Endothelial Vasodilator Function Research Articles

Negative Influence of Insufficient Sleep on Endothelial Vasodilator and Fibrinolytic Function in Hypertensive Adults.

[Figure: see text].

Reduced L-Arginine and L-Arginine-ADMA-Ratio, and Increased SDMA after Norseman Xtreme Triathlon.

Endothelial vasodilatory function is dependent on the NO synthesis from L-arginine by endothelial NO-synthetase (eNOS). eNOS can be inhibited by asymmetric dimethylarginine (ADMA) by competitive inhibition on the binding site, and symmetric dimethylarginine (SDMA) can reduce the L-arginine availability intracellularly through competing for transport over the cellular membrane. To study the NO synthesis after prolonged exercise, we assessed circulatory L-arginine, the L-arginine/ADMA ratio, and SDMA before, after, and on the day after the Norseman Xtreme triathlon, an Ironman distance triathlon. We found significantly reduced levels of L-arginine and the L-arginine/ADMA ratio and increased levels of SDMA after the race (all p < 0.05). L-arginine rose toward baseline levels the day after the race, but ADMA increased beyond baseline levels, and SDMA remained above baseline the day after the race. The reduced levels of L-arginine and the L-arginine/ADMA ratio, and increased SDMA, after the race indicate a state of reduced capability of NO production. Increased levels of ADMA and SDMA, and reduced L-arginine/ADMA ratio, as seen the day after the race, are known risk markers of atherosclerosis and warrant further studies.

Mitogen and Stress-Activated Kinases 1 and 2 Mediate Endothelial Dysfunction.

Inflammation promotes endothelial dysfunction, but the underlying mechanisms remain poorly defined in vivo. Using translational vascular function testing in myocardial infarction patients, a situation where inflammation is prevalent, and knock-out (KO) mouse models we demonstrate a role for mitogen-activated-protein-kinases (MAPKs) in endothelial dysfunction. Myocardial infarction significantly lowers mitogen and stress kinase 1/2 (MSK1/2) expression in peripheral blood mononuclear cells and diminished endothelial function. To further understand the role of MSK1/2 in vascular function we developed in vivo animal models to assess vascular responses to vasoactive drugs using laser Doppler imaging. Genetic deficiency of MSK1/2 in mice increased plasma levels of pro-inflammatory cytokines and promoted endothelial dysfunction, through attenuated production of nitric oxide (NO), which were further exacerbated by cholesterol feeding. MSK1/2 are activated by toll-like receptors through MyD88. MyD88 KO mice showed preserved endothelial function and reduced plasma cytokine expression, despite significant hypercholesterolemia. MSK1/2 kinases interact with MAPK-activated proteins 2/3 (MAPKAP2/3), which limit cytokine synthesis. Cholesterol-fed MAPKAP2/3 KO mice showed reduced plasma cytokine expression and preservation of endothelial function. MSK1/2 plays a significant role in the development of endothelial dysfunction and may provide a novel target for intervention to reduce vascular inflammation. Activation of MSK1/2 could reduce pro-inflammatory responses and preserve endothelial vasodilator function before development of significant vascular disease.

Taurine treatment reverses protein malnutrition-induced endothelial dysfunction of the pancreatic vasculature: The role of hydrogen sulfide

BackgroundProtein malnutrition in childhood predisposes individuals to vascular and pancreatic endocrine dysfunction, thus increasing the risk of diabetes and hypertension. Because taurine may reduce cardiometabolic risk, we hypothesized that taurine treatment has a beneficial effect on the pancreatic vasculature during protein restriction. Methods and resultsWeaned mice were fed a normal or a low-protein diet and were treated with or without taurine for 3 months. The lieno-pancreatic artery (LPA) from low-protein diet-treated mice exhibited impaired endothelium-dependent relaxation to acetylcholine that was associated with decreased endothelium-derived hyperpolarization (EDH), hydrogen sulfide (H2S) production, and H2S-synthesizing CBS expression and impaired vasorelaxation to an H2S-donor, NaHS. These changes were prevented by taurine treatment. We compared the effects of taurine with the effects of the direct vasodilator hydralazine and found that both normalized blood pressure and the endothelial vasodilator function of the LPA in the mice fed a protein-restricted diet. However, only taurine restored the CBS expression in the LPA and insulin secretion in response to high glucose. The LPA supplies the pancreas and shares morphometry with the mesenteric resistance artery (MRA). However, in the MRA, low-protein diet-induced endothelial dysfunction is driven by impaired NOS-derived NO with no changes in H2S signaling. ConclusionsThe results suggest that taurine protects against protein malnutrition-induced endothelial dysfunction in the LPA by upregulating the CBS-H2S pathway. Considering the importance of the pancreatic vasculature for endocrine islet activity, taurine may be a potential therapy for the vascular and metabolic dysfunction associated with malnutrition and comorbidities.

