NO代谢变化对缺血性脑组织内皮素产生的影响

在兔大脑中动脉阻断（ＭＣＡｏ）型局灶脑缺血前后分别应用外源性一氧化氮合成酶（ＮＯＳ）抑制剂Ｌ－ＮＮＡ和ＮＯ合成底物Ｌ－ａｒｇｉｎｉｎｅ，观察缺血４小时后脑组织内皮素（ＥＴ）含量的变化。结果发现Ｌ－ＮＮＡ组较缺血对照组脑组织ＥＴ含量明显增多（１２６２．９±３８７．６ｖｓ７８９．３±１８８．４ｐｇ／ｍｇ·ｐｒｏ，Ｐ值＜０．０１），脑水肿显著；而Ｌ－ａｒｇｉｎｉｎｅ用药组脑组织ＥＴ含量较缺血对照组明显减少（Ｐ值＜０．０５），且脑水肿减轻。本研究提示ＮＯ能抑制缺血脑组织ＥＴ的产生。ＮＯ对脑缺血影响可能与此途径有关。     

一氧化氮和内皮素-1在新生儿缺氧缺血性脑病中的作用

目的　研究新生儿缺氧缺血性脑病(HIE)患儿脑脊液一氧化氮(NO)和内皮素-1(ET-1)水平变化,探讨NO 和ET-1在HIE中的作用及相互关系。方法　检测24 例HIE患儿脑脊液NO和ET-1 水平,并与8 例对照组比较。结果　HIE组患儿脑脊液NO 和ET-1 水平明显高于对照组(P< 0.05),中、重度HIE组患儿脑脊液NO 和ET-1水平明显高于轻度HIE组(P< 0.05),头颅CT异常HIE患儿脑脊液ET-1 水平明显高于CT正常者(P< 0.01)。结论　NO和ET-1 参与新生儿HIE的病理生理过程,脑脊液NO和ET-1 是反映脑实质损伤的重要指标     

急性脑梗死患者血浆内皮素、血管紧张素、一氧化氮的动态变化及其临床意义

目的　探讨急性脑梗死患者血浆内皮素、血管紧张素、一氧化氮的动态变化及其临床意义。方法　测定2 0例健康对照组及 40例急性脑梗死患者急性期不同时段的血浆内皮素 (ET1)、血管紧张素Ⅱ (ATⅡ)、一氧化氮 (NO)的含量。结果　与健康组比较 ,急性脑梗死患者发病 2 4小时内ET1、ATⅡ 、NO均开始明显升高 ,第 3～ 4天仍维持于高水平 ,一周后开始下降 ,NO一周后下降至正常水平 ,ET1、ATⅡ二周后下降至正常水平。结论　急性脑梗死患者其血浆ET1、ATⅡ 、NO均发生动态变化 ,并在发病过程中发挥重要的作用。     

阿伐他汀对成年大鼠心肌成纤维细胞分泌内皮素-1及一氧化氮合酶/一氧化氮系统活性的影响

目的 :探讨阿伐他汀 (Atorvastatin)对大鼠心肌成纤维细胞 (CFs)分泌内皮素 1(ET 1)含量及一氧化氮合酶 /一氧化氮 (NOS NO)系统活性的影响。　方法 :采用胰蛋白酶和胶原酶混合消化法 ,差速贴壁获取CFs。应用放免法、硝酸还原酶法和分光光度法分别测定不同干预条件下CFs培养液中ET 1水平及NOS NO活性。　结果 :①阿伐他汀呈浓度依赖性抑制CFs分泌ET 1,10 -6、10 -5和 10 -4mol/L阿伐他汀组与对照组相比差异非常显著 (均P <0 .0 1) ;10 -5和 10 -4mol/L阿伐他汀组分别与 10 -7和 10 -6mol/L阿伐他汀组相比差异非常显著 (均P <0 .0 1)。②阿伐他汀可升高CFsNO含量 ,10 -5和 10 -4mol/L阿伐他汀组与对照组相比差异显著 (P <0 .0 5 )和非常显著 (P <0 .0 1) ;10 -4mol/L阿伐他汀组与 10 -7mol/L阿伐他汀组相比差异显著 (P <0 .0 5 )。③阿伐他汀可增强CFsNOS活性 ,10 -5和 10 -4mol/L组阿伐他汀与对照组相比差异显著 (P <0 .0 5 )或非常显著 (P <0 .0 1) ;10 -4mol/L与 10 -7mol/L阿伐他汀组相比差异显著 (P <0 .0 5 )。　结论 :阿伐他汀能抑制CFs分泌ET 1,提高CFsNOS NO系统活性 ,拮抗血管紧张素Ⅱ (AngⅡ )的部分生物活性 ,发挥其逆转心室重塑、改善心功能的作用     

