Plasma Endothelin-1 Concentrations Research Articles

#50 The relationship between pre-dialysis plasma endothelin-1 and the intradialytic decline in blood pressure

Abstract Background and Aims Endothelin-1 (ET-1), a potent vasoconstrictor, may play an important role in the blood pressure (BP) response to hemodialysis (HD). Patients receiving maintenance HD have higher concentrations of plasma endothelin-1 than non-HD patients with advanced chronic kidney disease or patients receiving peritoneal dialysis. We wished to examine the association between the pre-HD level of ET-1 and the magnitude of intradialytic systolic BP decline. Methods Data was collected in a prospective study of 50 patients receiving maintenance HD admitted to Brigham and Women's Hospital in Boston, MA, USA. BP was measured before and every 15 min during a single HD session using an automated BP cuff. The systolic BP decline was calculated as the pre-HD minus the lowest intradialytic systolic BP. Blood samples were collected pre-HD. Patients with missing data, HD <3 h, or pre-dialysis BP <85/55 mmHg were excluded from the analysis (n = 8). Spearman's rho (ρ) was used to assess the correlation between pre-HD ET-1 and intradialytic systolic BP decline. Results Of the 42 included patients, 17 were females, median age 62 [25th, 75th percentile: 50, 70] years. The median HD duration was 232 [210, 242] min and median ultrafiltration was 2.1 [2, 3] L. Before HD, the median ET-1 was 2.4 [1.9, 3.0] pg/mL, the median systolic BP was 141 [119, 167] mmHg, and the median diastolic BP was 68 [63, 84] mmHg. A moderate negative correlation was observed between the baseline ET-1 and the intradialytic decline in systolic BP (ρ = –0.34, P = 0.03). This correlation was stronger in patients with baseline systolic BP >120 mmHg (ρ = –0.51, P = 0.004, n = 30) and much stronger in patients with baseline systolic BP >140 mmHg (ρ = –0.66, P = 0.001, n = 21). Almost all cases (8 out of 9) with an intradialytic decline in systolic BP of >50 mmHg occurred in patients with baseline ET-1 below the pre-HD median level. Conclusions Our results suggest that hospitalized patients with pre-HD systolic BP >140 mmHg and lower baseline ET-1 may be more likely to experience larger intradialytic declines in systolic BP. Whether measurement of pre-HD ET-1 could help identify hypotensive-prone patients requires further investigation in larger studies.

Association of Helicobacter Pylori Infection with Endothelial Dysfunction in Metabolic Syndrome

Background: Metabolic risk factors play a critical role in metabolic syndrome (MetS), and endothelial dysfunction is important in its development. On the other hand, Helicobacter pylori (H. pylori) infection has an essential role in MetS. The goal of present study was to evaluate the effect of H. pylori infection on endothelial dysfunction in MetS patients.
 Methods: Based on the International Diabetes Federation (IDF) criteria, 80 MetS patients (59 females and 21 males, mean age: 48.94 ± 10.00 years) were selected. Plasma samples were assayed for H. pylori IgG using the ELISA method. Endothelial function was also evaluated by measuring plasma concentrations of endothelin-1 (ET- 1), E-selectin, and intracellular adhesion molecule (ICAM-1) using ELISA method. Also, NO2 −− and NO3 −− concentrations were measured by Griess method.
 Results: Fifty patients (62.5%) had H. pylori infection. Plasma concentrations of ET-1, NO2−−, and NO3−− were significantly higher in MetS patients with positive H. pylori infection than in MetS patients with negative H. pylori infection (ET-1: 2.92 ± 2.33 vs 1.9 ± 1.4 pg/ml; P = 0.037; NO2 −−:19.46 ± 7/11 vs 15.46 ± 4.56 μM; P = 0.003; NO3 −−: 20.8 ± 10.53 vs 16.85 ± 6.03 μM, P = 0.036). However, plasma concentrations of ICAM-1 and E-selectin did not show any significant difference in the two groups.
 Conclusion: The results showed a relationship between H. pylori infection and endothelial dysfunction. Helicobacter pylori infection can lead to atherosclerosis by causing chronic inflammation and affecting the factors contributing to the MetS.

Abstract 17167: Uncontrolled Hypertension Increases Endothelin-1-Induced Contractile Response of Coronary Microvasculature Both Before and After Cardioplegia and Cardiopulmonary Bypass

Introduction: Hypertensive patients undergoing cardiopulmonary bypass (CPB) have worse clinical outcomes, and coronary microvascular dysfunction may play a role. Endothelin-1 (ET-1), a vasoactive biopeptide, is increased in cardiomyocytes during the hypertrophic response to hypertension and in patients following CPB. Differential effects of hypertension on coronary microvascular reactivity and molecular signaling pathways following CPB have yet to be elucidated. Aims: This study investigated the effects of well-controlled and uncontrolled hypertension on CPB-induced changes in coronary microvascular vasoconstriction to ET-1 and associated signaling using unique in vitro microvascular reactivity studies, RNA deep sequencing, and established molecular methods. Methods: Coronary microvessels (<200um) were harvested from atrial samples from patients with no hypertension (NH), well-controlled hypertension (CH), and uncontrolled hypertension (UH) before and after CPB. In vitro contractile response to ET-1 was assessed using video microscopy. Protein expression and receptor localization were measured using immunoblotting and immunohistochemistry, respectively. Enzyme-linked immunosorbent assay was used to quantify plasma concentration of ET-1. Results: Pre-CPB contractile response of coronary microvessels to ET-1 in UH was increased compared to NH or CH (p <0.05). Post-CPB contractile response was impaired overall (p <0.05). Between groups, contractile response in CH and NH was comparable while response in UH was higher (p <0.05). Plasma ET-1 increased post-CPB (p = 0.18). Total protein levels and localization of ET A R and ET B R were unchanged post-CPB. Conclusions: While CPB overall blunted vasomotor contractile response of coronary microvessels to ET-1, UH was associated with relatively increased vasoconstriction compared to CH and NH. Changes in plasma ET-1, ET A R and ET B R levels or localization did not contribute to these effects.

