Plasma Endothelin-1 Concentrations Research Articles

Effect of trimetazidine on cardiac function and exercise tolerance in hypertension patients with diabetic

To determine the effect of trimetazidine on cardiac function and exercise tolerance in primary hypertension patients with type 2 diabetic. In this randomized, double-blind, placebo-controlled prospective study, 60 primary hypertensive patients with diabetic were equally assigned into two groups, patients received trimetazidine (20 mg, 3 times a day) or placebo for 1 year. Echocardiography, cardiopulmonary exercise testing were performed; and the plasma N terminal pro B type natriuretic peptide (NT-ProBNP), hr-CRP, TNF-α, angiotensin Ⅱ and endothelin concentration were determined before and after treatment. In trimetazidine group, the left ventricular mass index, the mitral flow velocity E wave to A wave ratio (E/A), the peak early diastolic velocity (VE) to late diastolic velocity (VA) ratio (VE/VA) and the peak systolic velocity (Vs) were significantly improved, the plasma NT-ProBNP level was significantly decreased, and the exercise time, metabolic equivalent, maximal oxygen uptake and anaerobic threshold were significantly increased (all P<0.05); plasma concentration of hr-CRP, TNF-α, angiotensin Ⅱ and endothelin were significantly reduced after trimetazidine treatment, compared with baseline (all P<0.05) and with placebo (all P<0.05). There were no significant differences in any of above parameters after treatment in placebo group (all P>0.05). No severe adverse reaction was observed in both groups. For patients with both hypertension and diabetes, trimetazidine can improve cardiac function and increase exercise tolerance.

Elevated plasma endothelin-1 is associated with reduced weight loss post vertical sleeve gastrectomy

BackgroundObesity and insulin resistance are positively correlated with plasma endothelin-1 (ET-1) levels; however, the mechanisms leading to increased ET-1 are not understood. Similarly, the full physiological complexity of ET-1 has yet to be described, especially in obesity. To date, one of the best treatments available for morbid obesity is bariatric surgery to quickly reduce body fat and the factors associated with obesity-related disease; however, the effects of vertical sleeve gastrectomy (SG) on plasma ET-1 have not been described. ObjectivesTo determine if SG will reduce plasma ET-1 levels and to determine if plasma ET-1 concentration is associated with weight loss after surgery. SettingThe studies were undertaken at a University Hospital. MethodsThis was tested by measuring plasma ET-1 levels from 12 obese patients before and after SG. All data were collected from clinic visits before SG, 6 weeks after SG, and 6 months after surgery. ResultsAt 6 weeks after SG, plasma ET-1 levels increased by 24%; however, after 6 months, there was a 27% decrease compared with presurgery. Average weight loss in this cohort was 11.3% ± 2.4% body weight after 6 weeks and 21.4% ± 5.7% body weight after 6 months. Interestingly, we observed an inverse relationship between baseline plasma ET-1 and percent body weight loss (R2 = .49, P = .01) and change in body mass index 6 months (R2 = .45, P = .011) post bariatric surgery. ConclusionsOur results indicate that SG reduces plasma ET-1 levels, a possible mechanism for improved metabolic risk in these patients. These data also suggest that ET-1 may serve as a predictor of weight loss after bariatric surgery.

The Effect of Circuit Resistance Training on Plasma Concentration of Endothelin-1, Nitric Oxide and Vascular Diameter in Elderly Men

Background: aging is associated with an increase in vascular dysfunction but it can be prevented by exercise training. However, the effect of circuit resistance training as a useful training method in improving cardio-respiratory and muscular strength is unclear. Objectives: The aim of this study was to investigate the effect of CRT on plasma endothelin-1, nitric oxide (NO) and vascular size in aged men. Methods: Twenty healthy aged men (55 ± 5 year) were randomly divided into control and CRT groups. CRT group performed circuit resistance training with 40 - 60 one repetition maximum for twelve weeks (3 times per week). Vascular size, plasma endothelin-1 and NO, blood pressure and heart rate were measured forty eight hours before and after the training period. Results: CRT increased the vascular size and decreased endothelin-1 and systolic blood pressure compared to the pre-test; however, it had no effect on NO concentration and heart rate. In comparison with the control group, CRT significantly increased the vascular size and decreased endothelin-1 and blood pressure but there was no significant difference in NO concentration and heart rate between the two groups. Conclusions: Circuit resistance training as a proper training method could induce the increase in endothelial function in aged individual and prevents vascular dysfunction related to aging.

