endothelin-1 and Hyperemia

We sought to clarify, using functional and biological approaches, the role of epoxyeicosatrienoic acids, nitric oxide (NO)/reactive oxygen species balance, and endothelin-1 in conduit artery endothelial dysfunction during essential hypertension.. Radial artery diameter and mean wall shear stress were determined in 28 untreated patients with essential hypertension and 30 normotensive control subjects during endothelium-dependent flow-mediated dilatation induced by hand skin heating. The role of epoxyeicosatrienoic acids and NO was assessed with the brachial infusion of inhibitors of cytochrome P450 epoxygenases (fluconazole) and NO synthase (N(G)-monomethyl-l-arginine [L-NMMA]). Compared with controls, hypertensive patients exhibited a decreased flow-mediated dilatation in response to postischemic hyperemia as well as to heating, as shown by the lesser slope of their diameter-shear stress relationship. In controls, heating-induced flow-mediated dilatation was reduced by fluconazole, L-NMMA, and, to a larger extent, by L-NMMA+fluconazole. In patients, flow-mediated dilatation was not affected by fluconazole and was reduced by L-NMMA and L-NMMA+fluconazole to a lesser extent than in controls. Furthermore, local plasma epoxyeicosatrienoic acids increased during heating in controls (an effect diminished by fluconazole) but not in patients. Plasma nitrite, an indicator of NO availability, increased during heating in controls (an effect abolished by L-NMMA) and, to a lesser extent, in patients, whereas, inversely, reactive oxygen species increased more in patients (an effect diminished by L-NMMA). Plasma endothelin-1 decreased during heating in controls but not in patients.. These results show that an impaired role of epoxyeicosatrienoic acids contributes, together with an alteration in NO/reactive oxygen species balance and endothelin-1 pathway, to conduit artery endothelial dysfunction in essential hypertension.. https://www.eudract.ema.europa.eu. Unique identifier: RCB2007-A001-10-53.

Topics: 14-alpha Demethylase Inhibitors; Adult; Eicosanoids; Endothelin-1; Endothelium, Vascular; Enzyme Inhibitors; Female; Fluconazole; Hot Temperature; Humans; Hyperemia; Hypertension; Male; Middle Aged; Nitric Oxide; omega-N-Methylarginine; Pulsatile Flow; Radial Artery; Reactive Oxygen Species; Skin; Stress, Mechanical

The present study investigates whether lower-limb dominant exercise training in patients with chronic heart failure (CHF) improves endothelial function primarily in the trained lower extremities or equally in the upper and lower extremities. Twenty-eight patients with CHF were randomized to the exercise or control group. The exercise group underwent cycle ergometer training for 3 months while controls continued an inactive sedentary lifestyle. Exercise capacity (6-min walk test) and flow-mediated vasodilation in the brachial and posterior tibial arteries were evaluated. After 3 months, walking performance increased only in the exercise group (488+/-16 to 501+/-14 m [control]; 497+/-23 to 567+/-39 m [exercise, p<0.05]). The flow-mediated vasodilation in the brachial arteries did not change in either group (4.2+/-0.5 to 4.5+/-0.4% [control]; 4.3+/-0.5 to 4.6+/-0.4% [exercise]), but that in the posterior tibial arteries increased only in the exercise group (4.1+/-0.5 to 4.1+/-0.3% [control]; 3.6+/-0.3 to 6.4+/-0.6% [exercise, p<0.01]). Cycle ergometer training improved flow-mediated vasodilation in the trained lower limbs, but not in the untrained upper limbs. Exercise training appears to correct endothelial dysfunction predominantly by a local effect in the trained extremities.

Topics: Arm; Brachial Artery; Endothelin-1; Endothelium, Vascular; Exercise Therapy; Exercise Tolerance; Female; Heart Failure; Humans; Hyperemia; Leg; Male; Middle Aged; Organ Specificity; Tibial Arteries; Ultrasonography; Vasodilation

