Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelins (ET) comprise a group of substances which are produced and have a regulatory function in different systems of the organism. The main cardiovascular ET is ET-1 which is so far the most potent vasoconstrictor substance. ET is important in the early stages of atherosclerosis as it is a strong chemical attractant of monocytes and macrophages and causes endothelial and vasomotor dysfunction. In later stages of atherosclerosis it can affect the firmness and integrity of the fibrous part of the atherosclerotic plaque. During myocardial infarction the ET level rises and this leads to vasoconstriction and reduction of the fibrillation threshold. In coronary angioplasty (PTCA) the ET-1 level rises depending on the applied mechanical stress. ET can participate in the formation of the neointima and the development of restenosis. ET increases also immediately after an aortocoronary bypass (CABG) and after reperfusion. Higher ET levels were found in patients with a positive ECG and echocardiographic loading test. In the latter after CABG normalization of ET was found. Raised ET levels were recorded also in patients where a coronary vasospasm can be provoked, in Prinzmetal's angina pectoris, coronary syndrome X, atrial tachystimulation. In unstable angina pectoris big-ET is elevated, the increase of the ET-1 level is not unequivocal. Stable angina pectoris does not affect ET-1. In the treatment of atherosclerosis for the selective ETA blocker reduction of the number and size of macrophage and foam cells was proved. In acute myocardial infarction a favourable effect for the non-selective ETA/ETB blocker and for the selective ETA blocker was found. In the treatment of restenosis after PTCA blockers of selective ETB receptors and inhibitors of endothelin converting enzyme seem hopeful. Th non-selective ETA/ETB blocker bosentan is in the stage of clinical tests and seems to be safe and perspective.
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PMID:[Endothelins and ischemic heart disease]. 1095 65

Endothelins, endothelin-1 (ET1), endothelin-2 (ET2) and endothelin-3 (ET3), are the most potent vasoconstrictor peptides released by endothelial cells. ET production is stimulated by vasopressor hormones, platelet-derived factors, coagulation products and cytokines, whereas nitric oxide and prostacyclin reduce ET production. ET bind to ETA and ETB receptors and produce marked and sustained rise in blood pressure, intense vasoconstriction of coronary arteries and have positive inotropic and chronotropic effects on myocardium. Besides, they influence neuroendocrine, renal and smooth muscle functions. ET appears to function mostly as a paracrine or an autocrine hormone. ET may have a role in hypertension, atherosclerosis, heart failure, coronary artery disease, renal insufficiency, vascular hypertrophy, respiratory and cerebrovascular conditions. Several antagonists of ET acting at receptor level or influencing endothelin converting enzyme (ECE) are under investigation and have great potential as agents for use in the treatment of wide spectrum of disease entities and as biologic probes for understanding the actions of ET in human beings.
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PMID:Endothelins and anti-endothelins. 1122 90

The endothelium plays a crucial role in the regulation of cardiovascular structure and function by releasing several mediators in response to biochemical and physical stimuli. These mediators are grouped into two classes: (1) endothelium-derived constricting factors (EDCFs) and (2) endothelium-derived relaxing factors (EDRFs), the roles of which are considered to be detrimental and beneficial, respectively. Endothelin-1 (ET-1) and nitric oxide (NO) are the prototypes of EDCFs and EDRFs, respectively, and their effects on the cardiovascular system have been studied in depth. Numerous conditions characterized by an impaired availability of NO have been found to be associated with enhanced synthesis of ET-1, and vice versa, thereby suggesting that these two factors have a reciprocal regulation. Experimental studies have provided evidence that ET-1 may exert a bidirectional effect by either enhancing NO production via ETB receptors located in endothelial cells or blunting it via ETA receptors prevalently located in the vascular smooth muscle cells. Conversely, NO was found to inhibit ET-1 synthesis in different cell types. In vitro and in vivo studies have started to unravel the molecular mechanisms involved in this complex interaction. It has been clarified that several factors affect in opposite directions the transcription of preproET-1 and NO-synthase genes, nuclear factor-KB and peroxisome proliferator-activated receptors playing a key role in these regulatory mechanisms. ET-1 and NO interplay seems to have a great relevance in the physiological regulation of vascular tone and blood pressure, as well as in vascular remodeling. Moreover, an imbalance between ET-1 and NO systems may underly the mechanisms involved in the pathogenesis of systemic and pulmonary hypertension and atherosclerosis.
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PMID:Reciprocal regulation of endothelin-1 and nitric oxide: relevance in the physiology and pathology of the cardiovascular system. 1158 Feb 2

