Long-lasting coronary vasoconstrictor effects and myocardial uptake of endothelin-1 in humans

The effect of intravenous administration of the endothelium-derived vasoconstrictor peptide endothelin-1 (ET-1 0.2, 1 and 8 pmol kg^?1 min^?1) on coronary blood flow in relation to plasma ET-1 as well as blood lactate and glucose levels were investigated in six healthy volunteers. Coronary sinus blood flow was measured by thermodilution. Administration of ET-1 elevated arterial plasma ET 35-fold, dose-dependently increased mean arterial blood pressure from 95±5 mmHg to 110±6 mmHg (P<0.01) and reduced heart rate from 64±4 beats min^?1 to 58±4 beats min^?1 (P<0.05) at 8 pmol kg^?1 min^?1. Coronary sinus blood flow was reduced maximally by 23±4% (P<0.01) and coronary vascular resistance increased by 48±11% (P<0.01). Coronary sinus oxygen saturation decreased from 35±1% to 22±2% at 2 min after the infusion (P<0.01). A coronary constrictor response was observed at a 4-fold elevation in plasma ET. The reduction in coronary sinus blood flow lasted 20 min and coronary sinus oxygen saturation was still reduced 60 min after the infusion. Myocardial oxygen uptake or arterial oxygen saturation were not affected by ET-1. Myocardial lactate net uptake decreased by 40% whereas glucose uptake was unaffected. At the highest infusion rate there was a net removal of plasma ET by 24±3% over the myocardium (P<0.05). The results show that ET-1 induces long-lasting reduction in coronary sinus blood flow via a direct coronary vasoconstrictor effect in healthy humans observable at a 4-fold elevation in plasma ET-1. Furthermore, there is a net removal of circulating ET-1 by the myocardium.     

老年男性高血压患者血浆ADM和ET-1含量变化的意义

目的:探讨老年男性高血压患者血浆肾上腺髓质素(ADM)、内皮素-1(ET-1)含量变化的临床意义.方法:用放射免疫分析测定62例老年男性高血压患者血浆ADM、ET-1含量,并与35例年龄、性别匹配的健康老年人对照.结果:高血压组血浆ADM、ET-1含量显著高于正常对照组(P＜0.01),两者均随高血压分级1、2、3级组逐渐递增(P＜0.01,＜0.05);血压控制不良者明显高于血压控制良好者(P＜0.01),病情重组显著高于病情轻组(P＜0.01);伴肾功能受损者也显著高于肾功能正常者(P＜0.01);血浆ET-1含量平均增幅明显高于血浆ADM(P＜0.01);高血压组血浆ADM与ET-1含量呈正相关(r=0.394,P＜0.01);正常对照组两者含量不相关(r=0.172,P＞0.05).结论:老年男性高血压患者血浆舒血管活性肽ADM含量显著增高,可能是机体的一种代偿性自身调节机制,以此抑制ET-1等缩血管活性肽增高对血压调节产生不良的影响,对机体起到自身代偿性保护作用.     

缺氧时心肌血流量的变化及一氧化氮和内皮素-1的调节作用

目的探讨一氧化氮和内皮素-1在缺氧时对心肌血流量的调节作用。方法大鼠随机分为平原组和急性缺氧组,用99mTc标记蟾蜍红细胞测定心肌血流量,用Gess法和放免法分别测量血浆和心肌NO2-、内皮素-1（endothelin-1,ET-1）含量,用双波长分光光度法测量一氧化氮氧合酶（nitric oxide synthase,NOS）活性。结果急性缺氧导致左右心室心肌血流量、血浆和心肌血NO2-、ET-1含量、NOS活性明显增高（P〈0.05）,左右心室心肌血管阻力和心肌ET-1/NO2-比值明显下降（P〈0.05）,血球压积（Hct）及心室重量指数无明显变化。结论急性缺氧时,左右心室心肌血流量增加,ET-1/NO参与了急性缺氧时心肌血流量的调节,以NO的扩血管作用为主。     