Associations Of Fitness, Physical Activity, And Fatness With A New Index Of Endothelial Function

Current methods for assessing endothelial function, an early marker of cardiovascular disease (CVD), are either invasive or use noninvasive methods that are highly operator dependent or require nonreusable expensive probes, thereby limiting their use for CVD risk prediction. PURPOSE: To assess the relationship of fitness, physical activity (PA), and fatness, each a CVD risk factor, with a novel measure of endothelial function. METHODS: This was a cross-sectional data analysis in adults recruited for a study examining the clinical utility of a new device that measures endothelial vasodilator function using a standard BP cuff. The resulting EnDys score is derived from direct calibrated measurements of brachial arterial compliance throughout the entire transmural pressure curve during a staged cuff release after 5 minutes of upper arm occlusion. A higher score means better endothelial function. Fitness was assessed by a 6-minute walk test (6MWT). Self-report of PA was assessed by the Rapid Assessment of Physical Activity tool. Body mass index (BMI) was used as a marker of general fatness and waist circumference (WC) as a marker of abdominal fatness. RESULTS: In all 153 subjects, 51% were female, 7% were smokers, 7% had CVD, and 10% had type 2 diabetes. The mean ± SD for age was 49.3 ± 17.2, EnDys was 80.8 ± 30.4, BMI was 29.3 ± 6.9 kg/m2, WC was 37.5 ± 6.7 inches, and 6MWT was 495.4 ± 113.5 meters. EnDys was higher in females, 87.6 ± 30.5, vs males, 73.8 ± 28.9, p<0.01. EnDys did not differ by being sedentary, 80.8 ± 27.6, or active, 81.0 ± 33.0, p=0.97. Using bivariate analysis, a lower EnDys was associated with higher BMI, r=-0.23, higher WC, r=-0.33, lower 6MWT, r=0.32, and older age, r=-0.20, all p<0.02 or less. In a multivariate model, 6MWT (β=-0.06, p<0.01), WC (β=-1.02, p<.02), and sex (female, β=6.9, p<0.01) were each independently associated with EnDys. There were no interactions for sex with 6MWT and WC. CONCLUSION: Among measures of fitness, PA, and fatness, and in both sexes, a lower walking distance and a higher waist circumference were each independently associated with a lower EnDys, indicating worse endothelial function. A next logical step is to assess if EnDys improves with interventions like exercise and weight loss, thereby providing a novel and relatively simple way to track progress towards CVD risk reduction.

Эндотелиопротекторные свойства ATACL и катехин гидрата в условиях истощающих нагрузок крыс

