失血性休克再灌注后血浆内皮素的变化及磷脂酶A_2阻断剂对它的影响

家兔出血性休克再灌注（Ｓ／Ｒ）后，放免分析发现血浆内皮素逐渐升高，同失血前比较第６ｈ有显著差异（Ｐ＜０．０５），假手术组没有改变。磷脂酶Ａ_２阻断剂氯喹、磷酸萘酚喹和抗氧化剂黄芪酮于失血后再灌注前使用可抑制Ｓ／Ｒ后２ｈ内血浆内皮素增高，后两者可更明显降低Ｓ／Ｒ后３０ｍｉｎ的内皮索水平，与失血前比较差异非常好著（Ｐ＜０．０１）。同时，ＨＣＯ~－_３和碱贮备（ＳＢＣ）显著降低，上述三种药物治疗显著增加ＨＣＯ~－_３和ＳＢＣ的含量，它们在Ｓ／Ｒ后２４ｈ明显高于Ｓ／Ｒ组的水平（Ｐ＜０．０１）。结果提示，Ｓ／Ｒ后血浆内皮素上升可能与代谢性酸中毒加重有一定联系。磷脂酶Ａ_２阻断剂和抗氧化剂可能通过早期抑制内皮素的释放，从而减轻２４ｈ后代谢性酸中毒程度。     

The effects of endothelin-1 on degranulation, cytokine, and growth factor production by skin-derived mast cells

Endothelin-1 (ET-1), originally described as a vasoconstrictor, is now known to be involved in pathogenesis of various disorders including vascular, inflammatory, and fibrotic diseases. Recent studies suggest that mast cells are also involved in the same pathological conditions. In this study, we tested a hypothesis that ET-1 would affect mast cell functions and contribute to such disease conditions, using fetal skin-derived cultured mast cells (FSMC) and bone marrow-derived cultured mast cells (BMMC). FSMC expressed ET receptors (ET(A) and ET(B)) at mRNA and protein levels, whereas BMMC expressed lower levels of ET(A), and little, if any, ET(B). ET-1 induced degranulation by FSMC, but not by BMMC through ET(A)-mediated pathways. ET-1 at different concentrations exerted the reciprocal effects on degranulation by IgE-bound FSMC. Furthermore, ET-1 induced TNF-alpha and IL-6 production by FSMC, but not by BMMC, and significantly enhanced VEGF production and TGF-beta1 mRNA expression by FSMC. Finally, ET-1 was produced by FSMC, but not by BMMC in response to Toll-like receptor ligands. These results indicate contrasting impacts of ET-1 on distinct mast cell populations. We propose that ET-1 may participate in pathological conditions of various disorders via its multi-functional effects on mast cells under certain conditions.     

菊苣提取物对高糖复合高血脂模型兔血浆vWF、ET及PGI2/TXA2含量的影响

观察高糖复合高血脂和菊苣提取物对复合模型兔血浆vWF、内皮素 (ET)、前列环素 (PGI2 )和血栓素 (TXA2 )水平变化 ;分析其抗动脉粥样硬化的机理。选用高脂饲料 ,Alloxan静注方法制造高血糖复合高血脂模型 ,预防给药。实验 10周后 ,以放射性同位素免疫法检测vWF、ET、PGI2 、TXB2水平。结果发现①模型动物与正常组比较 ,血浆vWF、ET水平明显升高 ,TXA2 水平升高 ,PGI2 含量明显下降。②菊苣提取物能降低模型动物vWF、ET、TXA2 含量 ,升高PGI2 水平 ,改善PGI2 /TXA2 比值。表明 :菊苣提取物能有效降低复合模型兔血浆vWF、ET、TXA2 含量 ,升高PGI2 含量 ,此作用可能与之抗动脉粥样硬化作用相关     

肾局部血流在蛋白尿产生中的机制初探

目的 了解肾局部血流在蛋白尿发生发展过程中的变化及产生机制。方法 ①一次性注射法复制大鼠阿霉素肾病综合征模型。并测取２４ｈ尿蛋白含量;②分别于蛋白尿的前期、上升期、高峰期及下降期和多功能监护仪测量血压变化,激光多普勒微血管流量测定仪测定肾皮质血流;③取血及肾皮质匀浆用放射免疫法检测内皮素（ＥＴ）含量,用Ｇｒｉｅｓｓ法检测一氧化氮（ＮＯ）代谢产物ＮＯ２＾－,代表ＮＯ水平;④分别研究肾皮质血流与血浆、肾皮质的ＥＴ、ＮＯ、尿蛋白排泌量的变化及相关性。结果 ①平均动脉压（ｍｍＨｇ）正常鼠４个时间点数值为１１８,１１９,１１８,１１７;肾病鼠为１１６,１２４,１２９,１２１;各时间点与同期正常鼠间差异无显著性;②肾局部血流量（Ｐｕ）：正常鼠４个时间点值为６６．２,６８．４,６７．２,７０;肾病鼠为５８,５２,１９,２３;     

