UMLS:C0042373 - FACTA Search

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Query: UMLS:C0042373 (vascular disease)
17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelins (ET) are a family of peptides with potent biological properties. Endothelial cells produce exclusively ET-1 while other tissues produce ET-2 and ET-3. The production of ET requires an increase in intracellular Ca2+. This increase can be induced by physical chemicals (i.e. hypoxia) or receptor-operated stimuli (i.e. thrombin, angiotensin II, arginine vasopressin, transforming growth factor beta 1, interleukin-1). Most of ET is released abluminally towards vascular smooth muscle and less luminally. The main vascular effect of ET are vasodilation (transient), profound and sustained vasoconstriction as well as proliferation of vascular smooth muscle. These biological effects are mediated by distinct receptors. Three ET receptors have been cloned, i.e. ETA-, ETB- and ETC-receptors. In vascular tissue ETA-receptors are expressed on vascular smooth muscle and responsible for vasoconstriction. ETB-receptors are expressed on endothelium and linked to nitric oxide and/or prostacyclin release. Activation of these receptors explains the transient vasodilation with intraluminal application of ET. Vascular smooth muscle cells can express ETB-receptors which contribute to ET-induced vasoconstriction particularly at lower concentrations. The role of the recently cloned ETC-receptor in the vasculature is still uncertain. ET production is increased (as judged from circulating plasma levels) in vascular disease and atherosclerosis in particular, in myocardial infarction and heart failure, pulmonary hypertension and renal disease. ET production is increased in arterial hypertension remains controversial. Non-peptidic ET antagonists have been developed which either block ETA- receptors or ETA- and ETB-receptors simultaneously. The advantage of ETA-receptors is that they leave the endothelium-dependent vasodilation to ET (via ETB-receptor) intact. However, ETB-mediated contraction remains unaffected by these antagonists. In contrast ETA-/ETB-antagonists fully prevent ET-induced vasoconstriction, however, they also inhibit the endothelial effects of the peptide. ET antagonists interfere with the effects of ET in isolated vascular tissue (including that obtained from humans) as well as in vivo. In humans, ETA as well as ETA-/ETB-antagonists inhibit endothelin-induced vasoconstriction. Hence in summary ET are a family of potent peptides with profound effects in the vasculature. Several studies suggest a role of ET in cardiovascular disease. The newly developed ET-antagonists are potent and selective tools to delineate the (patho-)physiological roles of ET and may become a new class of cardiovascular drugs.
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PMID:Endothelin and endothelin antagonists: pharmacology and clinical implications. 771 86

Endothelin, a vasoconstrictor peptide secreted from endothelial cells, has been thought to play a role in various forms of vascular disease. Diabetes mellitus is well known for its association with accelerated atherosclerosis and microvascular damage. Although the basis for the vessel insult is multifactorial, hyperinsulinemia is thought to contribute by an unknown mechanism. In this study, we sought to determine whether insulin stimulates the production and secretion of ET-1 as a possible basis for the association of hyperinsulinemia and vascular disease. We demonstrated that insulin significantly stimulates the gene expression and secretion of ET-1 from cultured BAEC, and that insulin increases ET-1 mRNA expressed in BBCEC. Insulin caused a maximal twofold inducement above control ET-1 mRNA expression in a dose-related fashion in BAEC. The increased mRNA resulted from increased transcription, as determined by nuclear run-off studies. Increased ET-1 mRNA was seen after 4 h of incubation with insulin: the peak occurred at 6-8 h and persisted for 24 h. Insulin caused as much as a fourfold stimulation of ET-1 secretion from BAEC in a dose-related fashion, including a twofold increase at a physiological concentration (10(-9) M): The increase began at 1 h of incubation and continued for the entire 24-h incubation period. The insulin-induced increases in both ET-1 mRNA and ET-1 protein secretion were significantly attenuated by genistein, a tyrosine kinase inhibitor. This stimulation probably occurred through the insulin receptor, because IGF-1 had no effect on ET-1 gene expression or secretion from these cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Insulin stimulates production and secretion of endothelin from bovine endothelial cells. 842 73

