endothelin-1 and Vascular-Diseases

To challenge the argument that continuous use of phosphodiesterase-5-selective inhibitors may reduce endothelial cell dysfunction in patients with vascular diseases or vascular risk conditions.. This study included systematic reviews and meta-analysis of randomized double-blind placebo-controlled trials dealing with the prolonged use of phosphodiesterase-5-selective inhibitors. The risk of bias and quality of trials were assessed by the Cochrane algorithm. Fixed or random effect models, standardised mean differences and heterogeneity were estimated in the study.. Systematic search for randomized double-blind placebo-controlled trials was done in PubMed, Scopus, CINAHL, Science direct and the Cochrane Library.. Randomized double-blind placebo-controlled trials reporting measures of endothelial cell dysfunction and/or endothelial cell activation were included.. On the whole, 469 subjects were allocated to the phosphodiesterase-5-selective inhibitor group, while 463 were assigned to the placebo group in 13 randomized double-blind placebo-controlled trials. Flow-mediated dilation of the brachial artery was found to improve after the administration of phosphodiesterase-5-selective inhibitors (P < 0.0001). The results were questioned by the elevated and uncorrectable heterogeneity (I. The results on the benefits of a prolonged use of phosphodiesterase-5-selective inhibitors, with the objective of lowering endothelial cell dysfunction in patients with vascular diseases or vascular risk conditions are not convincing. This is because of the overall low quality of evidence, giving an unclear scientific support to this treatment. Systematic review registration: PROSPERO registration: CRD42017055399.

Topics: Double-Blind Method; Endothelial Cells; Endothelin-1; Endothelium; Humans; Phosphodiesterase 5 Inhibitors; Randomized Controlled Trials as Topic; Vascular Diseases; Vascular Resistance; Vasodilation

The endothelium can evoke relaxations of the underlying vascular smooth muscle, by releasing vasodilator substances. The best-characterized endothelium-derived relaxing factor (EDRF) is nitric oxide (NO) which activates soluble guanylyl cyclase in the vascular smooth muscle cells, with the production of cyclic guanosine monophosphate (cGMP) initiating relaxation. The endothelial cells also evoke hyperpolarization of the cell membrane of vascular smooth muscle (endothelium-dependent hyperpolarizations, EDH-mediated responses). As regards the latter, hydrogen peroxide (H

Topics: Animals; Cyclic GMP; Endothelin-1; Endothelium, Vascular; Humans; Muscle, Smooth, Vascular; Nitric Oxide; Vascular Diseases; Vasoconstriction; Vasodilation

Angiotensin II, through activation of the angiotensin II-type 1 receptor, induces generation of inflammatory mediators in the blood vessel wall and as such plays an active role in the inflammation process. Direct stimulation of reactive oxygen species and nuclear factors seem to be key mechanisms through which this receptor induces inflammation. Inflammatory molecules are also known to modify endothelial cell function, especially endothelium-derived vasoactive agents, and inflammation is increasingly recognized as primary cause of major vascular disorders. There is accumulating evidence that stimulation of the type 1 angiotensin II receptor participates in vascular dysfunction by reducing activity of the endothelium-derived relaxants nitric oxide and hyperpolarizing factors. Furthermore activation of this angiotensin II receptor also enhances generation of endothelium-derived constricting factors, such as endothelin-1. This change in endothelial cell output not only impairs blood vessel relaxation but leads to pro-inflammatory and pro-coagulation conditions that are associated with disease initiation and progression. Pharmacological inhibitors of the angiotensin II pathway and the type 1 receptor subtype are in current clinical use for the treatment of hypertension. However evidence supports that these agents have a positive therapeutic benefit in other vascular pathologies with recognized inflammatory etiology, such as atherosclerosis.

Topics: Animals; Cytokines; Endothelin-1; Endothelium-Dependent Relaxing Factors; Endothelium, Vascular; Humans; Inflammation; Reactive Oxygen Species; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Vascular Diseases; Vasoconstriction; Vasodilation

Nitric oxide (NO) and endothelin-1 (ET-1) are natural counterparts in vascular function, and it is becoming increasingly clear that an imbalance between these two mediators is a characteristic of endothelial dysfunction and is important in the progression of vascular disease. Here, we review classical and more recent data that suggest that ET-1 should be regarded as an essential component of NO signaling. In particular, we review evidence of the role of ET-1 in models of acute and chronic NO synthase blockade. Furthermore, we discuss the possible mechanisms by which NO modulates ET-1 activity. On the basis of these studies, we suggest that NO tonically inhibits ET-1 function, and in conditions of diminished NO bioavailability, the deleterious effects of unmitigated ET-1 actions result in vasoconstriction and eventually lead to vascular remodeling and dysfunction.

Topics: Animals; Blood Vessels; Endothelin-1; Humans; Models, Animal; Nitric Oxide; Signal Transduction; Vascular Diseases; Vasoconstriction

Although being classified as autoimmune connective tissue disease, dominant components of the pathophysiology of systemic sclerosis (SSc) consists of mechanisms of vascular damage, which can occur early in the course of the disease. Amongst them are abnormal vasoreactivity, hypoxia, insufficient neoangiogenesis and direct damage of vascular and perivascular cells. They result in a decreased capillary blood flow, and subsequently in clinically overt symptoms such as Raynaud's syndrome and fingertip ulcers. In addition, in active disease vascular pathology can affect various other organs, predominantly the lung, the kidney, the heart but also the gastrointestinal tract. Vascular pathology contributes also significantly to overall morbidity and mortality in SSc patients and reduces life expectancy by at least a decade. Fortunately, molecular biology has revealed a number of underlying pathways on the cellular and subcellular levels, including key factors of the aberrant function of (peri)vascular cells and autoimmune effector cells, the dysregulation of vasoconstrictive molecules and their receptors, the upregulation of intracellular signaling kinases and the altered balance of hypoxia-induced vascular growth factors. This increasing knowledge of vascular pathology in SSc has also resulted in novel therapeutic approaches ranging from endothelin antagonists to application of progenitor cells to counteract this aberrant vascular pathology and to support the repair of the dysfunctional vasculature.

Topics: Apoptosis; Autoantibodies; Blood Vessels; Endothelin-1; Endothelium, Vascular; Epigenesis, Genetic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Intercellular Adhesion Molecule-1; Neovascularization, Pathologic; Polymorphism, Single Nucleotide; Scleroderma, Systemic; Vascular Diseases; Vascular Endothelial Growth Factor A

It is now two decades since it was demonstrated that ET-1 is one of the most powerful vasoconstrictors in biology. ET-1 mediates its effects through two membrane G-protein coupled receptors, ET(A) and ET(B), which exhibit a wide tissue distribution including the endothelial cells, vascular smooth muscle cells and adventitial fibroblasts. In recent years, ET-1 has been identified as a key player of endothelial dysfunction in various cardiovascular, autoimmune and CTDs. Endothelial dysfunction results from endothelial cell injury subsequently leading to the generation of an inflammatory process and endothelial cell activation. Thus, beyond its known 'classical' vasoactive effects, ET-1 is additionally considered to be an important mediator in vessel remodelling ultimately leading to major changes in cellular and tissue architecture; it also appears to function in conjunction with other growth factors and cytokines. Consequently, ET-1 receptor antagonists may be useful in ameliorating progression of vascular dysfunction and vascular disease due to their ability to negatively modulate vasoconstrictor pathways, cytokines and inflammatory markers production, and growth factor effects. This review briefly summarizes the current knowledge on the role of ETs in vascular dysfunction and vascular disease, with a particular emphasis on ET-1 in CTDs.

Topics: Endothelin-1; Endothelium, Vascular; Fibrosis; Humans; Muscle, Smooth, Vascular; Nitric Oxide; Receptors, Endothelin; Signal Transduction; Vascular Diseases; Vasoconstriction

There is conflicting evidence regarding the effect of endothelin-1 (ET-1) on platelets. Some studies show that ET-1 activates platelets, others show platelet inhibition with ET-1 and some studies did not detect an effect of ET-1. These conflicting results may be due to complex interactions between platelet ET(A) and ET(B) receptors. ET-1 antagonism may emerge as an important therapeutic strategy in the management of several vascular disorders. However, to date the only prescribed ET-1 antagonist is bosentan for pulmonary arterial hypertension. Bosentan is a 'dual' ET-1 antagonist (i.e. it acts on both ET(A) and ET(B) receptors). Whether this action involves an effect on platelets remains to be established. In this review some of the studies describing the effect of ET-1 on human platelets are discussed. Vascular diseases where ET-1 is implicated are also considered.

Topics: Animals; Blood Platelets; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Humans; Platelet Aggregation; Vascular Diseases

Vasospasm can have many different causes and can occur in a variety of diseases as well as in otherwise healthy subjects. We distinguish between primary vasospastic syndrome and secondary vasospasm. The term "vasospastic syndrome" summarizes the symptoms of patients having such a spasm to stimuli like cold or emotional stress. Patients with primary vasospastic syndrome tend to suffer from cold hands, low blood pressure, migraine and silent myocardial ischemia. The ocular vasospastic syndrome is clearly associated, among other manifestations, with glaucomatous optic neuropathy and non arteritic anterior ischemic optic neuropathy. The ocular vasospasm leads to a compromised autoregulation, and therefore sensitizes the eye to intraocular pressure or to a decrease in blood pressure. A variation in ocular perfusion may lead to an increase in free oxygen radicals and in glutamate. This may finally induce apoptosis cascade in retinal ganglion cells. Valuable diagnostic tools are nailfold capillary microscopy and angiography, but probably the best indicator is an increased plasma level of endothelin-1. The role of calcium channel blockers, magnesium, endothelin and glutamate antagonists are discussed.

Topics: Apoptosis; Calcium Channel Blockers; Diagnosis, Differential; Endothelin-1; Excitatory Amino Acid Antagonists; Eye; Eye Diseases; Free Radicals; Glutamic Acid; Humans; Optic Nerve Diseases; Syndrome; Vascular Diseases

Atherosclerosis is a major risk factor for both myocardial infarction and stroke. A key aspect of this disease is the imbalance of vasoactive factors. In this concise review, we focus on the role of endothelin-1 in the atherosclerotic process and other vasculopathies. Previously, we have demonstrated that there is a correlation between the expression of endothelin and the underlying atherosclerotic lesion. Immunoreactivity was observed for both ET-1 and ECE-1 in endothelial cells, smooth muscle cells, and macrophages within lesions. Endothelin's role in atherosclerosis must extend from its varying physiological activities, including vasoconstriction, mitogenesis, neutrophil adhesion, and platelet aggregation, and hypertrophy, as well as its propensity to induce the formation of reactive oxygen species. We also discuss regulation of endothelin by angiotensin II, reactive oxygen species, thrombin, aging, and LDL in the cardiovascular system. Finally, we demonstrate the role of endothelin in pulmonary hypertension and transplant associated vasculopathy.

