Big Endothelin-1 Research Articles

B-26 | Big Endothelin-1 and Long-term All-cause Death in Patients With Coronary Artery Disease and Prediabetes or Diabetes after Percutaneous Coronary Intervention

The aim of the present study is to examine the effects of big endothelin-1(big ET-1) on long-term all-cause death in patients with coronary artery disease (CAD) and different glucose metabolism status.

Mechanical stretch‐driven ROS generation stimulates endothelin production in neonatal pig renal epithelial and vascular endothelial cells

The circulating level of endothelin (ET), a potent vasoactive peptide, decreases with postnatal age. ET is also of pathophysiological significance in the kidney. ET is generated via endothelin converting enzyme (ECE)‐induced proteolytic processing of pro‐molecule big ET to biologically active peptides. Hydrogen peroxide (H2O2), a reactive oxygen species (ROS), transactivates the promoter of ECE1. Oxyradicals contribute to kidney pathophysiology, but whether ROS regulates ET production in the kidneys remains unresolved. The present study shows that ECE1 is the predominant isoform in neonatal pig kidneys. We also demonstrated that H2O2 induces ECE1‐dependent ET1‐3 production in the neonatal pig renal proximal tubules (PT) and vascular endothelial cells (EC). A uniaxial stretch of neonatal pig PT and EC increased NADPH oxidase (NOX) 2 and 4 levels and stimulated H2O2production. Mechanical stretch increased cellular ECE1 production in the PC and EC cells, which catalase mimetic EUK 134 and NOX inhibitor apocynin reversed. Mechanical stretch also triggered cellular ET1‐3 generation in PT and EC. Mechanical stretch‐induced ET1‐3 production was attenuated by EUK 134, apocynin, and a selective ECE1 inhibitor CGS 35066. Short‐term unilateral urinary tract obstruction (UUO), an inducer of the mechanical stretch of kidney cells and oxyradical production, increased ECE1‐dependent ET1‐3 production in neonatal pig kidneys. Despite removing the obstruction, acute UUO generated ROS, reduced kidney perfusion, and increased renal vascular resistance (RVR). UUO also elevated early biomarkers of acute kidney injury (AKI). Inhibition of ECE1 and ET receptors protected against UUO‐induced increase in RVR and early AKI. These data suggest that mechanical stretch‐driven ROS generation stimulates ET production in neonatal pig renal epithelial and vascular endothelial cells. ET then promotes AKI by causing renal hypoperfusion. This signaling pathway may underlie UUO‐induced renal insufficiency in infants.

TCTAP A-040 Big Endothelin-1 and Five-Year Long-term All-cause Death in Patients With Coronary Artery Disease and Prediabetes or Diabetes after Percutaneous Coronary Intervention

TCTAP A-040 Big Endothelin-1 and Five-Year Long-term All-cause Death in Patients With Coronary Artery Disease and Prediabetes or Diabetes after Percutaneous Coronary Intervention

ENDOTHELIN-1 AS A RISK FACTOR IN RETINAL VEIN OCCLUSION.

Retinal vein occlusion (RVO) risk factors largely coincide with cardiovascular risk factors. Endothelin-1 (ET-1), the most potent vasoconstrictor with proinflammatory properties, is a known cardiovascular risk factor. In this study, we explore the role of serum ET-1 as a potential risk factor for RVO. Endothelin-1 serum levels were measured in patients with RVO and control subjects. Samples were measured using the sandwich enzyme-linked immunosorbent assay for the quantitative determination of human big endothelin-1 (Biomedica Group, Austria). The study consisted of 147 RVO patients and 150 control subjects. Median serum ET-1 was significantly higher in RVO patients (0.26 pmol/L; range, 0.19-0.37 pmol/L) compared with control subjects (0.10 pmol/L; range, 0.05-0.22 pmol/L) (P < 0.0001) independent of the occlusion site. The difference remained significant after adjusting for arterial hypertension, diabetes mellitus, history of stroke, history of myocardial infarction, history of venous thromboembolism, glomerular filtration rate, and c-reactive protein. In conclusion, our results suggest that ET-1 is a potential risk factor for all types of RVO.

