Endothelin-1 immunoreactivity in plasma is elevated in HIV-1 infected patients with retinal microangiopathic syndrome

Endothelin-1 is a recently identified cytokine with potent vasoconstrictor activity which is associated with various diseases involving blood vessels. HIV-1 related retinal microangiopathic syndrome is a frequent finding in patients with AIDS or AIDS-related complex, presenting predominantly with retinal cotton-wool spots. We investigated 55 HIV-1 infected patients by ophthalmoscopy and for endothelin-I immunoreactivity in plasma and an additional 76 HIV-1 infected patients only for endothelin-1 levels. For reference values 13 age-matched healthy subjects were studied. In 18 of 55 patients (33%) investigated ophthalmoscopically we found evidence of microangiopathic syndrome. Overall, the mean endothelin-1 immunoreactivity in plasma of HIV-1 infected patients was significantly elevated as compared to controls (4.28 ± 3.62 versus 2.72 ± 0.67 fmol/ml, P < 0.0001). HIV-1 infected patients with retinal microangiopathic syndrome had significantly higher plasma levels of endothelin-1 immunoreactivity (4.59 ± 1.38 fmol/ ml) compared to HIV-1 infected patients without microangiopathic syndrome (3.18 ± 1.64 fmol/ml, P = 0.003). Correlation analysis revealed that endothelin-1 immunoreactivity in plasma had no significant association with disease progression, CD4 cell count, ₂-mi-croglobulin, neopterin, or age. Endothelin-1 immunoreactivity in plasma was correlated exclusively with retinal microangiopathic syndrome in one or both eyes (r = 0.45, P = 0.0006) and with the number of cotton-wool spots (r = 0.50, P = 0.0001). In conlusion, HIV-1 related retinal microangiopathic syndrome is associated with elevated plasma levels of endothelin-1. By virtue of its potent vasoconstrictor activity endothelin-1 may be involved in the pathogenesis of HIV-1 related vascular disease.Abbreviations AIDS aquired immunodeficiency syndrome - ET-1 endothelin-1 - HIV human immunodeficiency virus - IR immunoreactivity - WR Walter Reed classification Correspondence to: B. Rolinski     

肾通胶囊对单侧输尿管梗阻大鼠ET-1及AngⅡ含量的影响

目的研究单侧输尿管梗阻(UUO)后肾间质纤维化的发生机制及肾通胶囊对其的保护作用。方法24只大鼠随机分为假手术组及对照组、手术模型组和肾通治疗组,术后第8天观察各组肾组织病理改变,检测血浆和肾组织内皮素-1(ET-1)、血管紧张素Ⅱ(AngⅡ)的含量。结果模型组血浆和肾组织中ET-1、AngⅡ增高,与对照组比较有显著差异(P<0.01),肾通治疗组与模型组比较肾组织ET-1、AngⅡ明显降低(P<0.05)。结论肾通胶囊可通过影响血浆和肾组织中ET-1和AngⅡ含量而延缓肾间质纤维化的进程。     

Endothelin-1 expression in scleroderma renal crisis

The objective of the study was to investigate the role of endothelin-1 in the pathogenesis of scleroderma renal crisis in patients with systemic sclerosis. We used immunohistochemical analysis with anti-endothelin-1 and anti-von Willebrand factor antibodies in comparing kidney biopsies from patients with systemic sclerosis and scleroderma renal crisis (n = 14); from normal kidneys (n = 5); and from patients with typical hemolytic uremic syndrome and thrombotic microangiopathy (n = 5), antiphospholipid syndrome (n = 6), diabetic nephropathy (n = 5), minimal change disease with cyclosporine toxicity (n = 5), or nephroangiosclerosis (n = 5). Kidney biopsies from all systemic sclerosis patients presented specific lesions: glomerular lesions with thickened capillary walls (n = 6, 42.8%), mesangiolysis (n = 3, 21.4%), fibrin thrombi (n = 3, 21.4%), hypertrophy of juxtaglomerular apparatus (n = 5, 35.7%), arteriolar lesions showing mucinous intimal thickening and lumen mucoid occlusions (n = 13, 92.8%), proliferation of intimal cells (ie, "onion-skin" lesions; n = 13, 92.8%), fibrinoid necrosis (n = 3, 21.4%), and fibrin thrombosis (n = 4, 28.6%). Chronic lesions in large arteries showed modifications such as fibrous intimal thickening (n = 13, 92.8%). The pattern of endothelial staining for endothelin-1 in both glomeruli and arteriolar lesions appears to be specific for scleroderma renal crisis. Glomerular endothelin-1 staining without arteriolar staining was seen in hemolytic uremic syndrome; and isolated arteriolar staining (without glomerular staining) was seen in a number of conditions including antiphospholipid nephropathy, cyclosporine toxicity, and diabetic nephropathy. Endothelin-1 is overexpressed in glomeruli and arterioles of patients with scleroderma renal crisis, which suggests that endothelin-1 might be a therapeutic target in this condition.     

