NOS抑制剂对创伤性脑水肿的影响

一氧化氮(NO)是近几年在真核生物细胞中发现的一种重要的活性介质。NO在脑内具有重要的血管和神经作用,除作为血管内皮衍生松弛因子(EDRF)松弛血管平滑肌和抑制血小板聚集外,也作为神经递质参与脑保护、脑循环调节和脑细胞损伤。一氧化     

氧化应激对血管活性物质的影响及其机制研究进展

高血压是全球最普遍的一种心血管疾病,也是心血管疾病中重要的风险因素之一。因而,找到诱发高血压的影响因素并加以控制及治疗刻不容缓。正常情况下血管内皮通过释放内皮源性舒张因子和内皮源性收缩因子来维持血管正常生理功能。越来越多的研究表明氧化应激在高血压发生发展中发挥重要作用,氧化应激可以通过影响血管活性物质的合成来影响血管舒张与收缩。本文主要阐述了氧化应激通过对一氧化氮、前列环素、内皮素-1及血栓素A2的作用来影响内皮正常功能。     

二甲基精氨酸二甲胺水解酶与心血管疾病

二甲基精氨酸二甲胺水解酶(DDAH)是一种胞浆蛋白酶,包括DDAH1和DDAH2两种亚型,能特异性水解内源性一氧化氮合酶(NOS)抑制物非对称二甲基精氨酸而上调NOS活性。DDAH与NOS活性之间的相互作用在调节NO生成和血管内皮功能中起重要作用。DDAH还参与血管新生与细胞分化的调节,其活性变化与动脉粥样硬化等多种心血管疾病的发生发展密切相关,可能是一个新的心血管疾病相关蛋白和药物防治靶点。     

内源性一氧化氮合酶抑制物与动脉粥样硬化及药物的作用机制

一氧化氮（nitric oxide，NO）是机体重要的气体信息分子，具有多种生物学效应。NO由L-精氨酸在一氧化氮合酶（nitric oxide synthase，NOS）催化作用下生成。非对称二甲基精氨酸（asymmetric dimethylarginine，ADMA）是内源性的L-精氨酸类似物，能竞争性抑制NOS活性而减少NO生成，与动脉粥样硬化等多种心血管疾病密切相关，是一种新的心血管疾病危险因子。[第一段]     

神经元型一氧化氮合酶在心脏功能调节中的作用

神经元型一氧化氮合酶(nNOS)不仅在神经细胞中表达,也存在于心肌细胞。生理状况下,nNOS源性的一氧化氮(NO)通过自分泌以负反馈的调节方式维持细胞内Ca2+浓度稳态,防止细胞内Ca2+浓度超载,对于维持正常的心功能具有重要意义。病理状况下,nNOS的活性发生明显变化,nNOS源性的NO可能参与了心脏疾病的发生和发展。     

提升血小板药物的研究

血小板生成主要由血小板生成素(TPO)调节。多个细胞因子亦参与了该过程，包括白细胞介素-1(IL-1)、IL-3、IL-6、IL—11和血小板源性生长因子(PDGF)等。血小板减少症是临床上常遇到的问题，尚缺乏有效的治疗。尽管TPO已被克隆和纯化，还未能在临床上使用。因此，寻找有效的提升血小板的药物有重要的价值。我们的工作证明5-羟色胺(5-HT)是一个巨核细胞生长因子，它对血小板生成有促进效应。中国传统医学认为对虾等海洋生物有“补血”的作用，现代医学进一步发现对虾的“补血”作用可能是通过刺激体内的5-HT受体．从而促进造血功能。海洋植物富含多糖物质、多糖类已被证明通过增强造血生长因子活性和提升连血生长因子水平起促进造血细胞生长作用。如果能够在动植物中找到升血小板物质，开发为升血小板新药，将为血小板减少的病人带来新的治疗手段。     

