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Pulmonary arterial hypertension is a rare disease characterized by pulmonary microvasculature remodeling leading to right ventricular failure and death. Medical management of pulmonary hypertension has grown increasingly complex as more therapeutic agents have been developed. Evolving treatment strategies leveraging the endothelin, nitric oxide, and prostacyclin pathways lead to improved exercise capacity and outcomes in patients; however, significant opportunities for advancement remain.

Effects of sex hormones on stroke outcome is not fully understood. A deleterious consequence of cerebral ischemia is upregulation of vasoconstrictor receptors in cerebral arteries that exacerbate stroke injury. Here, we tested the hypothesis that female sex hormones alter vasocontractile responses after experimental stroke in vivo or following organ culture in vitro, a model of vasocontractile receptor upregulation. Female rats with intact ovaries and ovariectomized females treated with 17β-estradiol, progesterone or placebo were subjected to transient, unilateral middle cerebral artery occlusion followed reperfusion (I/R). The maximum contractile response, measured my wire myography, in response to the endothelin B (ETB) receptor agonist sarafotoxin 6c was increased in female arteries after I/R, but the maximum response was significantly lower in arteries from ovariectomized females. Maximum contraction mediated by the serotonin agonist 5-carboxamidotryptamine (5-CT) was diminished after I/R, with arteries from ovariectomized females showing a greater decrease in maximum contractile response. Contraction elicited by angiotensin II was similar in all arteries. Neither estrogen nor progesterone treatment of ovariectomized females affected I/R-induced changes in ETB and 5-CT induced vasocontraction. These findings suggest sex hormones do not directly influence vasocontractile alterations that occur after ischemic stroke; however, loss of ovarian function does impact this process.

Bosentan, clazosentan, and tezosentan are three small-molecule endothelin receptor antagonists (ERAs), displacing endothelin-1 (ET-1) from its binding site. A target-mediated drug disposition (TMDD) pharmacokinetic (PK) model described the non-linearity in the PK of bosentan caused by its high receptor binding affinity with time-dependent varying receptor expression or reappearance. The aim of this analysis was to investigate the presence of TMDD for clazosentan and tezosentan and to corroborate the hypothesis of a diurnal receptor synthesis. PK data from healthy subjects after intravenous (i.v.) administration of single ascending doses of bosentan, clazosentan, and tezosentan were analyzed. Frequent blood samples for PK measurements were collected. Population analyses, simulations, and evaluations were performed using a non-linear mixed-effects modeling approach. Two-compartment TMDD models were successfully developed describing the PK of all three ERAs with different receptor-complex internalization properties. The observed multiple peaks in the concentration-time profiles were captured with cosine functions on the receptor synthesis rate mimicking a diurnal receptor expression or reappearance. The results strongly suggest that TMDD is a class effect of ERAs. The developed TMDD PK models are a next step towards understanding the complex PK of ERAs and further support the hypothesis that TMDD is a class effect of ERAs.

Despite the achievements in the detection of calcium deposits in the walls of blood vessels, there is practically no data on the relationship of calcification of the coronary arteries with clinical and laboratory indicators of calcification in the blood, and the mechanisms of this process have not been fully established. The aim of the work was to establish the relationship between the severity of vascular calcification and clinical and laboratory markers of vascular calcification to improve the effectiveness of the diagnosis of diseases of the cardiovascular system and optimize therapy. The data obtained during the study indicate a high prevalence of vascular calcification in patients with atherosclerosis. Estimates of the calcium index and traditional risk factors are not always sufficient to predict cardiovascular complications. Thus, the identification of specific laboratory markers of calcification and predisposition to calcinosis is very relevant at the present time. Studies have shown that atherosclerosis with vascular calcification is combined with the development of chronic systemic inflammation and inflammation of the vascular wall. At the same time, there are elevated levels of C-reactive protein, endothelin, homocysteine, lipid metabolism indicators, and reduced levels of fetuin-A in the blood, which allows us to recommend these laboratory indicators to prevent cardiovascular complications.

Purpose: To investigate the efficacy of the combined use of sildenafil and magnesium sulfate in the treatment of persistent pulmonary hypertension of the newborn (PPHN), and its influence on hemodynamics.Methods: A total of 174 children with persistent pulmonary hypertension who were treated in Ganzhou People’s Hospital, Ganzhou, China were selected and randomly assigned to joint group (JG) and control group (CG), with 87 patients in each group. The CG group received magnesium sulfate, while the JG group received sildenafil plus magnesium sulphate. The respiratory parameters of the children were analyzed using blood gas analyzer, while their hemodynamic indices were evaluated using color Doppler echocardiography. The levels of cytokines and inflammatory factors were determined by enzyme-linked immunosorbent assay (ELISA).Results: Time taken for symptom disappearance, oxygen therapy, and hospitalization period were shorter in JG than in CG (p < 0.05). Post-treatment, the respiratory parameters (PaO2, PaCO2, and SaO2) in both groups s improved, with lower levels of PaO2 and PaCO2, and a higher level of SaO2 in JG (p < 0.05). Following treatment, the levels of systemic vascular resistance (SVR), posterior pulmonary vascular resistance (PVR) and pulmonary artery pressure (PA) in JG were significantly reduced, relative to CG (p < 0.05). Similarly, the expression of endothelin -1 (ET-1), brain natriureticpeptide (BNP), and angiotensin 1 (ANG-1) improved, with lower levels of ET-1 and BNP, and a higher level of ANG-1 in JG (p < 0.05). There was post-treatment reduction as well in IL-6 and TNF-α, with lower levels in JG (p < 0.05). Patients in JG showed higher total treatment effectiveness and a lowerincidence of adverse reactions than those in CG (p < 0.05).Conclusion: The combined use of sildenafil and magnesium sulfate enhances the management of PPHN, ameliorates respiratory parameters, hemodynamics, and levels of cytokines and inflammatory factors. These findings provide evidence-based medical references for a new treatment strategy for PPHN.

Objective: to study the effect of testosterone (T) levels on laboratory and instrumental markers of endothelial dysfunction (ED). Materials and methods: the study included 276 male patients with type 2 diabetes mellitus (DM). General clinical studies were carried out, analysis of parameters of carbohydrate metabolism, the content of hormones (total T, SHBG, free T, estradiol, LH, FSH, prolactin, TSH, DHEA) were performed. Endothelial secretory function was assessed using markers such as: nitric oxide (NO), endothelial NO synthase type 3, endothelin, ICAM-1, VCAM-1, p- and e-selectins, cadherin, PAI-1, VEGF-1. Additionally, the content of biologically active substances affecting endothelial function was studied: homocysteine B, C-reactive protein (CRP), osteoprotegerin, leptin, resistin, adiponectin. The vasomotor function of the endothelium was assessed by ultrasound examination of the endothelium-dependent vasodilation (EDVD) of the brachial artery (BA) during the reactive hyperemia test; in addition, the thickness of the intima-media complex (TIM) of the carotid arteries was measured. Correlation analysis was performed using Spearman’s method. Results: the level of total T is interrelated with the instrumental parameters of the endothelial function: the TIM of the carotid arteries (r = -0.26; p = 0.009), the time of maximum BA vasodilation development (r = -0.41; p Conclusion: T deficiency is associated with a deterioration in the vasomotor function of the endothelium: a decrease in EDVD along with an increase in the time of maximum BA vasodilation development and impaired endothelial secretory function: an increase in the concentrations of VCAM-1, ICAM-1, cadherin, VEGF and, on the contrary, a decrease in NO levels. A decrease in T levels is accompanied by an increase in the content of CRP, resistin, leptin and a decrease in adiponectin, which aggravates the dysfunction of the endothelium.

Obstructive sleep apnea (OSA) is highly prevalent during gestation and is linked with adverse fetal outcomes. We examined whether gestational intermittent hypoxia (GIH), the main feature of OSA, leads to sex-specific alterations in cardiovascular function and vascular mechanisms in the offspring. Pregnant rats exposed to intermittent hypoxia or ambient air from gestation days 10 to 21 and their offspring were used for the study. GIH exposure did not affect water and food intake in dams. Compared to controls, the male and female offspring born to GIH dams were smaller in weight by 14% and 12%, respectively, and exhibited catch-up growth. Cardiac function was not affected in either GIH males or females. At 12 weeks of age, blood pressure was increased in GIH males, but not GIH females, compared to their control counterparts. While mesenteric arterial contractile responses to phenylephrine and endothelin were unaffected in GIH males and females, relaxation response to acetylcholine was reduced in GIH males but not GIH females. Relaxation to sodium nitroprusside was unaffected in both GIH males and females. Total eNOS expression was not affected, but phospho(Ser1177)-eNOS levels were decreased in GIH males. eNOS expression and its phosphorylation status were unaffected in GIH females. Serum testosterone and estradiol levels were higher in GIH males but were unaltered in GIH females. Together, these findings suggest that GIH leads to a sex-specific increase in blood pressure in adult male offspring with blunted endothelium-mediated relaxation, decreased eNOS activity, and elevated sex steroid hormone levels.

