缺氧—再给氧对大鼠胸主动脉环内皮依赖血管舒张反应的影响

生物测定法观察大鼠胸主动脉环经缺氧－再给氧、机械去内皮后，血管内皮分泌内皮细胞舒张因子（ＥＤＲＦ）的能力，ＥＤＲＦ前体Ｌ－精氨酸（Ｌ－Ａｒｇ）及拮抗剂ＮＧ－甲基－Ｌ－精氨酸（Ｌ－ＮＭＭＡ）对大鼠胸主动脉内皮ＥＤＲＦ合成和分泌的影响。发现缺氧－再给氧及去内皮的血管环对乙酰胆碱（Ａｃｈ）的舒张反应明显减弱或丧失，而对硝酸甘油的舒张反应仍保存。Ｌ－Ａｒｇ可加强正常内皮环和缺氧－再给氧环对Ａｃｈ的舒张反应     

缺氧－再给氧对大鼠胸主动脉环内皮依赖血管舒张反应的影响

生物测定法观察大鼠胸主动脉环经缺氧－再给氧、机械去内皮后，血管内皮分泌内皮细胞舒张因子（ＥＤＲＦ）的能力，ＥＤＲＦ前体Ｌ－精氨酸（Ｌ－Ａｒｇ）及拮抗剂ＮＧ－甲基－Ｌ－精氨酸（Ｌ－ＮＭＭＡ）对大鼠胸主动脉内皮ＥＤＲＦ合成和分泌的影响。发现缺氧－再给氧及去内皮的血管环对乙酰胆碱（Ａｃｈ）的舒张反应明显减弱或丧失，而对硝酸甘油的舒张反应仍保存。Ｌ－Ａｒｇ可加强正常内皮环和缺氧－再给氧环对Ａｃｈ的舒张反应；Ｌ－ＮＭＭＡ则使该作用消失。Ｌ－ＮＭＭＡ和去内皮均使血管环丧失对Ａｃｈ的舒张反应。提示缺氧－再给氧和去内皮分别可使大鼠胸主动脉内皮分泌ＥＤＲＦ机制受损或丧失，提供外源性Ｌ－Ａｒｇ有促使正常内皮和受损内皮合成和释放ＥＤＲＦ的作用。     

美蓝与消炎痛对高血压大鼠内脏血管内皮依赖性舒张减弱的影响

本文应用双标本微量生物测定法观察自发高血压大鼠（ＳＨＲ）及其常压对照（ＷＫＹ）大鼠肠系膜动脉Ａｃｈ内皮依赖性舒张（ＥＤＲ）的变化，并对其机制进行初步探讨，结果发现：ＳＨＲ的ＡｃｈＥＤＲ显著弱于ＷＫＹ者；鸟苷酸环化酶抑制剂美蓝（５×１０－５ｍｏｌ／Ｌ）可明显减弱ＳＨＲ与ＷｋＹ的ＡＣｈＥＤＲ，此时ＳＨＲ的舒张仍明显弱于ＷＫＹ。灌流消炎痛（５×１０－５ｍｏｌ／Ｌ）后，卒中易感型自发高血压大鼠（ＳＨＲｓｐ）的ＡｃｈＥＤＲ增强，ＷＫＹ的舒张反应几乎不变。此时ＳＨＲｓｐ与ＷＫＹ的肠系膜动脉的ＡｃｈＥＤＲ的差异消失。以上结果支持高血压的内脏血管ＥＤＲ减弱的结论，并且可以认为乙酰胆碱（Ａｃｈ）激发的血管内皮舒张因子（ＥＤＲＦ）通过ｃＧＭＰ环节的功能发生变化。以及血管内皮细胞释放的收缩因子（ＥＤＣＦ）增多是这一减弱的原因之一。     