窒息新生儿脐血内皮素-1及降钙素基因相关肽的检测及意义

目的 :研究窒息新生儿脐血内皮素 - 1(ET - 1) ,降钙素基因相关肽 (CGRP)的水平及意义。方法 :用放射免疫法检测了 40例窒息新生儿及 40例正常新生儿脐血及生后 1天外周血ET - 1与CGRP的水平。结果 :与正常新生儿相比 ,窒息新生儿脐血及生后 1天外周血EF - 1、CGRP水平均显著升高 ,二者呈正相关。结论 :新生儿窒息ET - 1生成增加可能起着损伤机体的作用 ,而CGRP升高可能是机体的自我保护机制 ,检测脐血其变化可替代外周血检测。     

原发性下肢深静脉瓣膜功能不全激光微创治疗术后血浆ET-1、NO水平的变化

目的:探讨原发性深静脉瓣膜功能不全患者血浆内皮素-1(endothelin-1,ET-1)、一氧化氮(nitric oxide,NO)水平的变化及与病情轻重和临床治疗的关系.方法:分别选择495例原发性深静脉瓣膜功能不全住院患者和495例同期同龄同性别健康查体者,分别抽取空腹静脉血,制备相关标本,采用放射免疫分析和Gr...     

Sympathetic effects on cerebral and ocular blood flow in rabbits pretreated with indomethacin

The effects of unilateral stimulation of the cervical sympathetic chain on cerebral and ocular blood flow was investigated in 8 rabbits anesthetized with pentobarbital sodium and pretreated with indomethacin in order to inhibit the formation of prostaglandins. Blood flow determinations were made with the labelled microsphere method during normotension and acute arterial hypertension. Hypertension was induced by ligation of the thoracic aorta. Evans blue was given as a tracer for protein leakage during hypertension. Sympathetic stimulation had no significant effect on the blood flow in the brain under the two conditions studied. In the uvea marked effects of sympathetic stimulation were obtained at normotension as well as at hypertension. There were no indications of breakdown of the blood-brain barrier or the blood-aqueous barrier. Thus, there was no evidence for any prostaglandin-mediated inhibition of sympathetic effects in the brain or the eye.     

恶性葡萄胎患者化疗前后血浆leptin、ET-1和血清INH检测的临床意义

目的:探讨了恶性葡萄胎患者化疗前后血浆leptin、ET-1和血清INH水平变化及临床意义.方法:分别应用放射免疫分析和酶联法对31例恶性葡萄胎患者进行了化疗前后血浆leptin、ET-1和血清INH测定,并与35例正常健康人做比较.结果:恶性葡萄胎患者在化疗前血浆leptin、ET-1和血清INH水平变化均非常显著地...     

Augmented expression of endothelin-1, endothelin-3 and the endothelin-B receptor in breast carcinoma

AIMS: Endothelins (ETs) are peptides expressed in many tumours which may stimulate angiogenesis and desmoplasia. Because ETs have not been extensively studied mammary neoplasia, we assessed ET protein and mRNA expression and receptor mRNA expression in normal and neoplastic breast tissues. METHODS AND RESULTS: Tissues from five normal breasts, six fibroadenomas, seven ductal carcinomas in situ (DCIS) and 25 invasive carcinomas were stained with anti-ET-1 and anti-ET-3 antibodies and analysed using a grading system. ET-1, ET-3, ETA and ETB mRNA expression was assessed by quantitative RT-PCR from eight carcinomas and five normals. Weak staining for ET-1 and ET-3 was detected in all normals. Moderate to strong staining was seen in 72% and 64% of carcinomas for ET-1 and ET-3, respectively. Most fibroadenomas showed weak positivity for ET-1 (83%) and ET-3 (67%). ET-1 and ET-3 mRNA levels were upregulated in carcinomas compared with normal breast. No ETA mRNA was not detected in any tissue. ETB mRNA was detected in normal breast and was increased in carcinomas. CONCLUSION: These results suggest that the ET system is altered in breast carcinomas and this may be of importance in the progression from in-situ to invasive carcinoma.     