Endothelin-1 (ET-1) enhances bile canalicular contractions in cultured rat hepatocytes

Time lapse cinematographic analysis revealed that the frequency of canalicular contractions in primary monolayer-cultured hepatocytes (couples and triplets) isolated from a rat liver was increased by endothelin-1 (ET-1)-treatment as compared with that of a control group. By transmission electron microscopy, vesicles were more frequently observed to be opened to the canalicular lumens during the contracting stage of the bile canaliculi in the ET-1-treated couplets and triplets than in the control group. This study was presented at the 27th Annual Meeting of the Clinical Electron Microscopy Society of Japan, Kurashiki, September 28–30, 1995.     

The CSF concentration of ADMA,but not of ET-1, is correlated with the occurrence and severity of cerebral vasospasm after subarachnoid hemorrhage

Under physiological conditions, vasoconstrictors and vasodilators are counterbalanced. After aneurysmal subarachnoid hemorrhage (SAH) disturbance of this equilibrium may evoke delayed cerebral vasospasm (CVS) leading to delayed cerebral ischemia (DCI). Most studies examined either the vasoconstrictor endothelin-1 (ET-1) or the vasodilative pathway of nitric oxide (NO) and did not include investigations regarding the relationship between vasospasm and ischemia. Asymmetric dimethyl-l-arginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), decreases the concentration of NO. Studies have correlated increasing concentrations of ADMA with the course and degree of CVS after SAH. We sought to determine, if ADMA and endothelin-1 (ET-1) are associated with CVS and/or DCI after SAH. CSF concentrations of ADMA and ET-1 were retrospectively determined in 30 patients after SAH and in controls. CVS was detected clinically and by arteriogaphy. DCI was monitored by follow-up CT scans. 17 patients developed arteriographic CVS and 4 patients developed DCI. ADMA but not ET-1 concentrations were correlated with occurrence and degree of CVS. However, ET-1 concentrations were correlated with WFNS grade on admission. Neither ADMA nor ET-1 correlated with DCI in this cohort. ET-1 concentrations seem to be associated with the impact of the SAH bleed. ADMA may be directly involved in the development and resolution of CVS after SAH via inhibition of NOS disturbing the balance of vasodilative and -constrictive components.     

Amniotic Fluid Endothelin-1 Levels Are Increased in Pregnancy-Induced Hypertension and Intrauterine Growth Retardation

Endothelin-1 (ET-1) is a potent vasoconstrictor released by vascular endothelium. Because endothelial cell damage is considered determinant in the pathophysiology of pregnancy-induced hypertension (PIH), this study was conducted to evaluate the role of ET-1 produced by feto-placental tissues in PIH. Amniotic fluid samples obtained by amniocentesis from patients with PIH (N=33), intrauterine growth retardation (IUGR) (N=16), and PIH associated with IUGR (N=12) were evaluated for ET-1 and compared to 42 normotensive pregnancies using a specific radioimmunoassay. ET-1 levels were significantly increased in PIH (35.6 ± 1.9 pg/ml) and IUGR groups (33.8 ± 4.6 pg/ml) compared to controls (20.8 ± 1.4 pg/ml) (P <0.01). In patients with PIH associated with IUGR, ET-1 concentrations were higher (P <0.05) with no correlation with the severity of IUGR. Our data indicate that in PIH and IUGR ET-1 production and/or secretion is enhanced in the amniotic compartment, suggesting that the peptide may contribute to the pathophysiologic modifications observed in these conditions.     