血小板促炎的分子机制和干预药物

血小板生理功能主要为止血和保持血管内皮完整,病理学上参与血栓形成。20世纪80年代前后,逐渐确定血小板作为炎症细胞以及在宿主防御和过敏反应中的作用。血管炎症是心血管疾病发展的主要机制,血小板在血管炎症反应以及组织修复中起重要作用。血小板与活化的内皮和白细胞等相互作用,导致血小板及作用细胞的释放活动,通过脱颗粒或(和)释放5-羟色胺、细胞因子、组织胺等活性物质参与炎症。抗血小板治疗可能主要通过抑制血小板活化来减少血管炎症。本文就血小板与内皮细胞和白细胞的相互作用、介导炎症反应的分子机制和有关干预药物进行系统综述,以其为抗炎治疗提供参考依据。     

胰岛素抵抗与血管内皮功能障碍

胰岛素抵抗和血管内皮功能障碍是代谢性疾病和心血管疾病的重要危险因素。胰岛素抵抗状态下存在内皮依赖性血管舒张功能障碍,内皮源性一氧化氮产生减少,形成内皮细胞胰岛素抵抗的新观点。糖毒性、脂质毒性及炎性状态是胰岛素抵抗与血管内皮功能障碍共同发病机制。改善胰岛素抵抗和血管内皮功能障碍对预防和治疗代谢性疾病和心血管疾病具有重要意义。     

血小板相关抗体与血小板输注无效的关系

血小板输注是治疗因血小板减少或血小板功能缺陷引起的出血性疾病的一种有效的方法，因此。其治疗效果倍受关注。对输注血小板后其增加值明显低于预期值的状态。人们称之为“血小板输注无效”或“血小板无效性输注”。有多种原因可以导致血小板输注效果不佳，可以分为免疫和非免疫两类，除HIA同种免疫反应外。血小板相关抗体(PA IgG)的存在也是重要原因之一。为探讨PA IgG与血小板输注无效的关系，本文对42例特发性血小板减少性紫癜(nTP)患者及39例再生障碍性贫血患者的PA IgG进行了检测。并分析其与血小板输注无效的关系。     

中药有效成分抗血小板聚集作用机制研究进展

血小板聚集是导致动脉粥样硬化、心肌梗塞、中风等多种心脑血管疾病重要因素,本文从影响花生四烯酸代(AA)谢途径、促进血小板内环腺苷酸(cAM P)释放、拮抗膜糖蛋白(GP)受体、抑制血小板膜特异激动剂及受体及增加一氧化氮(NO)等多方面,综述了中药有效成分抗血小板作用机制研究进展,为阐明中药治疗心血管疾病的作用环节,扩展其临床应用提供依据。     

内源性一氧化氮合酶抑制物:一种新的内皮功能不全预测因子

血管内皮功能不全是多种心血管疾病的共同病理基础 .内源性一氧化氮合酶 (NOS)抑制物能阻止内皮细胞 (NO)合成 ,导致血管内皮功能降低 .高血压 ,动脉粥样硬化 ,糖尿病血管并发症等心血管疾病的内皮功能不全与内源性 NOS抑制物含量升高密切相关 .内源性 NOS抑制物可作为内皮功能不全的预测因子 ;阻止或抑制内源性 NOS抑制物生成可能是寻找防治心血管疾病药物的新途径 .     

Modulation of platelet function and signaling by flavonoids

Blood platelets play a crucial role in the primary hemostasis and vessel wall repair. However; platelet hyperactivation is implicated in the pathogenesis of cardiovascular diseases such as thrombosis, atherosclerosis and stroke. Epidemiological data have suggested that regular consumption of fruits and vegetables, which are rich in flavonoids, is associated to a reduction in cardiovascular events. The cardioprotective effect of flavonoids is partly due to the inhibition of platelet function. However; the mechanisms underlying the anti-platelet effect of these compounds remain unclear. The aim of this review is to discuss the role of platelets in cardiovascular disease and to provide an overview of the potential anti-platelet effect of flavonoids, focusing on the various platelet signaling pathways modulated by flavonoids, including oxidative stress, protein tyrosine phosphorylation, calcium mobilization and nitric oxide pathway. The understanding of these mechanisms will be helpful in the development of new anti-platelet agents based on flavonoids with fewer or no adverse effects.     