Цель исследования - изучение эндотелиопротекторных свойств ATACL и катехин гидрата в сравнении с известным лекарственным препаратом Сулодексид в условиях истощающих нагрузок крыс. Методика. Истощающие нагрузки воспроизводили методом Порсолта - принудительного плавания животных с нагрузкой до полного истощения и борьбы за жизнь. Эксперименты выполнены на 50 крысах-самцах Wistar (200-220 г), разделенных на 5 групп (n=10). Вазодилатирующую функцию эндотелия сосудов головного мозга оценивали методом допплерографии с использованием программного комплекса «Minimax Doppler», производства компании «Минимакс» (Санкт-Петербург, Россия). Результаты. Показано, что на фоне истощающих нагрузок наблюдалось значительное ухудшение вазодилатирующей и антитромботической функций эндотелия мозговых сосудов, что проявлялось снижением реакции сосудов в ответ на введение анализаторов (АЦХ и L- NAME), развитием «феномена L-аргининового парадокса», повышением как степени, так и агрегационной способности (скорости) тромбоцитов. Исследуемые соединения ATACL и катехин гидрат способствовали коррекции эндотелиальной дисфункции, что выражалось в статистически значимом увеличении скорости кровотока при внутривенном введении АЦХ у животных групп, получавших ATACL на 26,1%, катехин гидрат - на 24,5%, относительно исходной скорости кровотока. ATACL (4-гидрокси-3,5-ди-трет-бутилкоричнаякислота) оказывал выраженное влияние на антитромботическую функцию, при этом статистически значимо снижалась степень агрегации тромбоцитов на 99,3% и скорости агрегации - на 136,6%, относительно аналогичных показателей группы крыс негативного контроля. Заключение. Соединение ATACL представляет интерес для дальнейшего изучения в качестве актопротекторного средства, обладающего эндотелиопротекторной активностью. Aim. To study possible endothelium-protective properties of catechin hydrate and ATACL in comparison with a well-known drug Sulodexide in exhaustive physical exercise of rats. Methods. Exhaustive exercise was produced by forced swimming of rats with a load until exhaustion and struggle for life. Experiments were performed on 50 Wistar male rats (200-220 g) divided into 5 groups (n=10 in each group). The endothelial vasodilatory function of cerebral blood vessels was evaluated with the Doppler method using Minimax Doppler equipment and software (Minimax, St. Petersburg, Russia). Results. Exhaustive exercise induced a significant impairment of vasodilatory and antithrombotic endothelial functions, which was evident as decreased response of cerebral blood vessels to acetylcholine (ACH) and L-NAME, development of the L-arginine paradox, and increases in both platelet aggregation degree and rate. ATACL (4-hydroxy-3,5-di-tert-butyl cinnamic acid) and catechin hydrate provided correction of the endothelial dysfunction, which was evident from increased blood flow velocity in response to intravenous administration of ACH by 26.1% in the ATACL group (p&lt;0.05) and by 24.5% in the catechin hydrate group (p&lt;0.05) compared to the baseline blood flow velocity. ATACL exerted a pronounced effect on the endothelial antithrombotic function evident as decreases in aggregation degree by 99.3% (p&lt;0.05) and aggregation rate by 136.6% (p&lt;0.05) compared to the group of negative control. Conclusion. ATACL is of interest for further studies as an actoprotector with endothelium-protective activity.

Clinical significance of endothelial vasodilatory function evaluated by EndoPAT in patients with systemic sclerosis.

Endothelial dysfunction is a hallmark of vasculopathy associated with systemic sclerosis (SSc). Reactive hyperemia peripheral arterial tonometry is a rapid and non-invasive technique to assess peripheral microvascular endothelial function by measuring changes in digital pulse volume during reactive hyperemia. Low scores of the reactive hyperemia index (RHI) imply an impaired vasodilatory response and, accordingly, impaired endothelial and vascular health. To investigate the clinical significance of the RHI in SSc patients, RHI values were measured in 43 SSc patients and 10 healthy controls. In diffuse cutaneous SSc (dcSSc) patients, RHI values were significantly decreased compared with healthy controls, and inversely correlated with disease duration. In total SSc patients, there was a significant inverse correlation between RHI values and skin score, and interstitial lung disease was associated with the decrease in RHI values. Among vascular symptoms, the current and past history of digital ulcers was seen more frequently in patients with decreased RHI values than in those with normal RHI values. Although no SSc patients had pulmonary arterial hypertension, an inverse correlation was evident between RHI values and mean pulmonary arterial pressure measured by right heart catheterization. These results indicate that the decrease in RHI values is associated with skin fibrosis, interstitial lung disease, digital ulcers and pulmonary vascular involvement leading to pulmonary arterial hypertension, supporting the canonical idea that endothelial dysfunction is a critical event underlying the development of tissue fibrosis and vascular complications in SSc.

Abstract P545: Insufficient Sleep and Nitric Oxide-Mediated Endothelium-Dependent Vasodilation in Adults With Elevated Blood Pressure