Measurement of plasma endothelin-1 concentration in healthy horses and horses with cardiac disease during rest and after exercise.

Cardiac biomarkers are important tools for monitoring disease progress and can monitor progression of therapy. Endothelin-1 (ET-1) has been studied for its use as a cardiac biomarker in human and small animal medicine while in horses with cardiac disease it has not been evaluated yet. The objective of the present study was to determine the concentration of plasma ET-1 in healthy horses and compare it with ET-1 concentration in horses with cardiac disease during rest and after exercise. Fifty four horses admitted to the Equine Clinic of Free University of Berlin were used in the present study, of which 15 horses were clinically healthy with no evidence of cardiac disease (Group 1), 22 horses suffered from cardiac disease with normal heart dimensions (Group 2) and 17 horses with cardiac disease and enlarged heart diameters (Group 3). Clinical examination, electrocardiography and echocardiography were performed. Endothelin-1 concentration was determined using ET-1 ELISA kit. The concentration of plasma ET-1 was significantly increased in horses with cardiac disease and normal cardiac dimensions (Group 2) and in horses with cardiac disease and enlargement of the left atrium (Group 3) compared to its concentration in clinically healthy horses (Group 1). In addition, the concentration of plasma ET-1 after exercise was significantly increased in diseased horses compared to its concentration at rest. Detection of ET-1 plasma concentration in horses at rest may be useful for detecting horses with changes in left atrial cardiac dimensions.

Dynamics of еndothelin-1 level and the development of complications in patients with acute epididymoorchitis

In this study attempted to clarify the diagnostic and prognostic significance of changes in the content of endothelin-1 (ET-1) in plasma of patients with acute epididymoorchitis in connection with blood circulation in the testis of the appendage. To determine the concentration of ET-1 using ELISA method. In all examined patients before treatment revealed a significant increase in the concentration of ET-1. In the preoperative period, 43% of patients with irreversible complications (lack of blood flow to the testicle or appendage, the CDC-signal) concentration of ET-1 to the 7th day remained high (25,8±3,2 ng/ml, exceeding the norm by 2,5 times), which indicates the irreversible microcirculatory disorders in testicle (appendage), possibly by increasing vasoconstriction of blood vessels. In 57% of patients were observed for complications, processes are reversible ischemia, and the concentration of ET-1 gradually decreased until the 14th day amounted to 5,8±0,6 ng/ml, returning to the range of normal. Changes in the concentration of ET-1 in blood plasma indicates the reversibility of metabolic disorders related testicular tissue ischemia, as well as diagnostic and prognostic significance of this factor determining the relative risk of complications.

Reduced Hemoglobin Levels Combined with an Increased Plasma Concentration of Vasoconstrictive endothelin-1 are Strongly Associated with Poor Outcome During Acute Ischemic Stroke.

The association of poor outcome and mortality with low levels of hemoglobin (Hb) and hematocrit (HcT) in patients admitted after acute Ischemic Stroke (IS) was recently demonstrated. The mechanisms behind this still remain unclear. Our study aims to find out whether mRNA expressions and plasma concentrations of endothelin-1 (ET-l), endothelin-2 (ET-2) and endothelin-3 (ET-3) remain different in IS sufferers with low HcT and Hb levels in comparison with those whose HcT i Hb levels during a severe IS episode remain within the norm. The study included 60 patients treated consecutively for first-time IS. The assessment of mRNA gene expression and plasma concentration of ET-1, ET-2, ET-3 was conducted in the first, third and seventh day following the onset of stroke using qRT-PCR method and ELISA tests. We demonstrated that patients whose initial HcT and Hb levels were below the norm presented a deeper neurologic deficit on 1, 3 and 7 day following stroke with noticeable improvement no earlier than between day 3 and 7. We also found a negative correlation between the initial HcT and Hb and concentration of plasma ET-1 on the same days. The patients whose HcT and Hb levels were within normal limits showed a significant improvement in their neurologic condition on each consecutive day of the observation. Reduced levels of Hb and HcT combined with an increased plasma concentration of vasoconstrictive endothelin-1 are strongly associated with poor outcome and high mortality in acute ischemic stroke.