Enhanced external counterpulsation, focusing on its effect on kidney function, and utilization in patients with kidney diseases: a systematic review.

Enhanced external counterpulsation (EECP) is provided by a noninvasive device positively affecting cardiovascular function via mechanisms called diastolic augmentation and systolic unloading. The renal aspects of EECP therapy have not been extensively investigated. To assess the effect of EECP on renal function and to determine the application in patients with kidney disease. MEDLINE, EMBASE, SCOPUS, and Cochrane CENTRAL databases were searched for all studies involving EECP treatments. The title and abstract of all searched literatures were screened, and those focusing on renal outcome or conducting in kidney disease patients were selected. Eight studies were included in the qualitative analysis. EECP increases stroke volume, mean arterial pressure, renal artery blood flow, renal plasma flow, glomerular filtration rate (GFR), plasma atrial natriuretic peptide, urine volume, and urinary sodium chloride excretion, but reduces the plasma concentration of renin and endothelin-1 in healthy subjects. A single session of EECP after radioactive contrast exposure could provide increased contrast clearance, and this reduces contrast-induced kidney injury in patients, irrespective of previous kidney function. Thirty-five-hour sessions of EECP treatment were illustrated to increase long-term estimated GFR in patients with chronic angina and heart failure. In cirrhotic patients, EECP fails to improve GFR and renal vascular resistance. EECP device could maintain blood pressure, decrease angina symptoms, and increase cardiac perfusion in hemodialysis patients. EECP treatment potentially increases renal perfusion and prevents kidney injury in several conditions. EECP possibly provides beneficial effects on hemodynamics and cardiac function in hemodialysis patients.

Myoglobin-driven ET-1 production and downstream activation of TRPC3- but not TRPC6-dependent vasoconstriction contributes to rhabdomyolysis-induced AKI

Acute kidney injury (AKI) is the most severe and life-threatening complication of rhabdomyolysis, with 10-40% of patients developing some form of kidney insufficiency within days. Experimental evidence indicates that renal vasoconstriction plays a significant role in the pathophysiology of rhabdomyolysis-induced AKI. Rodents subjected to glycerol-induced rhabdomyolysis exhibited increased plasma concentrations of endothelin-1 (ET-1). Treating glomerular mesangial cells with myoglobin has also been shown to increase the cellular production of ET-1. The downstream effectors of ET-1-induced vasoconstriction are smooth muscle Ca2+ permeable transient receptor potential canonical (TRPC) channels. There are seven members of the TRPC gene family (TRPC1-7). Whereas TRPC2 and 7 are absent, TRPC1, 3, 4, 5, and 6 are expressed in renal vessels, with TRPC3 predominant. TRPC3, TRPC6, and TRPC7 are highly homologous. Although the ET system is known to be associated with rhabdomyolysis-induced AKI, the function of renal vascular ion channels in the disease is unclear. Here, we investigated the involvement of TRPC3 and TRPC6 in glycerol-induced rhabdomyolysis in rats. ET-1 production is increased in myoglobin-treated epithelial cells, the primary source of renal ET. Rhabdomyolysis also increased renal ET-1 production, decreased renal blood flow (RBF), and increased renal vascular resistance, effects attenuated by ET receptor and TRPC channel blocker Pyr3. Furthermore, we used TRPC3 and TRPC6 knockout (KO) rats to support the pharmacological approaches. Basal day and night arterial pressure, heart rate, GFR, plasma creatinine, and BUN were unchanged in WT vs. KO rats. Twenty-four h rhabdomyolysis led to comparable increases in urinary ET-1 production in WT and KO rats. However, rhabdomyolysis-induced decreases in GFR, elevations in BUN, and plasma creatinine were all attenuated in the TRPC3 but not TRPC6 KO rats. Similarly, morphological kidney damage (tubular necrosis, casts, and dilatation) was mitigated in the TRPC3 KO with no protection offered by the KO of TRPC6 channels. Together, our data suggest that myoglobin-driven ET-1 production and downstream activation of TRPC3- but not TRPC6-dependent vasoconstriction contributes to rhabdomyolysis-induced AKI. American Heart Association Predoctoral Fellowship This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Comprehensive assessment of the dynamics of angiogenesis in patients with psoriasis treated with methotrexate