Endothelin-1 localization in bone cells and vascular endothelial cells in rat bone marrow

Endothelin-1 (ET-1) localization in bone cells and associated vascular endothelial cells in metaphyseal bone marrow of the rat femur was examined by a biotin-streptoavidin-horseradish peroxidase method in paraffin sections and by indirect immunogold techniques in post-embedded ultrathin sections. Mouse anti-ET-1 monoclonal antibody was used as the primary antibody. In metaphyseal bone marrow, intense immunostaining was observed over osteoclasts, osteoblasts, young osteocytes, and vascular endothelial cells. But bone and cartilage matrices and chondrocytes in the proliferating zone were negative for immunoreaction. At the subcellular level, specific immunogold labeling was localized along plasma membranes and in the cytoplasm including those of ruffled borders and clear zones of osteoclasts. Some colloidal gold particles were also detectable within pale vacuoles of osteoclasts. Immunoreactivity was also found along the plasma membranes, cisterns of rough-surfaced endoplasmic reticulum, mitochondria, and cytoplasmic matrices of osteoblasts, but was less intense than that of osteoclasts. In endothelial cells of blood capillaries in close proximity to bone cells, intense immunolabeling occurred over the cytoplasm. None of the cases examined showed accumulation of immunogold particles in the secretion granules of these cells. © 1993 Wiley-Liss, Inc.     

Endothelin-1 in patients with complicated and uncomplicated myocardial infarction

Summary Endothelin-1 concentrations were measured in peripheral venous blood samples from 42 patients with acute myocardial infarction. In patients with ischemic or hemodynamic complications (n = l1), endothelin-1 concentrations were significantly higher already on admission (P = 0.008) and remained significantly higher until day 6 after admission compared to patients with uncomplicated infarctions (n = 31; P = 0.035). There were no close correlations between peak concentrations of endothelin-1 and creatine kinase or creatine kinase isoenzyme MB mass in either group. Only in complicated patients did left ventricular ejection fraction correlate closely and inversely with peak endothelin-1 concentrations (r = –0.71; P = 0.03). Therefore, plasma endothelin-1 concentrations in patients with acute myocardial infarction patients may reflect states of markedly depressed cardiac performance and recurrent myocardial ischemia.Abbreviations AMI acute myocardial infarction - CK creatine kinase - CKMB mass CK isoenzyme MB mass - LVEF left ventricular ejection fraction - ET-1 endothelin-1     

电烧伤大鼠创面组织中VEGF及血清ET-1表达水平的变化

目的 探讨电烧伤大鼠血管内皮生长因子(VEGF)和内皮素1(ET-1)的动态变化.方法 将大鼠64只随机分成2组:电烧伤组(56只)和对照组(8只).采用免疫组织化学方法测定伤后1d,3d,7d和14d的创周组织中VEGF的表达.采用ELISA方法测定烧伤后2h,6h,12h,24h血清ET-1的浓度.结果 伤后各个时间点创周组织VEGF蛋白表达均高于正常,VEGF表达在伤后第7天达到峰值.血清ET-1浓度显著升高,2h即明显高于正常值,6h达到峰值,此后逐渐下降,伤后24h仍明显高于正常.结论 电烧伤后VEGF和ET-1的表达均显著升高,这二种变化可能参与烧伤后微血管通透性的调节.     