Prognosis of cardiovascular events after implantation of a cardioverterdefibrillator in patients with chronic heart failure: the value of increasing concentration of endothelin-1 and soluble forms of ST2 protein in blood plasma

Aim.The purpose of this study was to examine the association of increasing concentrations of endothelin-1 and soluble forms of ST2 protein (sST2) in the blood plasma of patients with chronic heart failure (CHF) who underwent implantation of a cardioverter-defibrillator, with the development of cardiovascular events (death from cardiovascular diseases, decompensated CHF, acute coronary syndrome or acute ischemic stroke) to determine whether these biomarkers can be used as predictors of an unfavorable course of the disease.Material and methods. A 6-month cohort study included 40 patients with CHF who received an ICD 4-12 weeks before their inclusion in the study. At the beginning of the study the concentrations of endothelin-1 and sST2 in plasma by ELISA were analyzed, along with conventional diagnostic techniques typical of a specialized cardiology clinic.Results.Phenotype with a favorable course of the disease was identified in 21 patients (group 1), and with a unfavorable course was seen in 19 (group 2). The concentration of endothelin-1 and sST2 in the blood plasma of the 2nd group patients was higher than in patients of the 1st group. The link of cardiovascular events with high levels of soluble ST2 protein and endothelin-1 in blood plasma has been identified. Variation of the decision rule threshold on the ROC-curve has allowed sST2 concentration of 34.93 ng/ml to be determined as a cutoff point. Accuracy of two-class classification (determination of the posterior probability of cardiovascular events) after identifying such cut-off point was characterized by 93% sensitivity and 72% specificity (area under ROC-curve – 0.87). If the value of the plasma concentrations of sST2 more 34.93 ng/ml the relative risk of cardiovascular events was 4.4 (95% CI 1.7–11.1). The use of endothelin-1 surplus in plasma (cut-off point – 0.34 fmol/ml) in predicting cardiovascular events was lower: the sensitivity – 88%, specificity – 68% (area under ROC-curve – 0.74). When the concentration of endothelin-1 in blood plasma was more than 0.34 fmol/ml the relative risk of cardiovascular events was 2.7 (95% CI 1.2–6.3).Conclusion.The increase in the sST2 and endothelin-1 concentration in blood plasma may be considered as a predictor of cardiovascular events in CHF patients after implantation of cardioverter-defibrillator.

Combined hydroxyurea and ETA receptor blockade reduces renal injury in the humanized sickle cell mouse.

The objective of this study is to determine if ambrisentan (ETA selective antagonist) and hydroxyurea (HU) treatment has a synergistic effect on renal injury in sickle cell nephropathy when compared to HU treatment alone. The premise of the study is based on recent studies showing that endothelin-1 (ET-1) contributes to the pathophysiology of nephropathy in sickle cell disease (SCD) and that ETA receptor blockade improves renal function and protects against renal injury. Hydroxyurea (HU) is commonly prescribed for the treatment of SCD and has been shown to reduce renal injury in patients with SCD. Male 12-week-old humanized sickle mice (HbSS) and their genetic controls (HbAA) were treated with vehicle, HU, ambrisentan, or HU with ambrisentan for 2weeks and renal structure and function were assessed. Vehicle treated HbSS mice exhibited significant proteinuria compared to vehicle treated HbAA mice. HbSS mice also displayed significantly elevated plasma ET-1 concentrations and decreased urine osmolality compared to HbAA controls. Proteinuria was significantly lower in both HU and ambrisentan treated animals compared to vehicle treated HbSS mice; however, there was no additional improvement in HbSS mice treated with combined ambrisentan and HU. The combination of HU and ambrisentan resulted in significantly lower KIM-1 excretion, glomerular injury, and interstitial inflammation than HU alone. These findings indicate that HU and ETA receptor blockade produce similar reductions in renal injury in the humanized sickle mouse suggesting that both treatments may converge on the same mechanistic pathway.

