endothelin-1 and Metabolic-Syndrome

Aldosterone exerts direct effects on the vascular system by inducing oxidative stress, inflammation, hypertrophic remodeling, fibrosis, and endothelial dysfunction. Aldosterone exerts its effects through genomic and nongenomic pathways in a mineralocorticoid receptor (MR)-dependent or independent manner. Other aldosterone receptors such as GPR30 have been identified. A tight relation exists between the aldosterone and angiotensin II pathways, as well as with the endothelin-1 system. There is a correlation between plasma levels of aldosterone and cardiovascular risk. Recently, an increasing body of evidence has underlined the importance of aldosterone in cardiovascular complications associated with the metabolic syndrome, such as arterial remodeling and endothelial dysfunction. Blockade of MR is an increasingly used evidence-based therapy for many forms of cardiovascular disease, including hypertension, heart failure, chronic kidney disease, and diabetes mellitus.

Topics: Adipocytes; Aldosterone; Angiotensin II; Animals; Antihypertensive Agents; Blood Vessels; Cardiovascular Diseases; Endothelin A Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Fibrosis; Gene Expression Regulation; Humans; Hypertension; Hypertrophy; Metabolic Syndrome; Mineralocorticoid Receptor Antagonists; Mineralocorticoids; Muscle, Smooth, Vascular; Oxidative Stress; Receptor, Endothelin A; Receptors, Mineralocorticoid; Renin-Angiotensin System; Signal Transduction; Sodium; Vasculitis; Vasoconstriction

Benign prostatic hyperplasia (BPH) is a common disease in older men that can lead to lower urinary tract symptoms (LUTS). Male sexual dysfunction is also an age-related condition. Epidemiological studies have confirmed an association between BPH/LUTS and sexual dysfunction in ageing men that is independent of the effects of age, other co-morbidities and lifestyle factors. Proposed pathophysiological mechanisms for BPH/LUTS-associated sexual dysfunction include the nitric oxide/cyclic guanosine monophosphate (NO/cGMP) pathway, rho-kinase and endothelin-1 activity, autonomic nervous system overactivity and the metabolic syndrome, and pelvic organ atherosclerosis. Both BPH/LUTS and sexual dysfunction can have a substantial negative impact on a man's quality of life. However, urologists and primary care physicians appear to under-recognise sexual dysfunction in men with BPH/LUTS. Current guidelines recommend alpha-blockers and 5-alpha reductase inhibitors, either alone or in combination, among appropriate medical treatment options for BPH/LUTS. Randomised, controlled trials demonstrate that these therapies can be associated with sexual adverse effects (AEs) such as loss of libido, erectile dysfunction and ejaculatory disorders. Sexual dysfunction should be fully evaluated in men requiring treatment for BPH/LUTS using validated questionnaires. Management of sexual dysfunction in men treated for BPH/LUTS should involve assessment of co-morbidities and concomitant medications, consideration of lifestyle interventions such as weight loss and increased physical activity to improve risk factors and, if necessary, introduction of pharmacotherapies. In addition, physicians should provide patients with proper counselling on the possible sexual AEs of medical therapies for BPH/LUTS and their impact on sexual satisfaction, while being aware of the possibility that counselling in itself is likely to influence reported rates of sexual dysfunction.

Topics: 5-alpha Reductase Inhibitors; Adrenergic alpha-Antagonists; Adult; Aged; Atherosclerosis; Autonomic Nervous System Diseases; Cyclic GMP; Drug Combinations; Endothelin-1; Humans; Male; Metabolic Syndrome; Middle Aged; Nitric Oxide; Prostatic Hyperplasia; Prostatism; rho-Associated Kinases; Sexual Dysfunction, Physiological

There is increasing evidence to suggest that chronic activation of the endothelin-1 system can lead to heterologous desensitization of the glucose-regulatory and mitogenic actions of insulin with subsequent development of glucose intolerance, hyperinsulinemia, impaired endothelial function and exacerbation of cardiovascular disease. Effects are mediated through a variety of mechanisms that include attenuation of key insulin signalling pathways and decreased tyrosine phosphorylation of insulin receptor substrates IRS-1, SHC and G alpha q/11. Other actions involve hemodynamic changes leading to reduced delivery of insulin and glucose to peripheral tissues as well as enhanced hepatic glycogenolysis, decreased glucose-transporter translocation and modulation of various adipokines that regulate insulin action. Overall the data suggest that ET-1 antagonists may provide an effective means of improving cardiac dysfunction and favourably influencing glucose tolerance in obese humans and patients with early insulin sensitivity where there is clear evidence for activation of the ET-1 system. Although most effects of ET-1 that modulate mechanisms leading to glucose intolerance appear to involve the ETA receptor subtype recent data indicates that combined ETA/ETB receptor antagonists may function as effectively as selective ETA blockers. Prospective trials are needed to assess whether ET-1 antagonists, either alone or in combination, are superior to other more conventional therapies such as insulin sensitizers and to evaluate effects of combined treatments on the development of insulin resistance and the progression of diabetes. Early screening of patients at risk for evidence of ET-1 activation would help to identify subjects who may benefit most from such treatment.

Topics: Animals; Endothelin-1; Humans; Insulin Resistance; Metabolic Syndrome; Obesity

Two syndromes are called syndromes X: cardiac (effort anginal pain, positive exercise tolerance test and absence of angiographically documented critical stenosis in coronary arteries) and metabolic (according to WHO definition: impaired glucose tolerance and insulin resistance and > or = 2 risk factors from the following list: hypertension, dyslipidaemia, visceral obesity and microalbuminuria). Hyperinsulinaemia and endothelial dysfunction are present in both syndromes. The contribution of endothelial nitric oxide synthase gene mutations to the etiology of these syndromes is also studied. Several mechanisms may be involved in the development of endothelial dysfunction, such as reduced synthesis and release of nitric oxide (NO), enhanced inactivation of NO after its release from endothelial cells or enhanced synthesis of vasoconstricting agents. It has been demonstrated that insulin exerts a direct hypertrophic effect on the vascular endothelium and the smooth muscle cells. The hemodynamic properties of insulin have also been discussed. Some findings suggest that in the skeletal muscle circulation, insulin stimulates both endothelin-1 (ET-1) and nitric oxide activity and an imbalance between the release of these two substances may be involved in the pathophysiology of endothelial dysfunction.

Topics: Albuminuria; Endothelin-1; Humans; Hyperinsulinism; Hyperlipidemias; Hypertension; Insulin; Metabolic Syndrome; Microvascular Angina; Mutation; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Obesity; Risk Factors

The aim of this study was to evaluate the effect of virgin olive oils (VOOs) enriched with phenolic compounds and triterpenes on metabolic syndrome and endothelial function biomarkers in healthy adults. The trial was a three-week randomized, crossover, controlled, double-blind, intervention study involving 58 subjects supplemented with a daily dose (30 mL) of three oils: (1) a VOO (124 ppm of phenolic compounds and 86 ppm of triterpenes); (2) an optimized VOO (OVOO) (490 ppm of phenolic compounds and 86 ppm of triterpenes); and (3) a functional olive oil (FOO) high in phenolic compounds (487 ppm) and enriched with triterpenes (389 ppm). Metabolic syndrome and endothelial function biomarkers were determined in vivo and ex vivo. Plasma high density lipoprotein cholesterol (HDLc) increased after the OVOO intake. Plasma endothelin-1 levels decreased after the intake of the three olive oils, and in blood cell cultures challenged. Daily intake of VOO enriched in phenolic compounds improved plasma HDLc, although no differences were found at the end of the three interventions, while VOO with at least 124 ppm of phenolic compounds, regardless of the triterpenes content improved the systemic endothelin-1 levels in vivo and ex vivo. No effect of triterpenes was observed after three weeks of interventions. Results need to be confirmed in subjects with metabolic syndrome and impaired endothelial function (Clinical Trials number NCT02520739).