Endothelin-1 Promotes Cardiomyocyte Terminal Differentiation in the Developing Heart via Heightened DNA Methylation

Aims: Hypoxia is a major stress on fetal development and leads to induction of endothelin-1 (ET-1) expression. We tested the hypothesis that ET-1 stimulates the terminal differentiation of cardiomyocytes from mononucleate to binucleate in the developing heart.Methods and results: Hypoxia (10.5% O₂) treatment of pregnant rats from day 15 to day 21 resulted in a significant increase in prepro-ET-1 mRNA expression in fetal hearts. ET-1 ex vivo treatment of fetal rat cardiomyocytes increased percent binucleate cells and decreased Ki-67 expression, a marker for proliferation, under both control and hypoxic conditions. Hypoxia alone decreased Ki-67 expression and in conjunction with ET-1 treatment decreased cardiomyocyte size. PD145065, a non-selective ET-receptor antagonist, blocked the changes in binucleation and proliferation caused by ET-1. DNA methylation in fetal cardiomyocytes was significantly increased with ET-1 treatment, which was blocked by 5-aza-2''-deoxycytidine, a DNA methylation inhibitor. In addition, 5-aza-2''-deoxycytidine treatment abrogated the increase in binucleation and decrease in proliferation induced by ET-1.Conclusions: Hypoxic stress and synthesis of ET-1 increases DNA methylation and promotes terminal differentiation of cardiomyocytes in the developing heart. This premature exit of the cell cycle may lead to a reduced cardiomyocyte endowment in the heart and have a negative impact on cardiac function.     

黄连素对兔颈动脉球囊损伤后血管内皮功能及一氧化氮、内皮素-1水平的影响

目的动态观察黄连素对兔颈动脉球囊损伤后血清一氧化氮(NO)、血浆内皮素-1(ET-1)水平的影响,并探讨其改善血管内皮功能的可能机制。方法日本大耳白兔40只,随机分为假手术组、模型组、黄连素组和辛伐他汀组,除假手术组外各组均以球囊导管扩张损伤颈动脉内膜,并分别给予生理盐水、黄连素注射液和辛伐他汀配制液2.5mg/(kg.d)腹腔注射,假手术组仅普食喂养。分别于术后3、7及15d探测各组右侧颈总动脉直径,并于耳缘静脉采血,检测血清NO含量及血浆ET-1浓度。结果术后3、7及15d,黄连素组血清NO含量与假手术组无明显差异,但显著高于模型组及辛伐他汀组(P<0.01);黄连素组和辛伐他汀组血浆ET-1水平与假手术组均无明显差异,但显著低于模型组(P<0.01);术后15d,黄连素组和辛伐他汀组血管直径与假手术组均无明显差异,但显著大于模型组(P<0.01)。结论黄连素可通过抑制兔颈动脉球囊损伤后NO浓度降低及ET-1水平升高,改善动脉损伤后血管内皮功能。     

Oxytocin concentration changes in different rat brain areas but not in plasma during aging

The concentration of oxytocin was measured by radioimmunoassay in different brain areas, hypothesis, and plasma of male Wistar Kyoto rats during aging. Although no difference in the concentration of oxytocin in any of the above tissues among 2- and 6-month-old rats was found, in 12-month-old rats a 21 % decrease was observed in both septum and hippocampus, but not in the hypothalamus, hypophysis, and plasma, when compared to values of 2- and 6-month-old rats. In 18-month-old rats, the decrease of septal and hippocampal oxytocin content was higher than that found in 12-month-old rats, but no change was found in the hypothalamus, neurohypophysis, and plasma. In 24-month-old rats, oxytocin content was similar to that found in 18-month-old rats in all tissues analyzed. The results suggest that aging induces an impairment of oxytocinergic transmission in the central nervous system but not in the neurohypophyseal system.     

肺炎支原体肺炎伴喘息患儿白细胞介素13和内皮素1水平变化及意义

目的 测定肺炎支原体肺炎(MPP)急性发作期患儿血清中白细胞介素13(IL-13)和内皮素1(ET-1)的水平变化,并探讨其与喘息发作的关系.方法 收集MPP患儿50例,其中伴喘息的MPP患儿22例,非伴喘息的MPP患儿28例,以及对照组非MPP无喘息儿童20例.使用ELISA法测定三组中的血清中IL-13和ET-1的水平,比较其相关性和差异的显著性.结果 三组资料中,伴喘息组与非伴喘息组和对照组的IL-13和ET-1水平比较差异具有统计学意义(P＜0.05),但非伴喘息组与对照组之间差异不具有统计学意义(P＞0.05).结论 IL-13和ET-1参与了肺炎支原体肺炎引起喘息的发病过程,IL-13和ET-1水平升高在MPP患儿喘息的发生、发展过程中起重要作用.     