Background We tested the hypotheses that: 1) early exposure to increasing episodes of clinically relevant intermittent hypoxia (IH) is detrimental to the developing kidneys; and 2) there is a critical number of daily IH episodes which will result in irreparable renal damage that may involve angiotensin (Ang) II and endothelin (ET)-1. Methods At birth (P0), neonatal rat pups were exposed to brief IH episodes from the first day of life (P0) to P7 or from P0-P14. Pups were either euthanized immediately or placed in room air (RA) until P21. RA littermates served as controls. Kidneys were harvested at P7, P14, and P21 for histopathology; angiotensin converting enzyme (ACE), ACE-2, ET-1, big ET-1, and malondialdehyde (MDA) levels; immunoreactivity of ACE, ACE-2, ET-1, ET-2, ET receptors (ETAR, ETBR), and hypoxia inducible factor (HIF)1α; and apoptosis (TUNEL stain). Results Histopathology showed increased renal damage with 8–12 IH episodes/day, and was associated with Ang II, ACE, HIF1α, and apoptosis. ACE-2 was not expressed at P7, and minimally increased at P14. However, a robust ACE-2 response was seen during recovery with maximum levels noted in the groups recovering from 8 IH episodes/day. ET-1, big ET-1, ETAR, ETBR, and MDA increased with increasing levels of neonatal IH. Conclusions Chronic neonatal IH causes severe damage to the developing kidney with associated elevations in vasoconstrictors, suggesting hypertension, particularly with 8 neonatal IH episodes. ACE-2 is not activated in early postnatal life, and this may contribute to IH-induced vasoconstriction. Therapeutic targeting of ACE and ET-1 may help decrease the risk for kidney injury in the developing neonate to prevent and/or treat neonatal acute kidney injury and/or chronic kidney disease.

Актуальність. Ожиріння і цукровий діабет (ЦД) розглядаються як найважливіші фактори ризику перебігу артеріальної гіпертензії (АГ), що призводять до різних ускладнень. Однією з причин погіршення перебігу АГ є дисфункція ендотелію. Застосування різних схем комбінованої терапії призводить і до поліпшення стану ендотелію. Метою роботи було вивчення динаміки функції ендотелію при лікуванні хворих на АГ у поєднанні з ожирінням і ЦД. Матеріали та методи. Обстежено 54 хворих з визначенням антропометричних даних, функції ендотелію сонної артерії і аорти, ендотеліну, сумарної кількості нітратів/нітритів. Результати. В обстежуваних групах (як з нефіксованою базисною терапією, так і з додаванням трьохкомпонентної фіксованої комбінації) відбувалося зниження як систолічного (на 7,36 і 6,36 % відповідно, р < 0,05), так і діастолічного (на 9,2 і 8,29 % відповідно, р 0,1), товщина комплексу інтима­медіа (ТКІМ) — на 5,48 % (р > 0,1), рівень ендотеліну­1 — на 31,27 % (р > 0,1), тоді як рівень Total NO підвищився на 8,35 % (р > 0,1), а ендотелійзалежної вазодилатації (ЕЗВД) — на 10,5 % (р > 0,1). При комбінованій фіксованій комбінації гіпотензивних препаратів відбувалися більш виражені зміни з боку артеріальної стінки: ІЖА знизився на 10,96 % (р < 0,05), ТКІМ — на 8 %, ендотелін­1 — на 31,52 % (р < 0, 05), у той час як Total NO збільшився на 8,7 % (р < 0,05), а ЕЗДВ — на 11,8 % (р < 0,05). Висновки. У хворих на АГ з ожирінням і цукровим діабетом відбувається збільшення жорсткості артерій, товщини комплексу інтима­медіа, підвищення рівня ендотелінемії і зниження ЕЗВД і рівня загальних нітратів. Фіксована базисна гіпотензивна терапія стимулює ЕЗВД і істотно покращує механізми авторегуляції і пружно­еластичні властивості судин м’язового типу, статистично вірогідно краще знижує систолічний артеріальний тиск.

Morbidity and mortality risks are enhanced in preeclamptic (PE) mothers and their offspring. Here, we asked if sexual dimorphism exists in (i) cardiovascular and renal damage evolved in offspring of PE mothers, and (ii) offspring responsiveness to antenatal therapies. PE was induced by administering NG-nitro-L-arginine methyl ester (L-NAME, 50 mg/kg/day, oral gavage) to pregnant rats for 7 days starting from gestational day 14. Three therapies were co-administered orally with L-NAME, atrasentan (endothelin ETA receptor antagonist), terutroban (thromboxane A2 receptor antagonist, TXA2), or α-methyldopa (α-MD, central sympatholytic drug). Cardiovascular and renal profiles were assessed in 3-month-old offspring. Compared with offspring of non-PE rats, PE offspring exhibited elevated systolic blood pressure and proteinuria and reduced heart rate and creatinine clearance (CrCl). Apart from a greater bradycardia in male offspring, similar PE effects were noted in male and female offspring. While terutroban, atrasentan, or α-MD partially and similarly blunted the PE-evoked changes in CrCl and proteinuria, terutroban was the only drug that virtually abolished PE hypertension. Rises in cardiorenal inflammatory (tumor necrosis factor alpha, TNFα) and oxidative (isoprostane) markers were mostly and equally eliminated by all therapies in the two sexes, except for a greater dampening action of atrasentan, compared with α-MD, on tissue TNFα in female offspring only. Histopathologically, antenatal terutroban or atrasentan was more effective than α-MD in rectifying cardiac structural damage, myofiber separation, and cytoplasmic alterations, in PE offspring. The repair by antenatal terutroban or atrasentan of cardiovascular and renal anomalies in PE offspring is mostly sex-independent and surpasses the protection offered by α-MD, the conventional PE therapy.

Multikinase inhibitors, such as sorafenib, are used for the treatment of advanced carcinomas but the response shows limited efficacy or varies a lot with patients. Here we adopted the systems approach combined with high-throughput data analysis to discover key mechanism embedded in the drug response. When analyzing the transcriptomic data from the Cancer Cell Line Encyclopedia (CCLE) database, endothelin 1 (EDN1) was enriched in cancer cells with low responsiveness to sorafenib. We found that the level of EDN1 is higher in the tissue and blood of hepatocellular carcinoma (HCC) patients showing poor response to sorafenib. In vitro experiment showed that EDN1 not only induces activation of angiogenic-promoting pathways in HCC cells but also stimulates proliferation and migration. Moreover, EDN1 is related with poor responsiveness to sorafenib by mitigating unfolded protein response (UPR), which was validated in both transcriptomic data analysis and in silico simulation. Finally, we found that endothelin receptor B (EDNRB) antagonists can enhance the efficacy of sorafenib in both HCC cells and xenograft mouse models. Our findings provide that EDN1 is a novel diagnostic marker for sorafenib responsiveness in HCC and a basis for testing macitentan, which is currently used for pulmonary artery hypertension, in combination with sorafenib in advanced HCC patients.

Renal interstitial fibrosis is characterized by the development of myofibroblasts, originating from resident renal and immigrating cells. Myofibroblast formation and extracellular matrix production during kidney damage are triggered by various factors. Among these, endothelins have been discussed as potential modulators of renal fibrosis. Utilizing mouse models of adenine nephropathy (AN) and unilateral ureter occlusion (UUO), this study aimed to investigate the contribution of endothelin signaling in stromal mesenchymal resident renal interstitial cells. We found in controls that adenine feeding and UUO caused marked upregulations of endothelin-1 (ET-1) gene expression in endothelial and in tubular cells and a strong upregulation of ETA-receptor (ETA-R) gene expression in interstitial and mesangial cells, while the gene expression of ETB-receptor (ETB-R) did not change. Conditional deletion of ETA-R and ETB-R gene expression in the FoxD1 stromal cell compartment which includes interstitial cells significantly reduced renal ETA-R gene expression and moderately lowered renal ETB-R gene expression. ET receptor (ET-R) deletion exerted no apparent effects on kidney development nor on kidney function. Adenine feeding and UUO led to similar increases in profibrotic and proinflammatory gene expression in control as well as in ETAflflETBflfl FoxD1Cre+ mice (ET-Ko). In summary, our findings suggest that adenine feeding and UUO activate endothelin signaling in interstitial cells which is due to upregulated ETA-R expression and enhanced renal ET-1 production Our data also suggest that the activation of endothelin signaling in interstitial cells has less impact for the development of experimentally induced fibrosis.