Elevated blood pressure (BP ≥130/80 mmHg) is associated with increased risk for myocardial infarction, heart failure, stroke and vascular disease. Insufficient nightly sleep (&lt;7 h/night) has been linked not only to the etiology of elevated blood pressure but is a prevalent, often ignored, comorbidity. Indeed, short sleep duration is now considered to be a plausible risk factor for elevated blood pressure and a harbinger of increased cardiovascular risk. A high prevalence of insufficient nightly sleep has been reported in adults with elevated blood pressure. The influence of insufficient sleep on endothelial vasodilator function in adults with elevated blood pressure is unknown. We tested the hypotheses that chronic insufficient sleep is associated with diminished nitric oxide (NO)-mediated endothelium-dependent vasodilation in adults with elevated blood pressure. Moreover, the insufficient sleep-related reduction in endothelial vasodilator function is due, at least in part to increased oxidative stress. Thirty-five middle-aged and older adults with elevated blood pressure were studied: 15 with normal nightly sleep duration (11M/4F; age: 58±2 yr; BP: 136/82±1/2 mmHg; sleep: 7.6±0.2 h/night) and 20 with short nightly sleep duration (14M/6F; 58±1 yr; BP: 138/84±1/1 mmHg; sleep: 6.0±0.1 h/night). Forearm blood flow (FBF) responses to intra-arterial infusion of acetylcholine (ACh), in the absence and presence of the endothelial NO synthase inhibitor N G -monomethyl-L-arginine (L-NMMA) and the antioxidant vitamin C were determined by venous occlusion plethysmography. The FBF response to ACh was significantly lower (~20%) in the short sleep (from 3.8±0.2 to 11.0±0.6 ml/100 ml tissue/min) compared with the normal sleep duration group (from 4.2±0.2 to 13.6±0.6 ml/100 ml tissue/min). L-NMMA significantly reduced (~25%) the FBF response to ACh in the normal sleep but not the short sleep group. Vitamin C markedly increased (~35%; P&lt;0.05) the vasodilator response to ACh in short sleepers only. In summary, habitual short sleep duration worsens NO-mediated endothelium-dependent vasodilation in adults with elevated blood pressure. Furthermore, the sleep-related diminishment in endothelial vasodilator function is due, in part, to increased oxidative stress.

Significant impact of left ventricular assist device models on the value of flow-mediated dilation: effects of LVAD on endothelial function.

The precise physiological changes associated with the use of left ventricular assist device (LVAD) are not well characterized. We examined the impact of changes in hemodynamic state using LVAD on endothelial function. We measured flow-mediated vasodilation (FMD) to evaluate endothelial vasodilator function of the brachial artery in 53 patients (dilated cardiomyopathy: 39, ischemic cardiomyopathy: 4, and others: 10) with an implanted LVAD (DuraHeart, EVAHEART, or HeartMate II). We found that FMD value in the HeartMateII LVAD group (9.3% ± 2.9%) was significantly higher than those in the other two groups (EVAHEART: 6.7% ± 2.8% and DuraHeart: 6.2% ± 4.0%). Other factors that affected the FMD value were age (r = - 0.31, p = 0.026), Brinkman index (r = - 0.30, p = 0.029); however, aortic opening, aortic regurgitation, and other hemodynamic parameters such as cardiac index or pulmonary capillary wedge pressure did not correlate with FMD. Multivariate analyses revealed that the difference among the LVAD models most significantly affected the FMD values after adjusting for age and smoking status (t = 2.6, p = 0.014). Event free survival rate of death and cerebral infarction was not significantly different according to the value of FMD. The difference among the LVAD groups most significantly affected the state of endothelial function and it had more impact than other clinical factors.

Attenuation of Retinal Endothelial Vasodilator Function in a Rat Model of Retinopathy of Prematurity

ABSTRACTPurpose: Retinopathy of prematurity (ROP) is characterized by morphological abnormalities in retinal blood vessels, but how an episode of ROP affects vascular function remains to be fully elucidated. The purpose of the present study was to assess the distribution of pericyte/smooth muscle in retinal blood vessels and retinal vasodilator responses in a rat model of ROP.Methods: ROP was induced in rats by the subcutaneous injection of the vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor KRN633 (10 mg/kg) on postnatal day (P) 7 and P8. The distribution of pericyte/smooth muscle in retinal blood vessels was examined on P14 and P35 by immunohistochemistry. Retinal vasodilator responses were assessed on P35 by measuring the diameter of retinal arterioles in fundus images.Results: In retinas of KRN633-treated (ROP) rats, progressive angiogenesis, tortuous arteries, enlarged veins, and enhanced expression of α-smooth muscle actin in pericytes on capillaries and veins were observed on P14. These abnormalities in retinal vasculature showed a tendency to normalize by P35. Vasodilation of retinal arterioles induced by acetylcholine, an endothelium-dependent vasodilator, was smaller in P35 ROP rats than age-matched controls, whereas retinal vasodilator responses to the nitric oxide (NO) donor NOR3 were unaltered.Conclusions: Phenotypic changes in pericytes occur in the ROP model rats and endothelium-dependent vasodilatory mechanisms in retinal blood vessels are impaired. The impaired vasodilator function may contribute to the progression and pathogenesis of ROP.