Plasma Big Endothelin-1 Levels and Long-Term Outcomes in Patients With Atrial Fibrillation and Acute Coronary Syndrome or Undergoing Percutaneous Coronary Intervention.

BackgroundThis study aimed to evaluate the association between plasma big ET-1 levels and long-term outcomes in patients with atrial fibrillation (AF) and acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI).MethodsA total of 930 patients were enrolled and followed up for a median duration of 2.3 years. According to the optimal cutoff of big ET-1 for predicting all-cause death, these patients were divided into two groups. The primary endpoints were all-cause death and net adverse clinical events (NACE). The secondary endpoints included cardiovascular death, major adverse cardiovascular events (MACE), BARC class ≥ 3 bleeding, and BARC class ≥ 2 bleeding. Cox regressions were performed to evaluate the association between big ET-1 and outcomes.ResultsBased on the optimal cutoff of 0.54 pmol/l, 309 patients (33.2%) had high big ET-1 levels at baseline. Compared to the low big ET-1 group, patients in the high big ET-1 group tended to have more comorbidities, impaired cardiac function, elevated inflammatory levels, and worse prognosis. Univariable and multivariable Cox regressions indicated that big ET-1 ≥ 0.54 pmol/l was associated with increased incidences of all-cause death [HR (95%CI):1.73 (1.10–2.71), p = 0.018], NACE [HR (95%CI):1.63 (1.23–2.16), p = 0.001], cardiovascular death [HR (95%CI):1.72 (1.01–2.92), p = 0.046], MACE [HR (95%CI):1.60 (1.19–2.16), p = 0.002], BARC class ≥ 3 [HR (95%CI):2.21 (1.16–4.22), p = 0.016], and BARC class ≥ 2 bleeding [HR (95%CI):1.91 (1.36–2.70), p < 0.001]. Subgroup analysis indicated consistent relationships between the big ET-1 ≥ 0.54 pmol/l and the primary endpoints.ConclusionElevated plasma big ET-1 levels were independently associated with increased risk of all-cause death, NACE, cardiovascular death, MACE, BARC class ≥ 3 bleeding, and BARC class ≥ 2 bleeding in patients with AF and ACS or undergoing PCI.

Plasma Big Endothelin-1 Level Predicted 5-Year Major Adverse Cardiovascular Events in Patients With Coronary Artery Ectasia.

Background: Coronary artery ectasia (CAE) is found in about 1% of coronary angiography and is associated with poor clinical outcomes. The prognostic value of plasma big Endothelin-1 (ET-1) in CAE remains unknown.Methods: Patients with angiographically confirmed CAE from 2009 to 2015, who had big ET-1 data available were included. The primary outcome was 5-year major adverse cardiovascular events (MACE), defined as a component of cardiovascular death and non-fatal myocardial infarction (MI). Patients were divided into high or low big ET-1 groups using a cut-off value of 0.58 pmol/L, according to the receiver operating characteristic curve. Kaplan-Meier method, propensity score method, and Cox regression were used to assess the clinical outcomes in the 2 groups.Results: A total of 992 patients were included, with 260 in the high big ET-1 group and 732 in the low big ET-1 group. At 5-year follow-up, 57 MACEs were observed. Kaplan-Meier analysis and univariable Cox regression showed that patients with high big ET-1 levels were at increased risk of MACE (9.87 vs. 4.50%; HR 2.23, 95% CI 1.32–3.78, P = 0.003), cardiovascular death (4.01 vs. 1.69%; HR 2.37, 95% CI 1.02–5.48, P = 0.044), and non-fatal MI (6.09 vs. 2.84%; HR 2.17, 95% CI 1.11–4.24, P = 0.023). A higher risk of MACE in the high big ET-1 group was consistent in the propensity score matched cohort and propensity score weighted analysis. In multivariable analysis, a high plasma big ET-1 level was still an independent predictor of MACE (HR 1.82, 95% CI 1.02–3.25, P = 0.043). A combination of high plasma big ET-1 concentrate and diffuse dilation, when used to predict 5-year MACE risk, yielded a C-statistic of 0.67 (95% CI 0.59–0.74).Conclusion: Among patients with CAE, high plasma big ET-1 level was associated with increased risk of MACE, a finding that could improve risk stratification.