Erythrocyte,plasma and urinary magnesium in men before and after a marathon

Summary Erythrocyte, plasma and urinary magnesium (Mg²⁺) concentration was measured in 23 runners before and after a marathon race. Blood samples were drawn from an antecubital vein the morning before the race (baseline), at 3 p.m. (2 h before the start), upon finishing and 12 h later. Compared with the baseline values, the intra-erythrocyte and plasma Mg²⁺ were decreased (p<0.05 or less) immediately after the marathon, from 2.13±0.16 to 2.02±0.18 mmol · l^–1 cells and from 0.88±0.06 to 0.81±0.07 mmol · l^–1 respectively. The Mg²⁺ concentration returned to pre-race values 12 h after completion of the marathon. The urinary Mg²⁺ excretion rate decreased (p<0.001) from 29±13 to 5±3 mol · min^–1 during the marathon and increased (p<0.05) 12 h after the race to 38±18 mol · min^–1. It is concluded that the reduction in plasma Mg²⁺ ion concentration during the marathon cannot be attributed to erythrocyte uptake, urinary excretion or loss in sweat. It is suggested that Mg²⁺ may be released from erythrocytes into the extracellular fluids during sustained exercise and taken up from these fluids by the adipose cells.     

Urinary netrin-1 concentration in healthy full-term newborns

IntroductionMonitoring of renal function in acute kidney injury in the pediatric population is complicated by the lack of age-related reference values of new biomarkers. Urinary netrin-1 is a new marker to demonstrate early kidney damage. Netrin-1 has a molecular mass of 72 kDa. It is therefore unlikely that it is filtered by the glomerulus under normal conditions. However, netrin-1 is highly induced after acute and chronic kidney injury and excreted in urine in humans. The aim of the study was to determine the normal concentrations of urinary netrin-1 in healthy full-term newborns.Material and methodsThe study included 88 healthy full-term neonates (51 boys and 37 girls) born from normal, uncomplicated pregnancies. The concentration of netrin-1 was determined in urine obtained on the first or second day of life with a commercially available ELISA kit.ResultsThe urinary concentration of netrin-1 in newborns was independent of gender and time of urine collection. We found a negative correlation between both the urinary netrin-1 concentration and urinary netrin-1 concentration after normalization for urinary creatinine and the birth weight.ConclusionsThis is the first study showing the urinary netrin-1 concentration in healthy full-term newborns. Future investigation is needed to confirm its potential role as a marker of kidney function in this age group.     

先天性心脏病伴肺动脉高压内皮素-1和内皮型一氧化氮合酶的表达

目的：研究内皮素-1（ET-1）及内皮型一氧化氮合酶（eNOS）对先天性心脏病伴肺动脉高压（PH）的调控作用。 方法： 将40例先天性心脏病患儿按其肺动脉收缩压分为中重度PH组12例、轻度PH组14例、无PH组14例；另选取10例非心脏疾患手术病人10例作为对照组。采用放射免疫、硝酸还原酶、透射电镜、免疫组化等方法，观察各组患儿肺细小动脉超微结构、血ET-1、一氧化氮（NO）浓度及肺细小动脉ET-1、eNOS蛋白表达的变化。 结果： ①血浆ET-1水平，中重度PH组、轻度PH组明显高于无PH组（P<0.01）；血清NO浓度中重度PH组、轻度PH组明显低于无PH组（P<0.01）。 ②电镜下,中重度PH组肺细小动脉中膜平滑肌增生，外膜胶原纤维密集；轻度PH组肺细小动脉中膜平滑肌细胞和外膜胶原纤维增生轻于中重度PH组；无PH组肺细小动脉结构改变不明显。③免疫组化显示中重度PH组、轻度PH组肺细小动脉ET-1平均吸光度值显著高于无PH组(P<0.01)；而中重度PH组、轻度PH组肺细小动脉eNOS平均吸光度值显著低于无PH组(P<0.01)。 结论： ET-1、eNOS可能参与了先天性心脏病PH的形成与肺血管结构重建。     