Improving the effectiveness of drug therapy and reducing the risk of adverse cardiovascular and renal outcomes in patients with resistant hypertension (HTN) remains an unsolved problem of cardiology. The results of the PATHWAY-2, PATHWAY-3 and ReHOT studies have shown the clinical efficacy of spironolactone, amiloride and, to a lesser extent, the antiadrenergic drugs clonidine, bisoprolol and doxazosin in improving blood pressure (BP) control in this patient population. However, the inclusion of spironolactone and other known drugs in antihypertensive therapy does not ensure the achievement of target BP level in a significant proportion of these patients. The review presents the results of clinical studies of new approaches aimed at increasing the effectiveness of drug therapy in resistant HTN including sodium-glucose cotransporter type 2 inhibitors, brain aminopeptidase A inhibitors, and new antagonists of endothelin receptors.

Background: Propolis is a product of honeybees that contains a variety of different compounds, including caffeic acid phenethyl ester (CAPE). Propolis and its bioactive compounds are widely used in folk medicine and as a dietary supplement. Previously it has been shown that CAPE has antioxidant, anti-inflammatory, antimicrobial, antiviral, immunomodulatory, and anticancer activity. Objective: This in vitro study was designed to investigate the vasoactive effects of CAPE on quiescent and precontracted human umbilical arteries. Methods: Umbilical artery strips were suspended in aerated organ baths containing a buffer solution. The strips were randomly allocated to study groups (n=8). Via a transducer and computer, changes in isometric tension were recorded. The effects of cumulative CAPE (10-8-10-4M) on basal tone of the artery, and in different groups of strips, the vasodilatory effect of cumulative CAPE on the constriction elicited by endothelin (ET-1), prostaglandin F2α (PGF2α) and U46619, and the effect of incubation with NO synthase inhibitor L-NAME, were recorded. Conclusion: CAPE elicits concentration-dependent relaxation on precontracted human umbilical artery strips depending on the constrictor agent. NO plays significant role in CAPE’s vasorelaxant effect.

Introduction The podocyte is thought to be the mainly affected cell type in focal segmental glomerulosclerosis (FSGS). However, recent studies have also indicated a role for glomerular endothelial cells and podocyte−endothelial crosstalk in FSGS development. An experimental model for podocyte injury showed that increased endothelin-1 (ET-1) signaling between podocytes and endothelial cells induces endothelial oxidative stress and subsequent podocyte loss. In the current study, we investigated endothelial endothelin receptor A (ETAR) expression in patients with FSGS and its association with podocyte injury and glomerular oxidative stress. Methods We selected 39 biopsy samples of patients with FSGS and 8 healthy control subjects, and stained them for ETAR, nephrin and 8-oxo-guanine, a DNA lesion caused by oxidative damage. Glomeruli with ETAR-positive endothelium and with nephrin loss were scored, and the 8-oxo-guanine−positive glomerular area was measured. Results The mean percentage of glomeruli with ETAR-positive endothelial cells in patients with FSGS was higher compared to that in healthy control subjects (52% vs. 7%; P < 0.001). The presence of glomerular ETAR-positive endothelium was strongly associated with nephrin loss both on the biopsy level (rho = 0.47; P < 0.01), as on the level of individual glomeruli (odds ratio = 2.0; P < 0.001). Moreover, glomeruli with ETAR-positive endothelium showed more 8-oxo-guanine−positive staining (1.9% vs. 2.4%; P = 0.037). Finally, 8-oxo-guanine positivity in glomeruli was associated with increased levels of proteinuria. Conclusion Taking together our findings, we show that ETAR is increased in glomerular endothelial cells of patients with FSGS and associated with podocyte damage and glomerular oxidative stress. These findings support the hypothesis that ET-1 signaling in glomerular endothelial cells contributes to disease development in patients with FSGS., Graphical abstract

Purpose of review To summarize new clinical findings of endothelin receptor antagonists (ERA) in various etiologies of kidney disease targeted in clinical trials. Recent findings Endothelin-1 is a multifunctional peptide with potential relevance to glomerular and tubulointerstitial kidney diseases. The phase 3 SONAR trial demonstrated a significant reduction in clinically relevant kidney outcomes for patients with diabetic kidney disease (DKD) after long-term treatment with the ERA, atrasentan, in addition to blockade of the renin-angiotensin-aldosterone system. Promising preclinical disease models and small clinical trials in non-DKD resulted in the initiation of phase 3 trials investigating the effects of long-term treatment with ERA in patients with immunoglobulin A (IgA) nephropathy and focal segmental glomeruloscelerosis (FSGS). The mechanisms by which ERA protects the kidneys have been extensively studied with evidence for the protection of tubule cells, podocytes, mesangial cells, the endothelial glycocalyx, and a reduction in glomerular perfusion pressure. The occurrence of fluid retention during ERA treatment, particularly in susceptible populations, necessitates strategies to support safe and effective treatment. Summary Treatment with ERA induces long-term kidney protection in DKD. Phase 3 trials are underway to investigate ERA effects in patients with IgA nephropathy and FSGS.

BACKGROUND Hypertension is common in hemodialysis (HD) patients. Increased blood pressure (BP) variability, particularly higher and lower extremes, is associated with adverse outcomes. We explored the association of endothelin-1 (ET-1), a potent vasoconstrictor, with different BP parameters (pre-HD, intra-HD, and post-HD) during HD in a contemporary patient cohort. METHODS This study uses the DaVita Biorepository, a longitudinal prospective cohort study with quarterly collection of clinical data and biospecimens. Unadjusted and adjusted linear mixed effects regression models were fit to determine association of pre-HD ET-1 (log-transformed and quartiles) with HD-related systolic BP (SBP) parameters (pre-HD, nadir intra-HD, and post-HD). As ET-1 was measured at baseline, analyses were restricted to 1 year of follow-up. RESULTS Among 769 participants, mean age was 52 years, 42% were females, and 41% were Black. Mean pre-HD SBP was 152 (±28) mm Hg and mean ET-1 concentration was 2.3 (±1.2) ng/ml. In fully adjusted models, each unit increase in SD of log-transformed ET-1 was associated with a 2.7 (95% confidence interval [CI] 1.5, 4.0) mm Hg higher pre-SBP; 1.6 (95% CI 0.9, 2.3) mm Hg higher nadir SBP; and 2.0 (95% CI 1.1, 2.9) mm Hg higher post-SBP. Each SD increase in log-transformed ET-1 was associated with 21% higher odds of experiencing intradialytic hypertension (odds ratio 1.21; 95% CI 1.10–1.34). CONCLUSIONS Higher baseline ET-1 levels are independently associated with higher SBP and higher odds of intradialytic hypertension. These results highlight a potential role for ET-1 in BP control in HD patients and raise the possibility of ET-1 antagonism as a therapeutic target.

Background. Pathological activation of cytokines is one of the key links in the pathogenesis of diabetes mellitus (DM) and the development of its complications, in particular from the cardiovascular system. According to the vast majority of researchers, the imbalance of pro- and anti-inflammatory cytokines in patients with diabetes mellitus is a significant risk factor for mortality from cardiovascular disease. The purpose of the study was to determine the concentration of markers of a nonspecific inflammatory response (interleukin (IL) 6 and IL-10) in the blood of men with DM and their association with glycated hemoglobin levels and body mass index. Materials and methods. There were examined 46 men with type 2 DM and 28 men with type 1 DM. According to the results of the analysis of variance of the control group, type 2 DM and type 1 DM had significant differences in some indicators. Results. The correlation analysis of the obtained indicators of interleukin concentration showed that in men with type 2 DM under the age of 50 years, the indicators of IL-6 concentration significantly positively correlated with indicators of IL-10 concentration in blood (Spearman’s correlation coefficient 0.562, p, Актуальність. Патологічна активація цитокінів є однією з ключових ланок у патогенезі цукрового діабету і розвитку його ускладнень, зокрема, з боку серцево-судинної системи. На думку переважної більшості дослідників, дисбаланс про- і протизапальних цитокінів у хворих на цукровий діабет (ЦД) є вагомим фактором ризику смерті від серцево-судинних захворювань. Мета дослідження: визначення концентрації маркерів неспецифічної запальної реакції (інтерлейкін (ІЛ) -6, ІЛ-10) у крові в чоловіків із цукровим діабетом і їх асоціації з рівнями глікованого гемоглобіну й індексом маси тіла. Матеріали та методи. Обстежено 46 чоловіків, хворих на ЦД 2-го типу, і 28 чоловіків, хворих на ЦД 1-го типу. За результатами дисперсійного аналізу групи контролю, ЦД 2-го типу і ЦД 1-го мали вірогідні відмінності за низкою показників. Результати. Проведений кореляційний аналіз отриманих показників концентрації інтерлейкінів засвідчив, що в чоловіків, хворих на ЦД 2-го типу, віком до 50 років показники концентрації ІЛ-6 вірогідно позитивно корелювали з показниками концентрації ІЛ-10 у крові (коефіцієнт кореляції Спірмена 0,562; р