Background. Evaluation of the severity of pathological angiogenesis in patients with psoriasis can be considered as a promising direction for monitoring the activity of the disease and the effectiveness of systemic therapy.
 Aims. Evaluation of interconnections between indicators of angiogenesis in the skin and nail bed of psoriasis patients with clinical characteristics of disease course and therapeutic response to the use of methotrexate by a comprehensive study of the morphometric data dynamics of videodermatoscopy in vascular bed of the skin, the severity of blood flow in the dermis and nail bed during ultrasonic power dopplerography and plasma concentrations of vascular endothelial growth factor (VEGF) and endothelin-1 (En-1).
 Materials and methods. Work is based on the data analysis from a survey of 82 patients with moderate to severe psoriasis vulgaris in the acute stage, who were first prescribed methotrexate in the form of subcutaneous injections at a dose of 1015 mg per week in combination with folic acid 5 mg per week. Before treatment and three months after the start of methotrexate therapy, all patients underwent videodermatoscopy with dimension of the density and size of dilated skin capillaries, ultrasonography of psoriatic plaques and nail bed of affected nails and measurement of doppler blood flow parameters and concentration of VEGF and En-1 in blood plasma.
 Results. A direct correlation was established between the average diameter of dilated skin capillaries (vascular glomeruli), the degree of increased blood flow in the doppler energy study of psoriatic plaques skin area and the plasma concentration of VEGF and En-1 and values of PASI, BSA, sPGA and DLQI indices, as well as the severity of doppler blood flow of the nail bed and NAPSI index (r = 0.210.73). Under the influence of methotrexate treatment, a decrease in diameter and density of vascular glomeruli (16.2 [12.9; 22.5] versus 25.2 [17.1; 33.7] m before treatment (p = 0.002) and (44.6 [31.6; 53.3] versus 53.5 [34.6; 67.4] before treatment (p = 0.04), respectively), the degree of blood flow in area of psoriatic plaques and the concentration of VEGF and En-1 (12.5 [6.7; 26.8] pg/ml versus 19.5 [4.7; 48.1] pg/ml after treatment (p = 0.002) and En-1 (168.2 [97; 319] versus 274.5 [146; 439] pg/ml(p = 0.003), respectively) was observed.
 Conclusions. Studied indicators of angiogenesis can be used as additional criteria for assessing the degree of activity and achieving clinical improvement/remission during systemic therapy in patients with moderate and severe psoriasis.

Clinical significance of plasma markers of angiogenesis in patients with psoriasis

BACKGROUND: Currently, many researchers attach great importance in psoriasis pathogenesis to hyperproduction of vascular endothelial growth factor (VEGF) and endothelin-1, which leads to increased angiogenesis in dermis and mediates processes of immune inflammation. At the same time, possibility of using these angiogenesis biomarkers as additional indicators of immune inflammation activity and disease activity has been poorly studied.
 AIMS: the purpose of the study was to assess the relationship between serum concentrations of VEGF and endothelin-1, structural changes in the capillary bed according to videodermatoscopy, and severity and prevalence of skin lesions in patients with psoriasis, duration of disease, presence of nail lesions, synovitis, enthesitis and spondylitis, as well as concomitant diseases of the cardiovascular system.
 MATERIALS AND METHODS: The work is based on examination data analysis of 132 patients with moderate and severe psoriasis vulgaris for the period 20202022. Patients were determined the levels of VEGF and endothelin-1 in blood plasma and underwent digital dermatoscopy to study the characteristics of angiogenesis vascular loci (vascular glomeruli) in the papillary dermis. All psoriasis patients with symptoms of musculoskeletal system lesions were examined by a rheumatologist, which was supplemented by ultrasonography of the joints.
 RESULTS: According to the results of enzyme immunoassay, it was found that the examined patients had an increased concentration of VEGF and endothelin-1 in blood plasma compared to the control group (respectively 19.5 [4.7; 48.1] pg/ml and 274.5 [146; 439] pg/ml versus 5.2 [0.5; 9.8] pg/ml and 96.5 [32; 188] pg/ml, p=0.004 and p=0.002). It was found that an increase in plasma concentrations of VEGF and endothelin-1 correlates with an increase in density of vascular glomeruli (respectively r=0.65 and r=0.74) and the average diameter of the glomerulus (respectively r=0.58 and r=0.56). A more pronounced increase in plasma concentrations of VEGF and endothelin-1 in patients with psoriasis was noted in patients with psoriatic arthritis and in the presence of synovitis. VEGF levels were higher in patients with severe psoriasis and in patients with nail lesions. Correlation analysis showed the strongest relationship between VEGF concentration and DAS28, DLQI, PASI and NAPSI values, as well as endothelin-1 concentration and PASI, BSA and DLQI values.
 CONCLUSIONS: The work showed that the plasma concentration of VEGF and endothelin-1 characterizes the degree of angiogenesis expression in the psoriasis pathogenesis, reflects morphology changes in capillaries of the affected skin, and can also be used as a marker of severe psoriasis and an increased risk of developing damage to the nails and synovial membranes of the joints.

Deleterious effect in endothelin receptor–mediated coronary artery smooth muscle contractility in high-salt diet rats

Background and aimsHigh-salt diet has been suggested to increase the risk of heart disease. However, the mechanisms underlying coronary artery tension dysfunction caused by high-salt diet are unclear. Previous studies have shown that coronary artery spasm is often induced by endothelin-1 (ET-1) and thromboxane, leading to myocardial ischemia, while the store-operated Ca2+ entry (SOCE) function of coronary smooth muscle is very important in this process. Methods and resultsTension measurements of endothelium-denuded coronary artery ring segments showed that vasocontraction induced by U46619, ET-1, orSTIM1/Orai1-mediated SOCE was significantly lower in 4% high-salt diet rats than in control rats fed a regular diet. The results of western blotting and immunohistochemistry assays showed lower expression levels of endothelial receptors ETA and ETB, STIM1 and Orai1 in coronary artery of high-salt intake rats compared with control rats. Fibrosis was observed by using Masson's trichrome staining and picrosirius red staining. The plasma ET-1 concentration in high-salt diet rats was significantly higher than that of controls. The interventricular septum and posterior wall of high-salt diet rats were significantly thickened. ConclusionOur findings indicated that coronary artery tension was significantly decreased in 4% high-salt diet rats and that this decrease may be due to the change of endothelin receptor and its downstream pathway SOCE related protein expression in coronary artery. Coronary fibrosis was observed in rats fed with high-salt diet. This study provides potential mechanistic insights into high-salt intake–induced heart disease.