大鼠肝前性门静脉高压症形成中一氧化氮和内皮素-1水平的动态变化

目的:观察大鼠肝前性门静脉高压症形成中一氧化氮(NO)和内皮素-1(ET-1)水平的动态变化,探讨其在门静脉高压症高动力循环中的作用。方法:以部分门静脉结扎(PVL)法复制肝前性门静脉高压症大鼠模型,分别用硝酸还原酶和放免法检测正常组、假手术(SO)组及PVL组术后不同时点的门静脉血浆NO^-₂/NO^-₃、ET-1水平,并同步监测血流动力学指标的动态变化。结果:PVL术后各时点NO^-₂/NO^-₃水平显著高于而ET-1水平显著低于正常组,同时伴有血流动力学的明显变化。结论:门静脉高压症大鼠存在高动力循环状态(HCS)。NO和ET-1参与HCS的形成和维持。     

The concentrations of serum,plasma and platelet BDNF are all increased by treadmill VO2max performance in healthy college men

The most current human-based studies in which brain-derived neurotrophic factor (BDNF) levels in the peripheral blood system are analyzed use it as an indicator that represents BDNF levels in the CNS. However, whether circulating BDNF (serum and plasma) is positively or inversely associated with cardiorespiratory fitness levels (VO_2max) is still controversial, and no study has done to investigate exercise effects on the concentration of BDNF stored in circulating platelets which, in fact, store a large amount of circulating BDNF. Thus, the purpose of this study was to determine the relation between VO_2max and all circulating BDNF levels (serum, plasma and platelets) in college male students (N = 18; age, 19 ± 1 years; height, 173.22 ± 7.65 cm; weight, 78.25 ± 14.25 kg; body fat percent, 13.82 ± 5.68%). Dual X-ray energy absorptiometry whole body scan was used to measure their body composition. After the overnight fast, all participants were performed VO_2max test, and their blood was collected at rest and immediately after the exercise. Our data resulted in significant increases in platelet counts and serum, plasma and platelet BDNF levels immediately after the exercise (p < 0.01). VO_2max had a significant negative correlation with serum BDNF, plasma BDNF and platelet BDNF at rest (p < 0.05) but a significant positive correlation with serum, plasma BDNF, and platelet BDNF immediately after the exercise (p < 0.01). However, our data show no correlation between VO_2max and platelet count both at rest and immediately after the exercise. In conclusion, this is the first study showing that basal BDNF levels are inversely correlated with cardiorespiratory fitness levels but that the inverse correlations turn into positive correlations with all circulating BDNF levels immediately after the exercise. Moreover, it is the first time to provide evidence that platelet BDNF levels are also positively affected by the exercise. However, future studies will be needed to investigate what tissues provide BDNF into the circulating system and to elucidate the role of circulating BDNF.     

中药清脂降粘颗粒对高粘血症兔脑软膜微血管口径的影响及血液中ET-1和NO含量的变化

目的观察中药清脂降粘颗粒(QZJLp)对高粘血症模型兔软脑膜血管口径的影响及血浆内皮素-1(ET-1)和一氧化氮(NO)水平的变化。方法采用高胆固醇饲料喂养家兔法复制高粘血症模型,观察两种剂量(0.5g,3次/日和1.0g,3次/日)QZJLp喂饲实验兔14天和35天后,其软脑膜微血管的舒缩变化,同时检测ET-1和NO的血液含量。结果与对照组比较,模型兔软脑膜微血管口径缩小,ET-1明显增加,NO降低;QZJLp喂饲14天～35天,微血管逐步扩张,ET-1不断降低,NO显著升高。结论QZJLp能有效改善实验性高粘血症兔软脑膜微循环,这种作用可能与QZJLp对血管内皮细胞分泌ET-1/NO的调节作用有关。