血管内皮生长因子与糖尿病肾病

糖 尿病肾病 (ｄｉａｂｅｔｉｃｎｅｐｈｒｏｐａｔｈｙ ,ＤＮ)是糖尿病常见的微血管并发症之一 ,发病机制尚不完全清楚。研究表明 ,血管内皮生长因子 (ＶａｓｃｕｌａｒｅｎｄｏｔｈｅｌｉａｌｇｒｏｗｔｈｆａｃｔｏｒＶＥＧＦ)在ＤＮ的发生发展中可能起着重要作用。本文就目前国内外在这一领域中的研究进展介绍如下。1　ＶＥＧＦ及其受体ＶＥＧＦ是一种由几种类型细胞产生的同源二聚体糖蛋白生长因子 ,目前至少发现 5种亚型[1 ] ,根据分子量的不同 ,可分为ＶＥＧＦ1 2 1 ,ＶＥＧＦ1 38,ＶＥＧＦ1 65等。ＶＥＧＦ即一种能影响血管通透性的…     

肺血管内皮细胞对交感神经末梢去甲肾上腺素释放的影响

ｃＧＭＰ升高抑制肾上腺能神经末梢释放去甲肾上腺素（ＮＥ），内皮细胞释放的舒张因子（ＥＤＲＦ）增加ｃＧＭＰ，故其对交感神经ＮＥ的释放可能有调节作用。本文观察去内皮细胞或抑制ＥＤＲＦ合成后肺血管对跨膜交感神经刺激（ＴＮＳ）的反应及对２－〔１４Ｃ〕－ＮＥ的摄取和释放。利用磨擦损伤内皮细胞后或使用ＬＮＭＭＡ抑制ＥＤＲＦ合成后，肺血管对ＴＮＳ刺激的反应明显增加，尤以低频率刺激为甚。肺血管对２－〔１４Ｃ〕－Ｎ     

血管内皮释放因子与高血压的关系

生理条件下，血管内皮细胞释放的收缩和舒张活性物质处于动态平衡。但在高血压等病理条件下ＥＤＣＦ＿２生成增多，血管内皮依赖性收缩增强导致外周血管阻力升高。     

脑梗塞患者血清VEGF、NO和NOS测定及其意义

血管内皮生长因子(ｖａｓｃｕｌａｒｅｎｄｏｔｈｅｌｉａｌｇｒｏｗｔｈｆａｃｔｏｒ,ＶＥＧＦ),也称血管通透性因子(ＶＰＦ),由平滑肌细胞等产生和分泌,特异性地作用于血管内皮细胞,是一种强有力的多功能细胞生长因子,可促使血管内皮细胞分裂增生、转移,增加血管通透性并促使新血管形成[1]。为探讨ＶＥＧＦ与缺血性脑血管疾病的关系,本文检测38例脑梗塞患者血清ＶＥＧＦ浓度,同时测定一氧化氮(ＮＯ)、一氧化氮合酶(ＮＯＳ)的水平。1　方法和结果以脑梗塞患者为研究对象,健康献血者为对照组。ＶＥＧＦ采用双抗体夹心ＥＬＩＳＡ法;ＮＯ采用…     

VEGF、IFN-γ及NO与糖尿病视网膜病变的初步研究

近年来研究证实 ,生长因子与视网膜多种细胞生长增殖密切相关[1] ,而细胞生长因子可能是通过一氧化氮 (ＮＯ)的介导而导致血管内皮细胞的损坏[2 ] 。我们选用血管内皮生长因子 (ＶＥＧＦ)、γ 干扰素 (ＩＦＮ γ)和ＮＯ浓度变化作为指标 ,探讨糖尿病(ＤＭ)患者ＶＥＧＦ、ＩＦＮ γ、ＮＯ变化及其在糖尿病视网膜病变 (ＤＲ)发病机制中的重要作用。1　材料与方法1 1　研究对象　ＤＭ患者 74例 ,男 33例 ,女 4 1例。年龄 56.2 4± 14.0 5岁 ,按ＷＨＯ标准诊断分为①无眼底病变组 (ＮＤＲ) 33例 ,男 16例 ,女 17例 ,年龄 56.2 4± 17.4 4岁。②…     