Topics: Animals; Arteriosclerosis; Aspartic Acid Endopeptidases; Endothelin-1; Endothelin-Converting Enzymes; Humans; Metalloendopeptidases; Vascular Diseases

Several manifestations of neonatal pulmonary hypertension are associated with vascular remodeling, resulting in increased muscularity of the small pulmonary arteries. Abnormal structural development of the pulmonary vasculature has been implicated in persistent pulmonary hypertension of the newborn (PPHN). Increased plasma levels of the vasoconstrictor endothelin-1 (ET-1) have been demonstrated in patients with PPHN, which is likely to contribute to hypertension. In addition, several studies have identified a role for ET-1 in the proliferation of vascular smooth muscle cells (SMCs), suggesting that ET-1 may also be involved in the vascular remodeling characteristic of this disease. However, the mechanisms of ET-1-induced SMC proliferation are unclear and appear to differ between cells from different origins within the vasculature. In SMCs isolated from fetal pulmonary arterial cells, ET-1 stimulated proliferation via an induction of reactive species (ROS). Furthermore, other lines of evidence have demonstrated the involvement of ROS in ET-1-stimulated SMC growth, suggesting that ROS may be a common factor in the mechanisms involved. This review discusses the potential roles for ROS in the abnormal pulmonary vascular development characteristic of PPHN, and the treatment strategies arising from our increasing knowledge of the molecular mechanisms involved.

Topics: Animals; Antioxidants; Cell Division; Endothelin-1; Endothelium, Vascular; Humans; Hypertension, Pulmonary; Models, Biological; Nitric Oxide; Nitric Oxide Donors; Pulmonary Artery; Reactive Oxygen Species; Receptors, Endothelin; Vascular Diseases

Endothelin-1 (ET-1) is a powerful vasoconstrictor peptide and regulator of blood flow that plays an important role in blood pressure (BP) elevation in some models of experimental hypertension such as DOCA-salt rat, DOCA-salt-treated spontaneously hypertensive rats (SHR), stroke-prone SHR, Dahl salt-sensitive rats, angiotensin II-infused rats, and one-kidney, one-clip Goldblatt rats, but not in SHR, two-kidney, one-clip hypertensive rats, transgenic (mREN2)27 rats, or Nomega-nitro-L-arginine methyl ester chronically treated rats. In those models of hypertension in which ET-1 plays a vasoconstrictor role, ET-1 was shown to be overexpressed in the vessel walls, or BP has been lowered by administration of ET(A/B)- and ET(A)-selective receptor antagonists. In these experimental models, endothelin receptor antagonists also regressed vascular growth and inflammation, and improved endothelial dysfunction. Hypertensive rats treated with endothelin antagonists were protected from stroke and renal injury. In hypertensive rats without generalized vascular overproduction of ET-1, expression of ET-1 was often enhanced in intramyocardial coronary arteries, suggesting a role of ET in myocardial ischemia in hypertension. Moderate-to-severe hypertensive patients presented enhanced expression of pre-proET-1 mRNA in the endothelium of subcutaneous resistance arteries, suggesting that this stage of hypertension may respond particularly well to endothelin antagonism. In some hypertensive patients, exaggerated vascular responses to ET-1 were found. Hypertensive patients with coronary artery disease have increased arterial expression of ET-1. Increased plasma levels of immunoreactive ET have been described in African Americans. ET-1 plays an important role in atherosclerosis, for which hypertension is an important risk factor, and in ischemic heart disease and stroke. Endothelin-1 may also be involved in other forms of vascular disease, including pulmonary hypertension, after angioplasty restenosis, after allograft vasculopathy, and vasculitis. Thus, ET-1 may participate in vascular damage in cardiovascular disease and in BP elevation in experimental models and in human hypertension. Endothelin antagonists could become effective disease-modifying agents in different forms of cardiovascular disease.

Topics: Animals; Arteriosclerosis; Blood Vessels; Endothelin-1; Humans; Hypertension; Vascular Diseases

Endothelin-1 (ET-1) is a 21 amino acid peptide with diverse biological activity that has been implicated in numerous diseases. ET-1 is a potent mitogen regulator of smooth muscle tone, and inflammatory mediator that may play a key role in diseases of the airways, pulmonary circulation, and inflammatory lung diseases, both acute and chronic. This review will focus on the biology of ET-1 and its role in lung disease.

Topics: Amino Acid Sequence; Endothelin-1; Graft Rejection; Humans; Lung; Lung Diseases; Lung Neoplasms; Lung Transplantation; Molecular Sequence Data; Respiratory Distress Syndrome; Respiratory Tract Diseases; Vascular Diseases

The endothelial cells release both relaxing [nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF), prostacyclin] and contracting factors [endoperoxides, thromboxane A(2), superoxide anions, endothelin-1 (ET)]. The production of ET is inhibited by NO. The latter also strongly opposes the direct effects of the former on vascular smooth muscle. With aging and vascular disease, the production of enothelial NO declines, and thus ET can be released, act and contribute to the symptoms.

Topics: Animals; Endothelin-1; Endothelium, Vascular; Humans; Nitric Oxide; Vascular Diseases

Diabetes mellitus and impaired glucose tolerance are linked to increased cardiovascular morbidity and mortality. Vascular disease is directly associated with plasma glucose levels, and reduction of these levels forestalls to a certain extent the vascular complications of diabetes, such as myocardial infarction, nephropathies, and retinopathies. In addition to hyperglycemia, there are other risk factors that play a prominent role, such as hypertension, hyperlipidemia, and genetic factors. Endothelial dysfunction is one of the major factors in the development of cardiovascular disease. The vascular endothelium regulates the blood flow by tightly controlling the coagulation system, cell-cell interaction, and vascular tone. These functions are disturbed in diabetic patients. In diabetics, endothelin-1 levels are increased, leading to vasoconstriction. Endothelin levels are directly related to plasma glucose levels. In addition, the endothelial cell-NO axis is disturbed. NO release and function are impaired. This seems to be dependent upon hyperglycemia and genetic factors. Impaired NO function also results in vasoconstriction. Furthermore, enhanced vascular permeability is seen in diabetics. This appears to be related to impaired endothelial cell relaxation and reactive oxygen species as well as advanced glycosylated end products (AGEs). The complex changes seen in diabetes and even prediabetes are therefore related to numerous derailments related to endothelial dysfunction, and no single therapeutic approach is likely to solve the problem of vascular complications.

Topics: Diabetes Mellitus; Endothelin-1; Endothelium, Vascular; Glucose Intolerance; Humans; Vascular Diseases

Topics: Biomechanical Phenomena; Cell Adhesion; Chemokine CCL2; Endothelin-1; Endothelins; Endothelium, Vascular; Humans; Inflammation Mediators; Intercellular Adhesion Molecule-1; Platelet-Derived Growth Factor; Protein Precursors; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-sis; Thromboplastin; Transforming Growth Factor beta; Vascular Cell Adhesion Molecule-1; Vascular Diseases

Increased endothelin-1 (ET-1) levels in patients with sickle cell disease (SCD) and transgenic mouse models of SCD contribute to disordered hematological, vascular, and inflammatory responses. Mineralocorticoid receptor (MR) activation by aldosterone, a critical component of the Renin-Angiotensin-Aldosterone-System, modulates inflammation and vascular reactivity, partly through increased ET-1 expression. However, the role of MR in SCD remains unclear. We hypothesized that MR blockade in transgenic SCD mice would reduce ET-1 levels, improve hematological parameters, and reduce inflammation. Berkeley SCD (BERK) mice, a model of severe SCD, were randomized to either sickle standard chow or chow containing the MR antagonist (MRA), eplerenone (156 mg/Kg), for 14 days. We found that MRA treatment reduced ET-1 plasma levels (p = .04), improved red cell density gradient profile (D

Topics: Aldosterone; Anemia, Sickle Cell; Animals; Disease Models, Animal; Endothelial Cells; Endothelin-1; Humans; Inflammation; Mice; Mice, Transgenic; Mineralocorticoid Receptor Antagonists; Receptors, Mineralocorticoid; Vascular Diseases

Smoking is one of the most harmful lifestyles in the world. Very few studies have investigated the effects of melatonin in smoke-induced vascular injury. This study was designed to investigate whether melatonin could protect rats and humans from smoke-induced vascular injury. 32 male rats and a double-blind randomized controlled trial (RCT) containing 63 participants formed the subjects of this study. In rats, 10 mg/kg of melatonin was intraperitoneally injected. Blood samples and abdominal artery were harvested two weeks later. Melatonin decreased the expression of platelet endothelial cell adhesion molecule-1 (CD31), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and endothelin-1 (ET-1) compared with the smoke exposed group (P < 0.05), whereas endothelial nitric oxide synthase (eNOS), nuclear erythroid 2-related factor 2 (Nrf2), NAD(P)H quinone oxidoreductase 1 (NQO-1), catalytic glutamate cysteine ligase (GCLC) and heme oxygenase-1 (HO-1) recovered markedly (P < 0.05). In humans, 3 mg/day of melatonin was taken orally by the participants. Blood samples were drawn at baseline and after two weeks of treatment. Compared with the oral placebo group, melatonin decreased the concentration of fibrinogen (Fbg) (P = 0.04) and free fatty acids (FFA) (P = 0.04) in smokers, along with the decreased expression of ICAM-1, VCAM-1 and ET-1 (P = 0.004, P = 0.001, P < 0.0001, respectively). In contrast, Nrf2 and HO-1 expression were markedly increased (P = 0.0001, P = 0.0049, respectively) after smokers took melatonin orally. In summary, our present data suggest that melatonin could ameliorate smoke-induced vascular injury.

Topics: Administration, Oral; Adult; Animals; Cell Adhesion Molecules; Endothelin-1; Female; Gene Expression Regulation; Glutamate-Cysteine Ligase; Heme Oxygenase-1; Humans; Male; Melatonin; NAD(P)H Dehydrogenase (Quinone); NF-E2-Related Factor 2; Nitric Oxide Synthase Type III; Rats; Rats, Sprague-Dawley; Smoking; Vascular Diseases

Hyperhomocysteinemia is a risk factor for atherosclerosis and venous thrombosis, probably exerting its effects through endothelial function. Homocysteine levels are lowered by folate supplementation, and such treatment improves endothelial function. However, whether folate supplementation decreases vascular risk and improves survival is unknown. The aim of this study was to evaluate endothelial function and mononuclear leukocyte inflammatory activity during homocysteine lowering in patients with hyperhomocysteinemia and vascular disease.. Endothelial function assessed as plasma (p-)endothelin(ET)-1 and intraplatelet cGMP and cAMP, and mononuclear leukocyte inflammatory activity, assessed as p-neopterin were studied during homocysteine lowering in 50 patients with hyperhomocysteinemia and vascular disease, randomized to folate supplementation or no treatment for 3 months.. P-homocysteine decreased during the 3 months not only in patients on folate supplementation (from 27 [21-52] to 14 [8-41] micromol/l; p<0.001), but also in the untreated group (from 23 [20-35] to 19 [4-31] micromol/l; p<0.001). P-ET-1 decreased during folate supplementation (from 5.7 [2.7-11.6] to 4.1 [1.8-9.0] pg/ml; p<0.01), but was unchanged in the untreated group 4.1 [2.0-9.5] pg/ml and 4.5 [2.7-7.1] pg/ml). P-neopterin was unchanged in patients on folate supplementation (9.7 [5.1-54.4] and 7.6 [5.7-73.0] nmol/l), but increased in the untreated group (from 8.2 [4.7-19.5] to 8.6 [4.6-24.6] nmol/l; p<0.05). Intraplatelet cGMP decreased in patients on folate supplementation (from 0.86 [0.21-2.00] platelets to 0.56 [0.17-1.42] pmol/10(9) platelets; p<0.05), but was unchanged in the untreated group. No significant differences concerning intraplatelet cAMP occurred in either group.. Folate supplementation in hyperhomocysteinemia is associated with decreasing levels of both ET-1 and intraplatelet cGMP, and the absence of an increase in the levels of the inflammatory mediator neopterin.