Aging women and their endothelium: probing the relative role of estrogen on vasodilator function.

Despite significant decreases in cardiovascular disease (CVD) mortality in the past three decades, it still remains the leading cause of death in women. Following menopause and the accompanying loss of estrogen, women experience a unique, accelerated rise in CVD risk factors. Dysfunction of the endothelium represents an important antecedent to CVD development, with rapid declines in endothelial vasodilator function reportedly taking place across the menopause transition. Importantly, the decline in endothelial function is independent of chronological age and is associated with estrogen deficiency. Estrogen-mediated effects, including increasing nitric oxide bioavailability and attenuating oxidative stress and inflammation, contribute to preserving endothelial health. This review will discuss studies that have probed the role of estrogen on endothelial vasodilator function in women at discrete stages of the menopause transition and the effects of estradiol supplementation in postmenopausal women. Estrogen receptor signaling is also an important aspect of endothelial function in women, and studies suggest that expression is reduced with both acute and prolonged estrogen deficiency. Changes in regulatory mechanisms of estrogen receptor-α expression as well as sensitivity to estrogen may underlie the differential effects of estrogen therapy in early (≤5 yr past final menstrual period) and late postmenopausal women (>5 yr past final menstrual period). Lastly, this review presents potential therapeutic targets that include increasing l-arginine bioavailability and estrogen receptor activation to prevent endothelial dysfunction in postmenopausal women as a strategy for decreasing CVD mortality in this high-risk population.

Relationship between angiopoietin-2 and vascular endothelial factor and vasodilation function in hypertensive patients

Objective: To analyze the relationship between angiopoietin 2 (Ang2) and vascular endothelial factor and vasodilation function in hypertensive patients. Methods: Patients with new onset grade 1~2 hypertension (n=40) and healthy control group (n=25) wereenrolledprospectively. Serum Ang2 and nitric oxide (NO), nitric oxide synthase (eNOS), endothelin-1 (ET-1) were measured in both groups. Flow-mediated vasodilation (FMD) were measured in hypertensive patients. The above indicators were reviewed in hypertensive patients after antihypertensive treatment until blood pressure<140/90 mmHg. Results: Compared with the control group, serum Ang2 (P=0.049) and ET-1 (P<0.001) were significantly higher. Serum NO (P<0.001) and eNOS (P<0.001) was significantly lower in the hypertensive group. Compared with baseline, serum Ang2 (P=0.049) and ET-1 (P<0.001) were decreased significantly, meanwhile serum NO (P<0.001) and eNOS (P<0.001) were significantly increased. Serum Ang2 after antihypertensive treatment was not significantly different from that of the control group, but no statistical difference was observed in FMD after antihypertensive therapy. Correlation analysis found that serum Ang2 was positively correlated with mean arterial pressure (R=0.432, P<0.001), and negative correlated with serum NO(R=-0.374, P=0.001) and FMD (R=-0.368 0, P=0.002). Multiple linear regression found that serum Ang2 was independently associated with body mass index, mean arterial pressure, and serum NO. Conclusion: Serum Ang 2 can reflect the degree of endothelial and vasodilation impairment in hypertensive patients. Antihypertensive therapy can improve endothelial function, but whether it can restore damaged vasodilation function needs further verification.

Abstract P137: Impaired Microvascular and Endothelial Function Among African-Americans With Coronary Artery Disease

Background: African-Americans have disproportionately higher burden of mortality from coronary artery disease (CAD) compared to Caucasians even after adjusting for socioeconomic and cardiovascular risk factors. Racial differences in arterial stiffness have been described, but data on microcirculatory and endothelial vascular function are more limited and it is unknown whether they differ by race in CAD patients. Methods: We studied 313 patients with a recent history of myocardial infarction (MI). Microvascular function was assessed by digital pulse amplitude tonometry (EndoPAT) to determine reactive hyperemia index (RHI), and endothelial function as brachial artery flow mediated dilation (FMD) using ultrasound. Arterial stiffness was assessed using applanation tonometry (Sphygmocor) to determine pulse-wave velocity (PWV) and central augmentation index (C-AIx). Data on sociodemographics, cardiovascular risk factors, medication use, and CAD severity were collected. Multivariate linear regression models were used to assess the relationship between race and various vascular function measures with adjustment for risk factors. Measures of arterial stiffness were included as control factors in the adjusted model for FMD and RHI. Results: The mean age of this post-MI sample was 51 years (± 6.7 SD); 50% were African-Americans and 49% were female. Compared to Caucasians, African-Americans had worse microvascular function as indicated by lower mean (± SD) RHI (1.7±0.5 vs 2.0±0.6, p&lt;0.0001) and worse endothelial function [FMD mean (3.4±2.4 vs 4.7±3.1, p=0.0002)]. African-Americans also had greater arterial stiffness, including a higher mean C-AIx (26.5±9.0 vs 23.0±9.3, p=0.0019) and PWV (7.7±2.0 vs 7.1±1.8, p&lt;0.0267). After adjustment for cardiovascular risk factors, medications, CAD severity, and arterial stiffness (C-AIx and PWV), black race remained significantly associated with lower RHI (β=-0.30, p&lt;0.001) and FMD (β=-1.06, p=0.004). Conclusion: African-Americans with CAD have impaired microvascular and endothelial vasodilatory function compared to Caucasians, independent of CAD risk factors and arterial stiffness. Racial differences in microcirculatory and endothelial function may contribute to worse outcomes among African-Americans with CAD.

