1106

Endothelin (ET)-1, a 21-amino acid peptide, is the predominant isoform of the endothelin peptide family. ET-1 is ubiquitously expressed and stimulates vasoconstriction and cell proliferation. Enzymes such as endothelin converting enzymes (ECE), chymases, and non-ECE metalloproteinases contribute to the synthesis of ET-1, which is regulated in an autocrine fashion in vascular and nonvascular cells. Endothelin ET(A) receptors mediate vasoconstriction and cell proliferation, whereas ET(B) receptors are involved in the clearance of ET-1, inhibition of endothelial apoptosis, release of nitric oxide and prostacyclin, and inhibition of ECE-1 expression. Most cardiovascular diseases, such as arterial hypertension, atherosclerosis, restenosis, heart failure, idiopathic cardiomyopathy, pulmonary hypertension, and renal failure are associated with local activation of the endothelin system. Experimental studies and first clinical trials suggest that ET-1 is importantly involved in the functional and structural changes in the cardiovascular system, and that many of the actions of ET-1 are mediated through pressure-independent mechanisms. Endothelin antagonists promise to be successful as a new class of drugs for the treatment of cardiovascular diseases.
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PMID:The therapeutic potential of endothelin receptor antagonists in cardiovascular disease. 1147 15

Endothelins (ETs) are potent vasoconstrictors, promitogens, and inflammatory mediators. They have been implicated in the pathogenesis of various cardiovascular, renal, pulmonary, and central nervous system diseases. Since the final step of the biosynthesis of ETs is catalyzed by a family of endothelin-converting enzymes (ECEs), inhibitors of these enzymes may represent novel therapeutic agents. Currently, seven isoforms of these metalloproteases have been identified; they all share a significant amino acid sequence identity with neutral endopeptidase 24.11 (NEP), another metalloprotease. Therefore, it is not surprising that the majority of ECE inhibitors also possess potent NEP inhibitory activity. To date, three classes of ECE inhibitors have been synthesized: dual ECE/NEP inhibitors, triple ECE/NEP/ACE inhibitors, and selective ECE inhibitors. Potential clinical applications of these compounds in hypertension, chronic heart failure, restenosis, renal failure, and cerebral vasospasm deduced from studies with relevant animal models are reviewed.
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PMID:Nonpeptidic endothelin-converting enzyme inhibitors and their potential therapeutic applications. 1205 51

We tested the hypothesis that endothelin-converting enzyme (ECE) inhibition ameliorates end-organ damage in rats harboring both human renin and human angiotensinogen genes (dTGR). Hypertension develops in the animals, and they die by age 7 weeks of heart and kidney failure. Three groups were studied: dTGR (n=12) receiving vehicle, dTGR receiving ECE inhibitor (RO0687629; 30 mg/kg by gavage; n=10), and Sprague-Dawley control rats (SD; n=10) receiving vehicle, all after week 4, with euthanasia at week 7. Systolic blood pressure was not reduced by ECE inhibitor compared with dTGR (205+/-6 versus 206+/-6 mm Hg at week 7, respectively). In contrast, ECE inhibitor treatment significantly reduced mortality rate to 20% (2 of 10), whereas untreated dTGR had a 52% mortality rate (7 of 12). ECE inhibitor treatment ameliorated cardiac damage and reduced left ventricular ECE activity below SD levels. Echocardiography at week 7 showed reduced cardiac hypertrophy (4.8+/-0.2 versus 5.7+/-0.2 mg/g, P<0.01) and increased left ventricular cavity diameter (5.5+/-0.3 versus 3.1+/-0.1 mm, P<0.001) and filling volume (0.42+/-0.04 versus 0.16+/-0.06 mL, P<0.05) after ECE inhibitor compared with untreated dTGR. ECE inhibitor treatment also reduced cardiac fibrosis, tissue factor expression, left ventricular basic fibroblast growth factor mRNA levels, and immunostaining in the vessel wall, independent of high blood pressure. In contrast, the ECE inhibitor treatment showed no renoprotective effect. These data are the first to show that ECE inhibition reduces angiotensin II-induced cardiac damage.
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PMID:Endothelin-converting enzyme inhibition ameliorates angiotensin II-induced cardiac damage. 1246 67