Prognostic importance of endothelin-1 and endothelin receptor: a plasma levels in the early perimetric stage of primary open-angle glaucoma

An increasing amount of data suggests a role of the eye vascular system and oxidative stress in glaucoma pathogenesis. Reports have suggested endothelin-1 (ET-1) and its receptor (ETR-A) as possible glaucoma biomarkers. This study explored the diagnostic and prognostic abilities of ET-1 and ETR-A plasma concentrations in primary open angle glaucoma (POAG). Seventy-five participants were divided into three groups: controls, early and advanced POAG stage, graded by a perimetric visual field test. All of them underwent a standard ophthalmological examination including optical coherence tomography. The statistical analysis showed a significant difference between the ET-1 values in the controls (4.88 ± 1.75 pg/mL) and the glaucoma patients, but lack of statistical significance in the glaucoma severity (early POAG: 6.33 ± 2.38 pg/mL and advanced POAG: 6.34 ± 1.56 pg/mL). The mean ETR-A values were significantly different between the three groups (controls 1209.28 ± 314.48 pg/mL, early POAG: 673.44 ± 283.02 pg/mL and advanced POAG: 992.28 ± 264.22 pg/mL). Two mathematical models were developed concerning the two perimetric indices (MD/PSD) and ETR-A in the early glaucoma group. ETR-A showed a very high diagnostic accuracy. Only ETR-A had significant diagnostic ability for advanced glaucoma after the comparison between the two glaucoma groups. Every 1 pg/mL increase in the ET-1 plasma concentration increased the possibility for early glaucoma changes by 2.124 times, whereas every 1 pg/mL increase in the ETR-A level decreased this possibility by 1%. Our results indicate that ET-1 and ETR-A could be two very good diagnostic parameters for early POAG changes.

The Effect of Bariatric Surgery on Neprilysin and Vasoactive Factors

Objective: Since morbid obesity is associated with congestive cardiac failure and hypertension, and gastric bypass surgery is followed by a reduction in blood pressure and a reduction in the risk of congestive cardiac failure, we hypothesized that weight loss following bariatric surgery in morbidly obese patients is associated with a decrease in plasma concentrations of neprilysin, mediators of renin angiotensin system, catecholamines and endothelin-1 with an increase in the concentrations of vasodilators. Method: Fasting blood samples were obtained from fourteen patients with morbid obesity and diabetes prior to and 6 months after Roux-en-Y gastric bypass (RYGB) surgery. Plasma and serum were separated for the measurement of neprilysin; vasoconstrictors, angiotensinogen, renin, angiotensin II, endothelin-1, epinephrine and norepinephrine; and vasodilators, ANP, BNP, cGMP, and cAMP. The mRNA expression of angiotensin converting enzyme (ACE) and adenylate and guanylate cyclases in circulating mononuclear cells (MNC) was also measured. Results: Six months after RYGB, BMI fell from 52.1±4.8 to 40.4±4.0 kg/m2 and there were significant improvements in the HbA1c. Plasma concentrations of neprilysin, angiotensinogen, angiotensin II, renin and endothelin-1 fell significantly by 27±16%, 22±10% 22±8%, 35±13% and 17±6% (p&amp;lt;0.for all) respectively, while ANP concentrations increased significantly by 24±13% at 6 month following surgery. There was no significant change in aldosterone, BNP, cAMP or cGMP concentrations and ACE mRNA expression. Conclusion: RYGB suppressed neprilysin concentrations, which may contribute the observed increase in plasma ANP concentrations. In addition, RYGB resulted in a reduction in plasma angiotensinogen, angiotensin II, renin and endothelin-1 concentrations. These changes may contribute to the reduction in the risk of congestive cardiac failure and blood pressure after RYGB. Disclosure P. Dandona: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. H. Ghanim: None. S. Monte: Stock/Shareholder; Self; Mobile Pharmacy Solutions (Community Pharmacy). Employee; Self; Synergy Bariatrics, a Department of ECMC. K. Green: None. J.A. Caruana: None.

Effects of grape consumption on biomarkers of inflammation, endothelial function, and PBMC gene expression in obese subjects