Topics: Aged; Blood Platelets; Cyclic AMP; Cyclic GMP; Endothelin-1; Female; Folic Acid; Humans; Hyperhomocysteinemia; Male; Neopterin; Vascular Diseases

The aim of the study was to examine whether the circulating cell adhesion molecules, von Willebrand factor (vWf) and endothelin-1, are elevated in patients with essential hypertension with no other risk factors for atherosclerosis and thus may serve as a markers of endothelial dysfunction in uncomplicated hypertension. Furthermore, the effect of treatment with the ACE inhibitor, quinapril, on levels of endothelial dysfunction markers were studied. The levels of adhesion molecules (intercellular cell adhesion molecule-1 [ICAM-1], E-selectin, P-selectin), von Willebrand factor (vWf) and endothelin-1 were measured in patients with hypertension without any other risk factors of atherosclerosis before and after treatment with quinapril (n = 22) and in normotensive controls (n = 22). Compared with normotensive subjects, the hypertensive patients had significantly higher levels of ICAM-1 (238 vs 208 ng/ml, P = 0.02), vWf (119 vs 105 IU/dl, P < 0.05) and endothelin-1 (5.76 vs 5.14 fmol/ml, P < 0.05). Three-month treatment of hypertensive patients with quinapril led to a significant decrease in the levels of endothelin-1 (5.76 vs 5.28 fmol/ml, P < 0.01). We did not observe significant changes in the levels of adhesion molecules and vWf after ACE inhibitor treatment, although a trend toward a decrease was apparent with all these parameters. Patients with uncomplicated hypertension with no other risk factors of atherosclerosis had significantly elevated levels of ICAM-1, vWf, and endothelin-1. Our data suggest that these factors may serve as markers of endothelial damage even in uncomplicated hypertension. In hypertensive patients, treatment with the ACE inhibitor quinapril resulted in a significant decrease in endothelin-1 levels. These findings indicate a beneficial effect of ACE inhibitors on endothelial dysfunction in hypertensive patients.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Endothelin-1; Endothelium, Vascular; Humans; Hypertension; Intercellular Adhesion Molecule-1; Isoquinolines; Male; Middle Aged; Predictive Value of Tests; Quinapril; Tetrahydroisoquinolines; Vascular Diseases; von Willebrand Factor

Aging is a risk factor for many chronic noncommunicable diseases, including chronic obstructive pulmonary disease (COPD), which is often associated with cardiovascular disease (CVD). Moreover, aging is associated with a mild form of systemic inflammation. The aim of our study was to analyze the relationship between age, systemic and vascular inflammation, and the presence of CVD comorbidities in a stable COPD population. Forty COPD patients were divided into 2 age groups (<65 and ≥65 years of age), from which we collected the following inflammatory biomarkers: C-reactive protein, tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and endothelin-1 (ET-1). Elderly COPD patients had more frequent exacerbation events per year (2 vs 1, P = .06), a higher prevalence of CVD (3 vs 2, P = .04), more limited exercise tolerance (6-minute walking test distance, 343 [283-403] vs 434 [384-484]; P = .02), and mild systemic inflammation (TNF-α, 9.02 [7.08-10.96] vs 6.48 [5.21-7.76]; P = .03; ET-1, 2.24 [1.76-2.71] vs 1.67 [1.36-1.98] pg/mL; P = .04). A weak correlation between age and ET-1 (r = 0.32, P = .04) was observed. Mild systemic inflammation, characterized by a slightly increased level of TNF-α, and endothelial dysfunction, marked by elevated ET-1, could be liaisons between aging, COPD, and CVD comorbidities.

Topics: Aged; Biomarkers; Cardiovascular Diseases; Endothelin-1; Humans; Inflammation; Lung; Pulmonary Disease, Chronic Obstructive; Tumor Necrosis Factor-alpha; Vascular Diseases

Systemic sclerosis (SSc) is a chronic connective tissue disease characterized by progressive fibrosis, vascular impairment and immune abnormalities. In recent years, adipokines (mediators synthetized by adipose tissue) have been indicated as a possible missing link in the pathogenesis of SSc. The aim of this study was to investigate the serum concentration of metabolic adipose tissue factors: adiponectin, resistin, leptin and endothelial proteins: endothelin-1, fractalkine and galectin-3 in patients with systemic sclerosis. The study included 100 patients with confirmed SSc diagnosis and 20 healthy individuals. The concentration of respective proteins was determined by enzyme-linked immunosorbent assay. The following markers showed statistically significant increased mean concentrations in patients with SSc in comparison to healthy control: resistin (13.41 vs 8.54 ng/mL; P = 0.0012), endothelin-1 (1.99 vs 1.31 pg/mL; P = 0.0072) and fractalkine (2.93 vs 1.68 ng/mL; P = 0.0007). Elevated serum levels of galectin-3 (4.54 vs 3.26 ng/mL; P = 0.0672) and leptin (19,542 vs 14,210 pg/mL; P = 0.1817) were observed. Decreased concentration of adiponectin was found in patients with SSc (5150 vs 8847 pg/mL; P = 0.0001). Fractalkine and galectin-3 levels were significantly higher in diffuse cutaneous SSc than limited cutaneous SSc subset (3.93 ng/mL vs 2.58 ng/mL, P = 0.0018; 6.86 ng/mL vs 3.78 ng/mL, P = 0.0008, respectively) and correlated positively with modified Rodnan Skin Score in total SSc patients (r = 0.376, P = 0.0009; r = 0.236, P = 0.018, respectively). In conclusion, an increased serum level of resistin associated with increased endothelin-1 and fractalkine level and decreased adiponectin level may indicate a significant role of the adipose tissue in the development and progression of vascular abnormalities in patients with systemic sclerosis. Fractalkine and galectin-3 may participate in promoting and exacerbating the fibrotic process in SSc.

Topics: Adipokines; Adipose Tissue; Adult; Aged; Aged, 80 and over; Biomarkers; Chemokine CX3CL1; Endothelin-1; Female; Fibrosis; Galectin 3; Humans; Male; Middle Aged; Resistin; Scleroderma, Systemic; Up-Regulation; Vascular Diseases

Roles of nitric oxide (NO) and endothelin-1 (ET-1) in the local regulation of blood flow under physiological conditions are important and well known, while data on their effects and interactions in conditions of hyperbaric hyperoxia is still insufficient. This was a prospective observational study which included patients who underwent hyperbaric oxygen therapy (HBOT) in accordance with existing therapeutic protocol for peripherial arterial disease (PAD) during time period of six months, between january and july of 2016. Clinical stage of PAD according to Fontain was taken into account, as well as risk factors, demographic, anthropometric and clinical characteristics of studied patients. The study included 64 patients with a mean age (±Sd) 60.2±12.7 years, of whom 28 were female. Patients' NO serum levels in all observed categories before and after HBOT were not signifficantly different, except for stage II PAD (NObefore HBOT 21.9±9.6 vs. NOafter HBOT 26.2±12.1 (p = 0.04)). On the contrary, in all studied patients ET-1 level increased signifficantly after HBOT (ET-1before HBOT 4.2±11.6 vs. ET-1after 18.3±21.0 (p < 0.001)). Treatment of PAD using HBOT leads to the predominance of vasoconstrictor effects probably caused by elevation of serum ET-1 concentrations, while other factors such as exposure time to hyperbaric conditions, activation of antioxidant molecules, and the influx of other interfering substances must be considered in interpreting the effects of NO molecules.

Topics: Endothelin-1; Female; Humans; Hyperbaric Oxygenation; Male; Middle Aged; Nitric Oxide; Prospective Studies; Vascular Diseases

The aim is to analyze the value of endothelial dysfunction markers during pregnancy.. Materials and methods: We have examined 153 pregnant women to identify endothelial dysfunction markers of endothelin-1, nitrogen oxide (NO) that have been studiedusing immunoenzymometric sets for an uncomplicated and complicated pregnancy.. Results: We found that the concentration of endothelin-1 repeatedly exceeded the rates in pregnant women with miscarriages than during physiological pregnancy. The diametrically opposite pattern concerns the level of nitrogen oxide. These changes in the markers of the functional state of the endothelin indicate the development of the dysfunction of this system in women with the pathology of pregnancy.. Conclusions: Consequently, endothelial dysfunction can be considered to be one of the reasons for miscarriage in the examined women. Therefore, the definition of markersof endothelial dysfunction has prognostic value.

Topics: Abortion, Spontaneous; Biomarkers; Endothelin-1; Female; Humans; Pre-Eclampsia; Pregnancy; Vascular Diseases

Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene.. This study sought to test the association between the rs9349379 genotype and SCAD.. Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD.. The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence.. The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.

Topics: Adult; Aged; Australia; Case-Control Studies; Coronary Vessel Anomalies; Endothelin-1; Female; Fibromuscular Dysplasia; France; Genetic Loci; Humans; Male; Microfilament Proteins; Middle Aged; Prevalence; United Kingdom; United States; Vascular Diseases

Understanding mechanisms of chemotherapy cardiotoxicity is an important problem due to the lack of clear understanding of its occurrence. Development of endothelial dysfunction is considered to be one of possible ways in implementation of these side effects. The analysis of endothelin-1 and e-selectin levels in 26  patients with lymphoproliferative diseases before and after the completion of the treatment program was been performed. The results of the study showed normal values of E-selectin level and increased level of endothelin-1 in the whole group of patients before treatment. After completion of chemotherapy program, in the whole group, there was a decrease of these two markers. However, values of level of endothelin-1 with vasoconstrictor effect remained high even after the end of therapy. It is imp ortant that at detailed analysis the dynamics of investigated markers in patients of older age group (median age 64 years) was associated with worsening of endothelial dysfunction.

Topics: Biomarkers; Cardiotoxicity; Cytostatic Agents; Endothelin-1; Endothelium, Vascular; Humans; Middle Aged; Vascular Diseases

Genome-wide association studies (GWASs) implicate the PHACTR1 locus (6p24) in risk for five vascular diseases, including coronary artery disease, migraine headache, cervical artery dissection, fibromuscular dysplasia, and hypertension. Through genetic fine mapping, we prioritized rs9349379, a common SNP in the third intron of the PHACTR1 gene, as the putative causal variant. Epigenomic data from human tissue revealed an enhancer signature at rs9349379 exclusively in aorta, suggesting a regulatory function for this SNP in the vasculature. CRISPR-edited stem cell-derived endothelial cells demonstrate rs9349379 regulates expression of endothelin 1 (EDN1), a gene located 600 kb upstream of PHACTR1. The known physiologic effects of EDN1 on the vasculature may explain the pattern of risk for the five associated diseases. Overall, these data illustrate the integration of genetic, phenotypic, and epigenetic analysis to identify the biologic mechanism by which a common, non-coding variant can distally regulate a gene and contribute to the pathogenesis of multiple vascular diseases.

