endothelin-1 and dimethylarginine

Acute aerobic exercise prevents sitting-induced impairment of flow-mediated dilation (FMD). Further, evidence suggests that sitting-induced impairment of FMD occurs via an oxidative stress-dependent mechanism that disrupts endothelial function.. We hypothesized that acute aerobic exercise would prevent impairment of femoral artery FMD by limiting oxidative stress responses that increase endothelin-1 (ET-1) levels and disrupt nitric oxide (NO) status.. In a randomized, cross-over study, healthy men (n = 11; 21.2 ± 1.9 years) completed two 3 h sitting trials that were preceded by 45 min of either quiet rest (REST) or a single bout of continuous treadmill exercise (65% maximal oxygen consumption) (EX). Superficial femoral artery FMD, plasma glucose, malondialdehyde (MDA), ET-1, arginine (ARG) and its related metabolites [homoarginine (HA), asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA)] were assessed at baseline, 1 h following EX (or REST) (0 h), and at 1 h intervals during 3 h of uninterrupted sitting. Data were analyzed using repeated measures ANOVA.. During REST, femoral artery FMD declined from baseline (2.6 ± 1.8%) at 1, 2, and 3 h of sitting and resting shear rate decreased at 3 h. In contrast, when sitting was preceded by EX, femoral artery FMD (2.7 ± 2.0%) and resting shear rate responses were unaffected. No between trial differences were detected for plasma glucose, MDA, ET-1, ARG, HA, ADMA, or SDMA.. Prior aerobic exercise prevented the decline in femoral artery FMD that is otherwise induced by prolonged sitting independent of changes in oxidative stress, ET-1, and NO status.

Topics: Arginine; Blood Glucose; Endothelin-1; Endothelium, Vascular; Exercise; Exercise Therapy; Femoral Artery; Humans; Immobilization; Male; Malondialdehyde; Nitric Oxide; Peripheral Arterial Disease; Posture; Regional Blood Flow; Vasodilation; Young Adult

To determine whether postprandial metabolic and vascular responses induced by a high-fat and high-carbohydrate meal are attenuated by ingestion of the flavonol quercetin.. Twenty-two overweight-to-obese hypertensive patients participated in a randomized, double-blind, controlled, crossover meal study. They consumed a test meal (challenge) rich in energy (4754 kJ), fat (61.6 g), saturated fatty acids (53 % of total fatty acids), and carbohydrates (113.3 g) with either placebo or 54 mg quercetin. Blood pressure, reactive hyperemia index (RHI), high-sensitive C-reactive protein (hs-CRP), soluble endothelial-derived adhesion molecules, parameters of lipid and glucose metabolism, and markers of antioxidant status were measured before the meal and at 2 and 4 h postprandially.. Systolic and diastolic blood pressure increased significantly over time, but were not affected by treatment (placebo or quercetin). During both treatments, serum endothelin-1, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and plasma asymmetric dimethylarginine slightly decreased over time, whereas RHI increased. Serum triglycerides, total cholesterol, and insulin significantly increased, whereas HDL cholesterol and glucose significantly decreased over time, again with no effect of treatment. Plasma α-tocopherol significantly increased, and plasma Trolox equivalent antioxidative capacity decreased over time. Serum hs-CRP, plasma retinol, and β-carotene did not significantly change during the trial.. In hypertensive patients, a high-energy meal did not lead to postprandial impairment of vascular endothelial function. Postprandial metabolic responses induced by the challenge, such as lipemia and insulinemia, were not attenuated by the concomitant ingestion of quercetin.. This trial was registered at www.germanctr.de/ and http://apps.who.int/trialsearch/ as DRKS00000555.

Topics: Adult; Aged; Arginine; beta Carotene; Blood Pressure; C-Reactive Protein; Cholesterol; Cross-Over Studies; Double-Blind Method; Endothelin-1; Female; Humans; Hypertension; Insulin; Intercellular Adhesion Molecule-1; Male; Middle Aged; Obesity; Onions; Overweight; Plant Extracts; Postprandial Period; Quercetin; Triglycerides; Vascular Cell Adhesion Molecule-1; Vitamin A