This study investigated effects of grape consumption on biomarkers of cardiovascular health in obese participants in both postprandial and chronic settings. Twenty obese adults participated in this randomized, placebo controlled, double-blinded crossover trial. Participants were randomized to consume 60 g freeze-dried polyphenol-rich whole grape powder (GP) or placebo (PBO) followed by high fat high carbohydrate (HFHC) meal challenge. Following acute challenge, participants consumed their respective treatment daily for 4 weeks to determine effects of chronic consumption. Consumption of GP with HFHC meal significantly increased nuclear factor (erythroid-derived 2)-like 2 (NRF2) expression in peripheral blood mononuclear cells (PBMC) at 3 h (p < 0.05) and decreased plasma endothelin-1 (ET-1) concentration at 5 h (p < 0.05) after meal challenge compared with PBO. Following 4 weeks of daily GP consumption, soluble vascular cell adhesion molecule 1 (sVCAM-1) plasma concentration increased compared with PBO (p < 0.05), however baseline values differed between treatments. In conclusion, GP consumption resulted in decreased vasoconstrictor ET-1 concentration and increased gene expression related to oxidative stress defense following HFHC meal. Except for increase in sVCAM-1 concentration, 4 weeks of chronic GP consumption had little effect on cardiovascular biomarkers measured in this study. This trial was registered: clinicaltrials.gov NCT01674231.

Hemodynamic Hyper‐reactivity to Acute Stress in Individuals Reporting Adversity during Childhood: Role of Endothelin‐1

Individuals exposed to adverse childhood experiences (ACE) have an increased risk of developing cardiovascular disease versus those with no ACE. Moreover, these individuals also exhibit an exaggerated blood pressure response to an acute sympathetic stressor; a response that is associated with an increased risk of developing hypertension and shown to be mediated by endothelin‐1 (ET‐1) in animal models. The role of ET‐1 as a modulator of the hemodynamic response to acute stress in humans with high ACE, however, is unknown.PurposeTo compare hemodynamic and plasma ET‐1 responses to a cold pressor test (CPT) in individuals who reported high ACE versus matched controls with no reported ACE.Methods14 participants volunteered for this investigation; 7 of which reported an ACE score ≥4 via questionnaire (HI‐ACE; 5 men, 2 women) and 7 control participants (CON) who were matched for age, ethnicity, sex, and body composition. All participants underwent a CPT protocol which consisted of a 5 min baseline followed by immersion of the right hand up to the wrist in ice water (~2°C) for 3 min. Hemodynamic parameters including total peripheral resistance index (TPRI), cardiac index (CI), and systolic/diastolic blood pressure (SBP/DBP) were measured throughout the protocol using beat‐to‐beat monitoring of finger arterial pressure (Finapres NOVA). Plasma concentrations of ET‐1 were determined at baseline and during the second minute of the CPT.ResultsThere were no differences (all p&gt;0.05) between groups in age, ethnicity, sex, body composition, or fasting blood glucose. Similarly, there were no differences (all p&gt;0.05) in baseline values of TPRI (0.39 ± 0.31 vs. 0.43 ± 0.25 mmHg/ml/m2), CI (3.5 ± 0.8 vs. 3.5 ± 0.6 L/min/m2), SBP (134 ± 14 vs. 133 ± 12 mmHg), or DBP (83 ± 10 vs. 85 ± 11 mmHg) between HI‐ACE and CON. During CPT, a significantly greater increase in SBP (48 ± 20 vs. 29 ± 10 mmHg; p=0.041) and DBP (35 ± 15 vs. 19 ± 5 mmHg; p=0.028) occurred in HI‐ACE compared to CON. While concentrations of ET‐1 at baseline were similar between HI‐ACE and CON (1.28 ± 0.21 vs. 1.22 ± 0.33 pg/ml, respectively), the ET‐1 response during CPT tended (p=0.098) to be higher in HI‐ACE versus CON (Δ1.12 ± 0.03 vs. Δ0.50 ± 0.37 pg/ml).ConclusionThese data suggest that greater plasma concentrations of ET‐1 accompany the exaggerated hemodynamic response to a CPT in individuals who reported high ACE. Future studies are warranted to further elucidate the role of ET‐1 as a mediator of hemodynamic responses to acute stress in individuals with high ACE.Support or Funding InformationSupported in part by NIH/NHLBI P01HL06999.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Endothelium‐dependent vasorelaxation and blood pressure are preserved in mice with chronic hyperendothelinemia