Topics: Acetylation; Cells, Cultured; Chromatin; Chromosome Mapping; Chromosomes, Human, Pair 6; Coronary Artery Disease; Endothelial Cells; Endothelin-1; Epigenomics; Gene Editing; Gene Expression; Genetic Predisposition to Disease; Genome-Wide Association Study; Histones; Humans; Muscle, Smooth, Vascular; Polymorphism, Single Nucleotide; Vascular Diseases

To provide pharmacological data for future clinical studies, this study investigated the protective effects of diltiazem on vascular endothelial cell (VEC) injury induced by angiotensin-II (AngII), hypoxia, and a combination of both treatments. The concentration of intracellular free calcium and the mitochondrial membrane potential in VEC were assessed as indicators of cell injury. An in vivo hypoxic animal model was used to test the protective effect of diltiazem on vascular endothelial tissues. Our study showed that AngII and hypoxia decreased the mitochondrial membrane potential in VEC, which was significantly inhibited by diltiazem. Diltiazem protected against VEC injury induced by the increased concentration of intracellular free calcium, which was associated with AngII and hypoxia. Diltiazem reduced the apoptosis of rat VEC under a sustained hypoxic condition. In addition, it reduced AngII and endothelin I levels in rat vascular endothelial tissues. Our study confirmed that AngII and hypoxia induced VEC injury by regulating the levels of mitochondrial membrane potential and intracellular free calcium. Diltiazem, a calcium channel blocker, protected VEC from AngII- and hypoxia-induced injury.

Topics: Angiotensin II; Animals; Apoptosis; Calcitonin Gene-Related Peptide; Calcium Channel Blockers; Calcium Signaling; Cells, Cultured; Cytoprotection; Diltiazem; Disease Models, Animal; Endothelial Cells; Endothelin-1; Humans; Hypoxia; Male; Membrane Potential, Mitochondrial; Mitochondria; Nitric Oxide; Nitric Oxide Synthase Type III; Rats, Wistar; Vascular Diseases

It is generally accepted that blockade of endothelin receptors has potentially beneficial effects on vasculopathy associated with systemic sclerosis (SSc). The aim of this study was to clarify the molecular mechanism underlying these effects using endothelial cell-specific Fli-1-knockout (Fli-1 ECKO) mice, an animal model of SSc vasculopathy.. Levels of messenger RNA for target genes and the expression and phosphorylation levels of target proteins were determined in human and murine dermal microvascular endothelial cells by real-time quantitative reverse transcription-polymerase chain reaction and immunoblotting, respectively. The binding of Fli-1 to the target gene promoters was evaluated using chromatin immunoprecipitation. Expression levels of Fli-1 and α-smooth muscle actin in murine skin were evaluated using immunohistochemistry. Vascular structure and permeability were evaluated in mice injected with fluorescein isothiocyanate-dextran and Evans blue dye, respectively.. In human dermal microvascular endothelial cells, endothelin 1 induced phosphorylation of Fli-1 at Thr(312) through the sequential activation of c-Abl and protein kinase Cδ, leading to a decrease in Fli-1 protein levels as well as a decrease in binding of Fli-1 to the target gene promoters, whereas bosentan treatment reversed those effects. In Fli-1 ECKO mice, 4 weeks of treatment with bosentan increased endothelial Fli-1 expression, resulting in vascular stabilization and the restoration of impaired leaky vessels.. The vascular fragility of Fli-1 ECKO mice was improved by bosentan through the normalization of Fli-1 protein levels and activity in endothelial cells, which may explain, in part, the mechanism underlying the beneficial effects of endothelin receptor blockade on SSc vasculopathy.

Topics: Actins; Animals; Bosentan; Capillary Permeability; Cell Line; Cells, Cultured; Chromatin Immunoprecipitation; Endothelial Cells; Endothelin Receptor Antagonists; Endothelin-1; Gene Expression; Humans; Immunoblotting; Immunohistochemistry; Mice; Mice, Knockout; Microvessels; Phosphorylation; Promoter Regions, Genetic; Protein Kinase C-delta; Proto-Oncogene Protein c-fli-1; Proto-Oncogene Proteins c-abl; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Scleroderma, Systemic; Sulfonamides; Vascular Diseases

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system with possible involvement of vascular dysregulation secondary to endothelial dysfunction caused by destruction of the vessel wall. Vascular dysregulation leads to excessive vasoconstriction or insufficient vasodilatation, resulting in vasospasm mediated by endothelin-1 (ET-1), the most potent and long-lasting mediator. Vascular dysregulation can play an important role in the pathogenesis of some eye disorders and it has been hypothesized that it is a vascular risk factor for glaucomatous optic neuropathy. The aim of this study was to estimate endothelin-1 (ET-1) plasma levels in patients with MS.. The MS group consisted of 39 patients (9 males, 30 females), mean age: 38.8 ± 10.02 years, range: 22-62. The control group consisted of 27 healthy volunteers (3 males and 24 females), mean age: 37.4 ± 10.88 years, range: 20-62; clinically, in a non-active stage of the disease. ET-1 plasma levels were measured using the Endothelin-1 ELISA Kit (Immuno-Biological Laboratories Co., Japan). Statistical analysis was performed with the nonparametric Mann-Whitney U test for independent groups.. Endothelin-1 (ET-1) plasma levels were significantly lower in MS patients compared to healthy controls: mean value 0.55 ± 0.44 pg/ml (146.05 ± 118.27 fmol/ml) vs. 0.95 ± 0.48 pg/ml (252.83 ± 127.16 fmol/ml); P=0.012.. Significantly decreased ET-1 plasma levels in the MS patients could reflect the non-active disease at the time of ET-1 measurements or the effects of immunomodulatory treatment, but it cannot be excluded that decreased ET-1 plasma levels in these patients might result from vascular dysregulation.

Topics: Adult; Case-Control Studies; Endothelin-1; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Vascular Diseases; Young Adult

Despite increase in survival of HIV patients due to highly active antiretroviral therapy (HAART), non-infectious complications are still prevalent such as presentation of lung vasculopathy, even in asymptomatic patients. Endothelin-1 (ET-1) is a potent vasoconstrictor that causes pulmonary vasculopathy. Participation of this protein in the pulmonary circulation in HIV patients has not been elucidated. In this work we studied the presence and expression of ET-1 in pulmonary complex vascular lesions associated with human immunodeficiency virus (PCVL/HIV).. We used immunohistochemistry and immunochemiluminescence (imagej) to determine the different degrees of expression of ET-1 in PCVL/HIV in comparison with non-PCVL/HIV. Reagents used were anti-endothelin-1 and an automated system. All data are presented as mean and standard deviation (SD). Differences were analyzed with one-way ANOVA; p < 0.05 was accepted as statistically significant.. Lung tissues from 56 patients who died from complications of HIV pulmonary infection and with PCVL were studied. Histological evidence of pulmonary vasculopathy was shown as different types (proliferative, obliterative and plexiform). A statistically significant increase in ET-1 expression was observed in all PCVL/HIV tissue samples and is associated directly with different grades of severity of endothelial dysfunction.. ET-1 has a relevant role in the pathogenesis of pulmonary vasculopathy in acquired immunodeficiency syndrome (AIDS) patients. It is necessary to determine in the future the participation of ET-1 and other mechanisms involved in PCVL/HIV.

Topics: Acquired Immunodeficiency Syndrome; Adult; Endothelin-1; Female; Humans; Lung; Lung Diseases; Male; Middle Aged; Pulmonary Artery; Pulmonary Circulation; Vascular Diseases; Young Adult

Oxidative stress as well as inflammation processes are engaged in diabetic vascular complications. Rosmarinic acid, a natural phenol antioxidant carboxylic acid, was found to have multiple biological activity, including anti-inflammatory and antitumour effects, which are a consequence of its inhibition of the inflammatory processes and of reactive oxygen species scavenging. The aim of this work was to study effects of rosmarinic acid administration on vascular impairment induced by experimental diabetes in rats.. Diabetes was induced by streptozocin (3 × 30 mg/kg daily, i.p.) in Wistar rats. Rosmarinic acid was administered orally (50 mg/kg daily). Ten weeks after streptozocin administration, the aorta was excised for functional studies, evaluation by electron microscopy and real time PCR analysis.. In the aorta of diabetic rats, decreased endothelium-dependent relaxation was accompanied by overexpression of interleukin-1β, tumour necrosis factor-α, preproendothelin-1 and endothelin converting enzyme-1. Structural alterations in the endothelium, detected by electron microscopy, indicated aortic dysfunction caused by diabetes. The diabetes-induced aortic disorders were prevented by rosmarinic acid administration.. Rosmarinic acid protected aortic endothelial function and ultrastructure against diabetes-induced damage. Both antioxidant and anti-inflammatory effects of rosmarinic acid seemed to participate in the mechanism of this protection.

Topics: Animals; Antioxidants; Aorta; Aspartic Acid Endopeptidases; Cinnamates; Depsides; Diabetes Complications; Diabetes Mellitus, Experimental; Endothelin-1; Endothelin-Converting Enzymes; Endothelium, Vascular; Interleukin-1beta; Lamiaceae; Male; Metalloendopeptidases; Phytotherapy; Rats; Rats, Wistar; Rosmarinic Acid; Tumor Necrosis Factor-alpha; Vascular Diseases; Vasodilation

Exposure to ambient air particulate matter (particles less than 10μm or PM10) has been shown to be an independent risk factor for the development and progression of atherosclerosis. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have well-established anti-inflammatory properties. The aim of this study was to determine the impact of statins on the adverse functional and morphological changes in blood vessels induced by PM10. New Zealand White rabbits fed with a high fat diet were subjected to balloon injury to their abdominal aorta followed by PM10/saline exposure for 4weeks±lovastatin (5mg/kg/day) treatment. PM10 exposure accelerated balloon catheter induced plaque formation and increased intimal macrophages and lipid accumulation while lovastatin attenuated these changes and promoted smooth muscle cell recruitment into plaques. PM10 impaired vascular acetylcholine (Ach) responses and increased vasoconstriction induced by phenylephrine as assessed by wire myograph. Supplementation of nitric oxide improved the impaired Ach responses. PM10 increased the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in blood vessels and increased the plasma levels of endothelin-1 (ET-1). Incubation with specific inhibitors for iNOS, COX-2 or ET-1 in the myograph chambers significantly improved the impaired vascular function. Lovastatin decreased the expression of these mediators in atherosclerotic lesions and improved endothelial dysfunction. However, lovastatin was unable to reduce blood lipid levels to the baseline level in rabbits exposed to PM10. Taken together, statins protect against PM10-induced cardiovascular disease by reducing atherosclerosis and improving endothelial function via their anti-inflammatory properties.

Topics: Animals; Atherosclerosis; Blood Vessels; Cholesterol, Dietary; Cyclooxygenase 2; Cytokines; Endothelin-1; Endothelins; Endothelium, Vascular; Environmental Exposure; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunohistochemistry; Lipids; Lovastatin; Male; Nitric Oxide Synthase Type II; Particulate Matter; Plaque, Atherosclerotic; Rabbits; Reactive Oxygen Species; Urban Health; Vascular Diseases

Gastrointestinal blood flow can be compromised during and after cardiopulmonary bypass. Endothelin has been shown to be involved in the intestinal microcirculatory disturbance of sepsis. The aim of the present study was to analyze the involvement of the endothelin system on intestinal blood flow regulation during cardiopulmonary bypass and the effect of vasopressin given during cardiopulmonary bypass.. A total of 24 pigs were studied in 4 groups (n = 6): group I, sham; group II, ischemia/reperfusion with 1 hour of superior mesenteric artery occlusion; group III, cardiopulmonary bypass for 1 hour; and group IV, 1 hour of cardiopulmonary bypass plus vasopressin administration, maintaining the baseline arterial pressure. All the pigs were reperfused for 90 minutes. During the experiment, the hemodynamics and jejunal microcirculation were measured continuously. The jejunal mucosal expression of endothelin-1 and its receptor subtypes A and B were determined using polymerase chain reaction.. During cardiopulmonary bypass, superior mesenteric artery flow was preserved but marked jejunal microvascular impairment occurred compared with baseline (mucosal capillary density, 192.2 ± 5.4 vs 150.8 ± 5.1 cm/cm(2); P = .005; tissue blood flow, 501.7 ± 39.3 vs 332.3 ± 27.9 AU; P = .025). The expression of endothelin-1 after cardiopulmonary bypass (3.2 ± 0.4 vs 12.2 ± 0.8 RQ, P = .006) and endothelin subtype A (0.7 ± 0.2 vs 2.4 ± 0.6 RQ; P = .01) was significantly increased compared to the sham group. Vasopressin administration during cardiopulmonary bypass led to normal capillary density (189.9 ± 3.9 vs 178.0 ± 6.3; P = .1) and tissue blood flow (501.7 ± 39.3 vs 494.7 ± 44.4 AU; P = .4) compared with baseline. The expression of endothelin-1 (3.2 ± 0.4 vs 1.8 ± 0.3 RQ; P = .3) and endothelin subtype A (0.7 ± 0.2 vs 0.9 ± 0.2 RQ; P = .5) was not different from the sham group.. Cardiopulmonary bypass leads to microvascular impairment of jejunal microcirculation, which is associated with the upregulation of endothelin-1 and endothelin subtype A. The administration of vasopressin minimizes these cardiopulmonary bypass-associated alterations.