Circulating Levels of Endothelin-1 and Big Endothelin-1 in Patients with Essential Hypertension.

The role of endothelin-1 (ET-1) in the pathogenesis of hypertension (HTN) is not clearly established. There is evidence that its circulating levels are elevated in some forms of experimental and human HTN, but this was not a consistent finding. Based on these controversial data, we tested serum levels of ET-1 and Big ET-1 (the precursor of ET-1) in patients with essential HTN, comparing the results with those of healthy normotensive controls. The levels of ET-1 and Big ET-1 were measured by ELISA. Our results in patients with essential HTN showed that the mean levels of ET-1 (5.01 ± 2.1 pg/mL) were significantly higher (F = 6.34, p = 0.0144) than the mean levels in the control group (3.2 ± 1.0 pg/mL). The levels of Big ET-1 in patients with essential HTN (0.377 ± 0.1 pmol/L) were similar to those in the control group (0.378 ± 0.07 pmol/L) and did not differ significantly (F = 0.00, p = 0.9531). These data suggest that ET-1, but not Big ET-1, may play an important role in the pathogenesis of primary HTN.

Transmyocardial extraction of endothelin-1 correlates with increased microvascular resistance following percutaneous coronary intervention

Abstract Introduction Coronary microvascular dysfunction (CMD) can persist following successful percutaneous coronary intervention (PCI). Endothelin-1 (ET-1) is a potent vasoconstrictor and may be an important mediator of CMD. We sought to assess the trans-myocardial gradient (TMG – coronary sinus minus coronary root levels) of ET-1 and its precursor - Big ET-1 and assess the correlation with pressure-wire indices of CMD: coronary flow reserve (CFR) and index of microvascular resistance (IMR). Methods Paired blood samples from the aortic root and coronary sinus were collected before and after pressure wire guided PCI from patients with stable angina. Plasma was then analysed using specific enzyme linked immunosorbent assay (ELISA) for quantification of ET-1 and Big ET-1 and correlated with pressure-wire data. Results Samples were analysed from 66 patients. Both mean ET-1 and Big ET-1 concentrations increased post-PCI in both the aorta (ET-1: 1.0±0.4 pg/ml to 1.4±0.4 pg/ml, p&amp;lt;0.0001 and Big ET-1: 2.8±1.3 pg/ml to 3.4±1.6 pg/ml, p&amp;lt;0.0001) and coronary sinus (ET-1: 1.0±0.3 pg/ml to 1.2±0.3 pg/ml, p=0.03 and Big ET-1: 3.2±1.7 pg/ml to 3.8±1.5 pg/ml, p=0.01). TMG extraction of ET-1 increased following PCI: 0.05±0.25 pg/ml vs.-0.20±0.41 pg/ml, p=0.01. In contrast, there was TMG release of Big ET-1 before and after PCI: 0.46±1.26 pg/ml vs. 0.38±1.03 pg/ml, p=0.52. ET-1 extraction correlated with IMR post-PCI (Pearson's r=0.293, p=0.02). Patients with CFR&amp;lt;2 post-PCI demonstrated a numerical trend towards higher mean ET-1 extraction than those with preserved CFR post-PCI (0.30±0.51 pg/ml vs. 0.16±0.42 pg/ml, p=0.31) as did those with criteria for Type 4a Myocardial Infarction compared with those without (0.39±0.57 vs. 0.15±0.41, p=0.11). Conclusions ET-1 and Big ET-1 significantly increase post-PCI. Trans-myocardial extraction of ET-1 increases post-PCI and correlates with post-PCI CMD. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Jon Moulton Charity Trust.NIHR Cambridge Biomedical Research Centre Biomedical Resources Grant. TMG of ET-1 and Big ET-1ET-1 extraction and post-PCI IMR

