Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have recently found that nonselective endothelin ETA/ETB receptor blockade markedly improves survival rate and ameliorates end-organ damage in male homozygous rats transgenic (TGR) for the mouse Ren-2 renin gene without lowering blood pressure. Because activation of the ETA receptor may be responsible for the detrimental effects of ET in the development of hypertension, this study was performed to determine whether ETA or ETA/ETB receptor blockade exerts these beneficial effects. TGR and age-matched normotensive Hannover Sprague-Dawley rats fed a high-salt diet received either vehicle or bosentan and atrasentan (ABT-627) as nonselective ETA/ETB and selective ETA receptor blockers, respectively, from 29 until 90 days of age. The survival rate of 48% in untreated TGR was significantly (P<0.01) improved to 79% by bosentan and to 92% by ABT-627 (ABT-627 versus bosentan P<0.05). Proteinuria, glomerulosclerosis, and cardiac hypertrophy, as well as ET-1 content in left ventricular tissue, were significantly reduced by bosentan and to a greater degree by ABT-627, which also significantly attenuated the rise in blood pressure (P<0.05). Our data indicate that the ET system, especially via ETA receptors, plays an important role in the development of hypertensive end-organ damage and confirm the concept that the predominant role of ETB receptors within the peripheral vasculature is to mediate the vasorelaxant actions of ET-1. They also demonstrate that selective blockade of ETA receptors is superior to nonselective ETA/ETB in attenuating hypertension, hypertensive organ damage, and survival rate.
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PMID:Early endothelin-A receptor blockade decreases blood pressure and ameliorates end-organ damage in homozygous Ren-2 rats. 1615 96

Term human fetal membranes express prorenin, a key enzyme within the renin-angiotensin system. High levels of another vasoactive peptide, endothelin-1 (ET-1), are found in human amniotic fluid. To address the question of the relationship between these two vasoactive systems, we analyzed the expression of the components of the ET-1 system in fetal membranes in which cell types had been identified using different markers. Immunohistochemistry was performed with antibodies raised against the human proteins of the ET system. Term fetal membranes displayed ubiquitous labeling of endothelin-converting enzyme-1 (ECE-1) and ET-1. ETA receptors were detected in the chorionic connective tissue and the attached decidua; ETB receptors were localized to chorionic trophoblast cells and decidua. The localization of the ET-1 receptor subtype was confirmed by in-situ receptor binding. Renin immunoreactivity was detected in the chorionic connective tissue and the decidua. These findings suggest that ET-1 is produced ubiquitously in human fetal membranes, and its targets may be, trophoblast cells following ETB receptor activation, vascular structures and fibroblasts in the connective tissue and decidua via ETA and ETB receptors. It appears possible that renin and ET may contribute to the pathophysiological changes associated with premature labor and preeclampsia.
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PMID:The endothelin system and renin in human fetal membranes. 1637 20

Activation of the renin-angiotensin system (RAS), with ensuing aldosterone excess, detrimentally affects outcome in patients with hypertension and heart failure (HF). RAS blockade with angiotensin (Ang) 1-converting enzyme inhibitors (ACEIs) or Ang II type 1 receptor blockers (ARBs) is beneficial in such conditions. However, aldosterone secretion can persist despite these treatments. Hence, mechanisms besides Ang II acquire the role of aldosterone secretagogue. The RALES and EPHESUS studies have shown that this aldosterone "escape" or "breakthrough" is an important factor, because it is a determinant of outcome in HF patients. Endothelin (ET)-1, which stimulates aldosterone secretion via both A (ETA) and B (ETB) receptor subtypes, and which is increased in HF, is a candidate for the "aldosterone breakthrough." Moreover, the novel ET peptide ET-1(1-31) is involved in adrenocortical growth. Therefore, findings suggesting a role for the ET-1 system as an aldosterone secretagogue, along with the potential usefulness of endothelin antagonists for the prevention of "aldosterone breakthrough," are discussed.
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PMID:Aldosterone breakthrough during RAS blockade: a role for endothelins and their antagonists? 1714 26