Topics: Animals; Biopsy; Blood Flow Velocity; Capillaries; Cardiopulmonary Bypass; Endothelin-1; Ischemia; Jejunum; Mesenteric Artery, Superior; Mesenteric Ischemia; Microcirculation; Models, Animal; Real-Time Polymerase Chain Reaction; Receptor, Endothelin A; Receptor, Endothelin B; Regional Blood Flow; RNA, Messenger; Splanchnic Circulation; Sus scrofa; Time Factors; Vascular Diseases; Vasopressins

To explore the relationship between endothelial nitric oxide synthase (eNOS) activity, insulin resistance and macrovascular disease in patients with acute myocardial infarction (AMI).. AMI patients were grouped according to the presence (group A, n = 49) or absence (group B, n = 48) of macrovascular disease. A healthy control group was also recruited (group C, n = 43). eNOS activity and nitric oxide (NO), endothelin-1 (ET-1), fasting plasma glucose and fasting insulin levels were compared across groups. The homeostasis model assessment of insulin resistance (HOMA- IR) was calculated in each participant and correlations between biochemical parameters were determined.. eNOS and NO levels were significantly lower in group A compared with the other groups. Conversely, ET-1 levels and the HOMA-IR were significantly higher in group A. eNOS activity and NO levels were significantly lower, and ET-1 levels and HOMA-IR were significantly higher, in group B compared with controls. Across the groups there were inverse correlations in AMI patients between eNOS and HOMAIR, NO and HOMA-IR, eNOS and ET-1, and NO and ET-1, and positive correlations between eNOS and NO, regardless of whether macrovascular disease was present.. There is a close relationship between eNOS activity and the development of insulin resistance and macrovascular disease in AMI patients.

Topics: Adult; Aged; Blood Glucose; Endothelin-1; Endothelium, Vascular; Female; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Myocardial Infarction; Nitric Oxide; Nitric Oxide Synthase Type III; Vascular Diseases

Streptozotocin-induced diabetes leads to the development of endothelial dysfunction, as evidenced by decreased expression of endothelial nitric oxide synthase (eNOS) and increased expression of endothelin-1 as specific markers of endothelial disorders. All test substances showed endotelioprotective activity by increasing the concentration of eNOS and reducing the level of endothelin-1. With respect to the degree of impact on the eNOS and endothelin-1 levels, the compounds studied can be rated as follows: sulodexide > meksidol.

Topics: Animals; Biomarkers; Blood Glucose; Diabetes Mellitus, Experimental; Endothelin-1; Endothelium; Glycosaminoglycans; Immunohistochemistry; Male; Nitric Oxide Synthase Type III; Picolines; Rats; Vascular Diseases

Pulmonary vascular remodeling and dysfunction associated to tobacco smoking might pave the way for the subsequent development of pulmonary hypertension. Its prognosis is dreadful and its underlying mechanisms are so far largely unknown in humans. To assess the potential role of endothelin-1 and its receptors in smokers' pulmonary artery vasoactive properties. Endothelium-dependent vasodilation to ACh was assessed in pulmonary vascular rings from 34 smokers and compared with that of 10 nonsmokers. The effects of ET-A (BQ 123) or ET-B (BQ 788) blockers and that of an ET-B activator (sarafotoxin) were evaluated. Endothelin-1 was quantitated by ELISA. Expression of its receptors was quantitated by Western blotting. Smokers exhibited an impaired pulmonary endothelium-dependent vasodilation compared with nonsmokers (P < 0.01). In the former group, 8 of 34 subjects exhibited a marked endothelial dysfunction (ED(+)) whereas 26 (ED(-)) (P < 10(-4)) displayed a vasorelaxation to ACh that was comparable to that of nonsmokers. In ED(+) subjects, ET-A was overexpressed (P < 0.05) and inversely correlated (P < 10(-2)) with the response to ACh. Sarafotoxin significantly improved vasodilation in all subjects (P < 10(-2)). In conclusion, tobacco smoking is associated to an impaired pulmonary vasorelaxation at least partly mediated by an ET-1/ET-A-dependent dysfunction.

Topics: Acetylcholine; Adult; Aged; Antihypertensive Agents; Blotting, Western; Ciprofloxacin; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Oligopeptides; Peptides, Cyclic; Piperidines; Pulmonary Circulation; Receptor, Endothelin A; Receptor, Endothelin B; Smoking; Vascular Diseases; Vasodilation; Vasodilator Agents

Insulin stimulates both nitric oxide (NO)-dependent vasodilation and endothelin-1 (ET-1)-dependent vasoconstriction. However, the cellular mechanisms that control the dual vascular effects of insulin remain unclear. This study aimed to investigate the roles of the multidomain adaptor protein APPL1 in modulating vascular actions of insulin in mice and in endothelial cells.. Both APPL1 knockout mice and APPL1 transgenic mice were generated to evaluate APPL1's physiological roles in regulating vascular reactivity and insulin signaling in endothelial cells.. Insulin potently induced NO-dependent relaxations in mesenteric arteries of 8-week-old mice, whereas this effect of insulin was progressively impaired with ageing or upon development of obesity induced by high-fat diet. Transgenic expression of APPL1 prevented age- and obesity-induced impairment in insulin-induced vasodilation and reversed obesity-induced augmentation in insulin-evoked ET-1-dependent vasoconstriction. By contrast, genetic disruption of APPL1 shifted the effects of insulin from vasodilation to vasoconstriction. At the molecular level, insulin-elicited activation of protein kinase B (Akt) and endothelial NO synthase and production of NO were enhanced in APPL1 transgenic mice but were abrogated in APPL1 knockout mice. Conversely, insulin-induced extracellular signal-related kinase (ERK)1/2 phosphorylation and ET-1 expression was augmented in APPL1 knockout mice but was diminished in APPL1 transgenic mice. In endothelial cells, APPL1 potentiated insulin-stimulated Akt activation by competing with the Akt inhibitor Tribbles 3 (TRB3) and suppressed ERK1/2 signaling by altering the phosphorylation status of its upstream kinase Raf-1.. APPL1 plays a key role in coordinating the vasodilator and vasoconstrictor effects of insulin by modulating Akt-dependent NO production and ERK1/2-mediated ET-1 secretion in the endothelium.

Topics: Adaptor Proteins, Signal Transducing; Animals; Cells, Cultured; Endothelin-1; Endothelium, Vascular; Gene Expression Regulation; Gene Silencing; Human Umbilical Vein Endothelial Cells; Humans; In Vitro Techniques; Insulin; Insulin Resistance; Mesenteric Arteries; Mice; Mice, Knockout; Mice, Transgenic; Nitric Oxide; Obesity; Signal Transduction; Vascular Diseases; Vasoconstrictor Agents; Vasodilator Agents

Several important genes that are involved in inflammation and tissue remodeling are switched on by virtue of CRE response elements in their promoters. The upstream signaling mechanisms that inflammatory mediators use to activate cAMP response elements (CREs) are poorly understood. Endothelin (ET) is an important vasoactive mediator that plays roles in inflammation, vascular remodeling, angiogenesis, and carcinogenesis by activating 7 transmembrane G protein-coupled receptors (GPCR). Here we characterized the mechanisms ET-1 uses to regulate CRE-dependent remodeling genes in pulmonary vascular smooth muscle cells. These studies revealed activation pathways involving a cyclooxygenase-2 (COX-2)/prostacyclin receptor (IP receptor) autocrine loop and an interlinked calcium-dependent pathway. We found that ET-1 activated several CRE response genes in vascular smooth muscle cells, particularly COX-2, amphiregulin, follistatin, inhibin-beta-A, and CYR61. ET-1 also activated two other genes epiregulin and HB-EGF. Amphiregulin, follistatin, and inhibin-beta-A and epiregulin were activated by an autocrine loop involving cPLA2, arachidonic acid release, COX-2-dependent PGI(2) synthesis, and IP receptor-linked elevation of cAMP leading to CRE transcription activation. In contrast COX-2, CYR61, and HB-EGF transcription were regulated in a calcium-dependent, COX-2 independent, manner. Observations with IP receptor antagonists and COX-2 inhibitors were confirmed with IP receptor or COX-2-specific small interfering RNAs. ET-1 increases in intracellular calcium and gene transcription were dependent upon ET(a) activation and calcium influx through T type voltage-dependent calcium channels. These studies give important insights into the upstream signaling mechanisms used by G protein-coupled receptor-linked mediators such as ET-1, to activate CRE response genes involved in angiogenesis, vascular remodeling, inflammation, and carcinogenesis.

Topics: Autocrine Communication; Calcium; Cyclic AMP; Cyclooxygenase 2; Endothelin-1; Gene Expression Regulation; Humans; Muscle, Smooth, Vascular; Phospholipases A2; Phospholipases A2, Cytosolic; Pulmonary Artery; Receptors, Epoprostenol; Response Elements; Up-Regulation; Vascular Diseases

We recently demonstrated that non-toxic inhibition of the proteasome upregulates antioxidative enzymes and leads to an adaptive transcriptional pattern in endothelial cells. We therefore hypothesized that proteasome inhibition could prevent experimentally-induced endothelial dysfunction. As there are conflicting data about the effects of proteasome inhibition on endothelial function, we investigated whether proteasome inhibition could prevent experimentally-induced endothelial dysfunction.. Endothelial dysfunction in isolated rat aortic rings was induced by incubation of rings with TNFalpha for 48 h. To study the effects of the inhibition of the proteasome, selected rings were co-treated with proteasome inhibitors. Vasorelaxation and expression of genes involved in endothelial function were evaluated.. Incubation of rat aortic rings with TNFalpha for 48 h led to significant dose-dependent reduction of acetylcholine-induced vasorelaxation. Co-incubation with TNFalpha and the proteasome inhibitor MG132 resulted in dose-dependent improvement of endothelium-dependent vasorelaxation in comparison to rings treated with TNFalpha alone. Levels of eNOS mRNA and protein were reduced despite improved vascular function after treatment with MG132. MG132 markedly suppressed mRNA levels of NADPH oxidase subunits and increased SOD1 expression. Superoxide production was reduced in rings incubated with MG132 in comparison to controls. TNFalpha-induced upregulation of the potent vasoconstrictor endothelin was abolished by MG132.. Proteasome inhibition prevents TNFalpha-induced vascular dysfunction by reduction of superoxide production and suppression of endothelin levels. The balance between vasoconstriction and vasodilatation is shifted in favour of endothelium-dependent vasodilation.