妊高征患者血浆ET-1和血清INH、D-D检测的临床意义

目的:探讨了血浆内皮素-1(ET-1)和血清抑制素(INH)、D-二聚体(D-D)水平在妊高征患者发病中的变化和临床意义.方法:采用放射免疫分析、酶联法和生化法对32例妊高征患者进行了血浆ET-1和血清INH、D-D检测,并与35名正常孕妇作比较.结果:妊高征患者血浆ET-1和血清INH、D-D水平均非常显著地高于正常...     

妊高征肾病患者血浆ET-1、leptin和NPY检测的临床意义

目的：探讨了妊高征肾病患者血浆内皮素-1（ET-1）、leptin和NPY水平的变化及意义。方法：应用放射免疫分析对30例妊高征肾病患者进行了血浆ET-1、leptin和NPY测定,并与35名正常健康人作比较。结果：妊高征肾病患者血浆ET-1、leptin和NPY水平均显著高于正常人组（P〈0.01）,妊高征肾病患者血浆ET-1、leptin和NPY水平呈明显的正相关（r=0.5812、0.6015,P〈0.01）。结论：检测妊高征肾病患者血浆ET-1、leptin和NPY水平的变化对了解病情、观察预后均具有重要的临床价值。     

ACI患者治疗前后血浆ET-1和血清NSE、NPY联检的临床意义

目的:评估了急性脑梗死(ACI)患者治疗前后血浆内皮素-1(ET-1)和血清神经元特异性烯醇化酶(NSE)、神经肽-Y(NPY)水平的变化及临床意义.方法:应用放射免疫分析对32例ACI患者进行了治疗前后血浆ET-1和血清NSE、NPY检测,并与35名正常健康人作比较.结果:在治疗前血浆ET-1和血清NSE、NPY水平...     

哮喘儿童AIT治疗前后血浆ET-1和血清IgE水平变化

目的:观察哮喘儿童变应原免疫治疗(AIT)前后血浆内皮素-1(ET-1)与血清IgE水平变化,以探讨二者在哮喘变应原免疫治疗中的意义和关系.方法:应用放射免疫分析检测46例哮喘儿童变应原免疫治疗前后血浆ET-1与血清IgE水平,并与32例正常对照组进行比较.结果:治疗有效组(35例)治疗前血浆ET-1与血清IgE水平分别为(59.1±11.7)pg/ml和(11.1±3.2)IU/ml,均显著高于正常对照组(P＜0.01),AIT治疗后显著降低,分别为(52.7±11.1)和(8.2±2.4)IU/ml(P＜0.01).治疗无效组(11例)治疗前后ET与IgE水平无显著性变化.结论:治疗后血浆ET-1与血清IgE水平降低可能是哮喘患儿AIT治疗有效的重要机理.     

The interaction of tumour necrosis factor alpha and endothelin-1 in pathogenetic models of asthma

Background There is evidence that tumour necrosis factor alpha (TNFα) may be an important mediator in initiating asthmatic airway inflammation. It has been proposed that endothelin-1 (ET-1) is involved in bronchoconstriction and airway remodelling in asthma. It is not known, however, if there is any interaction between TNFα and ET in perpetuating airway inflammation in asthma. Objective The present study aimed to determine the activities of ET-1 and TNFα in ovalbumin-sensitized guinea pigs and their roles in the development of airway inflammation. Method Twelve guinea pigs were sensitized by ovalbumin injection and aerosol inhalation. ET-1 levels were measured in both bronchoalveolar lavage fluid (BALF) and plasma by ¹²⁵-labelled endothelin-1 (ET-1) radioimmunoassay. The TNFα activity released from alveolar macrophage (AM) in BALF was estimated by ELISA. Cultured bovine airway smooth muscle cells (BASMCs) were treated with TNFα (1000 units/5 ± 10⁴ cells) for different times. ET-1 levels in harvested medium from these cells were measured by radioimmunoassay. Cultured human fetal lung fibroblasts (HFLFs) were incubated with ET-1(10^–8–10^–6M), then ³HTdR incorporation to these cells and cell counting were performed. The effects of ET-1 stimulation on the granulocyte macrophage colony stimulating factor (GM CSF) gene expression in HFLFs were estimated by using RT- PCR method. Results ET-1 levels in both plasma and BALF were significantly higher in ovalbumin- sensitized guinea-pigs compared with those in controls (422.27 × 175.0pg/mL vs 277.311 × 88.0pg/mL, P < 0.05, 81.22 × 16.15 vs 49.81 × 12.64pg/mL, P < 0.05) while TNFα activity was also significantly increased in the OVA-sensitized group compared with that in the control group (6010 ± 1900pg/mL vs 2810 × 450 pg/mL, P < 0.05). The ET-1 level in harvested medium of BASMCs rose significantly in 12 h in the TNF-α treated group (from < 5pg/mL to53.72 × 14.3pg/mL, P < 0.001), and remained at a similar level for 24 h in the TNFα treated group. It was shown that ET-1 not only stimulated cell proliferation but also induced GM-CSF mRNA expression in HFLFs. Conclusion ET-1 levels in both plasma and BALF and TNFα release from macrophage are increased significantly in ovalbumin-sensitized guinea-pigs. TNFα stimulates ET-1 secretion from cultured BASMCsw; ET-1 accelerates cell proliferation and induces GM- CSF mRNA expression in the human fetal lung fibroblast.     