Endothelin‐1 (ET‐1) is a potent vasoactive peptide implicated in the development of glucose intolerance, endothelial dysfunction, and hypertension. However, whether the detrimental metabolic and vascular effects caused by chronically elevated circulating ET‐1 (i.e., hyperendothelinemia) are exacerbated by obesity remains unknown. Accordingly, six‐week‐old female transgenic mice overexpressing human preproET‐1 selectively in the endothelium (eET‐ 1) and non‐transgenic (i.e., wild‐type) littermates were fed either chow or a Western diet (46% Kcal fat, 36% Kcal carbohydrate) to induce obesity for 21 weeks, creating four distinct groups (n=9–11/group): wild‐type chow‐fed, eET‐1 chow‐fed, wild‐type Western diet‐fed, eET‐1 Western diet‐fed. eET‐1 mice exhibited a 27‐fold (chow) and 18‐fold (Western diet) elevation in plasma ET‐1 concentration relative to wild‐type mice. Notably, despite such marked elevations in plasma ET‐1, blood pressure (systolic and diastolic) and aortic stiffness, assessed by pulse wave velocity, were unaltered in eET‐1 mice relative to wild‐type counterparts, regardless of diet. Similarly, independent of diet, ex vivo endothelium‐dependent relaxation (i.e., vasomotor responses to acetylcholine and insulin) in femoral and coronary arteries were not different between eET‐1 and wild‐type mice, and modestly enhanced in the aorta of eET‐1 mice. eET‐1 mice also exhibited suppressed phenylephrine‐induced aortic vasoconstriction relative to wild‐type mice, an effect that was amplified by Western diet‐feeding. Chow‐fed eET‐1 mice exhibited mild glucose intolerance and this genotype effect was not aggravated by diet‐induced obesity. Collectively, contrary to our hypothesis, we find that endothelial overexpression of ET‐1 does not lead to impaired endothelial function in lean or obese mice. The retention of a functional endothelial phenotype and suppression of alpha‐adrenergic vasoconstriction in this model of chronic hyperendothelinemia may contribute to the preservation of normal blood pressure. Follow‐up experiments are ongoing to delineate potential homeostatic compensatory adaptations that underlie this largely conserved cardiometabolic phenotype in the presence of chronic hyperendothelinemia.Support or Funding InformationNIH, SCANThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The Role of Endothelin in the Pathophysiology of Migraine-a Systematic Review.

Vasoactive peptides play a key role in the attack-initiating cascade of migraine. Recent studies have highlighted a potentially important role for endothelin-1, a potent vasoconstrictor peptide, in migraine pathophysiology. Here, we review the current data on endothelin's involvement in migraine. We identified 23 articles. Nine studies reported on endothelin-1 plasma concentrations in patients with migraine, eight studies investigated relevant genetic associations, five studies investigated endothelin-1 and spreading depression in animals, and one randomized controlled clinical trial tested the efficacy of an endothelin antagonist in the acute treatment of migraine in patients both with and without aura. Elevated endothelin-1 plasma levels have been reported in the early phase of migraine attacks. Genetic abnormalities related to the endothelin type A receptor have been reported in migraineurs. Endothelin-1 potently induces spreading depression in animals, which may explain the connection between endothelial irritation and migraine aura. Endothelin-1 could be a primary factor in the attack-triggering cascade of migraine attacks with and without aura. Additional studies in humans and animal models are needed to further elucidate the role of endothelin-1 in migraine.

The effect of low and high-intensity cycling in diesel exhaust on flow-mediated dilation, circulating NOx, endothelin-1 and blood pressure.

IntroductionExposure to air pollution impairs aspects of endothelial function such as flow-mediated dilation (FMD). Outdoor exercisers are frequently exposed to air pollution, but how exercising in air pollution affects endothelial function and how these effects are modified by exercise intensity are poorly understood.ObjectivesTherefore, the purpose of this study was to determine the effects of low-intensity and high-intensity cycling with diesel exhaust (DE) exposure on FMD, blood pressure, plasma nitrite and nitrate (NOx) and endothelin-1.MethodsEighteen males performed 30-minute trials of low or high-intensity cycling (30% and 60% of power at VO2peak) or a resting control condition. For each subject, each trial was performed once while breathing filtered air (FA) and once while breathing DE (300ug/m3 of PM2.5, six trials in total). Preceding exposure, immediately post-exposure, 1 hour and 2 hours post-exposure, FMD, blood pressure and plasma endothelin-1 and NOx concentrations were measured. Data were analyzed using repeated-measures ANOVA and linear mixed model.ResultsFollowing exercise in DE, plasma NOx significantly increased and was significantly greater than FA (p<0.05). Two hours following DE exposure, endothelin-1 was significantly less than FA (p = 0.037) but exercise intensity did not modify this response. DE exposure did not affect FMD or blood pressure.ConclusionOur results suggest that exercising in DE did not adversely affect plasma NOX, endothelin-1, FMD and blood pressure. Therefore, recommendations for healthy individuals to moderate or avoid exercise during bouts of high pollution appear to have no acute protective effect.