Three endothelin family peptides (endothelin-1, -2 and -3) exert an extremely potent and long-lasting vasoconstrictor action as well as other various actions through stimulating two subtypes of receptor (ETA and ETB). Vascular endothelial cells produce only endothelin-1. Although the pharmacological actions of exogenous endothelin-1 have been extensively analyzed, the physiological roles of endogenous endothelin-1 have long been obscure. Using potent and selective receptor antagonists, endothelin-1 has been demonstrated to contribute slightly to the maintenance of regional vascular tone. In gene-targeted mice, endothelin family peptides and their receptors have been shown to play an important role in the embryonic development of neural crest-derived tissues. In addition to its potent vasoconstrictor action, endothelin-1 has direct mitogenic actions on cardiovascular tissues, as well as co-mitogenic actions with a wide variety of growth factors and vasoactive substances. Endothelin-1 also promotes the synthesis and secretion of various substances including extracellular constituents. These effects of endogenous endothelin-1 would appear to be naturally concerned with the development and/or aggravation of chronic cardiovascular diseases, e.g. hypertension, pulmonary hypertension, vascular remodeling (restenosis, atherosclerosis), renal failure, and heart failure. A great many non-peptide and orally active endothelin receptor antagonists have been developed, and shown to exert excellent therapeutic effects in animal models as well as human patients with these diseases.
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PMID:Basic and therapeutic relevance of endothelin-mediated regulation. 1172 53

The endothelins (ET) are among the most potent vasoconstrictors identified to date, and have been implicated in such diseases as renal failure, pulmonary hypertension, atherosclerosis, and congestive heart failure. There is currently interest in developing selective antagonists of the ET-A subtype receptor, and one such antagonist is SB-247083 ((E)-[1-butyl-5-[2-(2-carboxyphenyl) methoxy-4-chlorophenyl]-1H-pyrazole-4-yl]-2-[5-methoxydihydrobenzofuran-6-yl]methyl]-2-propionic acid). This investigation was conducted to evaluate the preclinical pharmacokinetics of SB-247083. Clearance of SB-247083 was low to moderate in the rat and monkey, and high in the dog. Oral bioavailability of SB-247083 administered as a solid formulation of the free acid was 24% in the rat, but low in the dog (4%) and the monkey (2%). An extensive in vitro salt form and formulation screen resulted in the identification of a formulation containing the monoarginyl salt with improved dissolution properties. This formulation provided a 2- to 4-fold increase in oral bioavailability in each of the preclinical species. In the dog, this improvement was reversed by the pre-administration of 0.1 N HCl to normalize the achlorhydric fasting dog stomach. These data show that SB-247083 may have suitable drug properties for progression in development.
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PMID:Pharmacokinetics of SB-247083, a potent and selective endothelin(A) receptor antagonist, in the rat, dog, and monkey. 1241 74