妊高征患者血浆ET-1、NO、INH和EGF检测的临床意义

目的:探讨了血浆ET-1、NO、INH和EGF水平在妊高征患者发病中的变化和意义.方法:分别采用生化法、ELISA法和放射免疫分析对41例妊高征孕妇进行了血浆ET-1、NO、INH和EGF水平测定,并与35名正常孕妇作比较.结果:妊高征患者血浆ET-1、INH水平显著地高于正常人组(P＜0.01),而NO、EGF水平则显著低于正常人组(P＜0.01).结论:检测妊高征患者血浆ET-1、NO、INH和EGF水平的变化对判断病情的严重程度、病情的发展均具有重要的临床价值.     

Arrhythmogenic effects of endothelin-1 under conditions of NO-synthase blockade with L-NAME in NMRI mice

Arrythmogenic effects of endothelin-1 were studied in NMRI mice under conditions of NO-synthase blockade with N-nitro-L-arginine methyl ester. Intravenous injection of endothelin-1 increased heart rate variability in awake mice. NO-synthase blockade potentiated the arrythmogenic effects of endothelin-1. In narcotized animals the arrythmogenic effect of endothelin-1 was not observed and was considerably weakened under conditions of NO-synthase blockade. Arrhythmia was paralleled by atrioventricular block and lengthening of the ST segment.     

阿司匹林抑制内皮素-1诱导的大鼠心脏成纤维细胞增殖

目的 探讨阿司匹林（Aspirin）对内皮素-1(ET-1)诱导的大鼠心脏成纤维细胞（CFs）增殖的干预作用及可能机制。方法 经差速贴壁法培养的新生大鼠CFs,随机分为7组：对照组、ET-1组、阿司匹林组、ET-1+ 阿司匹林1、2、5和10 mmol·L-1组。用四氮唑盐（MTT）法测定CFs数目,流式细胞仪检测CFs细胞周期,液体闪烁计数仪测定CFs 3H-脯氨酸掺入率,硝酸还原酶法测定细胞培养上清液中NO含量。结果 与对照组相比,10-7 mol·L-1 ET-1能显著促CFs增值及[3H]-Proline掺入率,降低CFs生成NO2-/NO3-的量（均P < 0.01）,1～10 mmol·L-1 阿司匹林呈浓度依赖性的缓解上述变化（均P < 0.05）; ET-1能显著提高S期细胞百分率（P < 0.01）,10 mmol·L-1 阿司匹林抑制ET-1诱导S期细胞百分率上升（P < 0.01）。结论 阿司匹林抑制ET-1诱导的CFs增殖及胶原合成可能和NO生成有关。     

Effects of indomethacin on regional blood flow in conscious rabbits—a microsphere study