Topics: Adult; Biomarkers; Cholesterol, HDL; Cross-Over Studies; Dietary Supplements; Double-Blind Method; Endothelin-1; Endothelium, Vascular; Energy Intake; Female; Food, Fortified; Humans; Male; Metabolic Syndrome; Middle Aged; Olive Oil; Phenols; Phytochemicals; Triterpenes

Previous studies of the health effects of low-fat milk or dairy consumption on the metabolic syndrome have yielded inconsistent results. The present study aimed to investigate the effects of low-fat milk consumption on traits associated with the metabolic syndrome, as well as inflammatory and atherogenic biomarkers, in Korean adults with the metabolic syndrome.. Overweight Koreans with the metabolic syndrome (n = 58) were recruited and randomly assigned to either the low-fat milk or control group. The low-fat milk group was instructed to consume two packs of low-fat milk per day (200 mL twice daily) for 6 weeks, and the control group was instructed to maintain their habitual diet. Clinical investigations were conducted during the screening visit, on study day 0, and after 6 weeks.. No significant differences in changes in body mass index, blood pressure, lipid profile and adiponectin levels, as well as levels of inflammatory markers, oxidative stress markers and atherogenic markers, were found between the low-fat milk and control groups. However, compared to the controls, significant favourable decreases in serum soluble vascular adhesion molecule-1 and endothelin-1 levels were found in the 12 subjects with high blood pressure and in the 18 subjects with hypertriglyceridaemia in the low-fat milk group.. The present study did not demonstrate an overall beneficial effect of low-fat milk consumption in subjects with the metabolic syndrome. However, low-fat milk consumption may have a favourable effect on atherogenic markers in subjects with high blood pressure or hypertriglyceridaemia.

Topics: Adult; Animals; Atherosclerosis; Biomarkers; Body Mass Index; Diet, Fat-Restricted; Endothelin-1; Follow-Up Studies; Humans; Hypertension; Hypertriglyceridemia; Inflammation Mediators; Insulin Resistance; Metabolic Syndrome; Middle Aged; Milk; Overweight; Oxidative Stress; Patient Dropouts; Republic of Korea; Risk Factors; Vascular Cell Adhesion Molecule-1

Patients with metabolically healthy obesity (MHO) do not present the cluster of metabolic abnormalities that define the metabolic syndrome (MetS). Whether MHO is associated with lower impairment of vasoreactivity than the MetS is unknown. For this purpose, forearm blood flow (FBF) responses were measured by strain-gauge plethysmography during the intra-arterial infusion of acetylcholine (ACh), sodium nitroprusside (SNP), and/or the selective endothelin type A (ETA) receptor blocker BQ-123 in 119 obese individuals with MHO (n = 34) or with the MetS (n = 85) and in healthy lean controls (n = 56). ACh and SNP caused a significant vasodilation in both obese and lean participants (all P < 0.001). However, the response to both agents was significantly lower in the obese than in the control group (both P < 0.001). Among the obese participants, the reactivity to ACh was higher in MHO than in MetS patients, whereas the responsiveness to SNP was equally impaired in both groups (P = 0.45). Infusion of BQ-123 significantly increased FBF in obese patients (P < 0001), but not in the lean participants; hence, FBF following ETA receptor blockade was higher in both obese groups than in controls (both P < 0.001). FBF response to BQ-123 was significantly higher in patients with the MetS than in those with MHO (P = 0.007). In conclusion, patients with MHO have abnormal vascular reactivity, although their endothelial dysfunction is less pronounced than in patients with the MetS. These findings indicate that obesity is associated with vascular damage independent of those metabolic abnormalities underlying the MetS.

Topics: Acetylcholine; Adult; Endothelin-1; Endothelium, Vascular; Female; Forearm; Humans; Male; Metabolic Syndrome; Middle Aged; Nitroprusside; Obesity, Metabolically Benign; Peptides, Cyclic; Regional Blood Flow; Vasoconstriction; Vasodilation

Leptin has nitric oxide (NO)-dependent vasodilator actions, but hyperleptinemia is an independent risk factor for cardiovascular disease.. The objective of the study was to investigate whether, in the human circulation, properties of leptin to release NO are opposed by stimulation of vasculotoxic substances, such as endothelin (ET)-1, and whether this mechanism might contribute to vascular damage in hyperleptinemic states like obesity.. Forearm blood flow responses (plethysmography) to ETA receptor antagonism (BQ-123, 10 nmol/min) and NO synthase inhibition [N(G)-monomethyl L-arginine (L-NMMA), 4 μmol/min] were assessed before and after intraarterial administration of leptin (2 μg/min) in lean controls (n = 8) and patients with obesity-related metabolic syndrome (MetS; n = 8).. Baseline plasma leptin was higher in patients than in controls (P < .001). Before infusion of leptin, the vasodilator response to BQ-123 was greater in patients than in controls (P < .001), whereas infusion of L-NMMA induced higher vasoconstriction in controls than in patients (P = .04). In lean subjects, hyperleptinemia resulted in increased vasodilator response to ETA receptor antagonism (P < .001 vs before) and enhanced vasoconstrictor effect of L-NMMA during ETA receptor blockade (P = .015 vs before). In patients with the MetS, by contrast, vascular responses to both BQ-123 and L-NMMA were not modified by exogenous leptin (both P > .05 vs before).. These findings indicate that, under physiological conditions, leptin stimulates both ET-1 and NO activity in the human circulation. This effect is absent in hyperleptinemic patients with the MetS who are unresponsive to additional leptin. In these patients, therefore, hyperleptinemia may be a biomarker of vascular dysfunction, rather than a mediator of vascular damage.

Topics: Adult; Antihypertensive Agents; Atherosclerosis; Endothelin A Receptor Antagonists; Endothelin-1; Enzyme Inhibitors; Female; Humans; Leptin; Male; Metabolic Syndrome; Middle Aged; Nitric Oxide; Nitric Oxide Synthase; Obesity; omega-N-Methylarginine; Peptides, Cyclic; Plethysmography; Receptor, Endothelin A; Risk Factors; Thinness; Vasodilation

Traffic-related air pollution is consistently associated with cardiovascular morbidity and mortality. Recent human and animal studies suggest that exposure to air pollutants affects vascular function. Diesel exhaust (DE) is a major source of traffic-related air pollution.. Our goal was to study the effects of short-term exposure to DE on vascular reactivity and on mediators of vascular tone.. In a double-blind, crossover, controlled exposure study, 27 adult volunteers (10 healthy and 17 with metabolic syndrome) were exposed in randomized order to filtered air (FA) and each of two levels of diluted DE (100 or 200 microg/m(3) of fine particulate matter) in 2-hr sessions. Before and after each exposure, we assessed the brachial artery diameter (BAd) by B-mode ultrasound and collected blood samples for endothelin-1 (ET-1) and catecholamines. Postexposure we also assessed endothelium-dependent flow-mediated dilation (FMD).. Compared with FA, DE at 200 microg/m(3) elicited a decrease in BAd (0.11 mm; 95% confidence interval, 0.02-0.18), and the effect appeared linearly dose related with a smaller effect at 100 microg/m(3). Plasma levels of ET-1 increased after 200 microg/m(3) DE but not after FA (p = 0.01). There was no consistent impact of DE on plasma catecholamines or FMD.. These results demonstrate that short-term exposure to DE is associated with acute endothelial response and vasoconstriction of a conductance artery. Elucidation of the signaling pathways controlling vascular tone that underlie this observation requires further study.

Topics: Adult; Brachial Artery; Catecholamines; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Endothelin-1; Female; Humans; Inhalation Exposure; Male; Metabolic Syndrome; Middle Aged; Particulate Matter; Time Factors; Ultrasonography; Vasoconstriction; Vasodilation; Vehicle Emissions

Endothelin plays an important role in the pathogenesis of atherosclerosis. The aim of the study was to evaluate the safety and hemodynamic and metabolic responses to 6 months treatment with atrasentan, the selective endothelin-A receptor antagonist. Seventy-two patients with multiple cardiovascular risk factors and nonobstructive coronary artery disease on coronary angiogram were randomly assigned in a double-blind manner to atrasentan or placebo. Mean aortic blood pressure decreased from 92+/-10 to 80+/-10 mm Hg (P<0.001) in the atrasentan group and did not change in the placebo group (93+/-10 and 92+/-11 mm Hg; P=0.84). The difference between the groups was significant (P<0.001). No effect on heart rate was observed. In a subgroup of patients not treated with angiotensin-converting enzyme inhibitor, creatinine level decreased in the atrasentan versus the placebo group (P=0.011). Fasting glucose (P=0.026), glycosylated hemoglobin level (P=0.041), triglyceride l (P=0.013), lipoprotein-A (P=0.046), and uric acid levels (P=0.048) decreased significantly in the atrasentan group compared with the placebo group. No progression of angiographic coronary disease was observed. The most common adverse effects with atrasentan were nasal stuffiness, headache, and edema. In conclusion, 6 months of treatment with atrasentan results in a reduction of blood pressure and improvement in glucose and lipid metabolism. These findings suggest the beneficial role of atrasentan in the treatment of hypertension and metabolic syndrome.