Association between plasma big endothelin-1 level and the severity of coronary artery disease in patients with non-ST segment-elevated myocardial infarction

Abstract Background This study aimed to evaluate the association between plasma big endothelin-1 (ET-1) level and the severity of coronary artery disease assessed by the SYNTAX score (SS) in patient with non-ST segment-elevated myocardial infarction (NSTEMI). Methods A total of 766 patients with NSTEMI undergoing coronary angiography were recruited. Patients were divided into divided into three groups: low SS (SS ≤22), intermediate SS (23–32) and high SS group (SS &amp;gt;32). Spearman correlation, smooth curve fitting, logistic regression and Receiver operating characteristic (ROC) curve analysis were performed to evaluated the association between plasma big ET-1 level and the SS. Results There was a significant correlation between the big ET-1 and the SS (r=0.378, p&amp;lt;0.001). Smoothing curve indicated a positive correlation between plasma big ET-1 level and the SS, after adjustment for potential confounders. The ROC curve analysis showed that the area under the curve was 0.695 (0.661–0.727) and the optimal cutoff of plasma big ET-1 level were 0.35pmol/l, with a sensitivity of 68.9% and a specificity of 62.9%. Logistic regression showed that elevated big ET-1 was an independent predictor of intermediate-high SS in patients with NSTEMI, no matter entered as a continuous variable [OR (95% CI): 1.110 (1.053–1.170), p&amp;lt;0.001] or as a categorical variable [OR (95% CI): 2.873 (2.016–4.094), p&amp;lt;0.001]. The association between big ET-1 and intermediate-high SS was consistent across subgroups without significant interactions. Conclusion In patients presenting with NSTEMI, plasma big ET-1 level was significantly correlated with the SS. Elevated plasma big ET-1 level was an independent predictor for intermediate-high SS. Funding Acknowledgement Type of funding sources: None. ROC of big ET-1 for high SYNTAX score

Effect of domperidone (leisguard\xae) on antibody titers, inflammatory markers and creatinine in dogs with leishmaniosis and chronic kidney disease

BackgroundImmunotherapeutic drugs, such as domperidone, have been shown to be promising treatments against canine leishmaniosis (CanL), but limited data are available. The aim of this pilot study (therapeutic, prospective and non-controlled) was to evaluate the effect of domperidone on serum antibody titers of Leishmania infantum, globulins, gamma globulins, acute-phase proteins (e.g. C-reactive protein [CRP]), big endothelin-1 (big ET-1), serum creatinine (SC) and proteinuria in dogs with leishmaniosis affected by chronic kidney disease (CKD).MethodsDogs were recruited if “exposed” to or “infected” with L. infantum and affected by CKD (IRIS stage 1 [proteinuric] or IRIS stage 2–3a [SC < 3.5 mg/dl; proteinuric or non-proteinuric]). After inclusion, an oral suspension of domperidone was administered, and the dogs were followed up for 180 days, with checks at 30, 60, 90 and 180 days after initial treatment.ResultsOf the 14 recruited dogs, nine showed a statistically significant reduction in SC (χ2 = 9.1, df = 3, P = 0.028), but not in the urine protein/creatinine ratio (χ2 = 6.43, df = 3, P = 0.092). All dogs showed a significant reduction in antibody titers for L. infantum (χ2 = 9.56, df = 2, P = 0.008), globulins (χ2 = 11.08, df = 3, P = 0.011) and gamma globulins (χ2 = 12.38, df = 3, P = 0.006) during the study period. There was also a statistically significant reduction in CRP (χ2 = 16.7, df = 3, P = 0.001), but not in big ET-1 (χ2 = 2.04, df = 3, P = 0.563).ConclusionsThis study provides preliminary results on the ability of domperidone to improve SC and reduce anti-L. infantum antibody titers, globulins, gamma globulins and CRP in dogs with leishmaniosis and CKD.Graphical abstract

Altered Vascular Adaptations to Pregnancy in a Rat Model of Advanced Maternal Age.