Dual pathway inhibition as compared to acetylsalicylic acid monotherapy in relation to endothelial function in peripheral artery disease, a phase IV clinical trial.

ObjectiveDual pathway inhibition (DPI) by combining acetylsalicylic acid (ASA) with low-dose rivaroxaban has been shown to reduce cardiovascular events in patients with peripheral arterial disease (PAD) when compared to ASA monotherapy. A potential explanation is that inhibition of factor Xa improves endothelial function through crosstalk between coagulation and inflammatory pathways, subsequently attenuating the occurrence of cardiovascular events. We hypothesize that the addition of rivaroxaban to ASA in PAD patients leads to improved endothelial function.DesignAn investigator-initiated, multicentre trial investigating the effect of DPI on endothelial function.MethodsPatients, diagnosed with PAD, were enrolled in two cohorts: cohort A (Rutherford I-III) and cohort B (Rutherford IV-VI). Participants received ASA monotherapy for a 4-weeks run-in period, followed by 12 weeks of DPI. Macro- and microvascular endothelial dysfunction were studied by measuring carotid artery reactivity upon sympathetic stimulus and by measuring plasma endothelin-1 concentrations, respectively. All measurements were performed during the use of ASA (baseline) and after 12 weeks of DPI.Results159 PAD patients (111 cohort A, 48 cohort B) were enrolled. Twenty patients discontinued study drugs early. Carotid artery constriction upon sympathetic stimulation at baseline (ASA) and after 12 weeks of DPI was similar in the total group, 22.0 vs. 22.7% (p = 1.000), and in the subgroups (Cohort A 22.6 vs. 23.7%, p = 1.000; cohort B 20.5 vs. 20.5%, p = 1.000), respectively. The mean concentration of plasma endothelin-1 at baseline and after 12 weeks of DPI did not differ, 1.70 ± 0.5 vs. 1.66 ± 0.64 pmol/L (p = 0.440) in the total group, 1.69 ± 0.59 vs. 1.62 ± 0.55 pmol/L in cohort A (p = 0.202), and 1.73 ± 0.53 vs. 1.77 ± 0.82 pmol/L in cohort B (p = 0.682), respectively.ConclusionMacro- and microvascular endothelial dysfunction, as reflected by carotid artery reactivity and plasma endothelin-1 concentrations, are not influenced in PAD patients by addition of low-dose rivaroxaban to ASA monotherapy for 12 weeks.Trial registrationhttps://clinicaltrials.gov/ct2/show/NCT04218656.

Efficacy of catgut-embedding therapy at “five neck points” on cervical spondylotic arteriopathy and effects on hemodynamics: A randomized clinical trial “颈五针”穴位埋线治疗椎动脉型颈椎病疗效及对血流动力学的影响-随机临床试验

ObjectiveTo observe the effect of catgut-embedding therapy at five neck points in the treatment of cervical spondylotic arteriopathy (CSA) and analyze its effects on the hemodynamics of patients with CSA. MethodsUsing the computer randomization method, 72 patients with CSA were divided into a catgut-embedding therapy group (n = 36, none dropped out) and a western medication group (n = 36, none dropped out). In the catgut-embedding therapy group, the therapy was applied to five neck points, i.e. bilateral Jĭngjiājĭ (颈夹脊) at C5, bilateral Jĭngjiājĭ (颈夹脊) at C6, and Dàzhuī (大椎GV14) once a week. One 3-week treatment session was required. In the western medication group, flunarizine hydrochloride 5 mg capsules were administered orally once daily for 3 weeks. Efficacy was assessed before and after 3 weeks treatment using a functional evaluation scale for cervical spondylotic arteriopathy (FS-CSA). Changes in vertebral-basilar arterial hemodynamics, serum nitric oxide (NO) level, and plasma endothelin (ET) level were detected. ResultsEfficacy was assessed when the treatment session was completed. The total efficacy rate was significantly higher in the catgut-embedding therapy group (86.1%) than in the western medication group (61.1%; P < 0.01). The after treatment FS-CSA score was reduced compared with baseline score in both groups (P < 0.05), and the reduction in the catgut-embedding therapy group was superior to that in the Western medication group (P < 0.05). Compared with baseline, the flow velocity and pulsatility index of the bilateral vertebral and basilar arteries increased at each period in both groups (P < 0.05) except for the left systolic velocity of the vertebral artery after treatment. The increase in the catgut-embedding therapy group was greater than that in the western medication group (P < 0.05). After treatment, the serum NO concentration was increased and the plasma ET concentration was reduced compared to baseline in both groups (P < 0.05), while the improvements in the catgut-embedding therapy group were superior to those in the western medication group (P < 0.05). ConclusionThe clinical efficacy in the catgut-embedding therapy group was superior to that in the western medication group. Catgut-embedding therapy at five neck points may effectively improve psychological and functional conditions, promote vertebral basilar arterial supply, and relieve clinical symptoms in patients with CSA.