In an attempt to reveal the importance of prostaglandins in the control of regional blood flow 20 mg/kg b.wt. indomethacin was given i.v. in conscious resting rabbits. Regional blood flow determinations were made before and 20 min after the injection using the labelled microsphere technique. The blood flow in the stomach wall was reduced by 0.75 ± 0.17 g·min^-1·g^-1 from a level of 1.64 ± 0.24 g·min^-1·g^-1. In jejunum the corresponding figures were 0.44 ± 0.12 and 1.26 ± 0.17 and in the brain 0.29 ± 0.10 and 1.24 ± 0.10. The blood flow in the liver via the hepatic artery increased by 0.20 ± 0.02 g·min^-1·g^-1 from a level of 0.13 ± 0.02 g·min^-1·g^-1. In the retina there was a reduction in blood flow by 2.75 ± 1.03 mg·min^-1 from a starting level of 15.1 ± 2.3 mg·min^-1. In a number of other tissues investigated there were no significant effects of the drug. The results suggest that under resting conditions prostaglandins play a role in the control of blood flow in the gastrointestinal tract, the brain and the retina—tissues which are likely to be rather active under such conditions.     

自发性高血压鼠脑基底动脉ET-1的表达及其意义

为探讨高血压时期内皮素-1(endothelin-1,ET-1)在脑血管神经源性调节中的作用,本研究应用反转录-聚合酶链式反应(RT-PCR)技术,检测了自发性高血压鼠脑基底动脉ET-1mRNA的表达变化;应用免疫印迹(Western blotting)方法,观察了自发性高血压鼠脑基底动脉ET-1的表达。结果显示:自发性高血压鼠脑基底动脉ET-1mRNA的表达较正常血压鼠明显增加;自发性高血压鼠脑基底动脉ET-1表达亦较正常血压鼠明显增加(P<0.05)。此结果提示自发性高血压鼠脑基底动脉高表达的ET-1和ET-1mRNA在自发性高血压鼠脑血管的神经源性调节中可能发挥重要作用。     

Pemphigus vulgaris: the role of IL-1 and IL-1 receptor antagonist in pathogenesis and effects of intravenous immunoglobulin on their production

Intravenous immunoglobulin (IVIG) is increasingly being used for the treatment of autoimmune diseases. In the present report, the role of IVIG on in vivo and in vitro production of IL-1 and IL-1 receptor antagonist (Ra) was studied in patients with pemphigus vulgaris (PV). Serum samples from 20 untreated patients with active PV prior to initiation of systemic therapy, 20 patients receiving IVIG treatment, 20 patients in clinical remission after conventional therapy, and 20 normal human controls were studied to determine the serum levels of IL-1alpha, IL-1beta, and IL-1Ra. The in vitro production of these cytokines was measured in the culture supernatant of peripheral blood mononuclear cells (PBMC) from 10 PV patients immediately before and after IVIG therapy and from age and sex-matched 10 healthy donors simultaneously. Elevated levels of IL-1alpha and IL-1beta were detected (i) in the serum of untreated PV patients with active disease prior to systemic therapy and (ii) before IVIG infusions in patients receiving IVIG therapy. These increased levels are statistically significant when compared to the levels in healthy controls (P < 0.01). A marked reduction of IL-1alpha and IL-1beta was detected (i) in the serum of patients in prolonged clinical remission and (ii) immediately after IVIG infusion in those patients on IVIG therapy. Increased level of IL-1Ra was detected in PV patients in prolonged clinical remission and after IVIG infusion in those receiving IVIG therapy. These differences were statistically significant when compared to the levels in normal controls and to the levels in the sera of patients with active disease (P < 0.01) or just before the beginning of IVIG infusion (P < 0.01). Similar differences in the levels of IL-1alpha, IL-1beta, and IL-1Ra were found in the culture supernatant of PBMC isolated from the PV patients pre and post IVIG therapy. These observations suggests that, compared to normal controls, patients with active PV have reversed levels of IL-1alpha, IL-1beta, and IL-1Ra. IVIG therapy may down-regulate production of IL-1alpha and IL-1beta and enhance production of IL-1Ra, in vivo and in vitro. This might be one of the important mechanisms by which IVIG produces its early therapeutic effects in pemphigus vulgaris.