一氧化氮合酶基因治疗在心血管疾病中的应用

一氧化氮(NO)为内皮细胞舒血管因子(EDRF)，是心血管系统重要的调节因子，NO功能异常在许多心血管系统疾病的发病中起重要作用。催化NO合成的酶称为一氧化氮合酶(NOS)，用转基因方法转移重组NOS基因，重建内源性NO功能，是治疗心血管系统疾病的新策略，本文就重组NOS转基因的研究进行综述。     

Effects of endothelial nitric oxide synthase gene polymorphisms on platelet function,nitric oxide release,and interactions with estradiol

Impaired platelet-derived nitric oxide (NO) contributes to acute coronary syndromes by enhancing platelet recruitment and thrombus formation. Polymorphic variants of the endothelial NO synthase (eNOS) gene have been associated with cardiovascular diseases. To examine whether eNOS variants affect platelet-derived NO and platelet function, and to assess the effects of estradiol on platelet function, we studied platelets from 47 healthy caucasians who were genotyped for eNOS polymorphisms in the promoter region (T-786 C), in intron 4, and in exon 7 (Glu298Asp). Platelet aggregation, platelet-derived NO and superoxide production were measured in control samples and samples pretreated with 17-alpha-estradiol (10 nmol/l). The occurrence of variants in the promoter region (P = 0.002) or in exon 7 (P = 0.007), but not in intron 4 (P > 0.05), were associated with lower levels of platelet-derived NO. An increased (P = 0.047) release of superoxide was observed with platelets from subjects with the variant in the promoter region, but not with other eNOS genetic variants. The eNOS gene polymorphisms did not affect ADP-induced platelet aggregation (P > 0.05). However, estradiol significantly increased platelet aggregation (P = 0.004), and platelet-derived superoxide (P = 0.047) in individuals homozygous for the variant in exon 7, but not in subject with other genotypes. These data demonstrate that the eNOS variants in the promoter region and in exon 7 decrease platelet-derived NO and that estradiol significantly increases platelet aggregation in homozygous for the variant in exon 7 but not in subjects with other genotypes, suggesting that eNOS variants may influence the thrombotic response.     

Direct vasorelaxation by a novel phytoestrogen tanshinone IIA is mediated by nongenomic action of estrogen receptor through endothelial nitric oxide synthase activation and calcium mobilization

Salvia miltiorrhiza (Danshen) has been widely used in China and other Asian countries for treating various cardiovascular diseases resulting from its ability to improve coronary microcirculation and increase coronary blood flow. Tanshinone IIA (Tan IIA), the major active lipophilic ingredient responsible for the beneficial actions of Salvia miltiorrhiza, has been shown to induce vasodilation in coronary arteries. Because our recent study identified Tan IIA as a new member of the phytoestrogens, we hypothesized that its action might be mediated by estrogen receptor (ER) in vascular endothelial cells. The aim of the present study was to assess whether cardiovascular protection exerted by Tan IIA is mediated by the ER signal pathway and whether the genomic or nongenomic action of ER is involved within arteries and vascular endothelial cells. The effect of Tan IIA on blood vessels was investigated by vascular ring assay using endothelium-intact and endothelium-denuded rat aortas. Similar to estrogen, Tan IIA caused an nitric oxide- and endothelium-dependent relaxation, which was blocked by ER antagonist ICI 182,780. Primary cardiac microvascular endothelial cells were used as a model to study the cellular and molecular mechanisms of Tan IIA-induced vasorelaxation. We demonstrate that Tan IIA is capable of activating the estrogen receptor signal pathway, leading to increased endothelial nitric oxide synthase gene expression, nitric oxide production, ERK1/2 phosphorylation, and Ca mobilization. Collectively, these effects contribute to Tan IIA's vasodilative activity effects of y ER antagonist Cnt of cardiovascular diseases. Our findings support a continued effort in discovering and developing novel phytoestrogens as an alternative hormone replacement therapy for safer and more effective treatment of cardiovascular diseases.     