Topics: Adult; Antihypertensive Agents; Atrasentan; Blood Glucose; Blood Pressure; Coronary Artery Disease; Edema; Endothelin A Receptor Antagonists; Endothelin-1; Female; Follow-Up Studies; Humans; Hypertension; Kidney; Lipid Metabolism; Male; Metabolic Syndrome; Middle Aged; Pyrrolidines; Receptor, Endothelin A; Risk Factors; Treatment Outcome

Endothelin-1 is a potent vasoconstrictor in the body. Previous studies have identified associations between the coding polymorphism K198N and hypertension, systolic blood pressure and HDL levels. We sought to examine the evidence for these associations and, additionally, the association between K198N, insulin resistance, metabolic syndrome and coronary artery disease (CAD). We used generalised linear modelling to test K198N for association with hypertension and systolic blood pressure, lipid levels, insulin resistance scores and metabolic syndrome in a general cross-sectional community sample. Mean carotid intima media thickness and risk of carotid plaque were examined in the general population sample, and Gensini score was examined in a sample of patients with CAD. A case/control sample was used to examine the association of K198N with risk of CAD. There was no significant evidence for association between K198N and hypertension, systolic blood pressure, lipid levels, insulin resistance or metabolic syndrome in either population. The minor allele was marginally associated with increased mean IMT levels (P = 0.02) in the general population sample, although not with CAD in the case/control study or with the severity of disease in patients with CAD. In conclusion, we found no robust evidence for the associations between K198N and hypertension, systolic blood pressure or HDL levels seen in previous studies.

Topics: Adult; Aged; Blood Pressure; Case-Control Studies; Cholesterol, HDL; Coronary Artery Disease; Cross-Sectional Studies; Endothelin-1; Female; Glucose; Humans; Hypertension; Insulin Resistance; Lipoproteins; Male; Metabolic Syndrome; Middle Aged; Polymorphism, Genetic; Surveys and Questionnaires

The mechanisms by which thiazolidinediones exert beneficial effects on the endothelium are still not clear. We examined the effects of rosiglitazone on the plasma markers of metabolic control (glucose, insulin, adiponectin, resistin, and lipid profiles), markers of inflammation (high-sensitivity C-reactive protein [CRP], interleukin-6, soluble CD40 ligand, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1), and markers of vasoreactivity (asymmetric dimethylarginine [ADMA] and endothelin-1) and analyzed the relations between changes in endothelium-dependent flow-mediated dilation of the brachial artery and changes in these markers to elucidate their roles in mediating the vascular protective effects of rosiglitazone. Of 70 nondiabetic patients who met a modified National Cholesterol Education Program definition of the metabolic syndrome, 35 were randomized to receive rosiglitazone (4 mg/day) and 35 to receive placebo for 8 weeks. At study end, treatment with rosiglitazone had significantly reduced plasma insulin (-25%, p = 0.004) and resistin (-16%, p <0.001), increased adiponectin (164%, p <0.001), low-density lipoprotein cholesterol (16%, p = 0.005), and apolipoprotein-B (14%, p = 0.003), and decreased CRP (-30%, p = 0.005), soluble CD40 ligand (-20%, p = 0.014), ADMA (-16%, p <0.001), and endothelin-1 (-11%, p <0.001) concentrations and systolic and diastolic blood pressures. Rosiglitazone treatment significantly improved flow-mediated dilation (p <0.001) and nitroglycerin-induced vasodilation (p = 0.001) of the right brachial artery. On multivariate analysis, changes in ADMA, endothelin-1, and CRP were independent predictors of improved endothelial reactivity with rosiglitazone. In conclusion, we have, for the first time, demonstrated the independent associations between the improvement in flow-mediated dilation and reductions in ADMA, endothelin-1, and CRP after 8 weeks of treatment with rosiglitazone in nondiabetic patients with the metabolic syndrome. These findings suggest that decreases in ADMA, endothelin-1, and CRP may serve as possible mechanisms for the improvement in endothelial function conferred by rosiglitazone treatment.

Topics: Arginine; Blood Pressure; Body Mass Index; C-Reactive Protein; Case-Control Studies; Cholesterol, HDL; Endothelin-1; Endothelium-Dependent Relaxing Factors; Female; Glucose; Humans; Insulin; Male; Metabolic Syndrome; Middle Aged; Regression Analysis; Rosiglitazone; Thiazolidinediones; Treatment Outcome; Vasodilator Agents

This study evaluated sE-selectin, Endothelin-1, and cardiovascular autonomic neuropathy (CAN) at early stages of glucose intolerance and in metabolic syndrome (MetS). A total of 87 subjects - 39 males, of mean age 45.7±11.6 years and mean BMI 31.4±6.6 kg/m

Topics: Adult; Aged; Blood Glucose; Body Composition; Body Mass Index; E-Selectin; Endothelin-1; Female; Glucose Intolerance; Humans; Male; Metabolic Syndrome; Middle Aged

To better understand the effects of a diet high in fat, sugar, and sodium on cerebrovascular function, Sprague Dawley rats were chronically exposed to a Cafeteria diet. Resting cerebral perfusion and cerebrovascular reactivity was quantified using continuous arterial spin labeling (CASL) magnetic resonance imaging (MRI). In addition, structural changes to the cerebrovasculature and susceptibility to ischemic lesion were examined. Compared to control animals fed standard chow (SD), Cafeteria diet (CAF) rats exhibited increased resting brain perfusion in the hippocampus and reduced cerebrovascular reactivity in response to 10% inspired CO

Topics: Animals; Blood-Brain Barrier; Cerebral Cortex; Cerebrovascular Circulation; Diet, Western; Disease Models, Animal; Endothelin-1; Hemodynamics; Hippocampus; Male; Metabolic Syndrome; Random Allocation; Rats, Sprague-Dawley; Stroke

To study the endothelial dysfunction by measuring Nitric Oxide and Endothelin-1, and inter-genotypic variation of inducible Nitric Oxide Synthase gene (C150T) polymorphism among the study subjects.. 50 diagnosed cases of metabolic syndrome as per International Diabetes Federation (IDF) criteria and 50 healthy volunteers as control were enrolled. Nitric Oxide, Endothelin were measured and PCR-RFLP was done to identify the iNOS gene C150T polymorphism and its effect on serum nitric oxide levels.. Subjects with metabolic syndrome had lower NO levels (16.3 ± 10.3 vs 20.9 ± 11 µM, p = 0.032) and higher endothelin (2.68 ± 1.73 vs 1.98 ± 0.82 fmol/ml, p = 0.011). The frequency of mutant T allele (10% vs 9%) was higher in cases. Serum nitric oxide levels were lower in cases expressing the Mutant T allele as compared to wild type C allele. However, the differences were not statistically significant.. The present study demonstrated that iNOS C150T polymorphism did not show significant association with metabolic syndrome. Serum nitric oxide levels could be influenced by factors other than genetic polymorphism of iNOS gene (C150T) which cause endothelial dysfunction in metabolic syndrome and associated co-morbidities.

Topics: Alleles; Endothelin-1; Endothelium; Female; Genetic Association Studies; Humans; Male; Metabolic Syndrome; Nitric Oxide; Nitric Oxide Synthase Type II; Polymorphism, Genetic

Adverse conditions during early developmental stages permanently modify the metabolic function of organisms through epigenetic changes. Exposure to high sugar diets during gestation and/or lactation affects susceptibility to metabolic syndrome or hypertension in adulthood. The effect of a high sugar diet for shorter time lapses remains unclear. Here we studied the effect of short-term sucrose ingestion near weaning (postnatal days 12 and 28) (STS) and its effect after long-term ingestion, for a period of seven months (LTS) in rats. Rats receiving sucrose for seven months develop metabolic syndrome (MS). The mechanisms underlying hypertension in this model and those that underlie the effects of short-term exposure have not been studied. We explore NO and endothelin-1 concentration, endothelial nitric oxide synthase (eNOS) expression, fatty acid participation and the involvement of oxidative stress (OS) after LTS and STS. Blood pressure increased to similar levels in adult rats that received sucrose during short- and long-term glucose exposure. The endothelin-1 concentration increased only in LTS rats. eNOS and SOD2 expression determined by Western blot and total antioxidant capacity were diminished in both groups. Saturated fatty acids and arachidonic acid were only decreased in LTS rats. In conclusion, a high-sugar diet during STS increases the hypertension predisposition in adulthood to as high a level as LTS, and the mechanisms involved have similarities (participation of OS and eNOS and SOD expression) and differences (fatty acids and arachidonic acid only participate in LTS and an elevated level of endothelin-1 was only found in LTS) in both conditions. Changes in the diet during short exposure times in early developmental stages have long-lasting effects in determining hypertension susceptibility.