Three isopeptides of endothelin (ET-1, -2, and -3) exert various actions through stimulation of two sub-types of receptor (ETA and ETB). Vascular endothelial cells produce only ET-1. In addition to its powerful vasoconstrictor action, ET-1 has direct mitogenic actions on cardiovascular tissues, as well as comitogennic actions with a wide variety of growth factors and vasoactive substances. ET-1 also promotes the synthesis and secretion of growth factors and various substances, including extracellular constituents. These effects of endogenous ET-1 would naturally be thought to be concerned with the development and/or aggravation of chronic cardiovascular diseases; e.g., hypertension, pulmonary hypertension, vascular remodeling (stenosis, atherosclerosis), renal failure, and heart failure. A large number of peptide and orally active non-peptide endothelin receptor antagonists have been developed, and utilized to analyze physiological and pathophysiological roles of endogenous ET-1. These antagonists have been shown to exert excellent therapeutic effects in animal models of various kinds of diseases by either acute or chronic treatment. Therapeutic treatment of patients suffering from the above-mentioned cardiovascular diseases with ET-receptor antagonists have also been taking place, and bosentan (ETA/ETB antagonist) was recently approved by the FDA as a formal therapeutic drug for pulmonary hypertension. In this review, perspectives for therapeutic applicability of ET-receptor antagonists will be explored.
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PMID:[New expansion of endothelin research: perspectives for clinical application of endothelin-receptor antagonists]. 1261 54

Endothelin-1 (ET-1) is a pleiotropic hormone produced primarily by the endothelium. Synthesis of ET-1 is stimulated by the major signals of cardiovascular stress, such as vasoactive agents (angiotensin II, norepinephrine, vasopressin, and bradykinin), cytokines (e.g., tumor necrosis factor alpha and transforming growth factor beta), and other factors, including thrombin and mechanical stress. ET-1 induces vasoconstriction, is proinflammatory, promotes fibrosis, and has mitogenic potential, important factors in the regulation of vascular tone, arterial remodeling, and vascular injury. These effects are mediated via two receptor types, ETA and ETB. The role ET-1 plays in normal cardiovascular homeostasis and in mild essential hypertension in humans is unclear. However, certain groups of essential hypertensive patients may have ET-1-dependent hypertension, including blacks (subjects of African descent), salt-sensitive hypertensives, patients with low renin hypertension, and those with obesity and insulin resistance. ET-1 has also been implicated in severe hypertension, heart failure, atherosclerosis, and pulmonary hypertension. In all of these conditions, plasma immunoreactive ET levels are elevated and tissue ET-1 expression is increased. Accordingly, it is becoming increasingly apparent that ET-1 plays an important role in cardiovascular disease and in some forms of hypertension in humans. Data from clinical trials using combined ETA-ETB receptor blockers have already demonstrated significant blood-pressure-lowering effects. Thus, targeting the endothelin system may have important therapeutic potential in the treatment of hypertension, particularly by contributing to the prevention of target organ damage and the management of cardiovascular disease.
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PMID:Role of endothelin in human hypertension. 1283 65

Investigation into the role of endothelin-1 (ET-1) in renal function has revealed two major direct actions leading to the control of extracellular volume and blood pressure. These are the regulation of renal hemodynamics and glomerular filtration rate and the modulation of sodium and water excretion. In the rat remnant kidney model of chronic renal failure, ET-1 production is increased in blood vessels and renal tissues. These changes are related to an increase in preproET-1 expression and correlate with the rise in blood pressure, the development of cardiovascular hypertrophy, and the degree of renal insufficiency and injury. Selective ETA receptor blockade prevents the progression of hypertension and the vascular and renal damage, supporting a role for ET-1 in chronic renal failure progression. The increase in ET-1 production can be associated with other local mediators, including angiotensin II, transforming growth factor-beta1 and nitric oxide, the local production of which is also altered in chronic renal failure. In human patients with essential hypertension, atherosclerosis, and nephrosclerosis, plasma ET-1 levels are increased compared with patients with uncomplicated essential hypertension. Similarly, plasma ET-1 concentrations are markedly increased in patients with end-stage renal disease undergoing dialysis, and this correlates with blood pressure, suggesting that ET-1 may contribute to hypertension in these patients. The treatment of anemia in patients with renal failure with human recombinant erythropoietin increases blood pressure by accentuating the underlying endothelial dysfunction and the elevated vascular ET-1 production. Overall, these results support a role for ET-1 in hypertension and the end-organ damage associated with chronic renal failure. ETA receptor blockade may then represent a potential target for the management of hypertension and cardiovascular and renal protection.
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PMID:Endothelin-1 in chronic renal failure and hypertension. 1283 72