The normal functional state of the vasculature and the events leading to the development of significant arterial disease involve the interaction of important vasoactive substances, which play important modulating or initiating roles in the development of hypertension and arteriosclerosis. Three endothelins have now been identified, of which ET-1 is the best characterized. ET-1 is produced by epithelial, mesangial, neuronal and glial, and liver cells, and is the most potent vasoconstrictor yet found. Each endothelin is derived from a different gene on separate chromosomes, and each binds to at least 2 types of receptor. The plasma half-life of ET-1 is about 7 min, and this provides a rapid mechanism for adjusting vascular resistance or blood pressure. The actions of endothelin are mediated through several pathways of postreceptor signaling, including activation of the mitogen-activated protein kinase cascade, which give rise to its growth-stimulating properties. Secretion of ET-1 from cultured endothelial cells is stimulated by a wide range of substances, and is inhibited by some prostaglandins. Endothelin in turn stimulates secretion of nitric oxide, arginine vasopressin and atrial natriuretic peptide, and participates in the hormonal control of salt and water balance. Hypoxia and ischemia augment ET-1 secretion, as does insulin, and this could play a role in the accelerated vascular disease of diabetes. ET-1 also causes bronchoconstriction and has been implicated in the development of acute asthma, primary pulmonary hypertension and pulmonary fibrosis. Its role in hypertension is still debatable, though most of the manifestations of congestive heart failure can theoretically be explained by the actions of ET-1. Endothelin also has extensive renovascular and parenchymal effects in the kidney. It is hoped that a fuller understanding of the role of endothelins in normal or pathologic vasculature will lead to effective therapy based on antagonism or augmentation of specific functions.
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PMID:Endothelins as cardiovascular peptides. 873 84

The electrophysiological effects of endothelin (ET)-1 were compared in myocytes isolated from rat small pulmonary artery, basilar artery and aorta. ET-1 evoked depolarization in all three smooth muscle cell types. Depolarizing oscillations in membrane current also were observed in pulmonary and aortic myocytes. In voltage-clamp experiments ET-1 induced a gradual inhibition of the Ca(++)-independent outward current (IK) in pulmonary and aortic myocytes, whereas in basilar myocytes ET-1 inhibited the Ca(++)-activated K+ current (IK(Ca)). ET-1 also evoked a transient enhancement of IK(Ca) and oscillations in inward current in aortic and pulmonary myocytes. The inward currents were inhibited by caffeine, which suggests Ca(++)-dependent activation. Ion-exchange experiments indicated that in pulmonary myocytes oscillatory currents were caused solely by the movement of Cl-, whereas in aortic myocytes they were the consequence of both Ca(++)-activated Cl-(ICl(Ca)) and non-selective cation currents (INS). No inward current was evoked in basilar myocytes in response to ET-1 or photorelease of Ca++, which suggests that these cells do not possess ICl(Ca). Experiments with ET receptor ligands indicated that in basilar myocytes ETA receptor stimulation is responsible for IK(Ca) inhibition, whereas in aortic and pulmonary myocytes ETB and ETA receptor stimulation mediates inhibition of IK and activation of ICl(Ca), INS and IK(Ca), respectively. In the future, it may be possible to exploit these differential effects of ET-1 pharmacologically to assist development of tissue-specific modulators for the treatment of vascular disease.
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PMID:Differential electrophysiological actions of endothelin-1 on Cl- and K+ currents in myocytes isolated from aorta, basilar and pulmonary artery. 949 74

Strategically located between the circulating blood and the vascular smooth muscle, endothelial cells release numerous vasoactive substances regulating the function of vascular smooth muscle and circulating blood cells. Endothelium-derived vasodilators include prostacyclin, nitric oxide and endothelium-derived hyperpolarizing factor. In particular, nitric oxide inhibits cellular growth and migration. In concert with prostacyclin, nitric oxide exerts potent antiatherogenic and thromboresistant properties by preventing platelet aggregation and cell adhesion. These effects are counterbalanced by vasoconstrictors, such as angiotensin II and endothelin (ET)-1, both of which exert prothrombotic and growth-promoting properties. In hypertension, elevated blood pressure causes vascular disease by inducing endothelial dysfunction. Hence, modern therapeutic strategies in human hypertension focus on preserving or restoring endothelial integrity. Beyond inhibiting the renin-angiotensin system, angiotensin-converting enzyme (ACE) inhibitors diminish the inactivation of bradykinin, thus leading to an augmentation of nitric oxide release. In addition, the compounds stabilize the B2-receptor, and reduce oxidative stress and tissue ET-1 levels. In patients with coronary artery disease, chronic ACE inhibition improves endothelial function. Further clinical studies are already under way which will prove whether these beneficial vascular effects of ACE inhibitors on endothelial dysfunction result in a clinical benefit for patients with hypertension.
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PMID:Angiotensin converting enzyme inhibitors and vascular protection in hypertension. 1049 58