Topics: Adiposity; Age Factors; Animals; Blood Glucose; Blood Pressure; Dietary Sucrose; Disease Models, Animal; Endothelin-1; Fatty Acids; Hypertension; Insulin; Insulin Resistance; Lipid Peroxidation; Lipids; Male; Metabolic Syndrome; Nitric Oxide; Nitric Oxide Synthase Type III; Oxidative Stress; Rats, Wistar; Superoxide Dismutase; Superoxide Dismutase-1; Time Factors; Weaning

We studied association of single nucleotide polymorphism Glu298Asp (rs1799983) of the NOS3 gene with the risk of metabolic syndrome in the Slavic population. Blood samples were obtained from 128 patients with metabolic syndrome and 100 healthy individuals. Polymorphism Glu298Asp of the NOS3 gene was genotyped by allele-specific PCR. Allele Asp (OR=1.95, 95%CI 1.29-2.95, p=0.007) and genotype Asp/Asp (OR=2.56, 95%CI 0.98-6.72, p=0.04) were associated with the risk of metabolic syndrome in Slavic population. Patients with metabolic syndrome carrying genotype Asp/Asp had higher serum endothelin-1 level in comparison with Glu/Asp and Glu/Glu carriers.

Topics: Adult; Case-Control Studies; Endothelin-1; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Male; Metabolic Syndrome; Middle Aged; Nitric Oxide Synthase Type III; Pilot Projects; Polymorphism, Single Nucleotide

Endothelial dysfunction has been considered as one of the important factors in pathogenesis of Metabolic Syndrome (Met S). Subclinical hypothyroidism (SCH) has also been reported to be associated with Met S. The aim of our study is to evaluate the association of raised TSH with mediators of endothelial dysfunction in Met S with Subclinical hypothyroidism as compared to healthy controls.. Study population consisted of 100 subjects, out of which 50 were cases of Met S and 50 were healthy controls. Met S group were further divided into two, based on the presence & absence of SCH. Serum insulin, T3, T4, TSH were measured by chemiluminescence based immunoassay (CLIA). Serum nitric oxide (NO) levels were measured by Modified Griess's method and serum endothelin-1 (ET-1) levels were measured by ELISA.. Out of 50 cases of Met S, SCH was diagnosed in 22. The mean serum TSH levels were significantly higher in Met S cases as compared to healthy controls (5.7 ± 1.2 μIU/mL vs. 2.3 ± 1.6 μIU/mL, P <0.0001). Mean serum NO levels were significantly lower in Met S cases as compared to healthy control (15.4 ± 10 μM vs. 21 ± 10 μM, p = 0.009). Mean serum ET-1 levels were significantly higher in Met S cases as compared to healthy controls (2.68 ± 1.7 fmol/mL vs. 2.1 ± 0.84 fmol/mL, p = 0.011). On Pearson's correlation analysis, TSH showed positive correlation with ET-1 (r = 0.341, p = 0.001) and negative correlation with NO (r = -0.331, p = 0.001). Binary logistic regression analysis showed that TSH, NO and ET-1 has significant odd's ratio for predicting Met S.. Met S cases were screened for thyroid abnormalities and found to have 44% of SCH along with co-existing endothelial dysfunction. Raised TSH in SCH could cause endothelial dysfunction which may lead to Met S and associated co-morbidities. Present study gives new insight in linking endothelial dysfunction and raised TSH in Met S. Therefore, Met S cases should be screened for SCH and treated appropriately to attenuate endothelial dysfunction and associated comorbidities in Met S.

Topics: Adult; Case-Control Studies; Endothelin-1; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hypothyroidism; Insulin; Luminescence; Male; Metabolic Syndrome; Nitric Oxide; Thyrotropin; Thyroxine; Triiodothyronine

Recent research has shown that hypovitaminosis D may increase the risk of hypertension, vascular disease, diabetes mellitus, obesity and Metabolic Syndrome (MetS). Endothelial Dysfunction (ED) is one of the key components of MetS which is associated with an imbalance between vasoactive substances such as Nitric Oxide (NO) and Endothelins (ET). In this study, we assessed the association of 25(OH) D3 level with endothelial dysfunction and subclinical atherosclerosis in MetS patients.. 105 MetS patients and 48 controls were included. 25(OH) D3 levels were measured using Ultra-High Performance Liquid Chromatography (UHPLC). NOx (NO2 plus NO3) and Endothelin- 1(ET-1) concentrations were determined along with routine biochemical tests. Flow-Mediated Dilatation (FMD) and carotid Intima-Media Thickness (cIMT) were measured by ultrasonography.. In MetS patients, vitamin D and NOx levels were significantly lower (p<0.001), while ET-1 levels were higher than controls (p<0.005). MetS patients with ED exhibited significantly lower vitamin D levels than their counterparts free of ED. Vitamin D levels were correlated positively with FMD and NOx, and negatively with systolic blood pressure and body mass index. Subclinical atherosclerosis as assessed by the cIMT did not associate with low vitamin D levels.. Vitamin D deficiency seen in MetS patients is more prominent in the presence of ED. Hypovitaminosis D may affect endothelial cells, and participate in the development of hypertension.

Topics: Adult; Asymptomatic Diseases; Atherosclerosis; Biomarkers; Calcifediol; Carotid Intima-Media Thickness; Case-Control Studies; Chromatography, High Pressure Liquid; Endothelin-1; Endothelium, Vascular; Female; Humans; Male; Metabolic Syndrome; Middle Aged; Nitrates; Nitrites; Prognosis; Risk Factors; Vasodilation; Vitamin D Deficiency

Objective: To trace the development of disorders intravascular platelet activity in experimental form of the metabolic syndrome. The study included 61 rat male Wistar rats at the age of 2.5-3 months. Animals were divided into 2 groups: 32 rats were given free access to drink 10% solution of fructose for 8 weeks and 29 rats were the control group. The level of the total cholesterol, high density lipoprotein cholesterol (HDLD cholesterol) and triglycerides were determined using colorimetric enzymatic method. The blood plasma content of endothelin-1 was determined by radioimmunoassay, thromboxane B2 and 6-keto-prostaglandin F(1α)--by ELISA. The total content of nitrogen oxide metabolites was revealed in blood. Intravascular platelet activity was assessed using phase contrast microscopy. In terms of fructose load in rats simultaneously with the increase of body weight and the development of biochemical disorders that are characteristic for the metabolic syndrome, there comes a marked progressive increase in intravascular platelet activity [reduction of the number of discocytes from 81.0 ± 0.1 to 61.3 ± 0.2%, increase in the number of reactive platelets from 19.0 ± 0.1 to 38.7 ± 0.2%, an increase in the number of freely moving in the blood of small units from 2.4 ± 0.0 to 14.6 ± 0.1 per 100 free platelets, and of medium and large units (from 4 or more cells) from 0.1 ± 0.03 to 2.3 ± 0.06 per 100 free platelets], largely due to the increase (p < 0.01) of the synthesis of thromboxane B2 (from 145.9 ± 0.2 to 232.6 ± 0.7 pg/ml), endothelin-4 (from 6.9 ± 0.2 to 12.5 ± 0.4 pg/ml) and reduction (p < 0.01) of the generation of 6-keto-prostaglandin F1α (from 75.9 ± 0.2 to 62.3 ± 0.4 pg/ml), and the total amount of nitric oxide metabolites (from 27.9 ± 0.3 to 23.2 ± 0.1 mmol/l).