Neprilysin inhibition and endothelin-1 elevation: Focus on the kidney

Increasing the degree of renin-angiotensin system (RAS) blockade by combining ≥2 RAS blockers marginally increases efficacy, but results in more side effects. Hence, interference with other systems is currently being investigated, like potentiation of natriuretic peptides with neprilysin inhibitors. However, the neprilysin inhibitor thiorphan was recently found to increase endothelin-1 when administered to TGR(mREN2)27 (Ren2) rats on top of RAS blockade. Here we investigated whether this effect is thiorphan-specific, by comparing the neprilysin inhibitors thiorphan and sacubitril, administered by osmotic minipumps at a low or high dose for 7 days, in Ren2 rats. Plasma and urinary levels of endothelin-1, atrial and brain natriuretic peptide (ANP, BNP) and their second messenger cyclic guanosine 3′5′ monophosphate (cGMP) were monitored. No significant differences were found in the plasma concentrations of endothelin-1, cGMP, ANP and BNP after treatment, although plasma ANP tended to be higher in the high-dose thiorphan treatment group and the low- and high-dose sacubitril treatment groups, compared with vehicle. Urinary endothelin-1 increased in the low-dose thiorphan and high-dose sacubitril groups, compared with baseline, although significance was reached for the former only. Urinary cGMP rose significantly in the high-dose sacubitril treatment group compared with baseline. Both urinary endothelin-1 and cGMP were significantly higher in the high-dose sacubitril group compared with the low-dose sacubitril group. In conclusion, endothelin-1 upregulation occurs with both thiorphan and sacubitril, and is particularly apparent in neprilysin-rich organs like the kidney. High renal neprilysin levels most likely also explain why sacubitril increased cGMP in urine only.

An acute bout of prolonged sitting impairs endothelial function and increases plasma concentrations of endothelin-1 in overweight/obese adults: Implications for glucose and insulin metabolism

BackgroundCompared to regular active breaks, prolonged uninterrupted sitting amplifies postprandial glucose and insulin in overweight/obese adults with and without type 2 diabetes; and impairs lower limb endothelial function (a predictor of cardiovascular disease) in healthy adults. However, the effects of prolonged sitting on endothelial function in those at heightened risk of cardiometabolic disease have not been investigated.MethodsOverweight/obese (BMI > 25kg/m2) adults (35–75y) completed two laboratory-based conditions in a random order: (i) 5h prolonged uninterrupted sitting (SIT); and (ii) 5h sitting interrupted with 3min of light-intensity simple resistance activities every 30min (SRA). Femoral artery endothelial function (flow mediated dilation; FMD) and shear rate was assessed at baseline, 1, 2 and 5h. Hourly plasma was collected for glucose, insulin and endothelin-1 measurement. Muscle sympathetic nervous activity (MSNA) was measured at 5h.2Preliminary resultsIn the current sample (n = 7), SIT impaired FMD (−2.6 ± 0.9%; p < 0.05) and shear rate iAUC (−39 ± 14%; p < 0.05), compared to SRA. There was an increase in glucose (40 ± 28%; p = 0.18) and insulin (46 ± 25%; p = 0.16) iAUC, and mean endothelin-1 plasma concentration (0.28 ± 0.09 pg/ml; p < 0.05) in SIT, compared to SRA. MSNA (n = 4) was reduced in SIT, compared to SRA (−4 ± 1 bursts/min; p < 0.05). Testing and analysis (n = 20 participants) is expected to be complete by August, 2017.ConclusionsThese findings are consistent with a potential mechanistic link between sitting- induced endothelial dysfunction, vasoconstriction and insulin resistance, via reduced delivery of glucose and insulin to nutritive vascular beds in muscle. Endothelial dysfunction associated with prolonged sitting may be related to reduced shear rate, and impaired MSNA.