Topics: Animals; Aorta; Endothelin-1; Endothelium, Vascular; Enzyme Inhibitors; Gene Expression Regulation; Male; Nitric Oxide Synthase Type III; Proteasome Inhibitors; Rats; Rats, Wistar; Reactive Oxygen Species; RNA, Messenger; Tumor Necrosis Factor-alpha; Vascular Diseases; Vasodilation

Pulmonary hypertension is rare in chronic respiratory diseases but has a strong impact on the prognosis and is partly underlined by factors other than hypoxaemia. The aim of the present study was to assess the potential role of endothelin-1 (ET-1) and nuclear factor (NF)-kappaB vasoconstrictive pathways in pulmonary hypertension. The effects of ET-1 receptors blockers (BQ 123 and 788) and of genistein were assessed on response to acetylcholine of pulmonary vascular rings from cystic fibrosis (CF) lung transplant recipients (n = 23). NF-kappaB and ET-1 receptor expression was immunodetected in pulmonary arteries and quantitated using Western blotting. ET-1 vascular content was quantitated using ELISA. In total, 14 out of 23 subjects exhibited strongly impaired pulmonary vasodilation (p<0.01 versus nine out of 23 subjects with a normal response) associated with an activation of ET-1 receptors A and NF-kappaB pathways. Genistein restored vasodilation in subjects with an abnormal response. Pulmonary vascular dysfunction is frequent in end-stage CF, involving the NF-kappaB pathway and that of ET-1 through ET-1 receptor A (ETAR). These data leave a conceptual place for ETAR blockers and isoflavones in the management of the devastating vascular complication of chronic obstructive respiratory diseases such as CF.

Topics: Acetylcholine; Adult; Cystic Fibrosis; Dose-Response Relationship, Drug; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation; Genistein; Homeostasis; Humans; Hypertension, Pulmonary; Male; NF-kappa B; Vascular Diseases

This study was designed to examine the effects of a high-fat, high-sucrose (HFHS) diet on vascular and metabolic actions of insulin. Male rats were randomized to receive an HFHS or regular chow diet for 4 wk. In a first series of experiments, the rats had pulsed Doppler flow probes and intravascular catheters implanted to measure blood pressure, heart rate, and regional blood flows. Insulin sensitivity and vascular responses to insulin were assessed during a euglycemic hyperinsulinemic clamp performed in conscious rats. In a second series of experiments, new groups of rats were used to examine skeletal muscle glucose transport activity and to determine in vitro vascular reactivity, endothelial nitric oxide synthase (eNOS) protein expression in muscle and vascular tissues and endothelin content, nitrotyrosine formation, and NAD(P)H oxidase protein expression in vascular tissues. The HFHS-fed rats displayed insulin resistance, hyperinsulinemia, hypertriglyceridemia, hyperlipidemia, elevated blood pressure, and impaired insulin-mediated renal and skeletal muscle vasodilator responses. A reduction in endothelium-dependent vasorelaxation, accompanied by a decreased eNOS protein expression in muscles and blood vessel endothelium, and increased vascular endothelin-1 protein content were also noted in HFHS-fed rats compared with control rats. Furthermore, the HFHS diet induced a reduced insulin-stimulated glucose transport activity in muscles and increased levels of NAD(P)H oxidase protein and nitrotyrosine formation in vascular tissues. These findings support the importance of eNOS protein in linking metabolic and vascular disease and indicate the ability of a Westernized diet to induce endothelial dysfunction and to alter metabolic and vascular homeostasis.

Topics: Animals; Blood Pressure; Blotting, Western; Body Weight; Deoxyglucose; Diet; Dietary Fats; Endothelin-1; Endothelium, Vascular; Fatty Acids, Nonesterified; Fluorescent Antibody Technique; Glucose Clamp Technique; Heart Rate; Insulin; Insulin Resistance; Male; Obesity; Organ Size; Rats; Rats, Sprague-Dawley; Sucrose; Triglycerides; Tyrosine; Vascular Diseases; Vascular Resistance

The pathogenesis of cigarette smoke-induced pulmonary hypertension is not understood. We have previously shown that smoke rapidly and persistently, but discoordinately, upregulates gene expression of mediators that control vasoconstriction, vasoproliferation, and vasorelaxation in small intrapulmonary arteries. To investigate the possibility that smoke also induces endothelial dysfunction, a finding common to other forms of pulmonary hypertension, we exposed guinea pigs to smoke or air (control) daily for 2 wk and then prepared precision-cut lung slices. After exposure to endothelin-1, a vasoconstrictor, intra-acinar arteries in lung slices derived from smoke-exposed animals constricted more rapidly (greater constriction at a given concentration of endothelin) than did vessels from air-exposed animals. To examine relaxation responses, arteries were constricted with the vasoconstrictor U-46619 and then relaxed with progressively increasing doses of acetylcholine. Vessels from smokers had a delayed response to acetylcholine compared with vessels from controls. The NO synthase inhibitor N(G)-nitro-L-arginine methyl ester reduced relaxation in both control and smoke-exposed arteries, whereas the NO donor sodium nitroprusside increased relaxation of the smoke-exposed arteries, confirming that endothelial dysfunction with decreased effective NO production is present. These findings show that precision cut lung slices can be used to examine the physiological effects of cigarette smoke on intra-acinar pulmonary arteries and indicate that even relatively short-term exposure to smoke produces endothelial dysfunction with a resulting tendency to earlier constriction and later relaxation in cigarette smokers. These changes may be important in the development of pulmonary hypertension.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Arteries; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Enzyme Inhibitors; Female; Guinea Pigs; Lung; Muscle Contraction; NG-Nitroarginine Methyl Ester; Nicotiana; Nitric Oxide Synthase Type III; Nitroprusside; Organ Culture Techniques; Pulmonary Circulation; Smoke; Vascular Diseases; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

Several congenital heart defects require surgery that acutely increases pulmonary blood flow (PBF). This can lead to dynamic alterations in postoperative pulmonary vascular resistance (PVR) and can contribute to morbidity and mortality. Thus the objective of this study was to determine the role of nitric oxide (NO), endothelin (ET)-1, and their interactions in the alterations of PVR after surgically induced increases in PBF. Twenty lambs underwent placement of an aortopulmonary vascular graft. Lambs were instrumented to measure vascular pressures and PBF and studied for 4 h. Before and after shunt opening, lambs received an infusion of saline (n = 9), tezosentan, an ETA- and ETB -receptor antagonist (n = 6), or Nomega-nitro-L-arginine (L-NNA), a NO synthase (NOS) inhibitor (n = 5). In control lambs, shunt opening increased PBF by 117.8% and decreased PVR by 40.7% (P < 0.05) by 15 min, without further changes thereafter. Plasma ET-1 levels increased 17.6% (P < 0.05), and total NOS activity decreased 61.1% (P < 0.05) at 4 h. ET-receptor blockade (tezosentan) prevented the plateau of PBF and PVR, such that PBF was increased and PVR was decreased compared with controls at 3 and 4 h (P < 0.05). These changes were associated with an increase in total NOS activity (+61.4%; P < 0.05) at 4 h. NOS inhibition (L-NNA) after shunt placement prevented the sustained decrease in PVR seen in control lambs. In these lambs, PVR decreased by 15 min (P < 0.05) but returned to baseline by 2 h. Together, these data suggest that surgically induced increases in PBF are limited by vasoconstriction, at least in part by an ET-receptor-mediated decrease in lung NOS activity. Thus NO appears to be important in maintaining a reduction in PVR after acutely increased PBF.

Topics: Animals; Blood Flow Velocity; Endothelin-1; Nitric Oxide; Pulmonary Artery; Pulmonary Circulation; Sheep; Vascular Diseases; Vascular Surgical Procedures

Endothelins (EDNs) are peptides, produced by various tissues, with potent vasoactive and mitogenic properties. Endothelin actions are mediated via specific G protein-coupled receptors of two subtypes, endothelin-receptor-A (EDNRA) and endothelin-receptor-B (EDNRB). Some polymorphisms of the EDN1, EDN2 and EDNRA genes may influence susceptibility to vascular diseases. Thus, genotyping for polymorphisms of these genes may represent a tool for predicting individual susceptibility to vascular diseases. Here, we report 11 fluorescence resonance energy transfer (FRET) assays for the detection of 15 polymorphisms, because the assays used in previous studies (allele-specific PCR and restriction fragment-length polymorphism assays) for some of these polymorphisms are laborious and time-consuming. The newly developed assays are fast and work without expensive ready-to-use mixtures.

Topics: DNA Probes; Endothelin-1; Endothelin-2; Fluorescence Resonance Energy Transfer; Genotype; Humans; Nucleic Acid Hybridization; Polymorphism, Single Nucleotide; Receptor, Endothelin A; Vascular Diseases; White People

The association of endothelin 1 (ET-1) and endothelial constitutive nitric oxide synthase (ecNOS) gene polymorphisms (G5665T and T8002C, VNTR and T-786C respectively) with the occurrence of acute chest syndrome and painful vaso-occlusive crises was evaluated in homozygous SS children. This retrospective study reveals that ET-1 T8002 and ecNOS C-786 alleles are associated with, respectively, an increased and a decreased risk of acute chest syndrome.

Topics: Adolescent; Anemia, Sickle Cell; Chest Pain; Child; Endothelin-1; Female; Genetic Predisposition to Disease; Humans; Male; Nitric Oxide Synthase Type III; Pain; Polymorphism, Genetic; Vascular Diseases

Regular, moderate consumption of red wine is linked to a reduced risk of coronary heart disease and to lower overall mortality, but the relative contribution of wine's alcohol and polyphenol components to these effects is unclear. Here we identify procyanidins as the principal vasoactive polyphenols in red wine and show that they are present at higher concentrations in wines from areas of southwestern France and Sardinia, where traditional production methods ensure that these compounds are efficiently extracted during vinification. These regions also happen to be associated with increased longevity in the population.

Topics: Aged; Biflavonoids; Catechin; Cells, Cultured; Endothelin-1; Endothelium, Vascular; Female; France; Humans; Longevity; Male; Proanthocyanidins; Protective Agents; Vascular Diseases; Wine

Immunosuppressive drugs common in clinical transplantation are known to have untoward effects on the vascular system. The effects of some drugs, notably cyclosporin A (CyA), have been studied on the vascular system, while those of others have not. In the vascular system, endothelial cells are the predominant cell type exposed to intravascular concentrations of immunosuppressive drugs. We therefore studied the effects of drugs common in clinical transplantation on endothelial cells in a capillary tube assay. The endothelial cells in the capillary tubes are morphologically more similar to those in the microvasculature than endothelial cells in monolayers. We studied the kinetics and extent of capillary tube formation and prostacyclin (PGI2) and endothelin-1 (ET-1) release from the in vitro capillaries to determine the morphological and biochemical effects of five immunosuppressive agents on endothelial function. We found a significant difference in the morphological and biochemical effects of the two common calcineurin inhibitors, CyA and tacrolimus (FK506) on capillary morphology in vitro. The former had a pronounced injurious effect on the morphology of the in vitro capillaries, while the latter did not. CyA also significantly increased ET-1 release by the capillaries, but FK506 did not. Mycophenolate mofetil (MMF) was the only other agent that had a moderately injurious effect on the morphology of the in vitro capillaries. Sirolimus (rapamycin) and dexamethasone, similar to FK506, had no effect on the capillary morphology. All these agents, except dexamethasone, increased PGI2 release. Our data suggest that CyA adversely affects the morphology of the microvasculature and that this is mediated, at least partly, by an increased ET-1 release by endothelial cells exposed to CyA. These findings describe a novel effect of CyA and MMF on endothelial cells that could be relevant to understanding the mechanisms of immunosuppressive drug-mediated endothelial injury in clinical transplantation.