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Platelets; Endothelin-1; Fructose; Male; Metabolic Syndrome; Nitric Oxide; Platelet Activation; Rats; Rats, Wistar; Thromboxane B2

Metabolic syndrome including obesity, dyslipidemia and hypertension is a cluster of risk factors of cardiovascular disease. Fermentation of medicinal herbs improves their pharmacological efficacy. Red ginseng (RG), a widely used traditional herbal medicine, was reported with anti-inflammatory and anti-oxidant activity. Aim in the present study was to investigate that the effects of fermented red ginseng (FRG) on a high-fructose (HF) diet induced metabolic disorders, and those effects were compared to RG and losartan. Animals were divided into four groups: a control group fed a regular diet and tap water, and fructose groups that were fed a 60% high-fructose (HF) diet with/without RG 250 mg/kg/day or FRG 250 mg/kg/day for eight weeks, respectively. Treatment with FRG significantly suppressed the increments of body weight, liver weight, epididymal fat weight and adipocyte size. Moreover, FRG significantly prevented the development of metabolic disturbances such as hyperlipidemia and hypertension. Staining with Oil-red-o demonstrated a marked increase of hepatic accumulation of triglycerides, and this increase was prevented by FRG. FRG ameliorated endothelial dysfunction by downregulation of endothelin-1 (ET-1) and adhesion molecules in the aorta. In addition, FRG induced markedly upregulation of Insulin receptor substrate 1 (IRS-1) and glucose transporter type 4 (Glut4) in the muscle. These results indicate that FRG ameliorates obesity, dyslipidemia, hypertension and fatty liver in HF diet rats. More favorable pharmacological effects on HF diet induced metabolic disorders were observed with FRG, compared to an equal dose of RG. These results showed that the pharmacological activity of RG was enhanced by fermentation. Taken together, fermentated red ginseng might be a beneficial therapeutic approach for metabolic syndrome.

Topics: Adipocytes; Alanine Transaminase; Animals; Aspartate Aminotransferases; Blood Glucose; Blood Pressure; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Disease Models, Animal; Down-Regulation; Endothelin-1; Fermentation; Fructose; Glucose Transporter Type 4; Insulin Receptor Substrate Proteins; Liver; Losartan; Metabolic Syndrome; Obesity; Organ Size; Panax; Phytotherapy; Plant Preparations; Rats; Triglycerides; Up-Regulation

The relationship between nitric oxide production and metabolic disorders and the role of endothelial nitric oxide synthase (eNOS or NOS3) in metabolic syndrome (MS) remain poorly understood and need deeper investigation. In this context the role of the NOS3 gene in pathogenesis of MS is of special interest. The aim of the study was to investigate association of NOS3 single nucleotide polymorphism C774T with risk of MS in the Slavic population of the Kaliningrad region and the relationship of this polymorphic variant with some parameters of endothelial dysfunction. The study included 128 patients (48 men and 80 women aged from 36 to 52 years) with MS. The control group consisted of 126 healthy volunteers (60 men and 66 women aged from 30 to 40 years). Genotyping was performed by real-time PCR. Serum nitrite levels were determined spectrophotometrically by the Griess method. Serum levels of endothelin-1 and eNOS were evaluated by ELISA. The study has shown association of T allele (OR=2.06; p=0.0004; CI: 1.38-3.08) and CT genotype (OR=1.97; p=0.014; CI: 1.14-3.40 ) C774T polymorphism of the NOS3 gene with risk of MS in the Slavic population of the Kaliningrad region. Allele C (OR=0.48; p=0.0004; CI: 0.32-0.72) and homozygous CC genotype (OR=0.41; p=0.001; CI: 0.24-0,69) C774T polymorphism of the NOS3 gene were associated with reduced risk of the development of MS. Significant differences in serum levels of eNOS and endothelin-1 depended on the CT and TT genotypes of C774T polymorphism of the NOS3 gene in MS.. Vzaimosviaz' produktsii oksida azota s metabolicheskimi narusheniiami i rol' éndotelial'noĭ sintazy oksida azota (eNOS ili NOS3) pri metabolicheskom sindrome (MS) nuzhdaiutsia v glubokom izuchenii. Osobyĭ interes predstavliaet rol' gena NOS3 v patogeneze MS. Izuchena assotsiatsiia odnonukleotidnogo polimorfizma C774T gena NOS3 s riskom razvitiia MS v slavianskoĭ populiatsii Kaliningradskoĭ oblasti i sviaz' dannogo polimorfnogo varianta s nekotorymi pokazateliami éndotelial'noĭ disfunktsii. Obsledovany 128 patsientov (48 muzhchin i 80 zhenshchin v vozraste ot 36 do 52 let) s MS. Kontrol'nuiu gruppu sostavili 126 zdorovykh donorov (60 muzhchin i 66 zhenshchin v vozraste ot 30 do 40 let). Genotipy analizirovali metodom PTsR v rezhime real'nogo vremeni. Urovni nitritov v syvorotke opredeliali spektrofotometricheskim metodom, osnovannym na reaktsii Grissa. Urovni éndotelina-1 i eNOS v syvorotke otsenivali metodom ELISA. Pokazana assotsiatsiia allelia T (OR=2,06; p=0,0004; CI:1,38-3,08) i genotipa CT (OR=1,97; p=0,014; CI:1,14-3,40) polimorfizma C774T gena NOS3 s riskom razvitiia MS v slavianskoĭ populiatsii Kaliningradskoĭ oblasti. Allel' S (OR=0,48; p=0,0004; CI:0,32-0,72) i gomozigotnyĭ genotip SS (OR=0,41; p=0,001; CI:0,24-0,69) polimorfizma C774T gena NOS3 assotsiirovany s ponizhennym riskom razvitiia dannogo sindroma. Vyiavleny statisticheski znachimye razlichiia v syvorotochnykh urovniakh eNOS i éndotelina-1 v zavisimosti ot genotipov CT i TT polimorfizma C774T gena NOS3 pri MS.

Topics: Adult; Case-Control Studies; Endothelin-1; Female; Humans; Male; Metabolic Syndrome; Middle Aged; Mutation, Missense; Nitric Oxide Synthase Type III; Nitrites; Polymorphism, Single Nucleotide

Cumulative evidence suggests that moderate red wine consumption protects the cardiovascular system. The effect of cultured cells derived from red grape berry (RGC) on blood pressure (BP) has not been investigated. We therefore studied the antihypertensive effects of oral consumption of RGC in experimental rat model of metabolic-like syndrome and assessed its effect on human umbilical vein endothelial cells (HUVECs).. Forty male Sprague-Dawley rats were fed for 5 weeks with either a high fructose diet (HFD) (n = 10) or HFD supplemented, during the last 2 weeks, with different doses (200, 400 and 800 mg/kg/day) of RGC suspended in their food (n = 30). BP, plasma triglycerides, insulin and adiponectin levels were measured at the beginning and after 3 and 5 weeks of diet. RGC effect on vasodilatation was evaluated by its ability to affect endothelin-1 (ET-1) production and endothelial nitric oxide synthase (eNOS) expression in HUVECs.. BP, plasma triglycerides, insulin and adiponectin increased significantly in rats fed with a HFD. The increase in BP, plasma triglycerides and insulin was attenuated by RGC supplementation. Incubation of HUVECs with RGC demonstrated a concentration-dependent inhibition of ET-1 secretion and increase in the level of eNOS, signaling a positive effect of RGC on vasodilatation.. In rats with metabolic-like syndrome, RGC decreased BP and improved metabolic parameters. These beneficial effects may be mediated by the cell constituents, highly rich with polyphenols and resveratrol, reside in their natural state.