The normal endothelium is characterised by the production of a number of molecules which affect the contractile state of adjacent myocytes and the behavior of formed elements within the blood stream, and by the absence of cell surface adhesion molecules. In addition, endothelial cells are important modulators of coagulation and fibrinolysis. Whilst effects of lipids have been documented on many of these endothelial processes, there is particularly strong evidence for effects on the vasodilatation mediated by endothelium derived nitric oxide and on the interaction between leukocytes and the endothelial surface. Both LDL cholesterol and triglyceride rich lipoproteins impair endothelium dependent vasodilatation. The effects of LDL cholesterol are primarily evident for lipoprotein particles that have been oxidised with evidence for effects of specific constituents of oxidised LDL, such as lysophosphatidylcholine (LPC). LDL effects have been demonstrated at numerous sites of the nitric oxide signaling pathway including receptor-G protein coupling, nitric oxide synthase and NO bioactivity, with evidence for enhanced superoxide formation and the consequent production of the less potent dilator peroxynitrite. The effects of lipids on endothelium dependent vasodilatation can be reversed not only by reducing the level of elevated lipids levels but also by provision of the NOS substrate, L-arginine and by the provision of antioxidants, although the mechanism for these effects are not fully elucidated. The adhesion of leukocytes to the endothelial surface is stimulated by low density and triglyceride rich lipoproteins. As with endothelium dependent vasodilatation, the effects of LDL cholesterol are primarily evident for low-density lipoprotein particles that have been oxidised, and many of the effects of oxidised LDL can be mimicked by LPC. HDL can overcome pro-adhesive effects of oxidised LDL. The effects of LDL on leukocyte adhesion are secondary to the expression of adhesion molecules on the luminal surfaces of endothelial cells. In addition to the likely deleterious effects of lipids on endothelium-mediated vasodilatation and leukocyte-endothelial cell interaction, lipids have been shown to affect a number of other endothelial processes and function. Thus, oxidised LDL affects endothelial ET1 and PGI2 release. Although effects have been shown on endothelial cell growth and apoptosis and on endothelial processes related to thrombosis and fibrinolysis, these effects have been less extensively studied than endothelial dependent vasodilatation and leukocyte-endothelial cell interaction. Many of the effects of elevated or modified low density and TG rich lipoproteins on endothelial cells and endothelial cell processes could be expected to contribute to the development of atherosclerosis and therefore, to the association between lipids and atherosclerotic, particularly coronary, vascular disease. However, the extent to which "endothelial dysfunction" accounts for the known relationships between serum lipid concentrations and CHD is yet to be established.
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PMID:Lipids and the endothelium. 1053 61

Hyperhomocysteinemia is an independent risk factor for vascular disease. In order to evaluate relations between hyperhomocysteinemia and endothelial and leukocyte function, the investigators related homocysteine to indices of endothelial function (plasma endothelin-1 [p-ET-1] and intraplatelet levels of the nitric oxide [NO] and prostacyclin mediators 3'-5' guanosine monophosphate [cGMP] and cyclic 3'-5' adenosine monophosphate [cAMP]) and the monocyte-derived inflammatory mediator neopterin in 168 men (mean age 69, range 49-72 years) with disturbed glucose metabolism and a reference group of 52 male subjects (mean age 70, range 61-79 years). Among the 168 patients with disturbed glucose metabolism plasma (p)-homocysteine correlated significantly with age (r=0.20; p<0.01), glycosylated hemoglobin (HbA1c) (r=0.17; p<0.05), triglycerides (r=0.20; p<0.05), intraplatelet GMP (r=0.16; p<0.05), p-ET-1 (r=0.21; p<0.05), and p-neopterin (r=0.31; p<0.001). The correlation between p-homocysteine and p-ET-1 persisted (p<0.01) in multiple regression analysis. Among the 52 reference subjects p-homocysteine correlated significantly with p-ET-1 (r=0.32; p<0.05) and p-neopterin (r=0.37; p<0.01). The correlation between p-homocysteine and p-neopterin persisted (p<0.05) in multiple regression analysis. In conclusion, homocysteine is related to neopterin and endothelin-1 in plasma of subjects with disturbed glucose metabolism and in reference subjects, suggesting that homocysteine exerts its deleterious effects on vascular function through interference with endothelial and leukocyte function.
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PMID:Homocysteine is related to neopterin and endothelin-1 in plasma of subjects with disturbed glucose metabolism and reference subjects. 1087 Aug 58