L－精氨酸二肽对大鼠异丙肾上腺素心肌损伤的影响

在大鼠异丙肾上腺素（ＩＳＯ）心肌坏死模型上发现心肌环─磷酸鸟苷（＿ｃＧＭＰ）含量明显减少，冠脉流量降低，冠血管对乙酰胆碱（Ａｃｈ）扩血管反应（内皮依赖性）减弱，而对硝普钠（ＮＰＳ）的扩血管反应（非内皮依赖性）无明显改变。用内皮衍生松驰因子（ＥＤＲＦ）前体Ｌ－精氨酸二肽（Ｌ－Ａｒｇ－Ａｒｇ－ＯＨ）治疗可明显减轻ＩＳＯ心肌损伤，增加心肌＿ｃＧＭＰ含量，增加冠脉灌流量，改善冠血管对Ａｃｈ的舒张反应。实验结果表明，ＩＳＯ心肌坏死时冠脉内皮ＥＤＲＰ生成减少，应用Ｌ－精氨酸二肽具有防治意义。     

VEGF家族新成员:VEGF-B,VEGF-C和VEGF

血管内皮生长因子（ Ｖ Ｅ Ｇ Ｆ） 近年又发现了下列新成员： Ｖ Ｅ Ｇ Ｆ Ｂ, Ｖ Ｅ Ｇ Ｆ Ｃ 及 Ｖ Ｅ Ｇ Ｆ Ｄ,三种因子与 Ｖ Ｅ Ｇ Ｆ 具有相似的结构、功能及分布。 Ｖ Ｅ Ｇ Ｆ Ｂ 的受体尚未明确,该因子具有促进内皮细胞生长的功能; Ｖ Ｅ Ｇ Ｆ Ｃ 主要作用于淋巴管内皮,其受体为 Ｖ Ｅ Ｇ Ｆ Ｒ２ 和 Ｖ Ｅ Ｇ Ｆ Ｒ３ ; Ｖ Ｅ Ｇ Ｆ Ｄ 与 Ｖ Ｅ Ｇ Ｆ Ｃ 的作用及结构相似,受体相同。     

内皮依赖性超极化因子在血管危险因素中的研究进展

目的：探讨内皮依赖性超极化因子（endothelium—derivedhyperpolarizingfactor,EDHF）与血管危险因素的关系。方法：参阅相关文献,分别简明叙述EDHF与年龄、高血压、糖尿病、高血脂、动脉粥样硬化之间联系。结果：EDHF是继一氧化氮（nitricoxide,NO）和前列环素（prostacyclin,PG12）后发现的第三类内皮源性血管舒张因子,受到年龄、高血压、糖尿病、高血脂、动脉粥样硬化等多种因素影响。结论：EDHF在调节血管紧张度方面有重要作用,并可能成为治疗与内皮功能障碍相关疾病的新靶标。     

Endothelium-derived hyperpolarizing factor as an in vivo back-up mechanism in the cutaneous microcirculation in old mice

There is now strong evidence that an endothelium-derived hyperpolarizing factor (EDHF), other than nitric oxide (NO) or prostaglandin (PG), exists for dilating arteries and arterioles. In vitro studies on isolated vessels pointed out a role for EDHF as a back-up mechanism when the NO pathway is impaired, but there was a lack of in vivo studies showing a functional role for EDHF. Ageing has pronounced effects on vascular function and particularly on endothelium-dependent relaxation, providing a novel situation in which to assess the contributions of EDHF. The purpose of the present study was thus to determine if, in vivo, there was a functional role for EDHF as a back-up mechanism in the cutaneous microcirculation in the ageing process. We investigated in vivo the contribution of each endothelial factor (NO, PG and EDHF) in the cutaneous vasodilatation induced by iontophoretic delivery of acetylcholine and local pressure application in young adult (6–7 months) and old (22–25 months) mice, using pharmacological inhibitors. The cutaneous vasodilator responses induced by acetylcholine and local pressure application were dependent upon NO and PG pathways in young adult mice, whereas they were EDHF-dependent in old mice. EDHF appears to serve as a back-up mechanism when ageing reaches pathological states in terms of the ability for NO and PG to relax cutaneous microvessels, allowing for persistent cutaneous vasodilatator responses in old mice. However, as a back-up mechanism, EDHF did not completely restore cutaneous vasodilatation, since endothelial responses were reduced in old mice compared to young adult mice.     