Endothelial Vasodilation After a High-Volume Training Load and Tapered Training in Collegiate Female Swimmers

Weihl, FM and Van Guilder, GP. Endothelial vasodilation after a high-volume training load and tapered training in collegiate female swimmers. J Strength Cond Res 35(3): 811-818, 2021-High-volume endurance training loads have been linked to adverse remodeling of the heart and large arteries; yet, data on the vascular endothelial function are unclear. Moreover, although collegiate-level endurance athletes often perform high-volumes of vigorous endurance training and resistance training as part of their strength and conditioning programs, it is unknown whether they also experience vascular abnormalities, particularly changes in endothelial function. The aim of this study was to verify the impact of a high-volume training load phase followed by low-volume tapered training on endothelial vasodilator function in National Collegiate Athletic Association (NCAA) Division I competitive female swimmers. Microvascular endothelial vasodilation was assessed by pulse arterial tonometry that provides a reactive hyperemia index in 10 female NCAA Division 1 swimmers after 4 weeks of a high-volume training load, and subsequently, after 3 weeks of low-volume tapered training as part of preparation for annual conference championships. The reactive hyperemia index was calculated as the ratio of the pulse volume amplitude after 5 minutes of left-arm brachial artery ischemia to the baseline amplitude, divided by same ratio in the contralateral arm. The high-volume training load included a 4-week block of dual-day sessions (120 minutes per practice) consisting of vigorous intensity endurance and high-intensity interval/sprint swim training, coupled with 5K running, resistance training, and Olympic weightlifting. Tapered training consisted of 3 weeks of 3-5 swims per week at ∼50% V̇o2max for 60 minutes per practice (∼4,000 minutes per practice). The reactive hyperemia index (1.73 ± 0.50) was low in athletes after the high-volume training load with 8 athletes demonstrating endothelial dysfunction. However, after tapered training, the reactive hyperemia index was ∼33% higher (2.29 ± 0.43; 95% confidence interval [CI]: 1.98-2.60, p = 0.0223 vs. the high-volume training load). Effect size, as expressed by the partial eta2 (0.46) and Cohen's dz (1.1923; 95% CI: 0.1687-2.4643) with tapered training, was large. These results demonstrate distinct differences in endothelial vasodilation after 4 weeks of a high-volume training load compared with a 3-week taper in NCAA Division I female swimmers.

CARDIOPROTECTIVE PROPERTIES OF LISINOPRIL: NEW POSSIBILITIES

Aim. To study the changes in the stiffness of the arterial wall, vasomotor function of the endothelium, and appearance of new cases of atrial fibrillation (AF) in patients with arterial hypertension with long-term treatment with lisinopril.Material and method. 66 hypertensive patients with cardiac sinus rhythm at the age of 48-64 years (mean age 58.4±4.2 years) were included into the study. They were randomized into 2 groups: patients of group 1 (n=35) were prescribed lisinopril or a combination of lisinopril with hydrochlorothiazide over the 5-year follow-up; patients of group 2 (control) did not receive angiotensin converting enzyme inhibitors or angiotensin II receptor blockers. The follow-up duration was from September 2010 until June 2016. It included telephone calls once every 3 months and annual clinical, instrumental and laboratory examination. The new-onset AF was identified by the 24-hour Holter ECG monitoring results and by patient symptom diaries.Results. New-onset AF was registered in 2 patients (6%) in the lisinopril group and in 4 patients (13%) from the control group (p=0.001) over the 5-year follow-up. Lisinopril significantly reduced AF incidence in hypertensive patients. The patients on lisinopril were found to have no significant changes in the left ventricular mass index and left atrial size according to echocardiography done after the 5-year follow-up whereas in the patients of control group both parameters increased significantly. Lisinopril contributed to the maintenance of endothelial vasodilator function and prevented increase in arterial wall stiffness.Conclusion. Long term lisinopril treatment was found to significantly reduce the AF incidence in hypertensive patients over the 5-year follow-up. Lisinopril demonstrated organoprotective properties throughout the cardiovascular disease continuum and can be recommended for primary prevention of arrhythmia in hypertensive patients.