Topics: Animals; Antihypertensive Agents; Cells, Cultured; Dietary Supplements; Endothelin-1; Fruit; Human Umbilical Vein Endothelial Cells; Humans; Hyperinsulinism; Hypertension; Hypertriglyceridemia; Hypolipidemic Agents; Male; Metabolic Syndrome; Nitric Oxide Synthase Type III; Pigments, Biological; Plant Extracts; Rats, Sprague-Dawley; Vasodilator Agents; Vitis

To determine whether endothelin (ET)-1 vasoconstrictor tone is greater in overweight and obese adults with the metabolic syndrome (MetS).. Forty overweight/obese middle-aged and older adults (age: 43-71 years; BMI: 25.1-36.9 kg/m²) were studied: 20 without MetS (13 M/7 F) and 20 with MetS (13 M/7 F). MetS was established according to NCEP ATP III guidelines. Forearm blood flow (FBF; plethysmography) responses to intra-arterial infusion of selective ET(A) receptor blockade (BQ-123; 100 nmol/min; for 60 min) and non-selective ET(A/B) receptor blockade (BQ-123 + BQ-788 [50 nmol/min for 60 min]) were determined.. In response to the selective ET(A) antagonism, there was a significant increase in forearm blood flow from baseline in both groups. However, the increase in forearm blood flow was significantly higher (P=0.03; ~45%) in the overweight/obese group with MetS than the group without MetS. In contrast, there were no significant group differences in FBF responses to non-selective ET(A/B) receptor blockade. Peak vasodilator responses to nonselective ET(A/B) blockade were ~50% higher than baseline blood flow in the overweight/obese groups without and with MetS.. MetS is associated with higher ET-1 vasoconstrictor tone in overweight/obese adults. The enhanced ET-1 vasoconstrictor activity with MetS is mediated by the ET(A) receptor subtype.

Topics: Adult; Aged; Blood Vessels; Body Mass Index; Cross-Sectional Studies; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Female; Forearm; Humans; Male; Metabolic Syndrome; Middle Aged; Obesity; Overweight; Prehypertension; Receptor, Endothelin A; Receptor, Endothelin B; Regional Blood Flow; Signal Transduction; Vasoconstriction; Vasodilation; Vasodilator Agents

Systemic hypertension is a prominent feature in humans with metabolic syndrome (MS) and this is partly caused by an enhanced endothelin-1 (ET-1) mediated vasoconstriction. There are indications that systemic hypertension might be a feature in equine metabolic syndrome (EMS) but if ET-1 is involved in the development of hypertension in horses is not known. Increased levels of cortisol have also been found in humans with MS but there are no reports of this in horses. Before blood pressure, plasma ET-1 and serum cortisol can be evaluated in horses with EMS, it is necessary to investigate the interday variation of these parameters on clinically healthy horses. The aims of the present study were therefore to evaluate the interday variation and influence of transportation on systemic blood pressure, plasma ET-1 and serum cortisol in healthy Standardbred and Icelandic horses, and to detect potential breed differences.. Nine horses of each breed were included in the study. Blood pressure was measured and blood samples were collected between 6 and 9 am on two separate days. Eight of the horses (four of each breed) were transported to a new stable were they stayed overnight. The next morning, the sampling procedure was repeated.. The interday variation was higher for plasma ET-1 (37%) than for indirect pressure measurements (8-21%) and serum cortisol (18%). There were no differences in systemic blood pressure between the two breeds. The Icelandic horses had significantly lower serum cortisol and significantly higher plasma ET-1 concentrations compared to the Standardbred horses. Plasma ET-1 was significantly elevated after transportation, but systemic blood pressure and serum cortisol did not differ from the values obtained in the home environment.. Indirect blood pressure, plasma ET-1 and serum cortisol are of interest as markers for cardiovascular dysfunction in horses with EMS. The elevated plasma ET-1 concentrations recorded after transportation was likely caused by a stress response. This needs to be considered when evaluating plasma ET-1 in horses after transportation. The differences detected in plasma ET-1 and serum cortisol between the two breeds might be related to differences in genetic setup, training status as well as management conditions.

Topics: Animals; Blood Pressure; Blood Pressure Determination; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Horses; Hydrocortisone; Male; Metabolic Syndrome; Oscillometry; Radioimmunoassay; Time Factors; Transportation

Metabolic alterations and endothelial dysfunction are interrelated processes in type 2 diabetes (T2D) and metabolic syndrome (MetS) that often develop in parallel. We assessed the association of vasoactive precursor peptides (VPPs) with MetS and T2D.. Plasma levels of C-terminal pro-endothelin-1 (CT-proET-1) and midregional pro-adrenomedullin (MR-proADM) were measured by novel sensitive assays in 1590 participants of the population-based KORA F4 study. The association of the VPPs with T2D, MetS defined by IDF criteria, the components of MetS, and insulin resistance (IR) was assessed in logistic regression models.. Elevated levels of CT-proET-1 and MR-proADM were associated with T2D, MetS, and IR in age- and sex-adjusted models. After adjustment for age, sex, former vascular complications, lifestyle factors, high-sensitive C-reactive protein, and serum creatinine, significant associations with MetS were found for MR-proADM (OR=5.94, 95% CI 3.78-9.33) and CT-proET-1 (OR=5.18, 95% CI 3.48-7.71) (top quartile vs bottom quartile). CT-proET-1 and MR-proADM were strongly associated with all components of MetS as defined by IDF criteria. After multivariable adjustment, association of CT-proET-1 and MR-proADM with pathological glucose tolerance and T2D disappeared and a borderline association with IR was found only for CT-proET-1 (OR=1.34, 95% CI 0.96-1.87).. We here demonstrate for the first time that plasma levels of both MR-proADM and CT-proET-1 levels are related to MetS and its components, thus suggesting that they possibly have a role as a surrogate biomarker for the disease and its complications.

Topics: Adrenomedullin; Adult; Aged; Endothelin-1; Female; Humans; Male; Metabolic Syndrome; Middle Aged; Peptide Fragments

The purpose of study was to develop and test the method of determination of destruction of endotheliocytes in blood-vascular system. The level of circulating endothelial cells was determined by enumeration of CD32+CD40+ micro particles by means of flow cytofluorometry. During the application of the modified method it is demonstrated that in patients with metabolic syndrome the amount of CD32+CD40+ micro particles is twice higher than in the control group (p < 0.05). The research data revealed the increase of content of big endothelin and atherogenic lipoproteids. The method of determination of the level of circulating CD32+CD40+ micro particles can be applied to assess the desquamationed endotheliocytes.

Topics: Aged; CD40 Antigens; Cell-Derived Microparticles; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Flow Cytometry; Humans; Male; Metabolic Syndrome; Middle Aged; Receptors, IgG

Accumulating evidence suggests that cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid into epoxyeicosatrienoic acids (EETs), which play crucial and diverse roles in cardiovascular homeostasis. The anti-inflammatory, antihypertensive, and pro-proliferative effects of EETs suggest a possible beneficial role for EETs on insulin resistance and diabetes.. This study investigated the effects of CYP2J3 epoxygenase gene therapy on insulin resistance and blood pressure in diabetic db/db mice and in a model of fructose-induced hypertension and insulin resistance in rats.. CYP2J3 gene delivery in vivo increased EET generation, reduced blood pressure, and reversed insulin resistance as determined by plasma glucose levels, homeostasis model assessment insulin resistance index, and glucose tolerance test. Furthermore, CYP2J3 treatment prevented fructose-induced decreases in insulin receptor signaling and phosphorylation of AMP-activated protein kinases (AMPKs) in liver, muscle, heart, kidney, and aorta. Thus, overexpression of CYP2J3 protected against diabetes and insulin resistance in peripheral tissues through activation of insulin receptor and AMPK pathways.. These results highlight the beneficial roles of the CYP epoxygenase-EET system in diabetes and insulin resistance.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Blood Pressure; Cytochrome P-450 Enzyme System; DNA Primers; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Fructose; Gene Expression Regulation; Glucose Tolerance Test; Hypertension; Insulin Resistance; Metabolic Syndrome; Mice; Nitric Oxide Synthase Type III; Rats; Receptor, Endothelin A; RNA, Messenger

One of the major obstacles in drug discovery is the lack of in vitro three-dimensional (3D) models that can capture more complex features of a disease.Here we established a in vitro physiological model of the metabolic syndrome (MS) using cell-assembly technique (CAT), which can assemble cells into designated places to form complex 3D structures. Adipose-derived stromal (ADS) cells were assembled with gelatin/alginate/fibrinogen. Fibrin was employed as an effective material to regulate ADS cell differentiation and self-organization along with other methods. ADS cells differentiated into adipocytes and endothelial cells, meanwhile, the cells were induced to self-organize into an analogous tissue structure. Pancreatic islets were then deposited at designated locations and constituted the adipoinsular axis with adipocytes. Analysis of the factors involved in energy metabolism showed that this system could capture more pathological features of MS. Drugs known to have effects on MS showed accordant effects in this system, indicating that the model has potential in MS drug discovery. Overall, this study demonstrated that cell differentiation and self-organization can be regulated by techniques combined with CAT. The model presented could result in a better understanding of the pathogenesis of MS and the development of new technologies for drug discovery.