Both coronary heart disease (CHD) and degenerative aortic valve (AoV) stenosis have common risk factors, such as age, high blood cholesterol, diabetes, smoking, high blood pressure, inflammation, and metabolic syndrome. However, these diseases are not always observed together, confirming the existence of risk and pathogenesis factors specific to each disease. The aim of this study was to identify presence and distribution of common and different homeostasis regulating factors, innervation, ischemia and inflammatory markers in the right atrial tissue from patients with degenerative AoV stenosis and CHD. During elective cardiac surgery, right atrial tissue fragments were taken from 20 patients with CHD and from 9 patients with degenerative AoV stenosis. All tissue fragments were stained for immunohistochemical detection of protein-gene peptide 9.5 (PGP 9.5), atrial natriuretic peptide (ANUP), vascular endothelial growth factor (VEGF), chromogranin A, endothelin, interleukin 1 and 10 (Il-1 and Il-10) and β defensins 2, and 3 (βD2 and βD3). For the quantification of structures, a semi-quantitative counting method was used. Mostly numerous Il-10 positive cardiomyocytes and epi-/endocardial endothelial cells were detected in all specimens taken from patients with CHD, and statistically more than in specimens taken from patients with degenerative AoV disease (p = 0.007 and p = 0.016). Also, the number of βD3 positive cardiomyocytes was higher in the coronary heart disease group (p = 0.026). All other tested markers such as PGP 9.5, ANUP, VEGF, endothelin, chromogranin A, Il-1 and βD2 showed similar expression in both groups. Increased production of ANUP in right atrial tissue characterises both CHD and degenerative AoV stenosis. Production of ChgA in right atrial endocardial endothelial cells might represent regulation of sympathetic activity as a compensatory homeostatic response. Increased PGP 9.5-containing innervation is characteristic in patients with degenerative AoV disease and secondary mitral insufficiency. A stable increase of VEGF and variations of endothelin without statistically significant difference suggest influence of ischemia on the local vascular blood supply. Decreased production of Il-1α together with moderate to rich production of Il-10, βD2, and βD3 indicates the dominance of the local immune system over inflammation.

Objective: The aim of this study was to explore the expression and effects of tumor necrosis factor alpha (TNFα) in maternal endothelial cells in preeclampsia (PE).Methods: Expression levels in primary microvascular endothelial cells (MVEC) isolated from patients with severe preeclampsia (PE) and normal pregnancies were determined by RT-qPCR with or without treatment of TNFα and inhibitors for downstream signaling.Results: PE MVEC exhibited increased basal TNFα expression. TNFα treatment increased TNFα, VCAM, and endocan expression in MVEC.Conclusion: TNFα expression is increased in PE MVEC and the treatment of these cells with exogenous TNFα modifies their gene expression.

Objectives This study sought to evaluate the effect of weight loss on the atrial substrate for atrial fibrillation (AF). Background Whether weight loss can reverse the atrial substrate of ...

Purpose. To assess the effectiveness of curative complex consisting of photodynamic therapy (PDT) + intravenous laser blood irradiation (ILBI) + local tumor irradiation (TR) at hemostatic parameters at the initial stages of squamous cell skin cancer (SCSC).Material and methods. The present work analyzes SCSC course in 185 patients who had outpatient and inpatient treatment in medical institutions of cities Engels and Saratov in 2015–2019. 129 (69.7%) males and 56 females (31.2%). Patients were divided into three groups. Group I – 74 (40%) patients who had combined treatment: surgery with wide tumor excision under intravenous anesthesia + PDT + ILBI + TR; Group II – 111 (60%) patients who had only surgical treatment. Group III was created for controlling and comparing the obtained laboratory parameters; it included 17 patients without established pathology.Results. It was found out that hemostatic disorders in SCSC are characterized by increased activity of AT III and vWF and by simultaneous decrease of tPA-PAI-1 complex as well as by increased activity of VIIIa factor and resistance of Va factor – indices which indicate dysfunction of endothelial vascular wall. Combination of PDT + ILBI + TR prior to surgical treatment in patients with squamous cell skin cancer at the initial stages of the disease allow to normalize homeostatic indices and reduce the number of complications.Conclusion. 1. Squamous cell skin cancer at the initial stages changes the hemostatic system. 2. Effects of SCSC mechanism may be characterized as follows: damage of the endothelium vascular wall which is confirmed by endothelin increase; it results in vasoconstriction and increased blood procoagulant activity and, ultimately, in changes of hemostatic parameters. 3. Combination of PDT + ILBI + TR applied before surgery in patients with squamous cell skin cancer at the initial stages of the disease normalizes homeostatic indices and reduces the number of complications.

Pulmonary artery hypertension (PAH) is a common and serious disease which is characterized by pulmonary vascular remodeling. Bosentan (BST) is the first approved oral targeted drug of endothelin-1 (ET-1) receptor antagonists for the treatment of PAH. MicroRNA-27a (miR-27a) and peroxisome proliferator-activated receptor γ (PPARγ) were found to be related to the pathogenesis of PAH. To further explore the signal transduction mechanism of BST in the treatment of PAH, we examined the effects of BST on endothelin receptors, miR-27a, and PPARγ. Meanwhile, the influence of miR-27a in the formation and development of PAH was discussed. Our results demonstrated that during the pathophysiology of PAH, miR-27a, PPARγ, and ET-1 were cross-inhibited, which indicated that the miR-27a/PPARγ/ET-1 signaling pathway was dysregulated; in addition, BST could competitively bind to ET-1 receptors and inhibit the miR-27a/PPARγ/ET-1 signaling pathway, thereby delaying the proliferation of PASMCs and affecting the development of PAH. Our results give a new understanding of the pathogenesis and treatment of PAH and provide more reliable evidence for the application of BST in the treatment of PAH in the clinic.

Histone/protein deacetylases (HDAC) 1 and 2 are typically viewed as structurally and functionally similar enzymes present within various co-regulatory complexes. We tested differential effects of these isoforms in renal ischemia reperfusion injury (IRI) using inducible knockout mice and found no significant change in ischemic tolerance with HDAC1 deletion, but mitigation of ischemic injury with HDAC2 deletion. Restriction of HDAC2 deletion to the kidney via transplantation or PAX8-controlled proximal renal tubule-specific Cre resulted in renal IRI protection. Pharmacologic inhibition of HDAC2 increased histone acetylation in the kidney but did not extend renal protection. Protein analysis demonstrated increased HDAC1-associated CoREST protein in HDAC2-/- versus WT cells, suggesting that in the absence of HDAC2, increased CoREST complex occupancy of HDAC1 can stabilize this complex. In vivo administration of a CoREST inhibitor exacerbated renal injury in WT mice and eliminated the benefit of HDAC2 deletion. Gene expression analysis of endothelin showed decreased endothelin levels in HDAC2 deletion. These data demonstrate that contrasting effects of HDAC1 and 2 on CoREST complex stability within renal tubules can affect outcomes of renal IRI and implicate endothelin as a potential downstream mediator.

Pulmonary hypertension is a debilitating chronic disease. In the last 20 years, there has been im-pressive progress in the treatment strategy of pulmonary arterial hypertension. This led to a significant increase in the awareness and improvement in the clinical outcome, though there was no substantial improvement in the rate of mortality. This review summarizes the current state of the art of the treat-ment of pulmonary arterial hypertension, including the three main categories of pulmonary hypertension specific medication which were introduced in the last 20 years. Mainly drugs that restore prostaglandins function of the endothelial cells, drugs that restore Cyclic GMP in the endothelial cells and various forms of medication that inhibit Endothelin receptors. The current strategy to treat patients with pulmonary arterial hypertension is to initiate drug therapy as early as possible and to adopt combinational therapy using two or more classes of drugs simultaneously. There are current efforts to introduce future medica-tion that can be more specific to a phenotype of pulmonary hypertension.

BACKGROUND: During uvulopalatopharyngoplasty (UPPP), cardiovascular adverse events may occur which can be harmful to patients. OBJECTIVE: To evaluate the effect of the protective ventilation strategy on the function of vascular endothelial cells. METHODS: Forty obstructive apnea syndrome (OSA) patients who underwent uvulopalatopharyngoplasty (UPPP) were enrolled. Patients were randomly divided into the control group (group C, PEEP = 0 cm H2O) and PEEP group (group P, PEEP = 5 cm H2O). Each group (n= 20) received intermittent volume controlled ventilation (VCV) with tidal volume 6 ml/kg of the predicted body weight, I:E 1:2, rate titrated for ETCO2 35–45, FiO2 0.7. Blood from the radial artery was sampled for blood gas analysis at four time points: the fifth minute of inhaling pure oxygen (T0), after tracheal intubation (T1), at the end of the operation (T2), and 20 minutes after extubation (T3). Three ml of arterial blood was retained, preserved at -20∘C after serum isolation, and plasma nitric oxide (NO), endothelin-1 (ET-1) and vascular celladhesion molecule-1 (VCAM-1) levels were determined by enzyme linked immunosorbent assay (ELISA). RESULTS: Compared with group C, plasma ET-1 at T3 decreased in group P, and plasma NO levels at T2 and T3 increased (P< 0.05). Compared with samples collected at T0, plasma VCAM-1 levels at T1, T2 and T3 increased in group C, while plasma VCAM-1 levels at T2 and T3 decreased in group P (P< 0.05). Compared with group C, plasma VCAM-1 levels T2 and T3 decreased in group P (P< 0.05). CONCLUSIONS: Positive end-expiratory pressure (PEEP) ventilation has a protective effect on vascular endothelial cell function in patients during UPPP.