Plasmatic Concentrations of ADMA and Homocystein in Llama (Lama glama) and Regulation of Arginase Type II: An Animal Resistent to the Development of Pulmonary Hypertension Induced by Hypoxia.

There are animal species that have adapted to life at high altitude and hypobaric hypoxia conditions in the Andean highlands. One such species is the llama (Lama glama), which seem to have developed efficient protective mechanisms to avoid maladaptation resulting from chronic hypoxia, such as a resistance to the development of hypoxia -induced pulmonary hypertension. On the other hand, it is widely known that different models of hypertension can arise as a result of changes in endothelial function. The respect, one of the common causes of deregulation in endothelial vasodilator function have been associated with down-regulation of the NO synthesis and an increase in plasma levels of asymmetric dimethylarginine (ADMA) and homocysteine. Additionally, it is also known that NO production can be regulated by plasma levels of L-arginine as a result of the competition between nitric oxide synthase (NOS) and arginase. The objective of this study, was to determine the baseline concentrations of ADMA and homocysteine in llama, and to evaluate their effect on the arginase pathway and their involvement in the resistance to the development of altitude-induced pulmonary hypertension. METHOD: Lowland and highland newborn sheep and llama were investigated near sea level and at high altitude. Blood determinations of arterial blood gases, ADMA and homocysteíne are made and the effect of these on the arginase activity was evaluated. RESULTS: The basal concentrations of ADMA and homocysteine were determined in llama, and they were found to be significantly lower than those found in other species and in addition, the exposure to hypoxia is unable to increase its concentration. On the other hand, it was observed that the llama exhibited 10 times less arginase II activity as compared to sheep, and the expression was not induced by hypoxia. Finally, ADMA y Hcy, has no effect on the type II arginase pathway. CONCLUSION: Based on our results, we propose that low concentrations of ADMA and homocysteine found in llamas, the low expression of arginase type II, DDAH-2 and CBS, as well as its insensitivity to activation by homocysteine could constitute an adaptation mechanism of these animals to the hypoxia.

Relaxin Deficiency Leads to Uterine Artery Dysfunction During Pregnancy in Mice.

The uterine vasculature undergoes profound adaptations in response to pregnancy. Augmentation of endothelial vasodilator function and reduced smooth muscle reactivity are factors contributing to uterine artery adaptation and are critical for adequate placental perfusion. The peptide hormone relaxin has an important role in mediating the normal maternal renal vascular adaptations during pregnancy through a reduction in myogenic tone and an increase in flow-mediated vasodilation. Little is known however about the influence of endogenous relaxin on the uterine artery during pregnancy. We tested the hypothesis that relaxin deficiency increases myogenic tone and impairs endothelial vasodilator function in uterine arteries of late pregnant relaxin deficient (Rln−/−) mice. Reactivity of main uterine arteries from non-pregnant and late pregnant wild-type (Rln+/+) and Rln−/− mice was studied using pressure and wire myography and changes in gene expression explored using PCR. Myogenic tone was indistinguishable in arteries from non-pregnant mice. In late pregnancy uterine artery myogenic tone was halved in Rln+/+ mice (P < 0.0001), an adaptation that failed to occur in arteries from pregnant Rln−/− mice. The role of vasodilator prostanoids in the regulation of myogenic tone was significantly reduced in arteries of pregnant Rln−/− mice (P = 0.02). Agonist-mediated endothelium-dependent vasodilation was significantly impaired in non-pregnant Rln−/− mice. With pregnancy, differences in total endothelial vasodilator function were resolved, although there remained an underlying deficiency in the role of vasodilator prostanoids and alterations to the contributions of calcium-activated K+ channels. Fetuses of late pregnant Rln−/− mice were ~10% lighter (P < 0.001) than those of Rln+/+ mice. In conclusion, relaxin deficiency is associated with failed suppression of uterine artery myogenic tone in pregnancy, which likely contributes to reduced uteroplacental perfusion and fetal growth restriction.