Topics: Adipocytes; Adipogenesis; Adipokines; Adipose Tissue; Alginates; Animals; Endothelin-1; Endothelium; Fatty Acids, Nonesterified; Fibrinogen; Gelatin; Glucose; Glucuronic Acid; Hexuronic Acids; Insulin; Insulin Secretion; Lipid Metabolism; Metabolic Syndrome; Microscopy, Electron, Scanning; Models, Biological; Nitric Oxide; Rats; Rats, Sprague-Dawley; Stromal Cells; Tissue Scaffolds

The increased plasma Endothelin-1 (ET-1) level has been associated with development of insulin resistance in obese and hypertensive patients. However, the underlying mechanism remains elusive. Here we investigate the potential role of endothelial cell-derived ET-1 in mediating insulin resistance induced by high-salt diet. To address this issue, we used vascular endothelial cell-specific ET-1 knockout (VEETKO) mice and its littermates fed with a high-salt diet containing 8% NaCl for 3 weeks, and evaluated the metabolic parameters. High-salt diet increased systolic blood pressure similarly in both genotypes. We observed impairment of glucose tolerance in control mice despite comparable increase of serum insulin concentration with VEETKO mice. We further found that VEETKO mice showed preservation of circulating adiponectin level - an adipokine with insulin-sensitizing property - and prevention of the upregulation of the pro-inflammatory adipokine TNF-α, which lead towards better insulin sensitivity. These results provide evidence that blockade of endothelin signaling may be proven beneficial in preventing high-salt induced insulin resistance.

Topics: Adiponectin; Animals; Blood Pressure; Disease Models, Animal; Endothelial Cells; Endothelin-1; Glucose Tolerance Test; Heart Rate; Humans; Insulin Resistance; Metabolic Syndrome; Mice; Mice, Knockout; Signal Transduction; Sodium Chloride, Dietary; Tumor Necrosis Factor-alpha

Topics: Endothelin-1; Endothelium, Vascular; Female; Ghrelin; Homeostasis; Humans; Male; Metabolic Syndrome; Nitric Oxide; Obesity; Risk Assessment; Sensitivity and Specificity

The very high carrier frequency of 21-hydroxylase deficiency worldwide has been postulated as indicating a survival advantage. The 'mediators' of such an effect remain speculative.. To look for possible differences in the metabolic and atherogenic risk profile of carriers and noncarriers of CYP21A2 gene mutations at puberty in order to identify possible mediators of the presumed survival advantage for the carriers. It is anticipated that by studying atherogenic risk factors at such an early developmental stage, age-related alterations in these factors may be minimized.. The study group included 45 adolescent girls diagnosed in our center with premature pubarche, 29 of whom were noncarriers and 16 carriers of CYP21A2 mutations. The two groups did not differ in chronological age, age at pubarche or menarche, pubertal stage, body mass index and waist-to-hip ratio. Biochemical and hormonal profile markers as well as markers of endothelial dysfunction were determined by appropriate methodology. Additionally, in each subject, an oral glucose tolerance test and a gonadotrophin-releasing hormone GnRH analogue stimulation test were carried out.. Endothelin-1 values were lower in the carriers compared to the noncarriers (p = 0.031). Higher tissue plasminogen activator and lower plasminogen activator inhibitor-1 values were found in carriers compared to noncarriers (p = 0.02 and <0.001, respectively). The ratio of the insulinogenic index/homeostasis model assessment for insulin resistance, which reflects beta-cell function, was higher in carriers (p = 0.048), indicating a more favorable beta-cell function in the carriers.. Our findings that carriers of CYP21A2 gene mutations have a more favorable internal milieu with regard to the metabolic syndrome and atherogenesis support the theory that heterozygous CYP21A2 mutations provide a survival advantage. The mechanisms involved may be related to the insulin secretion-action pathway, hypothalamic-pituitary-adrenal axis responsiveness or other still unrecognized factors.

Topics: Adolescent; Atherosclerosis; Case-Control Studies; Child; Endothelin-1; Female; Glucose Tolerance Test; Heterozygote; Humans; Hypothalamo-Hypophyseal System; Insulin; Insulin Resistance; Insulin Secretion; Metabolic Syndrome; Mutation; Pituitary-Adrenal System; Plasminogen Activator Inhibitor 1; Risk Factors; Steroid 21-Hydroxylase; Triptorelin Pamoate

Urate, a naturally-occurring antioxidant, is a marker/factor for cardiovascular disease. Hyperuricaemia is associated with IR, MetS and endothelial dysfunction. We characterised the associations between neurohormones, uricaemia, and glucose homeostasis in type 2 diabetes mellitus (T2DM) males. Cross-sectional; 705 T2DM males divided into two groups: uric acid < 7.0 mg/dl (normouricaemic; n=476) versus uric acid >or= 7.0 mg/dl (hyperuricaemic; n=229). HOMA beta-cell function (B), insulin sensitivity (S), hyperbolic product (BxS), and (BxS) loss rate were determined alongside neurohormones (Nt-proANP, BNP, Big ET-1 and UII). Mean age and diabetes duration were not different between groups. Hyperuricaemics had more macroangiopathy, total/central adiposity, IR, hypertension, dyslipidemia and MetS prevalence. Nt-proANP and BNP levels were more than twice as high in hyperuricaemics, whereas Big ET-1 and UII were higher by 46% and 14%, respectively. HOMA (BxS) was higher in hyperuricaemics: 31 (16)% vs. 26 (18)% (p=0.0004). BxS loss rate was faster in normouricaemics: 1.36 (0.54)% vs. 1.20 (0.43)%/year(-1) (p<0.0001 ). The proportion with HbA(1C) < 7.0% was 39% (normouricaemics) vs. 49% (hyperuricaemics; p=0.0091). In T2DM males, hyperuricaemia is associated with raised neurohormones together with better beta-cell indices. Urate's dual properties may translate into beneficial (glucose homeostasis) and detrimental (raised neurohormones) effects.

Topics: Aged; Atrial Natriuretic Factor; Biomarkers; Blood Glucose; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Endothelin-1; Glycated Hemoglobin; Humans; Hyperuricemia; Insulin; Insulin-Secreting Cells; Male; Metabolic Syndrome; Middle Aged; Natriuretic Peptide, Brain; Up-Regulation; Uric Acid

Elevated plasma triglyceride/free fatty acid (FFA) levels and insulin resistance may promote atherosclerosis through endothelial activation (ie, increased expression of intercellular adhesion molecule 1 [ICAM-1]/vascular adhesion molecule 1 [VCAM-1], and endothelin-1 [ET-1]) in patients with the metabolic syndrome, but this has never been directly tested. The authors measured endothelial activation and insulin sensitivity (euglycemic insulin clamp with [3-(3)H]-glucose) after a 4-day low-dose lipid infusion that elevated plasma FFA to levels observed in the metabolic syndrome in 20 lean, non-diabetic insulin-resistant subjects with a strong family history of type 2 diabetes mellitus (FH(+)) and 10 insulin-sensitive volunteers without a family history of type 2 diabetes mellitus (FH(-)). Low-dose lipid infusion reduced insulin sensitivity by approximately 25% in insulin-sensitive FH(-)controls but did not worsen preexisting insulin resistance in FH(+). Low-dose lipid infusion elevated plasma ICAM and VCAM levels similarly in both groups (approximately 12%-18%; P<.01 vs baseline), while plasma ET-1 levels increased more in FH(+)vs FH(-)(46% vs 10%; P=.005). Increased plasma FFA levels closely correlated with elevated ICAM (r=0.60; P<.01), VCAM, and ET-1 levels (r=0.39 and r=0.42, respectively; P<.05). Low-dose lipid infusion induces endothelial activation in both lean insulin-resistant (FH(+)) and insulin-sensitive (FH(-)) healthy patients, regardless of changes in insulin sensitivity. These results prove that even a modest lipid oversupply may be sufficient to trigger a deleterious endothelial response.