Acute kidney injury (AKI) occurs in 3.2 - 9.6% of hospital admissions and in 2.1 - 22.1% of prevalent intensive care unit patients, worldwide. There is a sexual dimorphism in the AKI evolution with implications of sex hormones, endothelin etc. We provide a mini-review on the gender-related differences in the AKI evolution.

Li Feng,* Songhua Wang,* Feng Chen,* Cheng Zhang, Qiao Wang, Yuting Zhao, Zifeng Zhang School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zifeng Zhang 101 Shanghai Road, Xuzhou, Jiangsu Province, 221116, People’s Republic of ChinaTel + 86 516 83403729Email zhangzifengsuper@jsnu.edu.cnBackground: Emerging evidence from animal studies and clinical trials indicates that systemic inhibition of endothelin1 (ET1) signaling by endothelin receptor antagonists improves pathological features of diabetes and its complications. It is indicated that endothelin type A receptor (ETAR) plays a major role in ET1-mediated pathophysiological actions including diabetic pathology. However, the effects as well as the mechanistic targets of hepatic ET1/ETAR signaling inhibition on the pathology of metabolic diseases remain unclear. This study aimed to investigate the beneficial effects as well as the underlying mechanisms of hepatic ETAR knockdown on metabolism abnormalities in high-fat diet (HFD)-fed mice.Methods: Mice were fed a HFD to induce insulin resistance and metabolism abnormalities. L02 cells were treated with ET1 to assess the action of ET1/ETAR signaling in vitro. Liver-selective knockdown of ETAR was achieved by tail vein injection of adeno-associated virus 8 (AAV8). Systemic and peripheral metabolism abnormalities were determined in vivo and in vitro. Mitochondrial fragmentation was observed by transmission electron microscope (TEM) and mitoTracker red staining.Results: Here we provided in vivo and in vitro evidence to demonstrate that liver-selective knockdown of ETAR effectively ameliorated hepatic insulin resistance and hyperglycemia in HFD-fed mice. Mechanistically, hepatic ETAR knockdown alleviated mitochondrial fragmentation and dysfunction via inactivating 66-kDa Src homology 2 domain-containing protein (p66Shc) to recover mitochondrial dynamics, which was mediated by inhibiting protein kinase Cδ (PKCδ), in the livers of HFD-fed mice. Ultimately, hepatic ETAR knockdown attenuated mitochondria-derived oxidative stress and related liver injuries in HFD-fed mice. These ETAR knockdown-mediated actions were confirmed in ET1-treated L02 cells.Conclusion: This study defined an ameliorative role of hepatic ETAR knockdown in HFD-induced metabolism abnormalities by alleviating p66Shc-mediated mitochondrial fragmentation and consequent oxidative stress-related disorders and indicated that hepatic ETAR knockdown may be a promising therapeutic strategy for metabolic diseases.Keywords: endothelin-1, endothelin type A receptor, 66-kDa Src homology 2 domain-containing protein, mitochondrial fragmentation, metabolism abnormality

We reported that high salt (HS) intake stimulates renal collecting duct (CD) endothelin (ET) type B receptor (ETBR)/nitric oxide (NO) synthase 1β (NOS1β)-dependent NO production inhibiting the epithelial sodium channel (ENaC) promoting natriuresis. However, the mechanism underlying the HS-induced increase of NO production is unclear. Histone deacetylase 1 (HDAC1) responds to increased fluid flow, as can occur in the CD during HS intake. The renal inner medulla (IM), in particular the IMCD, has the highest NOS1 activity within the kidney. Hence, we hypothesized that HS intake provokes HDAC1 activation of NO production in the IM. HS intake for 1 wk significantly increased HDAC1 abundance in the IM. Ex vivo treatment of dissociated IM from HS-fed mice with a selective HDAC1 inhibitor (MS-275) decreased NO production with no change in ET-1 peptide or mRNA levels. We further investigated the role of the ET-1/ETBR/NOS1β signaling pathway with chronic ETBR blockade (A-192621). Although NO was decreased and ET-1 levels were elevated in the dissociated IM from HS-fed mice treated with A-192621, ex vivo MS-275 did not further change NO or ET-1 levels suggesting that HDAC1-mediated NO production is regulated at the level or downstream of ETBR activation. In split-open CDs from HS-fed mice, patch clamp analysis revealed significantly higher ENaC activity after MS-275 pretreatment, which was abrogated by an exogenous NO donor. Moreover, flow-induced increases in mIMCD-3 cell NO production were blunted by HDAC1 or calcium inhibition. Taken together, these findings indicate that HS intake induces HDAC1-dependent activation of the ETBR/NO pathway contributing to the natriuretic response.

Sex dependent differences in coronary artery vasoregulation may be due to variations in responses to endogenous vasoactive compounds including endothelin (ET-1) and nitric oxide (NO).Septal coronary arteries (200 μm) from healthy, sexually mature male, female and ovariectomized (i.e. surgical menopause) Sprague-Dawley rats were used. Myogenic tone, measured by pressure myography, was initially determined for all vessel segments studied before and after exposure to the nonselective ETMyogenic tone was 26 ± 7% in male, 20 ± 7% in female (p = 0.04 versus male) and 24 ± 3% in ovariectomized (p = NS versus male/female) vessels. Antagonism of ET-1 receptors produced a greater reduction in myogenic tone in male, compared to female rats over a similar range of intraluminal pressure (20-80 mmHg). Robust constrictor responses to cumulative concentrations of ET-1 were observed in all vessels; however, male rats exhibited greater sensitivity to vasoconstrictor effects of ET-1. After exposure to L-NAME vessel responses to ET-1 were normalized in male and female (not studied in ovariectomized) groups.These findings confirm marked sex differences for myogenic tone and vessel constrictor responses to ET-1 in coronary resistance vessels. Results also suggest greater sensitivity to vasoconstrictor effects of ET-1 in male coronary resistance vessels.

Introduction: The Indonesian INOVASIA study is an ongoing multicentre randomized, open controlled trial of pravastatin for the prevention of preeclampsia in patients deemed to be high risk. Here we evaluate the effects of pravastatin on circulating inflammatory and endothelial markers, i.e. Vascular Endothelial Growth Factor (VEGF), Interleukin-6 (IL-6), Endothelin-1 (ET-1), and Nitric Oxide (NO). Methods: Pregnant women deemed to be at a high risk of developing preeclampsia women were recruited based on the Fetal Medicine Foundation preeclampsia screening test or a history of preterm preeclampsia, or clinical risk factors in combination with an abnormal uterine artery Doppler flow pattern at 11-20 week's gestation. This is a nested cohort study within the larger trial (INOVASIA); 38 patients were consecutively recruited and assigned to the pravastatin group and the control group. Participants in the pravastatin group received pravastatin (2 × 20 mg p.o) in addition to a standard regimen of aspirin (80 mg p.o) and calcium (1 g p.o), from 14 to 20 weeks until delivery. Blood samples to measure the various biomarkers were obtained in consecutive patients before starting the research medication and just before delivery (pre and post-test examination). Result: The number of samples on the 2 time points for the various biomarkers was: VEGF: 38, IL-6: 30, ET-1: 38, and NO: 35. IL-6 levels decreased significantly in the pravastatin group (mean ± SD): (191.87 ± 82.99 vs. 151.85 + 48.46, p = .013), while levels in the control group did not change significantly (median (interquartile range)) (144.17 (53.91) vs. 140.82 (16.18), p = .177). ET-1 levels decreased significantly in the pravastatin group (3.64 ± 0.85 vs. 3.01 ± 0.74, p = .006) while the control group had more or less stable levels (3.57 ± 1.12 vs. 3.78 ± 0.73 p = .594). NO was the only serum marker that showed significant changes in both groups. NO levels increased in pravastatin group (11.30 (17.43) vs. 41.90 (53.18), p = .044) and decreased in control group (38.70 (34.80) vs. 10.03 (26.96), p = .002). VEGF levels appeared to follow opposite trends in the 2 groups (NS) (Pravastatin: 3.22 (0.62) vs. 3.28 (0.75), p = .402. Control: 3.38 (0.83) vs. 3.06 (0.74), p = .287). Conclusion: Administration of 40 mg pravastatin resulted in an improvement in NO levels, and a decrease in IL-6 and endothelin (ET-1) levels. The direction of the effect of pravastatin on these biomarkers appears to underpin the potential for a beneficial effect of pravastatin in the prevention of preeclampsia.