Developmental changes in myoendothelial gap junction mediated vasodilator activity in the rat saphenous artery

A role for myoendothelial gap junctions (MEGJs) has been proposed in the action of the vasodilator endothelium-derived hyperpolarizing factor (EDHF). EDHF activity varies in disease and during ageing, but little is known of the role of EDHF during development when, in many organ systems, gap junctions are up-regulated. The aims of the present study were therefore to determine whether an up-regulation of heterocellular gap junctional coupling occurs during arterial development and whether this change is reflected functionally through an increased action of EDHF. Results demonstrated that in the saphenous artery of juvenile WKY rats, MEGJs were abundant and application of acetylcholine (ACh) evoked EDHF-mediated hyperpolarization and relaxation in the presence of N ^ω-nitro- l -arginine methyl ester (L-NAME) and indomethacin to inhibit nitric oxide and prostaglandins, respectively. Responses were blocked by a combination of charybdotoxin plus apamin, or 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34) plus apamin, or by blockade of gap junctions with the connexin (Cx)-mimetic peptides, ⁴³Gap26, ⁴⁰Gap27 and ^37,43Gap27. On the other hand, we found no evidence for the involvement of the putative chemical mediators of EDHF, eicosanoids , L-NAME-insensitive nitric oxide, hydrogen peroxide or potassium ions, since 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE), hydroxocobalamin, catalase or barium and ouabain were without effect. In contrast, in the adult saphenous artery, MEGJs were rare, EDHF-mediated relaxation was absent and hyperpolarizations were small and unstable. The present study demonstrates that MEGJs and EDHF are up-regulated during arterial development. Furthermore, the data show for the first time that this developmentally regulated EDHF is dependent on direct electrotonic coupling via MEGJs.     

The endothelium in health and disease--a target for therapeutic intervention.

In this review we discuss the contribution of NO, prostacyclin and endothelium-derived relaxing factor--endothelium-derived hyperpolarizing factor, or EDHF, to vascular function. We also explore the hypotheses (1): that tissues can store NO as nitrosothiols (RSNOs) and (2) that such RSNO stores can be modulated by physiological and pathophysiological processes. Notably in the microcirculation, EDHF appears to play an important role in the regulation of vascular tone. Leading candidates for EDHF include extracellular potassium (K+), an epoxygenase product, hydrogen peroxide and/or a contribution from myoendothelial gap junctions. Data from our laboratory indicate that in mouse vessels, different endothelium-dependent vasodilators, such as acetylcholine and protease-activated receptor (PAR) agonists, release different endothelium-derived relaxing factors. The combination of two K-channel toxins, apamin and charybdotoxin, inhibits EDHF activity in most protocols. Endothelial dysfunction is considered as the major risk factor and a very early indicator of cardiovascular disease including the cardiovascular complications of type I & types II diabetes. Impaired endothelium-dependent vasodilatation results primarily from a decreased synthesis of endothelium-derived nitric oxide (NO) and/or an increase in the production of reactive oxygen species such as superoxide. We have shown that the administration of tetrahydrobiopterin, an important co-factor for nitric oxide synthase (NOS) partially restores endothelial function (1) in leptin-deficient mice (db/db) with spontaneous type II diabetes, as well as (2) in human vascular tissue harvested for coronary artery bypass grafting (CABG). These data suggest that a deficiency in the availability of tetrahydrobiopterin plays an important role in vascular dysfunction associated with Type II diabetes. In addition, changes in the contribution of EDHF occur in vascular tissue from the db/db mice suggesting a compensatory increase in EDHF production; whether this alteration in EDHF production is physiological or pathophysiological remains controversial.     