Topics: Adult; Biomarkers; Blood Glucose; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Female; Follow-Up Studies; Glucose Tolerance Test; Humans; Infusions, Intravenous; Insulin Resistance; Intercellular Adhesion Molecule-1; Lipids; Male; Metabolic Syndrome; Prognosis; Reference Values; Vascular Cell Adhesion Molecule-1

Although much is known about the anti-inflammatory effects of an acute corticosteroid therapy, little is known about the effects on chronic hypercortisolism on endothelial dysfunction and proinflammatory alterations in patients with Cushing's disease (CD).. We studied 9 patients with CD, 10 patients with metabolic syndrome and 27 normal controls. The tests consisted of an intravenous bolus of 0.1 U/kg insulin combined with a euglycaemic clamp technique with an arterialized forearm and assessment of the training parameters deep-venous balance of forearm glucose uptake (as an index of insulin sensitivity); NO(x) (nitric oxide end-products), c-GMP (second messenger of nitric oxide) and endothelin-1 release, as indices of endothelial function and proinflammatory systemic markers.. Forearm glucose uptake incremental area was significantly lower in Cushing's disease and in the metabolic syndrome than in controls, suggesting a state of severe insulin resistance. Compared to controls and to the metabolic syndrome, basal and insulin-stimulated NO(x) release incremental areas were significantly reduced in Cushing's disease, while forearm c-GMP release was similarly decreased in CD and metabolic syndrome. By contrast, endothelin-1 incremental areas after insulin bolus were significantly higher in CD than in controls and the metabolic syndrome, in the presence of increased TNF-alpha, IL-6 and CRP levels. Forearm glucose uptake incremental area significantly correlated with NO(x) incremental area, forearm c-GMP release incremental area, TNF-alpha levels and ET-1 incremental area.. In patients with CD, supraphysiological insulin levels are not able to overcome the insulin resistance due to chronic hypercortisolism. Furthermore, an increased proatherogenic risk profile is characterized by decreased nitric oxide synthesis and activity, enhanced endothelin-1 levels and increased proinflammatory markers.

Topics: Adult; Analysis of Variance; C-Reactive Protein; Case-Control Studies; Cyclic GMP; Diagnosis, Differential; Endothelin-1; Female; Humans; Insulin; Interleukin-6; Linear Models; Male; Metabolic Syndrome; Nitric Oxide; Pituitary ACTH Hypersecretion; Tumor Necrosis Factor-alpha

Feeding high fructose (Frc) to rats induces a moderate increase in blood pressure, which is associated with insulin resistance. The present study was designed to evaluate the effect of the methanol extract of Sorbus commixta cortex (MSC) on vascular inflammation in a rat model of the metabolic syndrome induced by a high Frc-diet. Male Sprague-Dawley rats were divided into 4 groups and treated for 7 weeks as follows: 1) control, 2) high Frc-diet group, 3) Frc/MSC1 group; high Frc-diet group treated with MSC (100 mg/kg/day), and 4) Frc/MSC2 group; high Frc-diet group treated with MSC (200 mg/kg/day). High Frc-induced decreases of the expression level of aortic endothelial nitric oxide synthase (ecNOS) while the production of cyclic GMP (cGMP) was restored by treatment with MSC. On the contrary, increases of the expression level of endothelin-1 (ET-1) in the aorta, the transcription factor, the cytokine related with vascular inflammation, and the adhesion molecules were suppressed by MSC treatment. Moreover, MSC treatment was shown to lessen the thickening noted in the aortic intima and media of the high Frc-diet group. Our findings suggest that MSC may have an anti-vascular inflammatory effect on rats with a high Frc-induced metabolic syndrome.

Topics: Animals; Aorta, Thoracic; Cell Adhesion Molecules; Cyclic GMP; Disease Models, Animal; Endothelin-1; Endothelium, Vascular; Fructose; Guanosine Monophosphate; Inflammation; Male; Metabolic Syndrome; Methanol; NF-kappa B; Nitrites; Plant Extracts; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sorbus; Sweetening Agents; Triglycerides; Tunica Intima; Tunica Media

To estimate the influence of anthocyanins from Aronia melanocarpa on blood pressure, concentration of endothelin-1 (ET-1), serum lipids, fasting glucose, uric acid and membrane cholesterol in erythrocytes of patients (pts) with metabolic syndrome (MS).. The study comprised 22 healthy volunteers and 25 pts with MS treated with anthocyanins (3 x 100 mg/d) for 2 months. Waist circumference (> or = 80 cm for women and > or =94 cm for men), triglicerydes (TG) level >150 mg/dl (1.7 mmol/l), cholesterol-HDL (HDL-C) level < 40 mg/dl (1.0 mmol/l) for men and <50 mg/dl (1.3 mmol/l) for women, systolic blood pressure (SBP) >130 mmHg and/or diastolic blood pressure (DBP) >85 mmHg were inclusion criteria for patients with MS. Before and after 2 months of treatment the following parameters were determined: SBP, DBP, serum lipids (total cholesterol--TC, cholesterol LDL--LDL-C, cholesterol HDL--HDL-C, TG--by enzymatic method), membrane cholesterol in erythrocytes (method of IIcy), ET-1 (immunoenzymatic method), fasting glucose level was (colorimetric method), uric acid (enzymatic--colorimetric method).. After two months therapy of anthocyanins from Aronia melanocarpa in comparison with baseline it was observed a significant decrease of: SBP (144.20 +/- 9.97 vs. 131.83 +/- 12.24 mmHg, p < 0.001) and DBP (87.20 +/- 9.9 vs. 82.13 +/- 10.33 mmHg, p < 0.05), TC (242.80 +/- 34.48 vs. 227.96 +/- 33.07 mg/dl, p < 0.001), LDL-C (158.71 +/- 35.78 vs. 146.21 +/- 34.63 mg/dl, p < 0.01), TG (215.92 +/- 63.61 vs. 187.58 +/- 90 mg/dl, p < 0.05), ET-1 (2.44 +/- 0.51 vs. 1.74 +/- 0.42 pg/ml, p < 0.001) and membrane cholesterol (4.85 +/- 0.65 vs. 2.81 +/- 0.54 mmol/Lpc, p < 0.001), uric acid and fasting blood glucose levels did not change significantly after study cessation.. The results of our study show that anthocyanins from Aronia melanocarpa may be of benefit to patients with MS as for as atherosclerosis prevention is concerned. It seems to result from anthocyanins influence on blood pressure, serum lipid and endothelin-1 level.

Topics: Anthocyanins; Blood Glucose; Blood Pressure; Case-Control Studies; Cholesterol, HDL; Cholesterol, LDL; Endothelin-1; Female; Humans; Hyperinsulinism; Hypertension; Lipids; Lipoproteins; Male; Metabolic Syndrome; Middle Aged; Photinia; Plant Extracts; Triglycerides; Waist-Hip Ratio

1. Chronic feeding with a high-fat diet can cause metabolic syndrome in rodents similar to humans, but the role of saturated versus unsaturated fats in vascular tension remains unclear. 2. The present study shows that rats on a diet rich in either saturated or unsaturated fat had higher blood pressure compared with chow-fed rats (approximately 130 vs 100 mmHg, respectively), along with hyperlipidaemia and insulin resistance. Compared with responses of phenylephrine-preconstricted artery segments from chow-fed rats, vasorelaxation of isolated renal arteries from high-fat fed rats was reduced substantially (> 50%) in response to acetylcholine (0.01-10 micromol/L) and moderately to nitroprusside (>or=1 micromol/L) at low concentrations. Acetylcholine-induced vasorelaxation of arteries from high-fat fed rats was also more sensitive to inhibition by the nitric oxide (NO) synthase inhibitors NG-nitro-L-arginine and methylene blue. 3. In human umbilical vein endothelial cells, the production of NO and endothelin-1 was significantly inhibited by unsaturated fatty acids. In comparison, saturated fatty acids stimulated endothelin-1 production without altering NO production. 4. The data indicate that both saturated and unsaturated high-fat feeding may result in an increase in blood pressure owing to reduced endothelium-dependent vasorelaxation in the arterial system. The impaired endothelium-dependent vasorelaxation induced by saturated and unsaturated fatty acids may involve different mechanisms.

Topics: Acetylcholine; Animals; Blood Pressure; Cells, Cultured; Cholesterol; Diet, Fat-Restricted; Dose-Response Relationship, Drug; Endothelial Cells; Endothelin-1; Fatty Acids; Fatty Acids, Unsaturated; Humans; Insulin Resistance; Male; Metabolic Syndrome; Nitric Oxide; Nitric Oxide Synthase Type III; Rats; Rats, Wistar; Renal Artery; RNA, Messenger; Triglycerides; Vasodilation; Vasodilator Agents