Advanced maternal age (≥35 years old) increases the risk of pregnancy complications such as preeclampsia and fetal growth restriction. We previously demonstrated vascular dysfunction and abnormal pregnancy outcomes in a rat model of advanced maternal age. However, vascular adaptations to pregnancy in aging were not studied. We hypothesize that advanced maternal age is associated with a more vasoconstrictive phenotype due to reduced nitric oxide (NO) and increased activity of matrix metalloproteinases (MMPs), contributing to impaired vascular adaptations to pregnancy. A rat model of advanced maternal age was used: young (4 months) and aged (9.5 months; ∼35 years in humans) non-pregnant and pregnant rats. On gestational day 20 (term = 22 days; non-pregnant rats were aged-matched), blood pressure and heart rate were measured (tail cuff plethysmography) and vascular function was assessed in mesenteric arteries (wire myography). Endothelium-dependent relaxation to methylcholine (MCh) was assessed in the presence/absence of nitric oxide synthase inhibitor (L-NAME), or inhibitors of endothelium-dependent hyperpolarization (EDH; apamin and TRAM-34). Vasoconstriction responses to big endothelin-1 (bigET-1), in the presence/absence of MMPs-inhibitor (GM6001) or endothelin converting enzyme (ECE-1) inhibitor (CGS35066), in addition, ET-1 responsiveness, were measured. Blood pressure was elevated only in aged non-pregnant rats (p < 0.001) compared to all other groups. MCh responses were not different, however, L-NAME decreased maximum vasodilation in young (p < 0.01) and aged pregnant rats (p < 0.001), and decreased MCh sensitivity in young non-pregnant rats (p < 0.01), without effects in aged non-pregnant rats. EDH contribution to relaxation was similar in young non-pregnant, and aged non-pregnant and pregnant rats, while EDH-mediated relaxation was absent in young pregnant rats (p < 0.001). BigET-1 responses were enhanced in aged non-pregnant (p < 0.01) and pregnant rats (p < 0.05). No significant changes in bigET-1 conversion occurred in the presence of MMP-inhibitor, whereas ECE-1 inhibition reduced bigET-1 constriction in aged rats (p < 0.01). No differences in ET-1 sensitivity were observed. In conclusion, contrary to our hypothesis, reduced blood pressure, and an increased EDH-dependent contribution to vasodilation suggest a compensatory mechanism that may reflect beneficial adaptations in these aged rats that were able to maintain pregnancy. These data increase our understanding of how the vascular adaptive pathways in pregnancy compensate for advanced maternal age.

Plasma Levels of Big Endothelin-1 Are Associated with Renal Insufficiency and In-Hospital Mortality of Immune Thrombotic Thrombocytopenic Purpura.

Immune thrombotic thrombocytopenic purpura (iTTP) is caused by severe deficiency of plasma ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity. Despite advances in early diagnosis and management, the mortality rate of acute iTTP remains high in a large part of world where access to some of the most novel therapies is limited. To determine the role of plasma big endothelin-1 (bigET-1) or its bioactive product ET-1 as a biomarker and/or a pathogenic factor in acute iTTP, plasma levels of bigET-1 were determined using an immunoassay in patients with iTTP on admission and during remission, as well as in healthy controls; moreover, the biological effect of ET-1 in thrombus formation was determined by a microfluidic assay. We show that plasma levels of bigET-1 were dramatically increased in patients with acute iTTP on admission, which was significantly decreased during clinical response/remission; elevated admission levels of plasma bigET-1 were associated with low estimated glomerular filtration rate, the need for intensive care unit admission or intubation, and in-hospital mortality. Moreover, an addition of a bioactive product ET-1 to cultured endothelial cells in a microfluidic channel significantly accelerated the rate of thrombus formation under arterial flow. Our results demonstrate for the first time a potential role of measuring plasma bigET-1 in patients with acute iTTP in assessing the disease severity and risk of in-hospital mortality, which may help stratify patients for a more aggressive monitoring and therapeutic strategy; also, the bioactive ET-1, derived from bigET-1, may result in acute renal injury in TTP patient, likely through its vasoconstriction and prothrombotic properties.