In patients with glaucoma, one of the main initiating mechanisms that triggers the chain of events is disruption of the universal mechanism for regulating vascular tone due to endothelial dysfunction (ED). The main manifestation of ED is an imbalance of vasoconstrictor and vasodilator endothelial mediators, which inconsistency triggers the mechanisms of adaptive distress leading to the progression of morphological destruction, dyslipidemia, acceleration of atherogenesis, development of hemodynamic and hydrodynamic disorders. The drug Mexidol has a wide range of pharmacological activity and affects the main pathogenetic links of primary open-angle glaucoma (POAG).. The study analyzes the vascular remodulation, antioxidant and antihypoxic effects of the drug Mexidol in patients with PAOG.. The study included 78 patients with POAG of the early (. The following changes are observed in patients of the main group using Mexidol: the index of oscillatory potentials significantly increases, peak latency decreases, perimeter indices show positive trends, vascular endothelial function improves according to reactive hyperemia test, concentration of vasoconstrictor mediator ET-1 in blood plasma decreases and of nitrite (NO. The drug Mexidol proved to be an effective endothelial protector, a powerful antioxidant and antihypoxant, contributed to deceleration of atherogenesis in patients with POAG.. У пациентов с глаукомой одним из основных инициирующих механизмов, запускающих цепь событий, является нарушение универсального механизма регулирования сосудистого тонуса вследствие эндотелиальной дисфункции (ЭД). Основным проявлением ЭД служит дисбаланс вазоконстрикторных и вазодилататорных эндотелиальных медиаторов, рассогласованность которых запускает механизмы адаптационного дистресса, ведущего к прогрессированию морфологической деструкции, дислипидемии, ацеклерации атерогенеза, развитию гемодинамических и гидродинамических нарушений. Препарат Мексидол имеет широкий спектр фармакологической активности, действующий на основные патогенетические звенья первичной открытоугольной глаукомы (ПОУГ).. Изучить вазоремодулирующее, антиоксидантное и антигипоксантное действие препарата Мексидол у пациентов с ПОУГ.. В исследование включено 78 пациентов с ПОУГ начальной стадии (. На фоне применения препарата Мексидол у пациентов основной группы значимо повышается индекс осцилляторных потенциалов, снижается межпиковая латентность, наблюдаются положительная динамика периметрических индексов, улучшение функции эндотелия сосудов в пробе с реактивной гиперемией, уменьшение концентрации в плазме крови медиатора-констриктора ЕТ-1, умеренный рост нитрита (NO. Препарат Мексидол проявил себя как эффективный эндотелиопротектор, мощный антиоксидант и антигипоксант, способствовал снижению факторов ацеклерации атерогенеза у пациентов с ПОУГ.

Topics: Aged; Antioxidants; Cholesterol; Endothelin-1; Glaucoma, Open-Angle; Humans; Hyperemia; Nitrites

We studied relationship between markers of endothelial dysfunction and multifocal atherosclerosis and adverse coronary events in 82 patients with non-ST segment elevation acute coronary syndrome (NSTEACS). Eighteen patients (21.9%) had adverse events during one year of observation. Patients with adverse coronary events had impaired vasodilatory, vasoconstrictive, and adhesive endothelial function. Predictors of unfavorable prognosis in NSTEACS were signs of impaired endothelium-dependent vasodilation during test with reactive hyperemia, high soluble platelet selectin and endothelin-1 levels on day 10 of the disease. Endothelin-1 and soluble platelet-endothelial cell adhesion molecule-1 had greatest predictive power relative to development of non-fatal myocardial infarction.

Topics: Acute Coronary Syndrome; Aged; Biomarkers; Coronary Circulation; Coronary Vessels; Electrocardiography; Endothelin-1; Endothelium, Vascular; Female; Humans; Hyperemia; Male; Middle Aged; Myocardial Infarction; Platelet Endothelial Cell Adhesion Molecule-1; Predictive Value of Tests; Prognosis; Vasoconstriction; Vasodilation

Gap junctions play a key role in maintaining the functional integrity of the vascular wall. Using carbenoxolone (CBX) as a gap junction blocker, we aimed to assess the contribution of gap junctions in the vascular wall to flow-mediated vasodilatation (FMD) in healthy adults. Percentage FMD (%FMD) and circulating vasoactive molecules/activity, including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), aldosterone, cortisol, plasma renin activity (PRA), and endothelin (ET-1), were measured in 25 healthy volunteers (mean age: 30.1 ± 5.4 yr; 14 males) before and after oral administration of CBX (100 mg). %FMD decreased after ingestion of CBX (9.71 ± 3.1 vs. 3.40 ± 2.0%; P < 0.0001). The levels of ANP, BNP, cortisol, and ET-1 remained stationary, while both PRA and aldosterone decreased (P < 0.005) after CBX ingestion. Blood pressure and heart rate were minimally changed by CBX. Inhibition of gap junctional communication by CBX impairs FMD in healthy persons, suggesting that physiologically, vascular gap junctions participate in the maintenance of FMD. CBX does not induce the release of vasoconstricting molecules or enhance vasoconstriction, suggesting that inhibition of gap junctional communication by CBX underlies the impairment of FMD. Therefore, administering CBX in FMD examination can be a way to follow the effect of gap junctions on endothelial function, but further work remains to verify the specificity of CBX effect.