Human immunodeficiency virus (HIV)-related pulmonary hypertension (HRPR) is a cardiovascular complication of HIV infection that has been recognized in the last years with increasing frequency. The etiology of HRPH is unknown. All the attempts to isolate HIV on pulmonary vessels in HRPH patients failed, and an indirect role for HIV in this disease has been hypothesized. Current theories on the pathogenesis focus on abnormalities of endothelial and smooth muscle cells of pulmonary vasculature. Endothelial and smooth muscle cell injury could be due to a high production or to a reduced clearance of cytokines in these patients. In fact, in several studies high levels of ET-1, IL-1alpha, IL-6 and PDGF in primary pulmonary hypertension (PPH) and in HRPH have been found. HIV gp 120 could induce the production of these cytokines by a stimulation of monocytes/macrophages. A high alpha1-adrenoreceptors stimulation of pulmonary vessels could be also implicated in the pathogenesis of HRPH. Chronic hypoxia is observed with increased frequency in HIV patients, and this could induce a chronic stimulation of alpha1-receptors of pulmonary vasculature with typical pathological changes. However, only a small percentage of HIV- patients develop HRPH. This observation suggests the existence of an idiosyncratic susceptibility to the development of vascular disease. This susceptibility could have a genetic basis, and might be determined by particular major histocompatibility complex alleles.
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PMID:Pathogenesis of HIV-related pulmonary hypertension. 1176 97

The endothelins are synthesized in vascular endothelial and smooth muscle cells, as well as in neural, renal, pulmonal, and inflammatory cells. These peptides are converted by endothelin-converting enzymes (ECE-1 and -2) from 'big endothelins' originating from large preproendothelin peptides cleaved by endopeptidases. Endothelin (ET)-1 has major influence on the function and structure of the vasculature as it favors vasoconstriction and cell proliferation through activation of specific ET(A) and ET(B) receptors on vascular smooth muscle cells. In contrast, ET(B )receptors on endothelial cells cause vasodilation via release of nitric oxide (NO) and prostacyclin. Additionally, ET(B) receptors in the lung are a major pathway for the clearance of ET-1 from plasma. Indeed, ET-1 contributes to the pathogenesis of important disorders as arterial hypertension, atherosclerosis, and heart failure. In patients with atherosclerotic vascular disease (as well as in many other disease states), ET-1 levels are elevated and correlate with the number of involved sites. In patients with acute myocardial infarction, they correlate with 1-year prognosis. ET receptor antagonists have been widely studied in experimental models of cardiovascular disease. In arterial hypertension, they prevent vascular and myocardial hypertrophy. Experimentally, ET receptor blockade also prevents endothelial dysfunction and structural vascular changes in atherosclerosis due to hypercholesterolemia. In experimental myocardial ischemia, treatment with an ET receptor antagonist reduced infarct size and prevented left ventricular remodeling after myocardial infarction. Most impressively, treatment with the selective ET(A) receptor antagonist BQ123 significantly improved survival in an experimental model of heart failure. In many clinical conditions, such as congestive heart failure, both mixed ET(A/B )as well as selective ET(A) receptor antagonism ameliorates the clinical status of patients, i.e. symptoms and hemodynamics. A randomized clinical trial showed that a mixed ET(A/B) receptor antagonist effectively lowered arterial blood pressure in patients with arterial hypertension. In patients with primary pulmonary hypertension or pulmonary hypertension related to scleroderma, treatment with a mixed ET(A/B) receptor antagonist resulted in an improvement in exercise capacity. ET receptor blockers thus hold the potential to improve the outcome in patients with various cardiovascular disorders. Randomized clinical trials are under way to evaluate the effects of ET receptor antagonism on morbidity and mortality.
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PMID:Therapeutic potential for endothelin receptor antagonists in cardiovascular disorders. 1472 28

Adipose tissue has recently emerged as an active endocrine organ that secretes a variety of metabolically important substances, collectively called adipocytokines or adipokines. In this review we summarize the effects of the adipokines leptin, adiponectin, and resistin on the vasculature and their potential role for pathogenesis of vascular disease. Leptin is associated with arterial wall thickness, decreased vessel distensibility, and elevated C reactive protein (CRP) levels. Leptin possesses procoagulant and antifibrinolytic properties, and it promotes thrombus and atheroma formation, probably through the leptin receptors by promoting vascular inflammation, proliferation, and calcification, and by increasing oxidative stress. Research for development of pharmacologic antagonism for the leptin receptor is currently under way. Adiponectin inhibits the expression of the adhesion molecules ICAM-1, VCAM-1, and P selectin. Therefore, it interferes with monocyte adherence to endothelial cells and their subsequent migration to the subendothelial space, one of the initial events in the development of atherosclerosis. Adiponectin also inhibits the transformation of macrophages to foam cells in vitro and decreases their phagocytic activity. Resistin, discovered in 2001, represents the newest of the adipokines and was named for its ability to promote insulin resistance. Resistin increases the expression of the adhesion molecules VCAM-1 and ICAM-1, up-regulates the monocyte chemoattractant chemokine-1, and promotes endothelial cell activation via ET-1 release. Although many aspects of its function need further clarification, it appears that resistin will add significantly to our knowledge of the pathophysiology of vascular disease and the metabolic syndrome.
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PMID:Effects of adipocyte-derived cytokines on endothelial functions: implication of vascular disease. 1591 85

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