Elevated Plasma Big Endothelin-1 at Admission Is Associated With Poor Short-Term Outcomes in Patients With Acute Decompensated Heart Failure.

Objective: We aimed to evaluate the association between plasma big endothelin-1 (ET-1) at admission and short-term outcomes in acute decompensated heart failure (ADHF) patients.Methods: In this single-center, retrospective study, a total of 746 ADHF patients were enrolled and divided into three groups according to baseline plasma big ET-1 levels: tertile 1 (<0.43 pmol/L, n = 250), tertile 2 (between 0.43 and 0.97 pmol/L, n = 252), and tertile 3 (>0.97 pmol/L, n = 244). The primary outcomes were all-cause death, cardiac arrest, or utilization of mechanical support devices during hospitalization. Logistic regression analysis and net reclassification improvement approach were applied to assess the predictive power of big ET-1 on short-term outcomes.Results: During hospitalization, 92 (12.3%) adverse events occurred. Etiology, arterial pH, lactic acid, total bilirubin, serum creatine, serum uric acid, presence of atrial fibrillation and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were positively correlated with plasma big ET-1 level, whereas systolic blood pressure, serum sodium, hemoglobin, albumin, and estimated glomerular filtration rate were negatively correlated. In multivariate logistic regression, tertile 3 compared with tertile 1 had a 3.68-fold increased risk of adverse outcomes [odds ratio (OR) = 3.681, 95% confidence interval (CI) 1.410–9.606, p = 0.008]. However, such adverse effect did not exist between tertile 2 and tertile 1 (OR = 0.953, 95% CI 0.314–2.986, p = 0.932). As a continuous variable, big ET-1 level was significantly associated with primary outcome (OR = 1.756, 95% CI 1.413–2.183, p < 0.001). The C statistic of baseline big ET-1 was 0.66 (95% CI 0.601–0.720, p < 0.001). Net reclassification index (NRI) analysis showed that big ET-1 provided additional predictive power when combining it to NT-proBNP (NRI = 0.593, p < 0.001).Conclusion: Elevated baseline big ET-1 is an independent predictor of short-term adverse events in ADHF patients and may provide valuable information for risk stratification.

Cardioprotective Effects of Mebudipine in a Rat Model of Doxorubicin-Induced Heart Failure.

Background: Mebudipine, a dihydropyridine calcium-channel blocker (CCB), shows greater time- and voltage-dependent inhibitory effects than nifedipine. Its significant negative chronotropic effects without having considerable negative inotropic properties may make it a suitable candidate for the pharmacotherapy of heart failure (HF). This study aimed to investigate the possible beneficial action of mebudipine in a rat model of HF. Methods:The present study carried out in the Department of Pharmacology at the Iran University of Medical Sciences during the years of 2009-2011. An experimental model of HF was induced in male Wistar rats using doxorubicin (DOX). The rats were divided into five groups with seven animals in each group: normal control group, DOX-induced HF control groups, and treatment groups. The animals were administered DOX for 15 days. A consistent deterioration occurred after a four-week rest period. The animals were then treated with intraperitoneal mebudipine (0.5 mg/kg) and intraperitoneal amlodipine (0.35 mg/kg), as well as an equal volume of distilled water for 15 days. The plasma levels of big endothelin-1 (BET-1), creatine kinase-myocardial band (CK-MB), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and alanine aminotransferase (ALT), as well as the clinical status (heart rate and blood pressure), were assessed before and after treatment. Statistical analysis was performed with SPSS software using parametric and nonparametric ANOVA.Results: Mebudipine and amlodipine reversed the increased plasma BET-1 values in the treated animals when compared with the HF control group (0.103 and 0.112 vs 0.231 pg/mL, respectively). The increased plasma levels of AST, ALT, CK-MB, and LDH were also reversed in the HF animals that received mebudipine or amlodipine.Conclusion: The administration of mebudipine to HF animals, akin to amlodipine, palliated the clinical and biochemical signs of the disease in the present study. The abstract was presented in the Iranian Congress of Physiology and Pharmacology as a poster and published in the Scientific Information Database as a supplement (2015; Vol 22).