Topics: Administration, Oral; Adult; Aldosterone; Atrial Natriuretic Factor; Brachial Artery; Carbenoxolone; Endothelin-1; Endothelium, Vascular; Female; Gap Junctions; Humans; Hydrocortisone; Hyperemia; Linear Models; Male; Natriuretic Peptide, Brain; Regional Blood Flow; Renin; Time Factors; Ultrasonography; Vasodilation

1. The aim of the present study was to determine the relationship between plasma concentrations of nitrite/nitrate (NO(x)) and endothelin (ET)-1 and non-invasive measures of peripheral vasodilator function in patients with coronary artery disease (CAD). 2. Twenty-two patients with angiographic CAD underwent non-invasive measurement of peripheral vasodilator function in the brachial conduit artery (flow-mediated dilation (FMD) testing via ultrasound) and in the forearm resistance arteries (via venous occlusion plethysmography) during reactive hyperaemia after 5 min ischaemia. In addition, plasma NO(x) and ET-1 concentrations were determined. 3. The plasma concentration of NO(x) was related to the peak brachial FMD response when expressed as either the relative (%) or absolute (mm) change in diameter (r = 0.73, P < 0.001; and r = 0.64, P < 0.01, respectively). Moreover, plasma concentrations of NO(x) demonstrated a relationship with forearm vasodilation estimated by total forearm blood flow following 5 min ischaemia (r = 0.63, P < 0.01) and the flow debt repayment of the forearm (r = 0.54, P < 0.01). Finally, ET-1 concentrations were inversely related to FMD% (r = -0.45, P < 0.05). 4. The findings of the present study demonstrate a relationship between the plasma concentrations of NO(x) and measures of vascular reactivity in conduit and resistance arteries in patients with CAD. Therefore, measurement of plasma NO(x) may serve as a reliable marker for peripheral vasodilator dysfunction in patients with CAD.

Topics: Brachial Artery; Coronary Artery Disease; Endothelin-1; Female; Forearm; Humans; Hyperemia; Male; Middle Aged; Nitric Acid; Nitric Oxide; Reactive Nitrogen Species; Ultrasonography; Vasodilation

The authors studied vascular endothelium state in coal miners. Findings are lower endothelium-dependent and endothelium-independent vasodilatation, dysbalance of humoral markers--that prove endothelial dysfunction development and remodelling of vascular wall.

Topics: Adult; Blood Flow Velocity; Coal Mining; Endothelin-1; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Hemodynamics; Humans; Hyperemia; Male

1. The present study examined the potential for reduced exercise capacity observed in hypertensive patients as a result of elevated levels of endothelin (ET)-1. We have previously reported that ET-1 exerts low-dose stimulatory or high-dose inhibitory effects on the metabolism of the rat isolated perfused hindlimb from its vasoconstrictor activity. 2. Herein, we determined whether there are similar effects on tension development by the rat isolated constant-flow hindlimb during ET-1-mediated vasoconstriction. 3. The dose-dependent vasoconstrictor effects of ET-1 on metabolism in contracting muscle were the same as those observed previously in resting muscle. Highest concentrations of ET-1 gave rise to a transient stimulation followed by a marked inhibition of tension development, consistent with a decrease in aerobic capacity of the muscle. The vasoconstriction due to the higher doses of ET-1 was not dilated by electrical stimulation. 4. In conclusion, the biphasic nature of the actions of ET-1 suggests that although lower concentrations of ET-1 do not affect exercise capacity, higher concentrations that may occur in hypertension are inhibitory to metabolism and aerobic capacity of muscle. The inhibitory effects of ET-1 appear to result from enhanced functional shunting.