Intestinal flora and immunity response to different viscous diets in juvenile largemouth bass, Micropterus salmoides

An 8-weeks feeding trial was conducted to estimate the effects of different viscous cellulose on the intestinal flora and health in juvenile largemouth bass (Micropterus salmoides). Four isoproteic and isolipidic experimental diets were formulated (crude protein 42.50%, crude lipid 13.70%) to contain 8% cellulose (control group; 5.14 mPa s), 8% low viscous carboxymethyl cellulose (CMC) with 800 mPa s (Lvs-CMC group; 182.15 mPa s), 8% middle viscous CMC with 2000 mPa s (Mvs-CMC group; 320.48 mPa s) and 8% high viscous CMC with 5000 mPa s (Hvs-CMC group; 440.65 mPa s), respectively. The weight gain rate, specific growth rate, protein efficiency ratio, protein and lipid deposition rate in the CMC groups were dramatically lower than those in the control group, while feed conversion rate showed an opposite result. Plasma diamine oxidase activity, endothelin-1 and lipopolysaccharide concentrations in the Mvs-CMC and Hvs-CMC groups were significantly higher than in the control group, accompanied by a significant down-regulation of Occludin, Caludin-1 and Caludin-4. Intestinal glutathione concentration, superoxide dismutase and catalase activities in the CMC groups were significantly lower than in the control group, accompanied by a significant up-regulation of Keap1 and down-regulation of Nrf2. Moreover, CMC diets dramatically down-regulated the expression levels of IL-10 and TGF-β1. Digesta total short chain fatty acid and acetate concentrations in the CMC groups were dramatically higher than in the control group, while butyrate concentration showed an opposite result. The OTU, Sobs, Shannon and Simpson indices of intestinal flora in the CMC groups were dramatically lower than in the control group. Notably, structural analysis showed that dietary CMC dramatically increased the abundance of C. somerae and P. shigelloides, but reduced the abundance of C. colicanis and C. perfringens. In summary, increasing dietary viscosity adversely affects the intestinal flora structure and diversity, increases acetate/butyrate-producing bacterial ratio and the abundance of pathogenic microorganisms, disrupting intestinal flora homeostasis, impairs mucosa barrier function, induces intestinal inflammation and epithelial cell apoptosis in juvenile largemouth bass. Our findings demonstrate that soluble cellulose is more detrimental to intestinal health and growth in juvenile largemouth bass compared to insoluble cellulose, and the adverse effects of soluble cellulose are mainly caused by its viscosity. Importantly, this study demonstrate that viscosity is the main characteristic of non-starch polysaccharides that are detrimental to the intestinal health of fish.

Endothelin-1 as a novel target for the prevention of metabolic dysfunction with intermittent hypoxia in male participants.

We examined the effect of intermittent hypoxia (IH, a hallmark feature of sleep apnea) on adipose tissue lipolysis and the role of endothelin-1 (ET-1) in this response. We hypothesized that IH can increase ET-1 secretion and plasma free fatty acid (FFA) concentrations. We further hypothesized that inhibition of ET-1 receptor activation with bosentan could prevent any IH-mediated increase in FFA. To test this hypothesis, 16 healthy male participants (32 ± 5 yr, 26 ± 2 kg/m2) were exposed to 30 min of IH in the absence (control) and presence of bosentan (62.5 mg oral twice daily for 3 days prior). Arterial blood samples for ET-1, epinephrine, and FFA concentrations, as well as abdominal subcutaneous adipose tissue biopsies (to assess transcription of cellular receptors/proteins involved in lipolysis), were collected. Additional proof-of-concept studies were conducted in vitro using primary differentiated human white preadipocytes (HWPs). We show that IH increased circulating ET-1, epinephrine, and FFA (P < 0.05). Bosentan treatment reduced plasma epinephrine concentrations and blunted IH-mediated increases in FFA (P < 0.01). In adipose tissue, bosentan had no effect on cellular receptors and proteins involved in lipolysis (P > 0.05). ET-1 treatment did not directly induce lipolysis in differentiated HWP. In conclusion, IH increases plasma ET-1 and FFA concentrations. Inhibition of ET-1 receptors with bosentan attenuates the FFA increase in response to IH. Based on a lack of a direct effect of ET-1 in HWP, we speculate the effect of bosentan on circulating FFA in vivo may be secondary to its ability to reduce sympathoadrenal tone.

C-natriuretic peptide – as an indicator of persistent increase in blood pressure in men with hypertension