Prognostic power of big endothelin-1 in noncompaction cardiomyopathy

Prognostic power of big endothelin-1 in noncompaction cardiomyopathy

Evaluation of Urinary Big Endothelin-1 in Feline Spontaneous CKD.

Simple SummaryChronic kidney disease is a common and progressive disease of elderly cats. It is a cause of pet suffering and owner expense. Biologic biomarkers for early diagnosis and for noninvasive evaluation of kidney damage are certainly useful in both research and clinical practice. In this study, we evaluated the biomarker big endotelin-1 in the urine of cats affected with chronic kidney disease. Big endothelin-1 is molecule linked to inflammation and pressure regulation, and it was not previously evaluated in nephropathic cats. We found that urinary big endothelin was increased in patients at late stage of the disease and in patients with proteinuria (a marker of kidney damage). Despite that, big endothelin 1 seemed not to be a useful biomarker for disease progression. According to results of this preliminary study, we suggest this biomarker for future research on feline kidney disease.The endothelin-1 (ET-1) system has been implicated in the development and progression of chronic kidney disease (CKD). No information on big ET-1 in feline urine is available. The purpose of this study was to evaluate if urinary big endothelin-1 (bigET-1) is associated with feline CKD. Sixty urine samples were prospectively collected from 13 healthy cats at risk of developing CKD and 22 cats with CKD of different International Renal Interest Society (IRIS) stages (1–4). Urinary bigET-1 was measured using a commercially available ELISA. BigET-1 normalized to urine creatinine (bigET-1:UC) was compared amongst stages and substages, as proposed by IRIS, and correlated with serum creatinine concentration, proteinuria and blood pressure. BigET-1:UC at the time of inclusion was compared between cats that remained stable and cats that progressed after 12 months. BigET-1:UC was significantly higher (p = 0.002) in cats at IRIS stages 3–4 (median: 21.9; range: 1.88–55.6), compared to all other stages, and in proteinuric (n = 8, median: 11.0; range: 0.00–46.4) compared with nonproteinuric cats (n = 38 median: 0.33; range: 0.00–55.6) (p = 0.029). BigET-1:UC was not associated with CKD progression. Urinary bigET-1 increased in advanced stages of CKD and in proteinuric patients, suggesting that ET-1 may be indicative of the severity of feline CKD.

Mast Cell Degranulation Increases Mouse Mast Cell Protease 4–Dependent Vasopressor Responses to Big Endothelin-1 But Not Angiotensin I

Mouse mast cell protease 4 (mMCP-4), the murine functional analog to the human chymase, is a serine protease synthesized and stored in mast cell secretory granules. Our previous studies reported physiologic and pathologic roles for mMCP-4 in the maturation and synthesis of the vasoactive peptide endothelin-1 (ET-1) from its precursor, big ET-1. The aim of this study was to investigate the impact of mast cell degranulation or stabilization on mMCP-4-dependent pressor responses after the administration of big ET-1 or angiotensin I (Ang I). In anesthetized mice, mast cell degranulation induced by compound 48/80 (C48/80) or stabilization by cromolyn enhanced or repressed, respectively, the dose-dependent vasopressor responses to big ET-1 in wild-type (WT) mice but not in mMCP-4 knockout mice in a chymase inhibitor (TY-51469)-sensitive fashion. In addition, mMCP-4-dependent hydrolysis of the fluorogenic substrate Suc-Leu-Leu-Val-Tyr-7-amino-4-methylcoumarin was depleted or enhanced in peritoneal mast cells isolated from mice pretreated with C48/80 or cromolyn, respectively. Furthermore, C48/80 or cromolyn markedly increased or abolished, respectively, ET-1 (1-31) conversion from exogenous big ET-1 in WT mice peritoneal fluid-isolated mast cells, in vitro. Finally, the vasopressor responses to Ang I were unaffected by mast cell activation or stabilization, whereas those induced by the angiotensin-converting enzyme-resistant Ang I analog, [Pro11, D-Ala12] Ang I, were potentiated by C48/80. Altogether, the present study shows that mast cell activation enhances the mMCP-4-dependent vasoactive properties of big ET-1 but not Ang I in the mouse model. SIGNIFICANCE STATEMENT: The current work demonstrates a significant role for mast cell stability in the cardiovascular pharmacology of big endothelin-1 but not angiotensin I in the murine systemic circulation.