Endothelin-1 (ET-1) exerts multiple biological effects, including vasoconstriction and the stimulation of cell proliferation in tissues both within and outside of the cardiovascular system. ET-1 is synthesized by ET-converting enzymes (ECE), chymases (CMAs), and non-ECE metalloproteases through a process regulated in an autocrine fashion in vascular and nonvascular cells. ET-1 acts through the activation of G(i)protein-coupled receptors. ET(A) receptors mediate vasoconstriction and cell proliferation, whereas ET(B) receptors are important for aldosterone secretion, endothelial cell (EC) migration, the release of nitric oxide (NO) and prostacyclin, the clearance of ET-1, and the inhibition of ECE-1. ET is activated in scleroderma, hypertension, atherosclerosis, restenosis, heart failure, idiopathic cardiomyopathy, and renal failure. Tissue concentrations more reliably reflect the activation of the ET system because of the predominantly abluminal secretion of the peptide. Experimental studies and clinical trials have demonstrated that ET-1 plays a major role in normal cardiovascular homeostasis and in the functional and structural changes observed in arterial and pulmonary hypertension, glomerulosclerosis, atherosclerosis, and heart failure. Accordingly, ET antagonists are promising new agents in the treatment of cardiovascular diseases. Single nucleotide polymorphisms (SNPs) of the genes of preproET-1, ECE-1, CMA, ET(A) and ET(B) receptors have been identified and can be important for their functional regulation. However, for most of them the association with disease conditions and the evidence for a functional role remain controversial. Thus, even though ET antagonists are being used for the treatment of pulmonary hypertension, there is no convincing evidence for a role of SNPs in affecting the therapeutic strategies.
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PMID:Genetic variation in the endothelin system: do polymorphisms affect the therapeutic strategies? 1685 33

Inhibition of the metalloprotease ECE-1 may be beneficial for the treatment of coronary heart disease, cancer, renal failure, and urological disorders. A novel class of indole-based ECE inhibitors was identified by high throughput screening. Optimization of the original screening lead structure 6 led to highly potent inhibitors such as 11, which bears a bisaryl amide moiety linked to the indole C2 position through an amide group. Docking of 11 into a model structure of ECE revealed a unique binding mode in which the Zn center of the enzyme is not directly addressed by the inhibitor, but key interactions are suggested for the central amide group. Testing of the lead compound 6 in hypertensive Dahl S rats resulted in a decrease in blood pressure after an initial period in which the blood pressure remained unchanged, most probably the result of ET-1 already present. Indole derivative 6 also displays a cardio-protective effect in a mouse model of acute myocardial infarction after oral administration. The more potent chloropyridine derivative 9 antagonizes big-ET-1-induced increase in blood pressure in rats at intravenous administration of 3 mg kg-1. All ECE inhibitors of the indole class showed high selectivity for ECE over related metalloproteases such as NEP and ACE. Therefore, these compounds might have further potential as drugs for the treatment of coronary heart diseases.
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PMID:Selective indole-based ECE inhibitors: synthesis and pharmacological evaluation. 1689 41

Endothelin-converting enzyme I (ECE-1) is a mammalian type II integral membrane zinc-containing endopeptidase. ECE-1 catalyzes the final step in the biosynthesis of endothelins in a rate-limiting fashion, through post-translational conversion of the biologically inactive big endothelins. Endothelin-1 overproduction has been implicated in a heterogeneous list of diseases including systemic and pulmonary hypertension, stroke and asthma, cardiac and renal failure. Therefore, ECE-1 is a prime therapeutic target for the regulation of endothelin-1 production in vivo and there is considerable interest in selective inhibitors of this enzyme. Here, we present the crystal structure of the extracellular domain (residues 90-770) of human ECE-1 (C428S) with the generic metalloprotease inhibitor phosphoramidon determined at 2.38 A resolution. The structure is closely related to that of human NEP, providing essential information for a detailed understanding of ligand-binding, specificity determinants as well as selectivity criteria. Selective inhibitors of ECE-1s should have beneficial effects for the treatment of diseases in which an overproduction of ETs plays a pathogenic role.
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PMID:Structure of human endothelin-converting enzyme I complexed with phosphoramidon. 1899 53