Annotation. According to multiple studies hypertension (AH) is a multifactorial disease. It is recognized that one of the key mechanisms of persistent increase in blood pressure (BP) is the imbalance between vasoconstriction and vasodilation and endothelial dysfunction (ED) is one of the leading links in the pathogenesis of AH. The consequence of ED is a persistent vasoconstrictor reaction which results in myocardial remodeling in the form of left ventricular hypertrophy (LVH) and the subsequent development of congestive heart failure (CHF). One of the most important representatives of the group of vasoconstrictor peptides is endothelin-1 (ET-1). It has been previously shown that the polymorphism of the gene encoding it (Lys198Asn) is associated with fluctuations in ET-1 plasma concentration. In this regard, the corresponding changes in plasma levels of one of the most powerful vasodilators – C-natriuretic peptide (CNP) – remain poorly understood. CNP is a direct antagonist of ET-1 which increases in the blood in AH and can be used as a screening method to identify patients with high BP. The aim of the study – improving the detection of men with AH who has persistent long-term elevations in BP by using the plasma level of CNP and taking into account the carrier of polymorphic variants of the ET-1 gene. The study involved 191 men aged 40-60 years: 79 men were from control group, 62 patients with AH and LVH and 50 patients with AH complicated by CHF II-III classes for NYHA. Enzyme-linked immunosorbent assay was used to determine the plasma concentration of CNP. Genotyping of the ET-1 gene was performed using the polymerase chain reaction. Mathematical processing was performed on a personal computer using the standard statistical package STATISTICA 6.0. It is established that plasma CNP levels in men with AH and LVH (5.21±0.11) pmol/ml and in patients with AH and CHF (5.22±0.13) pmol/ml are significantly higher than in control patients (2.35±0.06) pmol/ml (p&lt;0.0001) however did not differ in patients with AH from different groups. The obtained results allowed to calculate the limit level of CNP which is ≥3.37 pmol/ml and can be used for screening detection of males with persistently elevated BP in the survey of large populations. It was found that in patients with AH as in the control group the Lys/Lys genotype and the Lys allele of the ET-1 gene predominate. There was no significant difference in the frequency of ET-1 gene between groups (p&gt;0.05). It should be noted that in patients with AH carrying all polymorphic variants of the ET-1 gene the level of CNP in blood was also significantly higher than in the control group, however in carriers of the Asn allele plasma level of CNP is higher than in individuals with the Lys/Lys genotype in all study groups. So it was investigated that the average plasma concentration of CNP in patients with AH is higher than in the control group which made it possible to establish a limit level of peptide for screening of individuals with persistent long-term elevation of BP. In men of the control group and in patients with AH the carrier of the Asn allele of the ET-1 gene is associated with a higher level of CNP but in all study groups the Lys/Lys genotype and the Lys allele of the ET-1 gene were dominant.

Dual endothelin receptor antagonism increases resting energy expenditure in people with increased adiposity.

Increased adiposity is associated with dysregulation of the endothelin system, both of which increase the risk of cardiovascular disease (CVD). Preclinical data indicate that endothelin dysregulation also reduces resting energy expenditure (REE). The objective was to test the hypothesis that endothelin receptor antagonism will increase REE in people with obesity compared with healthy weight individuals. Using a double blind, placebo-controlled, crossover design, 32 participants [healthy weight (HW): n = 16, BMI: 21.3 ± 2.8 kg/m2, age: 26 ± 7 yr and overweight/obese (OB): n = 16, BMI: 33.5 ± 9.5 kg/m2, age: 31 ± 6 yr] were randomized to receive either 125 mg of bosentan (ETA/B antagonism) or placebo twice per day for 3 days. Breath-by-breath gas exchange data were collected and REE was assessed by indirect calorimetry. Venous blood samples were analyzed for concentrations of endothelin-1 (ET-1). Treatment with bosentan increased plasma ET-1 in both OB and HW groups. Within the OB group, the changes in absolute REE (PLA: -77.6 ± 127.6 vs. BOS: 72.2 ± 146.6 kcal/day; P = 0.046). The change in REE was not different following either treatment in the HW group. Overall, absolute plasma concentrations of ET-1 following treatment with bosentan were significantly associated with kcal/day of fat (r = 0.488, P = 0.005), percentage of fat utilization (r = 0.415, P = 0.020), and inversely associated with the percentage of carbohydrates (r = -0.419, P = 0.019), and respiratory exchange ratio (r = -0.407, P = 0.023). Taken together, these results suggest that modulation of the endothelin system may represent a novel therapeutic approach to increase both resting metabolism and caloric expenditure, and reduce CVD risk in people with increased adiposity.NEW & NOTEWORTHY Findings from our current translational investigation demonstrate that dual endothelin A/B receptor antagonism increases total REE in overweight/obese individuals. These results suggest that modulation of the endothelin system may represent a novel therapeutic target to increase both resting metabolism and caloric expenditure, enhance weight loss, and reduce CVD risk in seemingly healthy individuals with elevated adiposity.

Macitentan attenuates cardiovascular remodelling in infant rats with chronic lung disease

BackgroundCardiovascular impairment contributes to increased mortality in preterm infants with chronic lung disease. Macitentan, an endothelin-1 receptor antagonist, has the potential to attenuate pulmonary and cardiovascular remodelling.MethodsIn a prospective randomized placebo-controlled intervention trial, Sprague–Dawley rats were exposed to 0.21 or 1.0 fraction of inspired oxygen (FiO2) for 19 postnatal days. Rats were treated via gavage with placebo or macitentan from days of life 5 to 19. Alveoli, pulmonary vessels, α-smooth muscle actin content in pulmonary arterioles, size of cardiomyocytes, right to left ventricular wall diameter ratio, and endothelin-1 plasma concentrations were assessed.ResultsFiO2 1.0 induced typical features of chronic lung disease with significant alveolar enlargement (p = 0.012), alveolar (p = 0.048) and pulmonary vessel rarefaction (p = 0.024), higher α-smooth muscle actin content in pulmonary arterioles (p = 0.009), higher right to left ventricular wall diameter ratio (p = 0.02), and larger cardiomyocyte cross-sectional area (p < 0.001). Macitentan treatment significantly increased pulmonary vessel count (p = 0.004) and decreased right to left ventricular wall diameter ratios (p = 0.002). Endothelin-1 plasma concentrations were higher compared to placebo (p = 0.015). Alveolar number and size, α-smooth muscle actin, and the cardiomyocyte cross-sectional area remained unchanged (all p > 0.05).ConclusionThe endothelin-1 receptor antagonist macitentan attenuated cardiovascular remodelling in an infant rat model for preterm chronic lung disease. This study underscores the potential of macitentan to reduce cardiovascular morbidity in preterm infants with chronic lung disease.