Endothelin-1 (ET-1) is a powerful vasoconstrictor and mitogen that contributes to blood pressure elevation and related vascular remodeling and target organ damage. ET-1 also influences salt and water homeostasis through effects on the renin-angiotensin-aldosterone system and vasopressin, thus elevating blood pressure and increasing vascular tone. Circulating ET-1 levels are elevated in a variety of animal models of hypertension, particularly those that are salt-dependent, and in a subset of human hypertensives, i.e. African-Americans and those with renal dysfunction. ET type B receptors, which normally have vasodilator functions, mediate vasoconstriction in some hypertensives, and hypertensive African-American patients may have increased numbers of vasoconstrictor ET-B receptors in their vascular smooth muscle. Whether selective ET-A or combined ET-A/ET-B receptor antagonists are more efficacious in treating hypertension and related cardiovascular disease is controversial. ET antagonists have only modest BP lowering effects in the general population of essential hypertensives, but show promise in patients with severe, treatment resistant hypertension.
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PMID:The role of endothelin-1 in human hypertension. 1764 6

Diabetic Nephropathy (DN) is a major chronic complication of diabetes mellitus (DM), and one of the main causes of new cases for dialysis, being associated with increasing mortality. The main risk factors for DN are hypertension, hyperglycemia, dyslipidemia, and genetic susceptibility. The renin-angiotensin system (RAS) plays an important role in genesis and progression of DN and there is evidence of an interrelationship between this system and the endothelins. Endothelins are powerful vasoconstrictor peptides and act as modulators of vasomotor tone, cell proliferation, and hormone production. These peptides act through two types of receptors (ET-A and ET-B) and are expressed on endothelial cells and vascular smooth-muscle cells. Activation of this receptor in renal cells leads to a complex signaling cascade resulting in stimulation of mesangial cell hypertrophy, proliferation, contraction, and extracellular matrix accumulation. These hemodynamic renal alterations are associated with the onset and progress of renal disease in DM. Elevated endothelin-1 (ET-1) levels have been reported in patients with DM. There is evidence suggesting that an increase in the production of ET-1 leads to glomerular damage. The use of ET receptor antagonists has been reported as renoprotective, correcting the early hemodynamic abnormalities in experimental DM, reinforcing the importance of this system in DN.
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PMID:[Endothelin system function in diabetic nephropathy]. 1860 70

The collecting duct (CD) endothelin (ET) system regulates blood pressure (BP) and Na excretion. CD-specific knockout (KO) of ET-1 causes hypertension, CD-specific KO of the ETA receptor does not alter BP, while CD-specific KO of the ETB receptor increases BP to a lesser extent than CD ET-1 KO. These findings suggest a paracrine role for CD-derived ET-1; however, they do not exclude compensation for the loss of one ET receptor by the other. To examine this, mice with CD-specific KO of both ETA and ETB receptors were generated (CD ETA/B KO). CD ETA/B KO mice excreted less urinary Na than controls during acute or chronic Na loading. Urinary aldosterone excretion and plasma renin concentration were similar during Na intake and both fell comparably during Na loading. On a normal sodium diet, CD ETA/B KO mice had increased BP, which increased further with high salt intake. The degree of BP elevation during normal Na intake was similar to CD ET-1 KO mice and higher than CD ETB KO animals. During 1 wk of Na loading, CD ETA/B KO mice had higher BPs than CD ETB KO, while BP was less than CD ET-1 KOs until the latter days of Na loading. These studies suggest that 1) CD ETA/B deficiency causes salt-sensitive hypertension, 2) CD ETA/B KO-associated Na retention is associated with failure to suppress the renin-angiotensin-aldosterone system, and 3) CD ETA and ETB receptors exerts a combined hypotensive effect that exceeds that of either receptor alone.
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PMID:Combined knockout of collecting duct endothelin A and B receptors causes hypertension and sodium retention. 1878 61

Endothelin is a potent vasoconstrictor substance that also can exert proliferative, inflammatory, and fibrotic changes in blood vessels and other organs. It acts on tissues in a paracrine and autocrine fashion, with local production and regulation occurring in both endothelial and nonendothelial cells. Endothelin stimulation of ETA and ETB receptors results in different and often opposing effects, which under physiologic conditions, establishes a balance that contributes to the regulation of vascular tone and blood pressure. Dysregulation of the endothelin system can induce or mediate endothelial dysfunction and organ damage in systemic hypertension (HTN), effects which may be ameliorated by endothelin antagonists. Endothelin receptor antagonists are currently being used in the treatment of pulmonary HTN. Both selective and dual-acting endothelin receptor blockers can also reduce systemic blood pressure in animal models and in hypertensive patients. Clinical trials evaluating the efficacy and safety of these agents are underway, and show potential as a new class of antihypertensives. Studies are also in progress with a single moiety dual angiotensin-endothelin A receptor antagonist, which is being evaluated in HTN. Issues that need to be addressed include the net contribution of endothelin in the pathophysiology of HTN, its interaction with other neurohormonal systems such as the renin-angiotensin-aldosterone system, and the clinical demonstration of the effect of endothelin receptor antagonism on end-organ damage in hypertensive patients.
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PMID:Endothelin as a clinical target in the treatment of systemic hypertension. 1952 80