Topics: Cell Survival; Cyclosporine; Dexamethasone; Endothelin-1; Endothelium, Vascular; Epoprostenol; Humans; Immunosuppressive Agents; In Vitro Techniques; Mycophenolic Acid; Sirolimus; Tacrolimus; Vascular Diseases

Fabry disease is an X-linked inborn error of glycosphingolipid metabolism due to the deficient activity of alpha-galactosidase A, a lysosomal enzyme. It is a multisystem disorder characterized by progressive renal insufficiency, with added morbidity from cardio- and cerebrovascular involvement. The recent availability of genetically engineered enzyme offers an effective targeted treatment approach, but also emphasizes the need for surrogate markers to delineate organ damage and monitor the efficacy of enzyme replacement therapy (ERT).. Multiple endothelial factors and plasma homocysteine concentrations were investigated in 12 consecutive hemizygous males with classic Fabry disease and 15 controls as part of an exhaustive baseline evaluation prior to ERT.. Compared with the controls, plasma concentrations of homocysteine were significantly (p < 0.01) higher in patients with Fabry disease in the absence of chronic renal failure or vitamin deficiency. Plasma concentrations of vascular cell adhesion molecule-1 were also significantly (p < 0.05) higher in the patients, and there was a trend for decreased endothelin-1 levels. No difference was found in serum intercellular adhesion molecule-1, plasma P-selectin, serum E-selectin and plasma thrombomodulin between the patients and controls.. The results do not reveal measurable evidence for endothelial and leukocyte activation that could reliably serve as surrogate markers for routine monitoring of the efficacy of ERT in patients with Fabry disease. While the exact origin and clinical significance of hyperhomocysteinaemia in Fabry disease remains to be studied in a larger cohort of patients carefully monitored for their concurrent medications, especially carbamazepine, we suggest that patients may benefit from folic acid or multivitamin therapy to treat this additional vascular risk factor, when present.

Topics: Adolescent; Adult; Cohort Studies; Creatinine; E-Selectin; Endothelin-1; Fabry Disease; Homocysteine; Humans; Intercellular Adhesion Molecule-1; Male; Middle Aged; P-Selectin; Thrombomodulin; Vascular Cell Adhesion Molecule-1; Vascular Diseases

The enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD) prevents inappropriate activation of the nonselective mineralocorticoid receptors by glucocorticoids. Renal activity of 11beta-HSD is decreased in patients with apparent mineralocorticoid excess (SAME), licorice-induced hypertension, and essential hypertension. Although expressed in vascular cells, the role of 11beta-HSD in the regulation of vascular tone remains to be determined.. lycyrrhizic acid (GA; 50 mg/kg IP, twice daily for 7 days) caused a significant inhibition of 11beta-HSD activity and induced hypertension in Wistar-Kyoto rats (157 versus 127 mm Hg in controls; P<0.01). After 11beta-HSD inhibition, aortic endothelial nitric oxide (NO) synthase (eNOS) protein content, nitrate tissue levels, and acetylcholine-induced release of NO were blunted (all P<0.05 versus controls). In contrast, vascular prepro-endothelin (ET)-1 gene expression, ET-1 protein levels, and vascular reactivity to ET-1 were enhanced by GA treatment (P<0.05 versus controls). Chronic ET(A) receptor blockade with LU135252 (50 mg. kg(-1). d(-1)) normalized blood pressure, ET-1 tissue content, vascular reactivity to ET-1, vascular eNOS protein content, and nitrate tissue levels and improved NO-mediated endothelial function in GA-treated rats (P<0.05 to 0.01 versus untreated and verapamil-treated controls). In human endothelial cells, GA increased production of ET-1 in the presence of corticosterone, which indicates that activation of the vascular ET-1 system by 11beta-HSD inhibition can occur independently of changes in blood pressure but is dependent on the presence of glucocorticoids.. Chronic ET(A) receptor blockade normalizes blood pressure, prevents upregulation of vascular ET-1, and improves endothelial dysfunction in 11beta-HSD inhibitor-induced hypertension and may emerge as a novel therapeutic approach in cardiovascular disease associated with reduced 11beta-HSD activity.

Topics: 11-beta-Hydroxysteroid Dehydrogenases; Acetylcholine; Animals; Blood Pressure; Body Weight; Cells, Cultured; Corticosterone; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Endothelium, Vascular; Gene Expression Regulation; Glycyrrhizic Acid; Heart Rate; Humans; Hydroxysteroid Dehydrogenases; Hypertension; Male; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Norepinephrine; Phenylpropionates; Potassium Chloride; Protein Precursors; Pyrimidines; Rats; Rats, Inbred WKY; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; RNA, Messenger; Vascular Diseases; Vasoconstriction; Vasodilation; Vasodilator Agents; Verapamil

Topics: Aspartic Acid Endopeptidases; Benzazepines; Benzhydryl Compounds; Benzofurans; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Enzyme Inhibitors; Heart Failure; Humans; Metalloendopeptidases; Organophosphonates; Pyrimidines; Vascular Diseases; Vasoconstrictor Agents

Clinical trials have shown that tight glycemic control reduces the risk of diabetic microvascular complications, namely retinopathy, nephropathy, and neuropathy. The mechanism of these microvascular complications is not yet fully elucidated. The present study describes the effect of different concentrations of glucose on vascular endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) in cell culture. Our objective was to shed some light through this biological study on the mechanism and prevention of diabetic microvascular complications.. ECs and VSMCs were treated with 5 mmol/L (90 mg/dL) or 30 mmol/L (540 mg/dL) D-glucose or D-glucose plus insulin or D-glucose plus insulin and heparin in culture. ECs were studied with light microscopy (LM), scanning electron microscopy (SEM), and transmission electron microscopy (TEM) for surface changes. The cultured ECs were treated with vimentin antibodies and VSMCs with actin antibodies for immunoflourescence microscopy (IFM) study. Endothelin-1 (ET-1) assay was done on ECs culture medium using enzyme-linked immunosorbent assay (ELISA).. LM, SEM, and TEM of ECs treated with a physiological concentration (90 mg/dL) of D-glucose appeared the same as control. However, LM and SEM of ECs treated with a high concentration of D-glucose (540 mg/dL) showed pronounced intercellular gaps. This finding was further confirmed by TEM study. These gaps were minimally or not at all discernible when insulin, heparin, or a combination of both was added to the culture medium. IFM showed increased vimentin expression with a high concentration of D-glucose. Vimentin expression was attenuated with the addition of insulin or heparin in the medium and more markedly with combined insulin and heparin. Significant correlations were obtained between glucose levels, vimentin expression, and ET-1 levels. The higher the glucose level, the higher is the ET-1 production and the greater vimentin expression in ECs. Cultured VSMCs treated with a high concentration of D-glucose showed enhanced actin expression. Actin expression was blunted with the addition of insulin or heparin in the culture medium.. These biological findings indicate the salutary effect of insulin or insulin and heparin in the mitigation of vascular disorganization caused by a high concentration of D-glucose.

Topics: Cell Line; Endothelin-1; Endothelium, Vascular; Fluorescent Antibody Technique; Glucose; Heparin; Insulin; Microscopy, Electron; Microscopy, Electron, Scanning; Osmolar Concentration; Vascular Diseases

Plasma endothelin-1, the nitric oxide (NO) mediator intraplatelet cyclic guanosine monophosphate (cGMP), the prostacyclin mediator cyclic adenosine monophosphate (cAMP) and the macrophage derived inflammatory mediator plasma neopterin were measured in men with Type 2 diabetes mellitus (n=91), impaired glucose tolerance (IGT; n=51), previously abnormal glucose tolerance (PAGT; n=20), and 34 healthy control men. Plasma endothelin-1was higher in men with Type 2 diabetes mellitus than in controls [4.1 (1.0-14.3) vs. 2.1 (0.2-8. 7) ng/l; P<0.001). Intraplatelet cGMP was higher in men with PAGT [0. 84 (0.57-2.76) pmol/10(9) platelets; P<0.05], IGT [0.85 (0.48-3.53); P<0.001] and Type 2 diabetes mellitus [0.90 (0.47-3.86); P<0.001] than in controls [0.70 (0.42-1.70]. No differences existed between groups concerning intraplatelet cAMP or plasma neopterin. Plasma endothelin-1 correlated with fasting plasma glucose (r=0.33; P<0.001) and HbA1(c) (r=0.29; P<0.001). In conclusion, elevated plasma endothelin-1 in Type 2 diabetes mellitus and its relationship to glucose and HbA1(c) suggest a putative role for endothelin-1 in diabetic endothelial cell damage. Increased cGMP indicating enhanced production/activity of NO suggests that factors other than reduced NO activity contribute to enhanced platelet aggregation in diabetes.

Topics: Aged; Blood Glucose; Blood Platelets; Blood Pressure; Cholesterol; Cyclic GMP; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelin-1; Glucose Intolerance; Glycated Hemoglobin; Humans; Leukocyte Count; Lipoproteins, HDL; Lipoproteins, LDL; Male; Middle Aged; Reference Values; Smoking; Vascular Diseases

Transplant vasculopathy in kidney and heart allografts is associated with marked elevation of endothelin-1 (ET-1), but a role for ET-1 in the pathogenesis of transplant vasculopathy and chronic rejection has not been established. We, therefore, tested whether inhibition of ET-1-converting enzyme by phosphoramidon (PA) would attenuate rejection in a rat model of chronic cardiac allograft rejection (Lewis [LEW] to F344).. Donor LEW rats were pretreated 24 hr before transplantation with a bolus injection of vehicle (water) or PA. Twenty- four hour after transplantation, water or PA was continuously administered through an osmotic mini-pump. Plasma ET-1 levels in Fisher 344 (F344) recipients were 0.8+/-0.1 pg/ml in water-treated rats and 0.2+/-0.2 pg/ml (P<0.01) in PA-treated rats, demonstrating that the PA treatment protocol effectively lowered ET-1 biosynthesis.. LEW cardiac allografts treated with water survived (i.e., palpable heart beat) for 16.0+/-0.5 days (n=6). Inhibition of ET-1 secretion by PA improved allograft survival to 28.8+/-3.3 days (P<0.01, n=8). An analysis of cardiac arteries demonstrated that PA treatment attenuated transplant vasculopathy. A morphometric scale of neointima formation (0-5) was 1.4+/-0.2 and 3.6+/-0.2 in PA- or water-treated rats, respectively (P<0.01). The percent of luminal occlusion, as measured by microscopic image analysis, was 19+/-6% in PA-treated animals and 38+/-6% (P<0.01) in animals treated with water. PA treatment also reduced infiltration of ED-1-positive monocytes/macrophages into the vascular neointima.. We conclude that, even in the absence of concomitant immunosuppression, inhibition of ET-1 biosynthesis significantly attenuates transplant vasculopathy and improves survival of LEW to F344 cardiac allografts.