Extracts from pine tree bark containing a variety of flavonoids have been used in traditional medicine. Pycnogenol is a proprietary bark extract of the French maritime pine tree (Pinus pinaster ssp. atlantica) that exerts antioxidative, anti-inflammatory, and anti-platelet effects. However, the effects of Pycnogenol on endothelial dysfunction, a precursor of atherosclerosis and cardiovascular events, remain still elusive.. Twenty-three patients with coronary artery disease (CAD) completed this randomized, double-blind, placebo-controlled cross-over study. Patients received Pycnogenol (200 mg/day) for 8 weeks followed by placebo or vice versa on top of standard cardiovascular therapy. Between the two treatment periods, a 2-week washout period was scheduled. At baseline and after each treatment period, endothelial function, non-invasively assessed by flow-mediated dilatation (FMD) of the brachial artery using high-resolution ultrasound, biomarkers of oxidative stress and inflammation, platelet adhesion, and 24 h blood pressure monitoring were evaluated. In CAD patients, Pycnogenol treatment was associated with an improvement of FMD from 5.3 ± 2.6 to 7.0 ± 3.1 (P < 0.0001), while no change was observed with placebo (5.4 ± 2.4 to 4.7 ± 2.0; P = 0.051). This difference between study groups was significant [estimated treatment effect 2.75; 95% confidence interval (CI): 1.75, 3.75, P < 0.0001]. 15-F(2t)-Isoprostane, an index of oxidative stress, significantly decreased from 0.71 ± 0.09 to 0.66 ± 0.13 after Pycnogenol treatment, while no change was observed in the placebo group (mean difference 0.06 pg/mL with an associated 95% CI (0.01, 0.11), P = 0.012]. Inflammation markers, platelet adhesion, and blood pressure did not change after treatment with Pycnogenol or placebo.. This study provides the first evidence that the antioxidant Pycnogenol improves endothelial function in patients with CAD by reducing oxidative stress.

Topics: Adult; Aged; Anti-Inflammatory Agents; Antihypertensive Agents; Antioxidants; Arginine; Biomarkers; Blood Platelets; Blood Pressure; C-Reactive Protein; Coronary Artery Disease; Cross-Over Studies; Double-Blind Method; Endothelin-1; Endothelium, Vascular; Female; Flavonoids; Humans; Male; Middle Aged; Oxidative Stress; Plant Extracts; Prospective Studies; Shear Strength; Treatment Outcome; Vasodilation; Vasodilator Agents

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

To explore noninvasively the complex interactions of the maternal hemodynamic system throughout pregnancy and the resulting after-effect six weeks postpartum.. Eighteen women were tested beginning at the 12th week of gestation at six time-points throughout pregnancy and six weeks postpartum. Heart rate, heart rate variability, blood pressure, pulse transit time (PTT), respiration, and baroreceptor sensitivity were analyzed in resting conditions. Additionally, hemoglobin, asymmetric and symmetric dimethylarginine and Endothelin (ET-1) were obtained.. Heart rate and sympathovagal balance favoring sympathetic drive increased, the vagal tone and the baroreflex sensitivity decreased during pregnancy. Relative sympathetic drive (sympathovagal balance) reached a maximum at 6 weeks postpartum whereas the other variables did not differ compared to first trimester levels. Postpartum diastolic blood pressure was higher compared to first and second trimester. Pulse transit time and endothelial markers showed no difference throughout gestation. However, opposing variables PTT and asymmetric dimethylarginine (ADMA) were both higher six weeks postpartum.. The sympathetic up regulation throughout pregnancy goes hand in hand with a decreased baroreflex sensitivity. In the postpartum period, the autonomic nervous system, biochemical endothelial reactions and PTT show significant and opposing changes compared to pregnancy findings, indicating the complex aftermath of the increase of blood volume, the changes in perfusion strategies and blood pressure regulation that occur in pregnancy.

Topics: Adult; Arginine; Baroreflex; Blood Pressure; Cardiovascular Physiological Phenomena; Endothelin-1; Endothelium; Female; Heart Rate; Hemodynamics; Hemoglobins; Humans; Postpartum Period; Pregnancy; Pregnancy Trimesters; Pressoreceptors; Prospective Studies