Endothelin-1 is associated with dilatation of the left atrium and can be an independent predictor of atrial fibrillation after mitral valve surgery

This study analysed the association between endothelin-1 (ET-1) and left atrial dimension (LAD) and evaluated whether ET-1 can be a predictor of postoperative atrial fibrillation (POAF) after mitral valve surgery. This is a prospective study that enrolled 80 patients who underwent isolated mitral valve surgery. Plasma concentrations of ET-1 from peripheral venous blood were tested. POAF was detected using a telemetry strip or 12-lead electrocardiogram until the time of discharge. Patients undergoing mitral valve surgery with preoperative sinus rhythm (n = 80; average age 63.9 ± 7.9 years) were recruited to this study. POAF was documented in 31 (38.8%) patients. Preoperative plasma ET-1 levels were higher in patients with POAF compared to those without POAF (2.23 ± 0.67 vs 1.68 ± 0.59 pg/ml; P < 0.001). The plasma concentrations of ET-1 were positively correlated with LAD (Pearson's r = 0.421; P < 0.001). Multivariate logistic regression analysis revealed that LAD (odds ratio 1.170, 95% confidence interval 1.039-1.317; P = 0.009) and preoperative plasma ET-1 levels (upper versus lower 50th percentile: odds ratio 3.713, 95% confidence interval 1.085-12.701; P = 0.037) were predictors of POAF after mitral valve surgery. Plasma levels of ET-1 were positively correlated with LAD in patients with mitral valve disease. An elevated preoperative plasma ET-1 level can be used as a predictor of POAF after mitral valve surgery.

Plasma endothelin-1 and endothelin-A receptor concentrations in patients with primary open-angle glaucoma

ABSTRACTEndothelin-1 (ET-1) is a potent vasoconstrictor and is considered to have a key role in the regulation of ocular perfusion and glaucoma pathogenesis. High ET-1 and ETA-receptor levels are reported in patients with primary open-angle glaucoma (POAG). We compared the mean plasma ET-1 and ETA-receptor concentration of controls and patients with early and advanced POAG stage, and assessed the correlation with the retinal nerve fibre layer (RNFL) thickness. The study included a total of 75 participants, aged 45–83 years: 25 (controls), 22 (early glaucoma) and 28 (advanced glaucoma). The plasma concentration of ET-1 and ETA-receptor was determined by enzyme-linked immunosorbent assay. The RNFL thickness was evaluated with spectral-domain optical coherence tomography. The mean ET-1 concentration was lower in the control group (4.88 ± 1.75 pg/mL) than in the early and advanced POAG group (6.33 ± 2.38 and 6.34 ± 1.56 pg/mL). Statistically significant difference was found between the mean ET-1 concentrations in controls and glaucoma patients (p = 0.029 – early glaucoma, p = 0.018 – advanced glaucoma), and no significant difference was observed between the two POAG groups (p = 0.998). The mean ETA-receptor concentration was highest in the control group (1209.28 ± 314.48 pg/mL) and the differences between the three groups were significant. Significant relationship was found only between ET-1 and RNFL. This study demonstrated the role of ET-1 in glaucoma pathogenesis based on the observed significant high ET-1 and ETA-receptor plasma levels in POAG patients. A new therapeutical approach needs to be considered in some patients.

Ultra-sensitive and selective quantification of endothelin-1 in human plasma using ultra-performance liquid chromatography coupled to tandem mass spectrometry

Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor peptide and the plasma concentrations are commonly quantified by immunoassays such as enzyme-linked immuno-sorbent assays (ELISA) with the disadvantage of possible cross-reactivity with closely related endothelin derivatives. The aim of this study was to develop and validate an ultra-sensitive and selective assay for the quantification of ET-1 in human plasma, using ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) after solid phase extraction. The assay fulfilled the requirements of the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) guidelines for assay validation, with a lower limit of quantification of 1.5pg/mL for ET-1. Recovery rates from plasma ranged between 80.8% and 93.6%, and matrix effect varied between 121% and 135%. The assay was successfully applied to assess the time course of plasma ET-1 concentrations in two human volunteers after co-administration of bosentan and clarithromycin. In this trial, the concentrations measured by UPLC-MS/MS were slightly lower than those measured by ELISA, with a strong positive correlation between the two methods. Our novel UPLC-MS/MS method is applicable to the clinical setting and may have better selectivity for ET-1 than ELISA.