Topics: Animals; Aspartic Acid Endopeptidases; Endothelin-1; Endothelin-Converting Enzymes; Glycopeptides; Graft Rejection; Graft Survival; Heart Transplantation; Macrophages; Metalloendopeptidases; Protease Inhibitors; Rats; Rats, Inbred F344; Rats, Inbred Lew; Transplantation, Homologous; Vascular Diseases

Treatment with intravenous recombinant human interleukin-2 (rh IL-2) is frequently accompanied by the capillary leak syndrome and disturbances of the coagulation system. Although the exact mechanisms are still not fully understood, the involvement of the endothelium is proven. This investigation aimed to elucidate more precisely the role of the endothelium in the generation of IL-2-based side-effects. In nine tumour patients receiving intravenous rh IL-2, parameters characterizing endothelial cell activation as well as activation of the coagulation system were evaluated. A significant increase of the circulating endothelial leucocyte adhesion molecule-1 (cELAM-1) and the vasoconstrictor peptide endothelin-1 (ET-1) was observed (P<0.05), indicating activation of endothelial cells. The simultaneous increase of tissue-plasminogen activator and plasminogen activator inhibitor type-1 during therapy (P<0.05) corroborated this observation. A decrease in platelet count parallelled by an increase of fibrin degradation products, the prolongation of partial thromboplastin time, and the decrease of fibrinogen (P<0.05) suggested the development of disseminated intravascular coagulation (DIC), induced by activated endothelium and intensified by transient hepatic failure. We concluded that activation of the endothelium mediated by IL-2 was accompanied by a loss of endothelial integrity and capillary leak. The activated endothelium can trigger DIC via activation of the coagulation cascade. The increased ET-1 might act as an endogenous counter-regulator of the disadvantageous haemodynamic side-effects induced by IL-2.

Topics: Blood Coagulation; Capillaries; Cell Adhesion Molecules; Cytokines; E-Selectin; Endothelin-1; Endothelium, Vascular; Fibrinolysis; Humans; Intercellular Adhesion Molecule-1; Interleukin-2; Neoplasms; Syndrome; Vascular Diseases

Raynaud's phenomenon has been suggested as a predisposing factor for pulmonary vasospasm which may lead to pulmonary hypertension, but the occurrence of cold stimulus-induced pulmonary vasospasm has been inconsistent. Such inconsistent pulmonary vascular responses may be caused by differences in the production of endogenous vasodilators and vasoconstrictors among patients. Fourteen patients with Raynaud's phenomenon associated with mixed connective tissue disease (n=10) or systemic sclerosis (n=4) participated in the study. Right heart catheterization was performed before and after a cold pressor test, immersing a hand in cold water (15 degrees C) for 5 min. Plasma levels of 6-keto prostaglandin (PG)F1alpha, thromboxane (TX)B2 and endothelin (ET)-1 in the mixed venous blood were measured. Mean pulmonary artery pressure increased after the cold pressor test in five of 14 patients, and the patients were divided into those with pulmonary vasospasm (responders) and those without vasospasm (nonresponders). After the cold pressor test, levels of 6-keto PGF1alpha increased significantly in nonresponders (p<0.01) and decreased significantly in responders (p<0.05). The ratios of 6-keto PGF1alpha to TXB2 significantly increased in nonresponders (p<0.01) but not in responders and the difference between responders and nonresponders after the cold pressor test was also statistically significant (p<0.05). No significant change in plasma ET-1 levels occurred in either responders or nonresponders. The results suggest that an impaired production of prostaglandin I2 and an imbalance between prostaglandin I2 and thromboxane A2 are associated with the occurrence of pulmonary vasospasm induced by Raynaud's phenomenon.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Cold Temperature; Endothelin-1; Female; Hemodynamics; Humans; Male; Middle Aged; Pulmonary Artery; Pulmonary Veins; Raynaud Disease; Respiratory Function Tests; Spasm; Thromboxane B2; Vascular Diseases

The relative contributions of microvascular inflammation and vasomotor dysregulation to the development of acute vaso-occlusive crisis in sickle cell disease have been intensely studied. The present observational study was designed to examine the levels of circulating proinflammatory cytokines, anti-inflammatory cytokines, and vasoactive mediators during and after acute painful crisis. In symptomatic sickle cell patients, plasma levels of endothelin-1 and prostaglandin E2 were elevated during crises compared with healthy African-American controls. These levels had decreased, but not normalized, when patients were seen 1 to 3 weeks after discharge from hospital. Other mediators (tumor necrosis factor alpha [TNFalpha], interleukin-1beta [IL-1beta], IL-6, IL-8, and IL-10) were neither elevated in asymptomatic sickle cell disease nor in acute vaso-occlusive crisis. As a potent long-acting mediator of vasoconstriction and inflammation, endothelin-1 may play a key role in the cycle of ischemia and inflammation that initiates and sustains pain of crisis. The downregulatory effects of prostaglandin E2 on immune cell function may contribute to the increased susceptibility to infection observed in patients with sickle cell disease.

Topics: Acute Disease; Adult; Anemia, Sickle Cell; Cell Adhesion Molecules; Cytokines; Dinoprostone; Endothelin-1; Humans; Ischemia; Microcirculation; Middle Aged; Monocytes; Pain; Vascular Diseases; Vasculitis; Vasoconstriction

Plasma endothelin-1 was measured around the clock in 72 subjects. Cosinor methods were used to assess circadian and other recurrent variation and trends, that is, the time structure (chronome) of this peptide. Multifactorial analyses of variance and linear regressions assessed chronome alterations associated with different risk factors: diabetes, obesity, high cholesterol, high blood pressure, vascular disease, smoking, and age. The rhythm-adjusted mean (MESOR) of endothelin-1 is elevated in diabetes and vascular disease. Diabetes is also associated with a larger circadian amplitude. A circadian variation in a subgroup of low-risk subjects is modulated by components with both lower and higher frequency.

Topics: Adult; Aged; Circadian Rhythm; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Endothelin-1; Female; Humans; Hypertension; Male; Middle Aged; Periodicity; Regression Analysis; Risk Factors; Time Factors; Vascular Diseases

Plasma ET-1 was measured around the clock on different calendar dates in healthy subjects and in subjects with diabetes and/or with high blood pressure and/or a history of vascular complications (HVDR). A transverse approach, with each subject contributing a single 24-h mean, assessed any about-weekly or half-weekly variation in ET-1. A circasemiseptan component resolved by single cosinor for nondiabetic (but not for diabetic) HVDR subjects (p = 0.010) differs in its timing of overall high values (p < 0.050) from that found in healthy subjects (p = 0.006). The results are aligned with circasemiseptan patterns in other circulatory variables and morbidity/mortality statistics.

Topics: Adult; Aged; Aged, 80 and over; Blood Pressure; Cardiovascular Diseases; Circadian Rhythm; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Endothelin-1; Female; Humans; Longitudinal Studies; Male; Middle Aged; Periodicity; Risk Factors; Vascular Diseases

To assess endothelin-1 (ET-1) response to cold stimulation in essential acrocyanosis (EA), the authors measured ET-1 plasma concentrations in 6 patients with EA (6 women, age range seventeen to thirty-seven years) and in 6 controls (5 women, 1 man, age range twenty-one to thirty-seven years) before and after cold challenge by unilateral hand immersion in water bath at 13 degrees C for five minutes. The contralateral upper limb was considered as control. Blood samples were simultaneously drawn from an antecubital vein in the cooled side and in the contralateral upper limb at baseline, at the end of cooling, and at ten and ninety minutes after cooling was begun. Plasma ET-1 was determined by a radioimmunoassay system. Results are mean +/- SD. Baseline ET-1 was higher in patients with EA (5.1 +/- 0.3 pmol/L) than in controls (1.9 +/- 0.1 pmol/L, P < 0.001). After hand cooling, ET-1 in the cold-exposed upper limb rose in patients with EA to a peak value of 7.2 +/- 0.7 pmol/L, which was greater than that observed in healthy subjects (2.7 +/- 0.4 pmol/L, P < 0.001). The absolute increase in ET-1 plasma concentrations from baseline to peak value was significantly higher in patients with EA than in controls (2.1 +/- 0.3 vs 0.8 +/- 0.2 pmol/L, respectively, P < 0.001). In patients with EA, but not in controls, the rise in ET-1 plasma concentrations was still detected ninety minutes after cooling. The same time course of the plasma ET-1 concentrations was observed in the noncooled upper limb, but the increases in ET-1 at different times after cold stimulus were smaller than in the cold-challenged upper limb in both groups (P < 0.001). In conclusion, the results demonstrate that in patients with EA, baseline plasma levels of ET-1 are enhanced and are further increased by cooling until ninety minutes after cold challenge. This rise in plasma ET-1 could contribute to potentiating and prolonging cold-induced vasoconstriction/vasospasm and/or could be a marker for endothelial damage in EA.

Topics: Adolescent; Adult; Cold Temperature; Cyanosis; Endothelin-1; Female; Humans; Vascular Diseases; Vasoconstriction

The present study was designed to examine the role of endothelin-1 (ET-1), an endothelium-derived potent long-acting vasoconstrictor peptide, in vascular acrosyndromes with hypersensitivity to cold. Plasma ET-1 concentration was measured, before and after cold test, in 12 subjects with "a frigore" vascular acrosyndromes (9 females and 3 males, age range 17-59 years), of whom 6 were with primary Raynaud's phenomenon and 6 with essential acrocyanosis, and in 6 controls (5 females and 1 male, age range 21-37 years). Cold stimulation was performed by immersion of one hand into a water bath at 13 degrees C for 5 minutes. Blood samples were simultaneously drawn from an antecubital vein in the cooled side and in the contralateral arm at baseline, at the stop of cooling, at 10 and 90 minutes from the beginning of the cold challenge. Mean (+/-SD) baseline ET-1 plasma levels, as measured by radioimmunoassay, were higher in patients with "a frigore" vascular acrosyndromes (4.8 +/- 0.3 pmol/l) than in control subjects (1.9 +/- 0.1 pmol/l, p < 0.001). After hand cooling ET-1 rose in patients with "a frigore" vascular disorders to a peak value of 7.0 +/- 0.4 pmol/l, which was much greater than that observed in healthy subjects (2.7 +/- 0.4 pmol/l, p < 0.001). Absolute increase in ET-1 plasma concentrations from baseline to peak value was significantly higher in patients with "a frigore" vascular acrosyndromes than in normal subjects (2.2 +/- 0.3 vs 0.8 +/- 0.2 pmol/l, p < 0.001), being only in the former group the rise in ET-1 still detected 90 minutes after cold test. Plasma levels of ET-1 in the controlateral arm raised in a similar fashion, but absolute values were lower than in cooled arm. Circulating ET-1 levels in patients with primary Raynaud's phenomenon and essential acrocyanosis showed a similar pattern during the study. Our data demonstrate that in patients with "a frigore" vascular acrosyndromes baseline and cold-stimulated plasma ET-1 concentrations are increased. Further, in these vascular disorders, exaggerated ET-1 response to cold is prolonged. These findings suggest that increased ET-1 may contribute to an imbalance between vasoactive mediators in the cutaneous blood vessels contributing to the abnormal vasoconstriction to cold in these disorders. Alternatively, the increment in ET-1 release may represent a marker for endothelial cell damage in "a frigore" vascular acrosyndromes.

Topics: Adolescent; Adult; Cold Temperature; Endothelin-1; Female; Humans; Male; Middle Aged; Raynaud Disease; Syndrome; Vascular Diseases