ZusammenfassungIn der Therapie der pulmonalarteriellen Hypertonie (PAH) kommen zahlreiche Medikamentenklassen zum Einsatz, u. a. Endothelinrezeptorantagonisten (ERA) und Phosphodiesterase-5-(PDE-5-)Inhibitoren. In einem humanen Ex-vivo-Modell sollte überprüft werden, ob durch die Kombination zweier Substanzklassen ein höherer Effekt erzielt werden kann oder – bei gleichem Effekt – eine niedrigere Dosierung der Einzelsubstanzen ausreicht. Wir etablierten ein Organbadmodell, welches uns die In-vitro-Untersuchung der dosisabhängigen Effekte von ERA und PDE-5-Inhibitoren auf die durch Norepinephrin und Endothelin-1 induzierte Kontraktilität humaner Pulmonalgefäße sowie den Vergleich von Mono- und Dualtherapie ermöglichte. Auch wenn die Übertragung der Ex-vivo-Daten auf die Situation im Patienten mit Vorsicht erfolgen muss, so hat sich das Organbad dennoch als hilfreiches Instrument zur Evaluation der dosisabhängigen Effekte von ERA, PDE-5-Inhibitoren und deren Kombination erwiesen. Die Wirksamkeit der Kombinationstherapie und das Potenzial zur Dosisreduktion waren in diesem Modell abhängig von den verwendeten Konzentrationen und vom Einfluss der Vorerkrankungen auf die Blutgefäßfunktion. Diese Arbeit beschreibt die bisherigen und wichtigsten Ergebnisse unserer experimentellen Untersuchungen und gibt einen Ausblick auf zukünftige Projekte.

Introduction: There is a bulk of literature data on the physiological roles of nitric oxide (NO) and endothelin- 1 (ET-1), but many facts remain unknown, especially in certain diseases such as peripheral arterial disease. Material and methods: This is an observational cross-sectional study. The subjects were patients diagnosed with PAD. Serum levels of NO and ET-1 were determined for all patients, and statistical data processing was performed according to the set goals. Results: The study included 64 patients with mean age 60.2 ± 12.7 years, mostly in stage II PAD according to Fontain (46.9%). Statistical analysis failed to determine a significant difference in serum NO or ET-1 values with respect to disease stage, sex, and body mass index (BMI). Certain oscillations were found in the mean values of NO related to smoking and diabetes but without statistical significance. There were also oscillations in the values of ET-1, with higher levels found in women, smokers and non-diabetics in whom this difference reached statistical significance (p = 0.041). Conclusion: Serum levels of NO and ET-1 in this study show some causal relationship with certain risk factors for PAD such as diabetes and smoking, but additional research is needed to fully understand their effects and interactions.

The peptide hormone endothelin-1 and its receptors are linked to several disease states. Pharmacological inhibition of this pathway has proven beneficial in pulmonary hypertension, yet its potential in other disease states remains to be realized. This review considers an often understudied aspect of endothelin biology, circadian rhythm regulation and how understanding the intersection between endothelin signaling and the circadian clock may be leveraged to realize the potential of endothelin-based therapeutics.

Pulmonary arterial hypertension (PAH) is an uncommon but lethal and progressive disease in which prostacyclin, nitric oxide and endothelin-1 pathways are disturbed and contribute to the pathophysiology of this disease. Endothelin receptor antagonists are a class of drugs that have been approved as PAH therapy. Macitentan is a lipophilic, tissue specific, dual receptor antagonist with a higher potency than bosentan and a reduced risk of hepatic injury. Macitentan has shown a reduction in morbidity and mortality due to PAH at long-term follow-up and improvements in hemodynamics, exercise capacity and functional class at the short term. Its main adverse events are nasopharyngitis, bronchitis and an increased risk of anemia. We review the clinical data of macitentan and its use in PAH.

A high salt intake exacerbates insulin resistance, evoking hypertension due to systemic perivascular inflammation, oxidative-nitrosative stress and endothelial dysfunction. Angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blockers (ARBs) have been shown to abolish inflammation and redox stress but only partially restore endothelial function in mesenteric vessels. We investigated whether sympatho-adrenal overactivation evokes coronary vascular dysfunction when a high salt intake is combined with insulin resistance in male Goto–Kakizaki (GK) and Wistar rats treated with two different classes of β-blocker or vehicle, utilising synchrotron-based microangiography in vivo. Further, we examined if chronic carvedilol (CAR) treatment preserves nitric oxide (NO)-mediated coronary dilation more than metoprolol (MET). A high salt diet (6% NaCl w/w) exacerbated coronary microvessel endothelial dysfunction and NO-resistance in vehicle-treated GK rats while Wistar rats showed modest impairment. Microvascular dysfunction was associated with elevated expression of myocardial endothelin, inducible NO synthase (NOS) protein and 3-nitrotyrosine (3-NT). Both CAR and MET reduced basal coronary perfusion but restored microvessel endothelium-dependent and -independent dilation indicating a role for sympatho-adrenal overactivation in vehicle-treated rats. While MET treatment reduced myocardial nitrates, only MET treatment completely restored microvessel dilation to dobutamine (DOB) stimulation in the absence of NO and prostanoids (combined inhibition), indicating that MET restored the coronary flow reserve attributable to endothelium-derived hyperpolarisation (EDH). In conclusion, sympatho-adrenal overactivation caused by high salt intake and insulin resistance evoked coronary microvessel endothelial dysfunction and diminished NO sensitivity, which were restored by MET and CAR treatment in spite of ongoing inflammation and oxidative-nitrosative stress presumably caused by uninhibited renin–angiotensin–aldosterone system (RAAS) overactivation.

Background/aim Vimentin3 (Vim3) was recently described as a tumour marker for the direct discrimination between benign and malignant kidney tumours. Here, we examined its expression in prostate cancer (PCa) cell lines and the regulation of its expression by endothelin receptors. Materials and methods Prostate cancer cell lines (PC3, DU145, LNCap) were incubated with endothelin 1 (ET-1), BQ123 [endothelin A receptor (ETAR) antagonist], BQ788 [endothelin B receptor (ETBR) antagonist], BQ123+ET-1, BQ788+ET-1 for 24 h and a scratch assay was performed. Cell extracts were analysed by western blotting and qRT-PCR. Results ET-1 induced Vim3 overexpression. Blocking the ETBR in the different prostate cancer cell lines yielded a higher migration rate, whereby Vim3 expression was significantly increased. Conclusion Vim3 concentration increases in cell lines without a functional ETBR and may be used as a marker for PCas where ETBR is frequently methylated.

Background Sex differences in experimental stroke outcomes are well documented, such that adult males have a greater infarct volume, increased stroke-induced mortality, and more severe sensory-motor impairment. Based on recent evidence that the gut is an early responder to stroke, the present study tested the hypothesis that sex differences in stroke severity will be accompanied by rapid and greater permeability of the gut-blood barrier and gut dysbiosis in males as compared to females. Method Male and female Sprague-Dawley rats (5–7 months of age) were subject to endothelin (ET)-1-induced middle cerebral artery occlusion (MCAo). Sensory-motor tests were conducted pre- and 2 days after MCAo. Gut permeability was assessed in serum samples using biomarkers of gut permeability as well as functional assays using size-graded dextrans. Histological analysis of the gut was performed with H&E staining, periodic acid-Schiff for mucus, and immunohistochemistry for the tight junction protein, ZO-1. Fecal samples obtained pre- and post-stroke were analyzed for bacterial taxa and short-chain fatty acids (SCFAs). Results After stroke, males displayed greater mortality, worse sensory-motor deficit, and higher serum levels of proinflammatory cytokines IL-17A, MCP-1, and IL-5 as compared to females. MCAo-induced gut permeability was rapid and severe in males as indicated by dextran extravasation from the gut to the blood in the hyperacute (< 2 h) and early acute (2 days) phase of stroke. This was accompanied by dysmorphology of the gut villi and dysregulation of the tight junction protein ZO-1 in the acute phase. Fecal 16s sequencing showed no differences in bacterial diversity in the acute phase of stroke. Predictive modeling indicated that markers of gut permeability were associated with acute sensory-motor impairment and infarct volume. Conclusions These data show that extensive leakiness of the gut barrier is associated with severe post-stroke disability and suggest that reinforcing this barrier may improve stroke outcomes.