Sustained inflammation, coagulation activation and elevated endothelin-1 levels without macrovascular dysfunction at 3 months after COVID-19

IntroductionEndothelial damage and thrombosis caused by COVID-19 may imperil cardiovascular health. More than a year since the WHO declared COVID-19 pandemic, information on its effects beyond the acute phase is lacking. We investigate endothelial dysfunction, coagulation and inflammation, 3 months post-COVID-19. Materials and methodsA cohort study was conducted including 203 patients with prior COVID-19. Macrovascular dysfunction was assessed by measuring the carotid artery diameter in response to hand immersion in ice-water. A historic cohort of 312 subjects served as controls. Propensity score matching corrected for baseline differences. Plasma concentrations of endothelin-1 were measured in patients post-COVID-19, during the acute phase, and in matched controls. Coagulation enzyme:inhibitor complexes and inflammatory cytokines were studied. Results and conclusionsThe prevalence of macrovascular dysfunction did not differ between the COVID-19 (18.6%) and the historic cohort (22.5%, RD −4%, 95%CI: −15–7, p = 0.49). Endothelin-1 levels were significantly higher in acute COVID-19 (1.67 ± 0.64 pg/mL) as compared to controls (1.24 ± 0.37, p < 0.001), and further elevated 3 months post-COVID-19 (2.74 ± 1.81, p < 0.001). Thrombin:antithrombin(AT) was high in 48.3%. Markers of contact activation were increased in 16–30%. FVIIa:AT (35%) and Von Willebrand Factor:antigen (80.8%) were elevated. Inflammatory cytokine levels were high in a majority: interleukin(IL)-18 (73.9%), IL-6 (47.7%), and IL-1ra (48.9%). At 3 months after acute COVID-19 there was no indication of macrovascular dysfunction; there was evidence, however, of sustained endothelial cell involvement, coagulation activity and inflammation. Our data highlight the importance of further studies on SARS-CoV-2 related vascular inflammation and thrombosis, as well as longer follow-up in recovered patients.

Vasoprotective effects hypotensive therapy in patients with coronary heart disease combined with chronic kidney disease stage 2-3 after coronary stenting

Aim To study the condition of coronary vasculature by data of coronarography (CG) in patients with chronic ischemic heart disease (IHD) and arterial hypertension (AH) associated with stage 2-4 chronic kidney disease (CKD) and to evaluate the effect of a 12-week complex treatment with perindopril or with a combination of perindopril/amlodipine on changes in vascular wall stiffness, endothelial function, and structure and function parameters in this patient category after coronary stenting.Material and methodsr This study included 87 patients with chronic IHD and AH associated with stage 2-3 CKD for whom CG was performed due to ineffectiveness of the antianginal therapy. The patients were divided into three subgroups: subgroup 1 included 28 patients who received a conservative treatment with perindopril 10 mg/day; subgroup 2 consisted of 25 patients who underwent coronary stenting and were prescribed perindopril; subgroup 3 consisted of 34 patients who underwent stenting and were prescribed the perindopril/amlodipine combination. The reference group included 47 patients with IHD and AH with preserved kidney function. Anatomic and functional parameters of the heart, arterial stiffness, pulse wave velocity, cardio-ankle vascular index, augmentation index, central aortic systolic and pulse pressure, endothelium-dependent vasodilation, plasma concentration of endothelin-1 (ET-1), and plasma concentration of nitric oxide metabolites were evaluated at baseline and after 12 weeks of treatment.Results In patients with IHD, AH, and stage 2-3 CKD, arterial stiffness was more pronounced than in patients with preserved kidney function. Concentrations of ET-1 were significantly higher and levels of nitric oxide were lower in CKD. Supplementing the complex therapy with perindopril resulted in a considerable hypotensive effect in all subgroups, improvement of the kidney function, and positive dynamics of arterial stiffness and endothelial function. Changes in these parameters were more pronounced in patients after coronary stenting than in patients receiving only a conservative treatment. The use of perindopril/amlodipine following stenting exerted the most significant angioprotective and cardioprotective effect.Conclusion Patients with IHD and AH in combination with early CKD have pronounced impairment of the condition of arterial blood vessels and the heart. Addition of perindopril to the treatment not only exerted a hypotensive effect but also beneficially influenced mechanisms of progression of this combined pathology.

Aprocitentan, A Dual Endothelin Receptor Antagonist Under Development for the Treatment of Resistant Hypertension.