Rhynchophylla total alkaloid rescues autophagy, decreases oxidative stress and improves endothelial vasodilation in spontaneous hypertensive rats.

Autophagy plays an important role in alleviating oxidative stress and stabilizing atherosclerotic plaques. However, the potential role of autophagy in endothelial vasodilation function has rarely been studied. This study aimed to investigate whether rhynchophylla total alkaloid (RTA) has a positive role in enhancing autophagy through decreasing oxidative stress, and improving endothelial vasodilation. In oxidized low-density lipoprotein (ox-LDL)-treated human umbilical vein endothelial cells (HUVECs), RTA (200 mg/L) significantly suppressed ox-LDL-induced oxidative stress through rescuing autophagy, and decreased cell apoptosis. In spontaneous hypertensive rats (SHR), administration of RTA (50 mg·kg-1·d-1, ip, for 6 weeks) improved endothelin-dependent vasodilation of thoracic aorta rings. Furthermore, RTA administration significantly increased the antioxidant capacity and alleviated oxidative stress through enhancing autophagy in SHR. In ox-LDL-treated HUVECs, we found that the promotion of autophagy by RTA resulted in activation of the AMP-activated protein kinase (AMPK) signaling pathway. Our results show that RTA treatment rescues the ox-LDL-induced autophagy impairment in HUVECs and improves endothelium-dependent vasodilation function in SHR.

Effects of Long-Chain Omega-3 Polyunsaturated Fatty Acids on Endothelial Vasodilator Function and Cognition-Are They Interrelated?

Long-chain omega-3 polyunsaturated fatty acids (LCn-3 PUFA) may improve brain functions by acting on endothelial cells in the cerebrovasculature to facilitate vasodilatation and perfusion. The aim of this review is to explore this hypothesis by analyzing the effect of LCn-3 PUFA supplementation on systemic vasodilator and cognitive function and finding evidence to link LCn-3 PUFA intake, vasodilator function and cognition. Forty randomized controlled trials examining the effect of LCn-3 PUFA supplementation in humans on either endothelial vasodilator function or cognition were identified and pooled effects measured with a weighted analysis. Compared to placebo, LCn-3 PUFA tended to increase flow-mediated dilatation and significantly improved cognitive function. Emerging evidence links vasodilator dysfunction to cognitive impairment, but evidence that LCn-3 PUFA can improve cognition through enhancements of vasodilator function is still lacking. Further research is needed to determine: (1) whether LCn-3 PUFA can enhance dilatation of cerebral vessels; (2) if improvements in cerebrovascular responsiveness by LCn-3 PUFA are accompanied by cognitive benefits; and (3) the target population groups.

Improvements in Endothelial Function Following Whole-Body Vibration Training in Overweight and Obese Young Women

Brachial artery flow-mediated dilation (FMD) is a significant predictor of future cardiovascular disease and preferred non-invasive marker for endothelial vasodilatory function. Importantly, central/abdominal obesity and physical inactivity are associated with endothelial dysfunction. Whole-body vibration training (WBVT) has been shown to improve overall arterial function in sedentary obese pre- and post- menopausal women. Yet, the impact of WBVT on endothelium-mediated vasodilation has not been examined. PURPOSE: To determine whether WBVT would induce greater benefits than a non-exercising control (CON) on endothelial function in young overweight/obese women. METHODS: Thirty-seven young overweight/obese women (age: 21 ± 2 years; body mass index: 31.4 ± 3.4 kg/m2) were randomized into WBVT (n=24), or CON (n=13) for 6 weeks (3 days/week). Brachial artery diameter was measured using Doppler ultrasound before and after 5 min of forearm ischemia. FMD was measured before and after the 6-week period. RESULTS: There were no between-group differences at baseline in any of the variables. Following 6 weeks, brachial artery FMD increased (Δ 3.80 ± 1.03%, P < 0.01) in the WBVT when compared to CON. No significant differences were observed in resting brachial artery diameter after WBVT. CONCLUSIONS: Six weeks of WBVT elicited a significant improvement in brachial artery vasodilatory function in young sedentary overweight/obese women. Collectively, WBVT may be considered an effective alternate exercise modality for the prevention and treatment of arterial dysfunction in young overweight/obese women.