Toxic excess of biologically active substances named middle molecules (MM), which include byproducts of normal and altered metabolism, products of inflammation and oxidation, bacterial remnants, antibodies and immunoactive substances, plays an important role in pathogenesis of gallbladder diseases and biliary autonomous viscero-visceral cardioneuropathy (BAVVCNP). In order to assess activity of the endogenous intoxication syndrome secondary to BAVVCNP, we examined 20 patients with coronary heart disease to determine the levels of MM in the blood (total and at 238, 254, 266, and 280 nm waves); the levels of MM in urine (at 238, 254, 266, 282, 288, and 310 nm waves) with calculation of aromaticity index (MM 238/280), peptide-nucleotide index (MM 238/266), distribution index (MM 280/254), and L-arginine, and nitrites of the urine. The results were statistically processed. It was revealed that in case of BAVVCNP the severity of the endogenous intoxication syndrome was higher for all specific parameters of endotoxicosis, and especially for the total level of MM in blood (0.77 ± 0.13 units vs. 0.46 ± 0.13 units, p = 0.08), the MM level at 238 nm wave (1.53 ± 0.55 vs. 0.49 ± 0.06, p = 0.08) and hydrophilic MM level in the urine at 288 nm long waves (0.72 ± 0.12 vs. 0.40 ± 0.11, p = 0.05) and 310 nm (0.27 ± 0.08 vs. 0.10 ± 0.03, p

Endothelial dysfunction (ED) is a key feature of diabetes and is a major cause of diabetic vasculopathy. Diabetic patients who also exhibit hyperlipidaemia suffer from accelerated vascular complications. While the deleterious effects of high glucose levels (HG) and hyperlipidaemia alone on ED are well established, the effects of combined hyperlipidaemia and HG have not been thoroughly studied. Therefore, the current study examines whether HG and hyperlipidaemia exert synergistic ED, and explores the mechanisms underlying this phenomenon. We applied multi‐disciplinary approaches including cultured HUVECs and HMEC‐1 as well as knockout mice CByJ.129S7(B6)‐Ldlrtm1Her/J (LDLR−/−) to investigate the mechanisms underlying combined HG and hyperlipidaemia‐induced ED. Incremental doses of glucose in the presence or absence of OxLDL were added to HUVECs and HMEC‐1. After 5 days, the status of nitric oxide (NO) and endothelin (ET)‐1 systems as well as their signal transduction were assessed using Western blot, ELISA and immunoreactive staining. The effects of chronic combination of HG and hyperlipidaemia on endothelial integrity and function as well as alterations in circulatory NO and ET‐1 systems were examined in knockout mice LDLR−/− and their wild‐type. HUVEC cells exposed to HG and OxLDL displayed enhanced ET‐1 production, more than HG or OxLDL when added alone. Overproduction of ET‐1 stems from up‐regulation of endothelin converting enzyme (ECE)‐1 as observed under these conditions. In contrast, combination of HG and OxLDL dramatically decreased both total endothelial NO synthase (eNOS) by 60%, and activated eNOS (peNOS) by 80%. Moreover, NRF2 decreased by 42% and its active form (pNRF2) by 56%, as compared to baseline. Likewise, ETB levels decreased by 64% from baseline on endothelial cells. Furthermore, diabetic LDLR−/− mice displayed a higher blood pressure, plasma triglycerides, cholesterol, ET‐1 and NO2/NO3 levels, when compared with normoglycemic LDLR−/− and BALB mice. Combined hyperglycaemia and hyperlipidaemia activates the ET system and attenuates the nitric oxide system with the Nrf2 signalling pathway. These findings suggest that perturbations in these paracrine systems may contribute to ED.

Introduction: Endothelial dysfunction is an imbalance in bioavailability of endothelium-derived relaxing (Nitric Oxide) and contracting factors (Endothelin). Studies have shown that NO has antiatherogenic property as it inhibits vascular smooth muscle contraction and proliferation, platelet aggregation and leukocyte adhesion. On the other hand, Endothelin-1 causes proliferation and vasoconstriction of myocytes resulting in elevated vascular tone thereby contributing to endothelial dysfunction. This dysfunction is a well-established response to cardiovascular risk factors and precedes the development of atherosclerosis. As a result, status of an endothelial dysfunction may reflect the propensity to develop atherosclerotic disease and may serve as a marker of an unfavourable cardiovascular prognosis. Materials and Methods: 50 cases of angiographically proven ischemic heart disease and 50 age and sex matched patients with no evidence of ischaemic heart disease on angiography were selected from G.B Pant Hospital, New Delhi, India. Serum levels of Endothelin were estimated by sandwich ELISA and nitric oxide levels by modified Griess reaction. Results: Serum levels of Endothelin were raised while nitric oxide levels were significantly reduced (p=0.049) in the cases as compared to controls. The mean plasma nitric oxide level in the study group (cases) was 23.51±13.48 µM and in the control group was 29.35±15.73 µM. The difference between the two was significant (p=0.049*). The mean plasma endothelin level in the study group was 3.04±1.37fmol/ml and in the control group was 2.95±1.70 fmol/ml. The difference between the two was not significant (p = 0.764). Conclusion: Higher Endothelin-1 and lower NO levels in cases suggest their role in causing endothelial dysfunction in ischemic heart disease patients. However, larger sample size is required to assess the role of Endothelin as a biomarker of endothelial dysfunction in patients of ischemic heart disease.

The purpose of this study was to investigate changes in plasma endothelin, platelet granule membrane protein and anticoagulant protein. In addition, the mechanism of action between blood stasis syndrome of chronic renal failure (CRF) and granule membrane protein was analyzed, and the relationship between activation release detection technology and blood stasis syndrome was discussed. There were significant differences in endothelin (ET), granule membrane protein-140 (GMP-140) and ceruloplasmin (CP) between the group with severe CRF and the group with mild CRF (P < 0.01). The blood stasis syndrome of CRF was positively correlated with ET and GMP-140 and negatively correlated with CP, which indicated that ET, GMP-140 and CP were some of the objective indexes for the diagnosis and treatment of CRF. Based on the theory of the treatment of CRF with a combination of traditional Chinese and Western medicine at the molecular level, this paper provides a new basis for the treatment of CRF with blood stasis syndrome.

Objective To observe the anti-hypertensive effect of time acupuncture on primary hypertension so as to provide the therapeutic regimen for the treatment of primary hypertension. Methods A total of 120 patients with primary hypertension were randomized into a western medication group and an acupuncture-medication group, 60 cases in each one. In the western medication group, levoamlodipine maleate tablets were prescribed for oral administration. In the acupuncture-medication group, on the base of the treatment as the western medication group, time acupuncture was combined in the period of a day from 7:00 a.m. to 9:00 a.m. The duration of treatment was 4 weeks in the two groups. Before and after treatment, blood pressure, serum endothelin (ET) and nitrious oxide (NO) were measured successively and the clinical therapeutic effect was evaluated. Results (1) Blood pressure: the systolic and diastolic pressure after treatment were all lower than that before treatment in the two groups, indicating statistical differences (all P Conclusion The combined treatment of western medication and time acupuncture (7:00 am to 9:00 am) achieves better effect on primary hypertension as compared with simple western medication and its anti-hypertensive effect is probably related to the decrease of ET and the increase of NO.

BACKGROUND Diabetic nephropathy (DN) is the main cause of chronic kidney disease and end-stage renal disease worldwide. Although available clinical trials have shown that endothelin receptor (ER) antagonists may be a novel and beneficial drug for DN, no consistent conclusions regarding their sufficient effectiveness and safety for patients with DN have been presented. AIM To assess the effectiveness and safety of ER antagonists among patients with DN. METHODS The EMBASE, PubMed, MEDLINE, Cochrane, and ClinicalTrials.gov databases were searched without any language restrictions. Relative risks with 95% confidence intervals (CIs) for dichotomous data and mean differences or standardized mean difference with 95%CIs for continuous data were calculated using Review Manager 5.3 software. Publication bias was assessed using Egger’s test with Stata/SE software. RESULTS We enrolled seven studies with six data sets and 5271 participants. The ER antagonists group showed a significantly greater reduction in albuminuria and more patients with 40% reduction in urinary albumin-to-creatinine ratio than the control group (P < 0.0001 and P = 0.02, respectively). Subgroup analysis for reductions in estimated glomerular filtration rate (eGFR) showed that for the middle-dosage subgroup, the ER antagonists group exhibited lower eGFR reduction than the control group (P < 0.00001; mean difference, 0.70 95%CI: 0.66, 0.74). Moreover, significant reductions in systolic and diastolic blood pressure were observed in the invention group. CONCLUSION ER blockades combined with angiotensin converting enzyme inhibitor /angiotensin II type 1 receptor blockers may be an effective treatment to lower blood pressure and reduce proteinuria in DN with declined eGFR. However, attention should be given to adverse events, including cardiac failure, anemia, and hypoglycemia, as well as serious adverse events.