Affinity enhancement of complementary peptide recognition

A peptide hydropathically complementary to Big Endothelin [Big ET] residues 16-29 has been synthesized in a multimeric form starting from an octadentate poiylysine core, essentially in a way similar to the procedure used for the production of multiple antigenic peptides [MAP's], Interaction between the multimeric complementary peptide [8δET] and the Big ET fragment 16-32 containing the target complementary region, also synthesized in a multimeric form [8ET], was evaluated by analytical high performance affinity chromatography and solid phase binding assays. While the binding interaction between the monomerics peptide pair was in the micromolar range, the recognition between the corresponding multimeric form was characterized by enhanced binding affinity of at least two orders of magnitude. In solution, complex formation between multimeric complementary peptide and target Big ET sequence in the monomeric and multimeric form was accompanied by precipitation at concentrations higher than 0.5 mg/mL and 0.1 mg/mL, respectively. Polyclonal antibodies raised against the multimeric target sequence recognized multimeric and monomeric ET target sequences with binding affinities similar to binding affinities exhibited by the multimeric complementary peptide. Multimerization of hydropathically complementary peptides could provide an improved opportunity to measure and thus probe quantitative binding properties of complementary peptides.     

Change in digital blood flow with simultaneous reduction in plasma endothelin induced by hand-arm vibration

Involvement of endothelium-derived relaxing factor (EDRF) or endothelium-derived constricting factor (EDCF) has been proposed as the pathophysiologic mechanism of vibration-induced white finger (VWF). Recent evidence that endothelin is a potent vasoconstrictor peptide indicates that it may play a role in vasoregulation during vibration exposure through the local actions of EDRF or EDCF. Therefore, we examined the effects of grasping (50 N) and hand-arm vibration (50 m/s² rms, 120 Hz, x-axis) on digital blood flow (DBF) and on the level of plasma endothelin in seven healthy male office workers. Grasping decreased DBF without affecting endothelin, and vibration increased DBF with a simultaneous reduction in endothelin. The grasping-induced decrease in DBF seemed to be due to mechanical compression of the vessels. The negative correlation between DBF and endothelin during vibration exposure suggests that a reduction in release of endothelin from smooth muscle into the vessel cavity during vibration leads to vasodilatation, possibly attributable to the local axon reflex.     

Effects of blockade of the endothelin receptor A and inhibition of nitric oxide synthesis on uteroplacental and renal blood flow in awake pregnant rats

OBJECTIVE: The aim of this study was to evaluate the role of the ETA receptor and nitric oxide (NO) in the regulation of uteroplacental and renal blood flow in pregnant rats. STUDY DESIGN: Regional blood flows were measured by the microsphere technique in pregnant Sprague-Dawley rats (term 23 days). Blood flow was measured before and after ETA receptor blockade (BQ-123, 1 mg/kg) at gestational day (GD) 19 or 21 (n=8 and n=9, respectively). In 2 additional groups blood flow was measured before and after NO synthase inhibition (L-NAME 2 microg/min) at GD 19 or 21 (n=10 in each group). RESULTS: BQ-123 significantly increased placental and myometrial blood flows by almost 80% and 35%, respectively, at both gestational ages. BQ-123 did not alter renal blood flow. No effect on placental or myometrial blood flow was observed after L-NAME infusion, neither at GD 19 nor GD 21. Renal blood flow decreased by nearly 35% in both groups after L-NAME. CONCLUSION: There is an important role for endogenous ET in the regulation of uteroplacental blood flow in the rat. NO contributes to a significant vasodilatation in the renal vasculature; however, NO appears not to be involved in the maintenance of uteroplacental blood flow in the awake pregnant rat.     