Topics: Aerobiosis; Angiotensin II; Animals; Dose-Response Relationship, Drug; Electric Stimulation; Endothelin-1; Hindlimb; Hyperemia; Hypertension; Norepinephrine; Oxygen Consumption; Physical Exertion; Rats; Rats, Wistar; Regional Blood Flow; Serotonin; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

To examine if the decline in post-ischemic hyperemic flow after repeated brief periods of myocardial ischemia is accompanied by augmented cardiac release of the vasoconstrictors endothelin-1 (ET-1) and norepinephrine (NE).. Mid-LAD (left anterior descending coronary artery) was occluded for 10 min with 30 min intervals a total of four times in six anesthetized pigs. Blood from the anterior interventricular coronary vein was drained through a shunt to the right atrium to facilitate blood sampling. Plasma concentrations of ET-1 and NE were repeatedly measured in arterial and coronary venous blood to estimate cardiac vasoconstrictor release.. Plasma concentrations of ET-1 and NE remained unaltered, but cardiac release of both vasoconstrictors rose briefly during reperfusion due to the hyperemia. However, release declined progressively after repeated periods of ischemia and reperfusion and amounted to 53% (NE) and 17% (ET-1) of initial release after the fourth period of ischemia.. The decline in post-ischemic hyperemia after repeated brief periods of myocardial ischemia is not accompanied by a progressive accentuation of cardiac ET-1 and NE release.

Topics: Analysis of Variance; Animals; Biomarkers; Coronary Circulation; Disease Models, Animal; Endothelin-1; Female; Hemodynamics; Hyperemia; Male; Myocardial Ischemia; Norepinephrine; Random Allocation; Recurrence; Risk Factors; Sensitivity and Specificity; Statistics, Nonparametric; Swine; Time Factors; Vasoconstrictor Agents

Taking into consideration age-related changes in endothelium, the ability of endothelium to produce vasoactive substances has been studied in healthy subjects of various age. Under experimental conditions, the activity of constitutive and inducible NO-synthase has been studied as well. The clinical part of the study involved investigation of 38 healthy subjects aged 60-79. The study has been designed to investigate vasomotor function of the endothelium, the levels of endothelin-1, NO2, prostacyclin, thromboxan, the level of adhesive molecules and inhibitor of tissue plasminogen activator. The levels of endothelial and inducible NO-synthases in tissues of the myocardium and the aorta has been investigated in healthy rats of various age. The data obtained show a decrease in the production of relaxation factors: NO and prostacyclin with aging. An important mechanism of deterioration of NO-synthesizing function of the endothelium is a decrease in endothelial NOS activity. The synthesis of endothelial vasoconstricting agents increased with ageing. This in combination with decreased production of vasodilating substances results in deterioration of defence properties of the endothelium. The increase in titer of adhesive molecules and inhibitors of tissue plasminogen activator testifies to age-dependent deterioration of anti-inflammatory and antithrombotic activities of the endothelium.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Aging; Animals; Aorta; Biological Factors; Blood Flow Velocity; Cell Adhesion Molecules; Endothelin-1; Endothelium, Vascular; Erythrocytes; Forearm; Humans; Hyperemia; Laser-Doppler Flowmetry; Middle Aged; Myocardium; Nitric Oxide; Nitric Oxide Synthase; Rats; Thromboxane B2

Southwest Metropolitan Mexico City (SWMMC) children are chronically exposed to complex mixtures of air pollutants. In a cross-sectional arm of our study, we investigated the association between exposure to SWMMC atmosphere and nasal abnormalities, hyperinflation, and interstitial markings assessed by chest X-rays, lung function changes, several serum cytokines, and endothelin-1 in 174 children aged 5-17 years vs. 27 control children residents in low-polluted areas. Control children had no nasal lesions, and only one child showed an abnormal chest X-ray. SWMMC children exhibited nasal abnormalities (22%), hyperinflation (67%), interstitial markings (49%), and a mild restrictive pattern by spirometry (10%). Interstitial markings were associated with a decrease in predicted values of FEF(25-75), FEF(75), and the FEV(1)/FVC ratio. Boys had a higher probability of developing interstitial markings with age (P = 0.004). Blood smear findings included toxic granulations in neutrophils and schistocytes. SWMMC children had more serum IL10 and IL6 and less IL8 than controls. In a longitudinal arm of our study, we found a significant seasonal drop in FVC and FEV(1) associated with a 6-month period of high ozone and PM(10) levels. Our data strongly suggest that a lifelong exposure to urban air pollution causes respiratory damage in children. Moreover, a cytokine network becomes imbalanced, with a shift towards upregulation of anti-inflammatory cytokines. Consequently, these children are potentially at risk for developing chronic lung disease and other systemic effects later in life.