Aim To study the association between concentrations of endothelial dysfunction (ED) markers and arterial hypertension (AH) in people who were exposed to long-term action of “low-dose” ionizing radiation.Material and methods The study subjects were men of middle age (45–55 years) who were workers of the Siberian Integrated Chemical Plant with the length of service on the shop floor of at least 5 years. The subjects were divided into the main group (n=96) consisting of workers with grade 1-2 AH and the control group (n=48) consisting of arbitrarily healthy workers. Both groups contained workers who had been exposed to long-term occupational low-intensity irradiation (γ-radiation) and those not exposed to this irradiation. The study evaluated risk factors for cardiovascular diseases, presence of concomitant diseases, blood biochemistry (concentrations of glucose, high-sensitivity C-reactive protein (hsCRP), total cholesterol, low-density lipoproteins, high-density lipoproteins, triglycerides, creatinine, and ED markers, including endothelin, angiotensin II, von Willebrand factor, C-type natriuretic peptide, tissue plasminogen activator, tumor necrosis factor α (TNF-α), and homocysteine, major clinical data, total dose of external irradiation, and the content of 239Pu in the body.Results AH was associated primarily with excessive body weight and severity of atherogenic dyslipidemia and homocysteinemia. Higher plasma concentrations of TNF-α and a tendency to increasing hsCRP in the AH group, as distinct from the control group of arbitrarily healthy men, indicated a proinflammatory shift. The ED markers were related with clinical data of AH patients and associated with the lipid profile and increased blood concentrations of inflammatory mediators. The radiation exposure did not change the ED marker array in AH patients, which did not allow recommendation of the studied plasma indexes for detection of vascular endothelial injury in workers with AH of the Siberian Integrated Chemical Plant.Conclusion The study results evidenced the absence of adverse effects of long-term occupational exposure to low-intensity radiation on the vascular endothelium as evaluated by ED markers. In men aged 45–55 years, AH was associated primarily with excessive body weight, homocysteinemia, and atherogenic dyslipidemia.

Background Intestinal ischemia is a highly morbid and mortal condition with no specific treatment. The present study aimed to investigate the effects of cyclooxygenase (COX) inhibition synchronized with nitric oxide (NO) release and endothelin (ET) receptor blockade on oxidative stress, inflammation, vasoconstriction, and bacterial translocation which occur during ischemia-reperfusion (I/R) injury in in-vivo rat intestinal I/R model. Materials and methods 36 male Wistar rats were randomly divided into six groups (n = 6). Superior mesenteric artery blood flow (SMABF) was recorded; SMA was occluded for 30 min; SMABF was re-recorded at the beginning of the reperfusion phase. Rats were sacrificed after the reperfusion period of 60 min. Blood and tissue samples were obtained. Acetylsalicylic acid (ASA), NO-ASA, flurbiprofen (FLUR), and Tezosentan (TS) were administered 15 min after ischemia. Histopathological examination, bacterial translocation, and biochemical analysis were performed in plasma and tissue samples. Results SMABF difference, mean Chiu's score and bacterial translocation were increased in the I/R group and decreased in the treatment groups. Plasma LDH, transaminases, intestinal fatty acid-binding protein (I-FABP), TNF-α, ICAM-1, interferon-gamma (IFN-Ɣ) and proinflammatory cytokine panel; tissue lipid peroxidation, MPO, xanthine oxidase (XO), NO, NF-kB levels and the expression of TNF-α were significantly elevated in the I/R group and markedly decreased in the treatment groups. The tissue antioxidant status was decreased in the I/R group and increased in the treatment groups. Conclusion It is suggested that NO-ASA, TS, and FLUR can be introduced as promising therapeutics to improve intestinal I/R injury. Institutional protocol no 2018-29-05 (Animal Experimentations Ethics Committee, Hacettepe University).

The G protein-coupled estrogen receptor 1 (GPER1) mediates rapid estrogenic signaling. We recently reported that activation of GPER1 in the renal medulla evokes endothelin-1-dependent natriuresis in female, but not male, rats. However, the involvement of the ET receptors, ETA and ETB, underlying GPER1 natriuretic action remain unclear. In this study, we used genetic and pharmacologic methods to identify the contributions of ETA and ETB in mediating this female-specific natriuretic effect of renal medullary GPER1. Infusion of the GPER1-selective agonist G1 (5 pmol/kg per minute) into the renal medulla for 40 minutes increased Na+ excretion and urine flow in anesthetized female ETB-deficient (ETB def) rats and littermate controls but did not affect blood pressure or urinary K+ excretion in either group. Pretreatment with the selective ETA inhibitor ABT-627 (5 mg/kg, intravenous) abolished G1-induced natriuresis in ETB def rats. To further isolate the effects of inhibiting either receptor alone, we conducted the same experiments in anesthetized female Sprague-Dawley (SD) rats pretreated or not with ABT-627 and/or the selective ETB inhibitor A-192621 (10 mg/kg, intravenous). Neither antagonism of ETA nor antagonism of ETB receptor alone affected the G1-induced increase in Na+ excretion and urine flow in SD rats. However, simultaneous antagonism of both receptors completely abolished these effects. These data suggest that ETA and ETB receptors can mediate the natriuretic and diuretic response to renal medullary GPER1 activation in female rats. SIGNIFICANCE STATEMENT: Activation of G protein-coupled estrogen receptor 1 (GPER1) in the renal medulla of female rats evokes natriuresis via endothelin receptors A and/or B, suggesting that GPER1 and endothelin signaling pathways help efficient sodium excretion in females. Thus, GPER1 activation could be potentially useful to mitigate salt sensitivity in females.

Background. Endothelin (ET) is one of the most significant regulators of the functional state of vascular endothelium. ET‑1 is the principal cardiovascular isoform of the endothelin system. ET‑1 has both inflammatory and proliferative affects and contributes to pathogenic processes in the cardiovascular system. In diabetes, the rise of glucose concentration effects the formation of ET‑1. The aim of the work was to study the content of ET‑1 in the blood of patients with diabetes treated with various hypoglycemic agents. Material and methods. The amount of ET‑1 was evaluated via ELISA in 103 individuals: 17 healthy volunteers and 86 patients with diabetes. To determine the concentration of ET‑1 the endothelin (1-21) EIA kit (Biomedica) was used. Glycated hemoglobin wasdetermined using one HbA1c FS kit — DiaSys Diagnostic Systems. Results. The average level of endothelin in the blood of patients with diabetes was 0.536±0.047 fmol/ml vs. control — 0.118±0.017 fmol/ml. We did not observed changes of ET‑1 levels during monotherapy with metformin or insulin. At metformin + insulin + dapagliflosin, insulin + metformin and sulfonylurea + metformin but not DPP‑4 inhibitor + metformin combinations (T2D) there was decrease of ET‑1 level in the blood. It is of interest that DPP‑4 inhibitor + metformin caused significant increase (0.767±0.043 fmol/ml) of ET‑1 concentration. Conclusion. Thus, with combination therapy, except pair DPP‑4 inhibitor + metformin, the level of ET‑1 in the blood of patients with diabetes decreased significantly more than with monotherapy.

Hypertension and kidney involvement are common in patients with autoimmune disease. Sodium intake is linked to hypertension in both human and animal studies. Evidence suggests that dietary salt may be an important environmental factor that promotes autoimmune activity. Therefore, we hypothesized that a long-term high-salt diet would accelerate the progression of autoimmunity, hypertension, and albuminuria during systemic lupus erythematosus (SLE), an autoimmune disease that predominantly affects young women and has a high prevalence of hypertension and renal disease. To test this hypothesis, an established experimental model of SLE (female NZBWF1 mice) that develops hypertension and renal disease was used. SLE mice were fed a high-salt (4% NaCl) or normal (0.4% NaCl) diet for 24 wk beginning at 10 wk of age and ending at 34 wk of age, a time by which female NZBWF1 mice typically have hypertension and exhibit signs of renal disease. Plasma anti-dsDNA autoantibodies were measured as an indicator of active SLE disease, and urinary albumin was monitored longitudinally as a marker of renal disease. Arterial pressure was measured in conscious, freely moving mice at 34 wk of age. Urinary endothelin-1 (ET-1) excretion, renal endothelin A and B receptor protein expression, and renal mRNA expression of NOS1, NOS2, NOX2, MCP-1, TNF-α, serum- and glucocorticoid-regulated kinase 1, and interleukin-2 (IL-2) were assessed to determine the impact on gene products commonly altered by a high-salt diet. SLE mice fed a high-salt diet had increased circulating autoantibodies, but the high-salt diet did not significantly affect albuminuria or arterial pressure. Urinary ET-1 excretion was increased, whereas renal endothelin A receptor and IL-2 expression were decreased in response to a high-salt diet. These data suggest that a chronic high-salt diet may not accelerate cardiovascular and renal consequences commonly associated with SLE.