Hydrogen peroxide as an endothelium-derived hyperpolarizing factor

The endothelium plays an important role in maintaining cardiovascular homeostasis by synthesizing and releasing several vasodilating substances, including vasodilator prostaglandins, nitric oxide (NO), and endothelium-derived hyperpolarizing factor (EDHF). Since the first report on the existence of EDHF, several substances/mechanisms have been proposed for the nature of EDHF, including epoxyeicosatrienoic acids (metabolites of arachidonic P450 epoxygenase pathway), K ions, and electrical communications through myoendothelial gap junctions. We have demonstrated that endothelium-derived hydrogen peroxide (H₂O₂) is an EDHF in animals and humans. For the synthesis of H₂O₂/EDHF, endothelial NO synthase system that is functionally coupled with Cu,Zn-superoxide dismutase plays a crucial role. Importantly, endothelium-derived H₂O₂ plays important protective roles in the coronary circulation, including coronary autoregulation, protection against myocardial ischemia/reperfusion injury, and metabolic coronary vasodilatation. Indeed, our H₂O₂/EDHF theory demonstrates that endothelium-derived H₂O₂, another reactive oxygen species in addition to NO, plays important roles as a redox-signaling molecule to cause vasodilatation as well as cardioprotection. In this review, we summarize our current knowledge on H₂O₂/EDHF regarding its identification and mechanisms of synthesis and actions.     

Nandrolone decanoate pre-treatment attenuates unweighting-induced functional changes in rat soleus muscle

Extracellular nucleotides have been shown to induce vasodilatation of conductance arteries by release of the endothelium-derived hyperpolarizing factor (EDHF). As small resistance arteries are of greater importance for blood pressure regulation, a whole rat mesenteric arterial bed preparation was used in the present study when evaluating the physiological relevance for EDHF in mediating nucleotide dilatation. Dilatory responses were examined after pre-contraction with noradrenaline in the presence of 10 mM indomethacin. Adenosine-5'-O-thiodiphosphate (ADPbetaS), adenosine triphosphate (ATP) and uridine triphosphate (UTP) induced vasodilatation (pEC50=6.5-7 and E(max)=40-70%), while uridine diphosphate (UDP) was ineffective. Endothelium-derived hyperpolarizing factor was studied in the presence of 0.5 mM Nvarpi-nitro-L-arginine (L-NOARG). ADPbetaS and UTP induced strong and potent EDHF-dilatations, while ATP only had a weak effect (E(max)=25%). After P2X1 receptor desensitization with 10 microM alphabeta-methylene-adenosine triphosphate, the ATP response was significantly increased (E(max)=65%). Putatively, this could be because of simultaneous activation of both endothelial P2Y receptors and P2X1 receptors on smooth muscle cells, which resulted in the release of EDHF and subsequent hyperpolarization, and depolarization, respectively. Nitric oxide (NO) was studied in the presence of 60 mM K+. ADPbetaS, ATP and UTP induced weak NO dilatations, suggesting a minor role for NO as compared with EDHF. In conclusion, extracellular nucleotides stimulate dilatation by activating P2Y(1) and P2Y(2)/P2Y(4) receptors, but not P2Y(6) receptors. The dilatory responses are mediated primarily by EDHF in the peripheral vascular bed.     

内皮依赖性超极化因子的研究进展

Until now,although the molecule of EDHF has not been cloned,some characteristics of EDHF has been clarified by scientists.It is different from NO and prostacyclin,and it is considered to play an important role in the regulation of vascular tone by stimulating the channels of K^ d and Ca^2 .     