Aprocitentan (ACT-132577) is an orally active, dual endothelin-1 (ET-1) receptor antagonist that prevents the binding of ET-1 to both ETA/ETB receptors. It is an active metabolite of macitentan (obtained by oxidative depropylation), an orphan drug used for the treatment of pulmonary arterial hypertension. Aprocitentan is highly bound to plasma proteins and is eliminated in both urine and feces. It is well tolerated across all doses (up to 600 mg with single dose and 100 mg once a day at multiple doses). Its pharmacokinetic profile shows a half-life of 44 h, fitting a once-daily dosing regimen with plasma ET-1 concentrations (reflecting ET receptor antagonism), significantly increasing with doses ≥ 25 mg. Only minor differences in exposure between healthy females and males, healthy elderly and adult subjects, fed and fasted conditions, and renal function have been observed. Aprocitentan in patients with resistant hypertension is currently under investigation in the PRECISION phase III trial (ClinicalTrials identifier: NCT03541174). Nonetheless, results of pre-clinical data and studies in humans support the potential role of aprocitentan in this clinical setting. The absolute blood pressure (BP) reductions with aprocitentan are in the ranges established as a surrogate for reduction in cardiovascular morbidity in hypertension. Significant changes in BP with aprocitentan are observed within 14 days, and its BP-lowering effects have also been documented with ambulatory BP monitoring. Finally, aprocitentan enhances the BP-lowering effects of other antihypertensive drugs, including renin-angiotensin-system blockers. In conclusion, aprocitentan ameliorates the effects of ET-1 and could potentially reduce BP and provide broader cardiovascular protection in patients with resistant hypertension. Available data support the hypothesis that this new agent could expand our antihypertensive arsenal in resistant hypertension, making aprocitentan an attractive candidate for further large-scale trials.

Endothelin-1 induces changes in the expression levels of steroidogenic enzymes and increases androgen receptor and testosterone production in the PC3 prostate cancer cell line.

Endothelin-1 (ET-1) is involved in the regulation of steroidogenesis. Additionally, patients with castration-resistant prostate cancer (PCa) have a higher ET-1 plasma concentration than those with localized PCa and healthy individuals. The aim of the present study was to evaluate the effect of ET-1 on steroidogenesis enzymes, androgen receptor (AR) and testosterone (T) production in PCa cells. The expression levels of endothelin receptors in prostate tissue from patients with localized PCa by immunohistochemistry, and those in LNCaP and PC3 cells were determined reverse transcription-quantitative PCR (RT-qPCR) and western blotting. Furthermore, the expression levels of ET-1 were determined in LNCaP and PC3 cells by RT-qPCR and western blotting. The ET-1 receptor activation was evaluated by intracellular calcium measurement, the expression levels of AR and enzymes participating in steroidogenesis [cytochrome P450 family 11 subfamily A member 1 (CyP11A1), cytochrome P450 family 17 subfamily A member 1, aldo-keto reductase family member C2 and 3β-hydroxysteroid dehydrogenase/isomerase 2 (3β HSD2)] were determined by western blotting and T concentration was determined by ELISA using PC3 cells. The present results revealed higher expression levels of endothelin A receptor (ETAR) in tissues obtained from samples of patients with PCa with a low Gleason Score. No changes were identified for endothelin B receptor (ETBR). PC3 cells expressed higher levels of ET-1 and ETAR, while LNCaP cells exhibited higher expression levels of ETBR. Blocking of ETAR and endothelin B receptor decreased the expression levels of CyP11A1 and 3β HSD2 enzymes and AR in PC3 cells, as well as T secretion. These findings suggested that ET-1 has a potential role in modulating the intratumoral steroidogenesis pathway and might have relevance as a possible therapeutic target.

Paroxetine Administration Alter some Biochemical Parameters in Male Wistar Rats Over a Systemic Period of Thirty-Five Days

Paroxetine is often used to treat patients with psychotic disorders, one of the side effects of this medication is that it causes erectile dysfunction in such individuals. There is a little or no information on the effect of paroxetine on some biochemical and endothelial markers of experimental models, hence the need for this research. Biochemical and endothelial functional makers in male Wistar rats were evaluated after oral administration of paroxetine for 4, 7, 21, 28 and 35 days. Seventy-two (72) male Wistar rats were grouped into two of thirty-six rats in group A (control) which received normal saline and thirty-six rats in group B (paroxetine-treated) which received 10 mg/Kg body weight of paroxetine hydrochloride for 4, 7, 14, 21, 28, and 35days respectively. During this period, six animals from the two groups were sacrificed on days 4,7,14, 21, 28 and 35 by anaesthesia using diethyl ether, blood was collected into lithium–heparinized bottles and the tissues of interest (penile and heart) of the rats were excised and preserved in ice-cold sucrose-tris buffer. Phosphodiesterase 5, arginase, nitric oxide were evaluated from the isolated tissue homogenates while cGMP, endothelin-1, creatine kinase, lipid profile and testosterone concentrations were evaluated from the plasma. The results revealed that during pre-treatment with paroxetine, there was significant (p &lt; 0.05) 85.19 ± 4.64 and 92.58 ± 0.57 respectively PDE 5 inhibition in the penile and cardiac homogenates of rats. Nitric oxide concentration was significantly (p&gt; 0.05) 2.96 ± 0.27 and 4.82 ± 0.05reduced while arginase activities increased significantly (p &gt; 0.05) 272.16 ± 5.07 and 201.93 ± 11.82 during paroxetine treatment. Same trend of results were observed with plasma endothelin-1 concentration (12.88 ± 0.78), cGMP concentration (0.14 ± 0.00) and Testosterone concentration (0.46 ± 0.03) was significantly (p &gt; 0.05) decreased during paroxetine-treatment. However, plasma creatine kinase 463.6 ± 50.96, triacyl glycerol 58.61 ± 5.49, total cholesterol 181.55 ± 9.72 and low-density lipoprotein cholesterol 165.86 ± 9.72 were significantly (p &lt; 0.05) increased during paroxetine-treatment. However, no significant (p &gt; 0.05) difference was observed in the high-density lipoprotein cholesterol 8.07 ± 0.46 during administration with paroxetine. From this study, it can be concluded that paroxetine administration altered erectile and endothelial markers throughout the period of administration and as such should be prescribed to patients with caution.