Topics: Adolescent; Age Factors; Air Pollutants; Case-Control Studies; Child; Child, Preschool; Cross-Sectional Studies; Cytoplasmic Granules; Endothelin-1; Erythrocytes, Abnormal; Female; Humans; Hyperemia; Inhalation Exposure; Interleukins; Longitudinal Studies; Lung; Male; Mexico; Nasal Cavity; Neutrophils; Ozone; Radiography; Seasons; Sex Factors; Urban Population

The mechanisms controlling the coronary vascular responses of vessels perfusing the left ventricular (LV) myocardium that is hypertrophied from chronic volume overload are unclear. We hypothesised that endothelial function is compromised, and receptor-mediated contraction is exacerbated, in coronary resistance vessels from rabbits with LV hypertrophy compared to controls. The mitral valve of 10 rabbits was damaged surgically to cause mitral regurgitation and chronic volume overload, resulting in LV hypertrophy (LV hypertrophy rabbits). Echocardiographic assessment at 12 weeks verified that mitral regurgitation was present in LV hypertrophy but not sham-operated, weight- and age-matched animals (control rabbits; n = 17). Percentage increases from weeks 0 to 12 in LV cross-sectional area (47 +/- 7 % vs. 2 +/- 8 %), LV volume (47 +/- 14 % vs. 7 +/- 10 %) and LV mass (27 +/- 4 % vs. 3 +/- 6 %), were greater (all P < 0.05) in LV hypertrophy vs. control rabbits, respectively. At 12 weeks, coronary resistance vessel (approximately 130 microm, internal diameter) reactivity was evaluated using wire myography. Endothelium-dependent (i.e. acetylcholine, 10(-8)-10(-5) M) and -independent (i.e. sodium nitroprusside, 10(-9)-10(-4) M) relaxation, and receptor-mediated vasocontraction (i.e. endothelin-1, 10(-11)-10(-7) M) were similar between groups. However, tension development in response to nitric oxide synthase inhibition (10(-6) M N (G)-monomethyl-L-arginine) was greater (P < 0.05) in LV hypertrophy compared to control rabbits. These results indicate that while coronary resistance vessel function is similar between groups, our estimate of basal nitric oxide production is greater in vessels from LV hypertrophy than control rabbits.

Topics: Acetylcholine; Animals; Blood Vessels; Chronic Disease; Coronary Circulation; Endothelin-1; Hyperemia; Hypertrophy, Left Ventricular; Male; Microcirculation; Mitral Valve Insufficiency; Myocardial Contraction; Nitric Oxide; Nitric Oxide Donors; Nitroprusside; Rabbits; Reference Values; Vasodilation; Vasodilator Agents; Ventricular Function, Left

1. Endothelium-dependent vasodilatation via nitric oxide in response to muscarinic stimulation is decreased in chronic heart failure while basal release of nitric oxide may be increased. As production of the endothelium-derived vasoconstrictor endothelin-1 is increased in chronic heart failure, endothelin-1 may act in an autocrine manner to modulate these effects. 2. To test this, we determined whether prolonged endothelin infusion in normal subjects would reproduce the alterations in basal and stimulated nitric oxide release observed in patients with chronic heart failure. Basal nitric oxide production was determined by measurement of forearm blood flow using strain gauge venous occlusion plethysmography before and after brachial artery infusion of a nitric oxide synthase inhibitor (NG-monomethyl-L-arginine). Stimulated nitric oxide production was determined by brachial artery infusion of acetylcholine. As metabolic vasodilatation is thought to be mediated in part via nitric oxide and is decreased in chronic heart failure, forearm blood flow during peak reactive hyperaemia was also measured. Studies were then repeated during brachial artery infusion of endothelin-1 and a non-specific vasoconstrictor, noradrenaline. 3. Neither basal nor stimulated nitric oxide production was altered by endothelin-1 and noradrenaline infusion. However, absolute forearm blood flow responses to peak reactive hyperaemia were decreased during infusion of endothelin-1 in comparison to noradrenaline. These data suggest that increased endothelin-1 may not contribute greatly to altered basal and stimulated nitric oxide production in patients with chronic heart failure but may contribute to impaired metabolic vasodilatation, by mechanisms presumably unrelated to altered nitric oxide production.

Topics: Acetylcholine; Adult; Endothelin-1; Endothelium, Vascular; Female; Forearm; Heart Failure; Humans; Hyperemia; Male; Nitric Oxide; Nitric Oxide Synthase; Norepinephrine; omega-N-Methylarginine; Regional Blood Flow; Stimulation, Chemical; Vasoconstriction; Vasoconstrictor Agents