Oestrous cycle and pregnancy alter the reactivity of the rat uterine vasculature

Isolated uterine vascular beds from virgin and pregnant rats were used to assess vascular reactivity and the ability of nitric oxide (NO), prostanoids and endothelium-derived hyperpolarizing factor (EDHF) to modulate these responses. One uterine horn from female rats in each oestrous cycle day and gestation day 17 was removed and perfused with physiological saline solution. Tone was induced with cirazoline (1 micromol/l), and concentration-response curves to acetylcholine (ACh) generated. Responsiveness to ACh was tested in the presence of N-nitro-L-arginine (L-NA), ibuprofen (IBU) and tetrabutylammonium (TBA), to inhibit NO synthase, cyclo-oxygenase and K+ channels respectively. Cirazoline-induced tone was smaller in the pregnant compared with the proestrous group. Sensitivity to ACh was cycle day and pregnancy dependent with pregnant > dioestrous day-1 > dioestrous day-2 > proestrous and oestrous. L-NA shifted the curve to the right in all groups except dioestrous day-1. IBU inhibited the ACh response in the pregnant group only. TBA virtually abolished the response in all groups. These results suggest that in the uterine vascular bed from pregnant rats, EDHF, along with NO and a dilator prostanoid mediate ACh-induced dilatation. In contrast, in the dioestrous day-1 group, only EDHF seems to be released by ACh in this vascular bed. In the oestrous, dioestrous day-2 and proestrous groups, ACh releases both EDHF and NO.     

高钾溶液对猪冠状动脉内皮细胞功能影响的实验研究

目的 :探讨高钾溶液对猪冠状动脉内皮细胞功能的影响及其机制。方法 :取新鲜猪心外膜下冠状动脉前降支下三分之一 ,切成 3mm长的血管环。采用器官槽法 ,分别用Krebs Henseleit重碳酸盐缓冲液 (KH)、2 0mmol/L的高钾溶液、50mmol/L的高钾溶液浸泡血管环 1h后 ,检测在 7μmol/L环加氧酶阻断剂消炎痛、3 0 0 μmol/L一氧化氮合成酶阻断剂N 硝基 L 精氨酸、1mmol/L钙激动性钾通道阻断剂四乙胺、或 3μmol/LATP敏感性钾通道阻断剂优降糖的作用下 ,3 0nmol/L前列腺素F2α引发的预收缩强度和非受体介导钙离子载体 ( 10 -1 0 ～ 10 -6mol/L)引发的内皮源性舒张反应。结果 :与单纯浸泡于KH的冠状动脉相比 ,内皮源性超极化因子 (EDHF)介导的内皮源性舒张反应 ,经 2 0mmol/L、50mmol/L高钾溶液及四乙胺作用后显著降低 ,但加入优降糖后改变不明显。结论 :EDHF在冠状动脉内皮源性舒张中起重要的作用 ,高浓度钾离子抑制EDHF的作用、EDHF介导血管舒张的作用过程主要与钙激动性钾通道有关     

Effects of vanadate on vascular contractility and membrane potential in the rabbit aorta.

Isolated rabbit aortic ring with intact endothelial cell preparations precontracted with NE (10(-7) M) were relaxed by vanadate in a dose dependent manner (from 0.2 to 2 mM). Application of vanadate and ACh during the tonic phase of high K+(100 mM)-induced contraction showed a slight relaxation in contrast to that in NE-induced contraction, but sodium nitroprusside (10 microM) more effectively relaxed the aortic ring preparations in high K+ contraction than that of vanadate. Vanadate-induced relaxation in NE-contracted aortic rings was reversed by application of BaCl2 (50 microM) or glibenclamide (10 microM). Furthermore, Vanadate hyperpolarized membrane potential of smooth muscle cells in endothelium-intact aortic strips and this effect was abolished by application of glibenclamide. The above results suggest that vanadate release EDHF (Endothelium-Derived Hyperpolarizing Factor), in addition to EDRF (Endothelium-Derived Relaxing Factor) from endothelial cell. This EDHF hyperpolarize the smooth muscle cell membrane potential via opening of the ATP-sensitive K+ channel and close a voltage dependent Ca++ channel. So it is suggested that the vanadate-induced relaxation of rabbit thoracic aortic rings may be due to the combined effects of EDRF and EDHF.