Prognostic value of plasma big endothelin-1 in left ventricular non-compaction cardiomyopathy

ObjectiveTo determine the prognostic role of big endothelin-1 (ET-1) in left ventricular non-compaction cardiomyopathy (LVNC).MethodsWe prospectively enrolled patients whose LVNC was diagnosed by cardiac MRI and who had big ET-1...

Metformin prevents the development of monocrotaline-induced pulmonary hypertension by decreasing serum levels of big endothelin-1.

Pulmonary hypertension (PH) is a disease with poor prognosis, and it is characterized by the progressive elevation of pulmonary vascular resistance and pressure. Various factors are associated with the pathology of PH, including AMP-activated protein kinase (AMPK) deficiency. The present study aimed to evaluate the therapeutic effect of metformin, an AMPK activator, in a monocrotaline (MCT)-induced PH rat model. Rats were randomly divided into the following three groups: i) Saline-injected group (sham group); ii) monocrotaline (MCT)-injected group (PH group); iii) MCT-injected and metformin-treated group (MT group). Four weeks following MCT injection, cardiac ultrasonography, invasive hemodynamic measurements, measurement of serum levels of big endothelin-1 (big ET-1) and histological analysis were performed to evaluate the effect of metformin treatment in PH. Pulmonary arterial pressure and serum big ET-1 concentrations were reduced in the MT group compared with the PH group. Medial wall thickness and wall area of the pulmonary arterioles in the MT group were decreased compared with the PH group. Comparing the right heart functional parameters among groups revealed that the acceleration time/ejection time ratio improved in the MT group compared with the PH group. Thus, the present study demonstrated the efficacy of metformin in an MCT-induced PH rat model and suggested that metformin may be a valuable, potential novel therapeutic for the treatment of PH.

Characteristics and long-term survival of patients with chronic thromboembolic pulmonary hypertension in China.

The purpose of this study was to report the characteristics and long-term survival of patients with CTEPH treated in three distinct ways: PEA, BPA and medical therapy. Patients diagnosed with CTEPH were included in the registry that was set up in 18 centres from August 2009 to July 2018. The characteristics and survival of patients with CTEPH receiving the different treatments were reported. Prognostic factors were evaluated by Cox regression model. A total of 593 patients with CTEPH were included. Eighty-one patients were treated with PEA, 61 with BPA and 451 with drugs. The estimated survival rates at 1, 3, 5 and 8 years were, respectively, 95.2%, 84.6%, 73.4% and 66.6% in all patients; 92.6%, 89.6%, 87.5% and 80.2% in surgical patients; and 95.4%, 88.3%, 71.0% and 64.1% in medically treated patients. The estimated survival rates at 1, 3, 5 and 7 years in patients treated with BPA were 96.7%, 88.1%, 70.0% and 70.0%, respectively. For all patients, PEA was an independent predictor of survival. Other independent risk factors were CHD, cardiac index, PVR, big endothelin-1, APE and 6MWD. This is the first multicentre prospective registry reporting baseline characteristics and estimated survival of patients with CTEPH in China. The long-term survival rates are similar to those of patients in the international and Spanish registries. PEA is an independent predictor of survival.