Although hypertension is a major risk factor for atherosclerosis, its underlying mechanisms remain to be delineated. We have recently reported that both endothelin-1 (ET-1) and vascular cellular adhesion molecule-1 (VCAM-1) levels, key early markers of atherosclerosis, are significantly elevated in carotid arteries of deoxycorticosterone acetate (DOCA)-salt hypertensive rats, a model known for its suppressed plasma renin levels. This study tested the hypothesis that ET-1 augments arterial VCAM-1 expression through NADPH oxidase-derived superoxide (O2-). Carotid arteries of DOCA-salt or sham-operated rats were transduced ex vivo with extracellular superoxide dismutase (EC-SOD), dominant negative HA-tagged N17Rac1 that inhibits Rac1, the small GTPase component of NADPH oxidase, or beta-galactosidase (beta-gal) reporter gene (5x10(10) plaque formation units [pfu]/mL), and the effect of transgene expression on O2- and VCAM-1 levels was assayed 24 hours afterward. The arterial activity of NADPH oxidase but not xanthine oxidase was significantly higher in DOCA-salt than in sham rats, which was abolished by the selective ETA receptor antagonist ABT-627 (3x10(-8) mol/L), NADPH oxidase inhibitor apocynin (10(-4) mol/L), or dominant negative Rac1 gene transfer. The levels of O2- and VCAM-1 were significantly increased in arteries of DOCA-salt rats, an effect that was ameliorated after EC-SOD or dominant negative Rac1 but not beta-gal reporter gene transfer. ABT-627 and apocynin also significantly reduced elevated VCAM-1 levels in ET-1-treated arteries of normal rats and arteries of DOCA-salt rats. The results of this study indicate that ET-1 stimulates arterial VCAM-1 expression by producing O2- from an ETA receptor/NADPH oxidase pathway in low-renin mineralocorticoid hypertension.
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PMID:Endothelin-1 stimulates arterial VCAM-1 expression via NADPH oxidase-derived superoxide in mineralocorticoid hypertension. 1451 26

The reactivity of the vascular wall to endothelin-1 (ET-1) is influenced by cholesterol, which is of possible importance for the progression of atherosclerosis. To elucidate signaling steps affected, the cholesterol acceptor methyl-beta-cyclodextrin (mbetacd, 10 mmol/L) was used to manipulate membrane cholesterol and disrupt caveolae in intact rat arteries. In endothelium-denuded caudal artery, contractile responsiveness to 10 nmol/L ET-1 (mediated by the ETA receptor) was reduced by mbetacd and increased by cholesterol. Neither ligand binding nor colocalization of ETA and caveolin-1 was affected by mbetacd. Ca2+ inflow via store-operated channels after depletion of intracellular Ca2+ stores was reduced in mbetacd-treated caudal arteries, as shown by Mn2+ quench rate and intracellular [Ca2+] response. Expression of TRPC1, 3, and 6 was detected by reverse transcriptase-polymerase chain reaction, and colocalization of TRPC1 with caveolin-1 was reduced by mbetacd, as seen by immunofluorescence. Part of the contractile response to ET-1 was inhibited by Ni2+ (0.5 mmol/L) and by a TRPC1 blocking antibody. In the basilar artery, exhibiting less store-operated channel activity than the caudal artery, ET-1-induced contractions were insensitive to the TRPC1 blocking antibody and to mbetacd. Increased store-operated channel activity in basilar arteries after organ culture correlated with increased sensitivity of ET-1 contraction to mbetacd. These results suggest that cholesterol influences vascular reactivity to ET-1 by affecting the caveolar localization of TRPC1.
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PMID:Cholesterol depletion impairs vascular reactivity to endothelin-1 by reducing store-operated Ca2+ entry dependent on TRPC1. 1455 Dec 43


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