Chemokines promote vascular inflammation and play a pathogenic role in the development and maintenance of hypertension. However, in our previous study, chemokine CCL5 was shown to reduce Ang II-induced 12-lipoxygenase (12-LO) production as well as proliferation in vascular smooth muscle cells (VSMCs) obtained from spontaneously hypertensive rats (SHR). Dimethylarginine dimethylaminohydrolase (DDAH) acts as an important regulator of vascular function by metabolizing and regulating plasma asymmetric (N(G),N(G)) dimethylarginine (ADMA), a major risk factor for cardiovascular disease. Therefore, in this study, we investigated the effect of CCL5 on DDAH-1 production in SHR VSMCs. Constitutive expression of DDAH-1 in VSMCs from SHR was higher than that in VSMCs from normotensive Wistar Kyoto rats (WKY), whereas expression of DDAH-2 was not significantly different between SHR and WKY VSMCs. CCL5 increased DDAH-1 production and attenuated Ang II-induced DDAH-1 inhibition in SHR VSMCs. In addition, although CCL5 did not affect the level of asymmetric (N(G),N(G)) dimethylarginine (ADMA), it attenuated Ang II-induced ADMA production through DDAH-1 activity. DDAH-1 induction by CCL5 was mediated by the Ang II subtype 2 receptor (AT2 R) pathway. Further, attenuation of Ang II-induced 12-LO and endothelin-1 (ET-1) expression by CCL5 could be attributed to DDAH-1 activity. These findings combined with our previous results suggest that CCL5 is a potential down-regulatory factor in Ang II-induced vascular hypertension.

Topics: Amidohydrolases; Angiotensin II; Animals; Arginine; Blood Pressure; Cell Proliferation; Chemokine CCL5; Endothelin-1; Hypertension; Male; Muscle, Smooth, Vascular; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 2; RNA Interference; RNA, Small Interfering

There has been little information demonstrating the roles of dimethylarginine dimethylaminohydrolase (DDAH), which is the hydrolyzing enzyme of endogenous nitric oxide synthase (NOS) inhibitors and, in turn, modulates the intracellular concentrations of NOS inhibitors, in the myometrium during the course of pregnancy. Therefore, the present experiments were designed to investigate whether or not DDAH activity, protein and mRNA expression levels are altered during gestation of the rat and, if altered, those changes reflect on the levels of endogenous inhibitors and endothelin-1 (ET-1), and NO-dependent cyclic GMP generation in the myometrium. The up-regulated changes in DDAH activity, DDAH-2 protein and DDAH-2 mRNA expression at mid-gestation were accompanied by the reduced monomethylarginine and asymmetric dimethylarginine as NOS inhibitors, and ET-1 levels, and by the enhanced NO-dependent cyclic GMP production. At term gestation, on the other hand, down-regulated changes in DDAH activity, DDAH-2 protein and DDAH-2 mRNA expression were accompanied by the increased NOS inhibitors and ET-1 levels, and decreased NO-dependent cyclic GMP generation. These results suggest that alterations in DDAH/NOS inhibitors/NO-dependent cyclic GMP/ET-1 pathway are possibly involved in maintaining myometrial quiescence during gestation and controlling delivery at term.

Topics: Amidohydrolases; Animals; Arginine; Blotting, Western; Cyclic GMP; Endothelin-1; Female; In Vitro Techniques; Myometrium; Pregnancy; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Uterine Contraction

An increasing number of studies have examined the role of emotional stress and coronary heart disease; the underlying pathophysiology is still poorly understood. The present study was designed to evaluate the relationship between acute (epi- and norepinephrine) and chronic stress hormones (dexamethasone, beta-endorphin, corticotropin releasing hormone) and endothelial dysfunction.. Human microvascular endothelial cells were incubated with stress hormones for 6 and 24 h. ET-1 release and ADMA were quantified via ELISA, NO release by using cell permeable 4.5-diaminofluorescein diacetate (DAF2-DA), oxidative stress fluometrically by the ROS-sensitive carboxy-H2-DCFDA method, mitochondrial metabolic activity by using the colorimetric assay WST-1, ET-1 receptor type A (ET(A)R) protein expression by Western blot, and cell proliferation activity was assessed by the colorimetric assay BrdU.. With respect to analysed acute and chronic stress hormones, ET-1 release was significantly increased. Likewise, protein expression was enhanced after long term incubation (24 h) with norepinephrine and dexamethasone. In contrast, endothelial NO-levels were only influenced by short term stimulation of dexamethasone (upregulation of NO release) and norepinephrine (downregulation of NO release), whereas modified NO concentration mimics altered mitochondrial metabolic activity. Unexpectedly, both oxidative stress and cell proliferation were not modified by stress hormones.. Results suggest that acute and chronic stress hormones induce a significant ET-1 release whereas NO release remained mainly unchanged. The imbalance of pro- and antiatherosclerotic factors may play a pivotal role in the initiation of stress-related endothelial dysfunction up to myocardial infarction.

Topics: Arginine; beta-Endorphin; Catecholamines; Cell Proliferation; Cell Survival; Cells, Cultured; Corticotropin-Releasing Hormone; Dexamethasone; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Epinephrine; Hormones; Humans; Nitric Oxide; Norepinephrine; Oxidative Stress; Receptor, Endothelin A