前列腺素E_1降低糖尿病肾病患者血浆内皮素水平

目的 :研究静脉输注前列腺素E1(PGE1)对 2型糖尿病患者血浆内皮素 (ET)水平影响。观察PGE1治疗 /ACEI治疗对糖尿病蛋白尿的影响。方法 :观察PGE1治疗组、ACEI治疗及普通治疗组对糖尿病蛋白尿水平的疗效 ,并对前列腺素E1治疗前后糖尿病患者血浆内皮素水平进行检测。结果 :糖尿病患者血浆内皮素水平明显高于正常对照组。静脉输注PGE1可显著降低糖尿病患者血浆内皮素水平。PGE1可显著降低糖尿病患者蛋白尿水平 ,效果明显高于ACEI治疗组 ,而后者疗效又显著高于非ACEI治疗组。结论 :PGE1可显著降低糖尿病患者蛋白尿水平 ,此作用可能与降低糖尿病患者血浆内皮素水平有关。     

福辛普利对高血压患者降压疗效及对血浆内皮素的影响

目的 :观察福辛普利 (Fusinpril)对高血压 (EH )患者的降压作用及对高血压患者血浆内皮素 (ET)的影响。方法 :测定 5 2例EH患者口服福辛普利前后和 3 0例健康者的血浆ET含量 ,动态观察福辛普利对EH组治疗前后血压变化。结果 :EH组血浆ET水平明显高于对照组 (P <0 0 1)。在高血压组中 ,ET随着血压水平程度的增高 ,而增高 ,轻、中、重组间比较有统计学意义 (P <0 0 1)。结论 :福辛普利在EH患者产生降压作用的同时降低血浆ET水平。     

哮喘患儿血浆内皮素、降钙素基因相关肽和一氧化氮的测定及临床意义

目的 研究内皮素（ET）、降钙素基因相关肽9CGRP）和一氧化氮（NO）在哮喘患儿的发病作用及临床意义。方法 对22例重度哮喘发作患儿治疗前后用放射免疫法测定血浆ET、CGRP含量,用比色法测定NO含量,并与20例健康儿童作对照分析。结果 哮急性发作期血将ET、NO水平均高于绥解期及正常对照组,P＜0.01,哮喘解期ET含理仍高于正常对照组,P＜0.01,CGRP在急性发作期、缓解期与正常对照组差异无显著性,P＞0.05。结论 ET、NO参与哮喘发病过程,ET和NO升高是哮喘生发作的重要实验室依据。     

脑血管病急性期血中心肌肌钙蛋白释放与内皮素及一氧化氮的关系

目的：探讨脑血管病急性期ｃＴｎＴ释放与ＥＴ、ＮＯ之间的关系及其在心肌损伤中的意义。方法：对３１例脑血管病患者以ＳＮＳＳ评分分为三组：分别检测在发病＜２４、７２、１２０小时的ｃＴｎＴ、ＥＴ、ＮＯ水平。结果：在三组患者之间ｃＴｎＴ水平均存在显著性差异（Ｐ＜０．０１）。结论：脑血管病急性期存在心肌损伤,其为发病早期各种心律失常的原因之一,并与ＥＴ有明显相关。ＮＯ对病情的好转有积极意义。     

内皮素受体拮抗剂对低氧性肺动脉高压的影响

为了探讨内皮素(ET)在低氧性肺动脉高 压发病中的作用和评价ETA受体拮抗 剂的预防效应,将30只Wistar大鼠分为对照组、低氧组和低氧＋BQ-123组,以常压低氧复 制 大鼠肺动脉高压模型,采用微导管法测定肺动脉平均压,放射免疫法检测血浆ET-1含量, 对 肺组织切片进行图象分析。结果发现：低氧3周后,大鼠形成明显的肺动脉高压、肺小动脉 管壁增厚和右心室肥厚,WT%和WA%均明显升高,低氧大鼠血浆ET-1含量为192.3±43.1pg/m l,明显高于对照组的128.2±28.1pg/ml (P＜0.01);经BQ－123处理,可明显减轻低氧 所致的 肺动脉压升高、肺血管壁增厚和右心室肥厚。提示慢性低氧可导致肺动脉高压和血浆ET-1 水平升高,ETA受体拮抗剂对低氧性肺动脉高压具有显著的预防效应。     

Atrasentan for the treatment of diabetic nephropathy

Introduction: Endothelin-1 (ET-1) is the most potent vasoconstrictor, and is involved in the renal regulation of salt and water homeostasis. When produced in excess in the kidney, ET-1 promotes proteinuria and tubulointerstitial injury. There is great interest in the clinical use of endothelin receptor antagonists (ERAs) in chronic kidney disease (CKD), mainly in diabetic nephropathy (DN).

Areas covered: Physiopathological actions of ET-1 on the kidney. Both dual ETAR/ET_BR (bosentan) or ET_AR specific endothelin antagonists (avosentan and atrasentan, among others), which have progressed to early clinical development, with particular emphasis on atrasentan.

Expert opinion: Different phase I and II clinical trials with ERAs in DN, mostly with atrasentan, have shown that these drugs have a marked anti-proteinuric effect on residual proteinuria when administered as add-on therapy in addition to ACEi or ARAII treatment. In the past few years, a series of randomized controlled trials investigating new approaches to DN have provided negative or inconclusive data, or even were terminated due to safety concerns or lack of efficacy. Therefore, we eagerly but cautiously await the results of the ongoing SONAR trial with atrasentan in more than 4,000 patients including assessment of renal and cardiovascular hard-end points (estimated primary completion date, July 2018).