Current Therapy of Pulmonary Hypertension

Abstract Pulmonary arterial hypertension (PAH) affects vascular proliferation and remodeling in small pulmonary arteries and results in right ventricular failure and death due to a progressive increase in pulmonary vascular resistance. Recent advances in understanding of the molecular mechanisms involved in PAH suggest that endothelial dysfunction plays a major role. Impaired production of vasoactive mediators, such as prostacyclin and nitric oxide, accompanied with prolonged overexpression of vasoconstrictors such as endothelin-1, affects vascular tone and reinforces vascular remodeling. As the latter substances represent logical pharmacological targets, new drugs affecting these mechanisms have evolved during the past 2 decades and led to umpteen placebo-controlled trials in bygone years. Prognosis and quality of life of patients suffering from PAH seem to improve due to these new treatment strategies resulting in a reduction of mortality and morbidity, but there is still a substantial need for further long-term and head-to-head trials.     

内皮素受体在雄激素非依赖性前列腺癌中的作用

目的 研究雄激素非依赖性前列腺癌株PC3中内皮素(ET)受体表达及受体阻断后PC3细胞的凋亡情况。方法 RT-PCR法测定PC3中ET受体的表达以及采用受体拮抗剂干预后其表达的变化,通过流式细胞仪和透射电镜研究干预后PC3细胞凋亡的情况。结果 PC3中ETA表达较高,而ETB表达非常弱。ETA受体拮抗剂干预后,ETA表达明显减少,随干预浓度的增加,PC3细胞凋亡的比例逐渐增加;而ETB受体拮抗剂干预后无明显改变。结论 PC3中ET-1的作用主要通过ETA受体介导,ETB受体是静止的。ETA受体阻断后,表达减少,PC3细胞出现凋亡,并呈剂量依赖关系。     

Endothelin-1 levels and cardiovascular risk factors in renal transplant patients

OBJECTIVE: Circulating endothelin-1 (ET-1) levels have been reported to be associated with vascular complications and endothelial dysfunction in nontransplanted patients. The aim of this study was to investigate the relationship between ET-1 levels and major cardiovascular (CV) risk factors in renal transplant (RTX) patients with stable graft function. METHODS: ET-1 levels were determined in 156 RTX patients and the relationship between circulating ET-1 levels and CV risk factors including age, gender, kidney function, blood lipids, diabetes, and hypertension was studied. RESULTS: Circulating ET-1 levels were found to be positively correlated with creatinine (r = 0.25, p < 0.01) and systolic blood pressure (r = 0.20, p < 0.05) and inversely correlated with high-density lipoprotein cholesterol (HDL-C) levels (r = -0.27, p < 0.01). Patients with high and intermediate total cholesterol/HDL-C ratios (TC/HDL-C) had significantly higher ET-1 levels when compared to patients with low ratios (7.02 +/- 3.74, 6.79 +/- 2.67, and 5.37 +/- 3.04 pg/ml, respectively, p < 0.002). Only creatinine, HDL-C, and age >40 years were shown to be independent correlates for ET-1 levels according to multivariate analyses. Interestingly, ET-1 levels were significantly higher (+26%, p < 0.03) in RTX patients with documented CV disease, as compared to those without, when matched for age, gender, and presence of diabetes. CONCLUSIONS: Increased circulating ET-1 levels are associated with low HDL-C and documented CV disease in RTX. This is likely a reflection of vascular endothelial damage and dysfunction and therefore may represent an increased risk for atherosclerosis.