It is now becoming clear that two major systems namely the sympathetic nervous system and the renin-angiotensin system are activated in response to ischemic injury; these result in the elevation of plasma catecholamines and angiotensin II during the development of myocardial infarction as well as congestive heart failure. Although plasma levels of several other hormones including aldosterone, endothelin, vasopressin, natriuretic peptides, growth factors and inflammatory cytokines are also increased in heart failure, their relationship with changes in catecholamine and/or angiotensin levels as well as their significance for the induction of congestive heart failure are poorly understood. In this article we have examined the evidence regarding the role of endothelin and vasopressin in the pathogenesis of cardiac hypertrophy and congestive heart failure in addition to evaluating the significance of their antagonism by using their receptor blockade for treatment of congestive heart failure. Endothelin appears to maintain blood pressure by its vasoconstricting action whereas vasopressin primarily produces similar effect by retention of body fluid. Myocardium is also known to express both ET-A and ET-B receptors in addition to V1 and V2 receptors for vasopressin, which have been shown to induce cardiac remodeling. Out of various ET-1 receptor antagonists, which are available, a non-selective endothelin receptor antagonist, bosentan, as well as an ET-A receptor antagonist, BQ-123, seem most promising for the treatment of congestive heart failure. Likewise, vasopressin antagonists such as a non-selective antagonist, conivaptan, as well as V2 selective antagonist, tolvaptan, may prove highly valuable for the therapy of this condition. Since most of the existing interventions are helpful in treating patients with congestive heart failure only partially, there appears to be a real challenge for developing some combination therapy for the treatment of congestive heart failure.
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PMID:Potential of endothelin-1 and vasopressin antagonists for the treatment of congestive heart failure. 1976 21

The prevalence of hypertension is increased in winter and in cold regions of the world. Cold temperatures make hypertension worse and trigger cardiovascular complications (stroke, myocardial infarction, heart failure, etc.). Chronic or intermittent exposure to cold causes hypertension and cardiac hypertrophy in animals. The purpose of this review is to provide the recent advances in the mechanistic investigation of cold-induced hypertension (CIH). Cold temperatures increase the activities of the sympathetic nervous system (SNS) and the renin-angiotensin system (RAS). The SNS initiates CIH via the RAS. Cold exposure suppresses the expression of eNOS and formation of NO, increases the production of endothelin-1 (ET-1), up-regulates ETA receptors, but down-regulates ETB receptors. The roles of these factors and their relations in CIH will be reviewed.
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PMID:Cardiovascular responses to cold exposure. 2003 96

ET (endothelin)-1 was first described as a potent vasoconstrictor. Since then, many other deleterious properties mediated via its two receptors, ETA and ETB, have been described, such as inflammation, fibrosis and hyperplasia. These effects, combined with a wide tissue distribution of the ET system, its up-regulation in pathological situations and a local autocrine/paracrine activity due to a high tissue receptor binding, make the tissue ET system a key local player in end-organ damage. Furthermore, ET-1 interacts in tissues with other systems such as the RAAS (renin-angiotensin-aldosterone system) to exert its effects. In numerous genetically modified animal models, non-specific or organ-targeted ET-1 overexpression causes intense organ damage, especially hypertrophy and fibrosis, in the absence of haemodynamic changes, confirming a local activity of the ET system. ET receptor antagonists have been shown to prevent and sometimes reverse these tissue alterations in an organ-specific manner, leading to long-term benefits and an improvement in survival in different animal models. Potential for such benefits going beyond a pure haemodynamic effect have also been suggested by clinical trial results in which ET receptor antagonism decreased the occurrence of new digital ulcers in patients with systemic sclerosis and delayed the time to clinical worsening in patients with PAH (pulmonary arterial hypertension). The tissue ET system allows therapeutic interventions to provide organ selectivity and beneficial effects in diseases associated with tissue inflammation, hypertrophy or fibrosis.
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PMID:At the heart of tissue: endothelin system and end-organ damage. 2071


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