The induction of nitric oxide synthase activity is inhibited by TGF-beta 1, PDGFAB and PDGFBB in vascular smooth muscle cells.

The effect of transforming growth factor-beta 1 (TGF-beta 1) and platelet-derived growth factor (PDGF) was investigated on the induction of nitric oxide synthase activity caused by interleukin-1 beta in cultured smooth muscle cells from rat aorta. TGF-beta 1, PDGFAB and PDGFBB but not PDGFAA inhibited in a concentration-dependent manner the production of nitrite, an oxidation product of nitric oxide, evoked by interleukin-1 beta. The growth factors alone did not stimulate the release of nitrite. The addition of interleukin-1 beta-treated smooth muscle cells to suspensions of indomethacin-treated human washed platelets inhibited the aggregation evoked by thrombin whereas no effect was observed with untreated cells. Platelet aggregation was not inhibited by smooth muscle cells that had been pretreated with interleukin-1 beta in combination with either TGF-beta 1, PDGFAB or PDGFBB but not with PDGFAA. These observations demonstrate that platelet-derived products such as TGF-beta and PDGFs inhibit the induction of nitric oxide synthase activity in vascular smooth muscle cells.     

An update on hybrid drugs in cardiovascular drug research

Background: Several different strategies are commonly used in medicinal chemistry to develop new molecules targeted at improving the current pharmacotherapy of cardiovascular diseases and hypertension. Among these, in the past years, we could observe an increasing development of new hybrid compounds in which two or more mechanisms of action are combined together to give a new pharmacological entity targeting, simultaneously, several factors involved in complex cardiovascular diseases. Objective: The aim of this review is to present the rational pharmacological bases and the chemical approaches used for the development of representative hybrid drugs. Conclusions: In this paper, some promising multi-targeted enzyme inhibitors and dual receptor antagonists are reported. Some examples of pharmacodynamic hybrids compounds, in which a suitable nitric oxide releasing functionality has been added to known cardiovascular drugs, are also shown.     

Processing of amyloid precursor protein as a biochemical link between atherosclerosis and Alzheimer's disease

Macrophage activation in atherosclerotic plaques plays a role in plaque destabilization, rupture and subsequent atherothrombosis. Platelet phagocytosis that occurs within human atherosclerotic plaques can activate macrophages and it has been suggested that the platelet constituent amyloid precursor protein (APP) is involved. Recent studies show that amyloid beta (Abeta), a peptide extensively studied in Alzheimer's disease and that is cleaved from APP by beta- and gamma-secretase, and/or Abeta-like peptides are also present in human atherosclerotic plaques, in particular in activated, inducible nitric oxide synthase (iNOS) expressing perivascular macrophages that had phagocytized platelets. In vitro studies confirm that platelet phagocytosis leads to macrophage activation and suggest that platelet-derived APP is proteolytically processed to Abeta-like peptides, resulting in iNOS induction. In addition, non-steroidal anti-inflammatory drugs (NSAIDs) and HMG-CoA reductase inhibitors (statins), two classes of drugs reported to affect APP processing and Abeta formation in Alzheimer's disease, have been evaluated for their capacity to inhibit macrophage activation evoked by platelet phagocytosis. Remarkably, the same NSAIDs reported to alter gamma-secretase activity in Alzheimer's disease also reduce macrophage activation after platelet phagocytosis and inhibit formation of Abeta-containing peptides. From the statins investigated (fluvastatin, atorvastatin, simvastatin, pravastatin, lovastatin and rosuvastatin) only fluvastatin and atorvastatin selectively inhibit macrophage activation after platelet phagocytosis, possibly through inhibition of Rho activity. Taken together, these new findings point to the involvement of platelet-derived APP in macrophage activation in atherosclerosis and suggest a biochemical link between atherosclerosis and Alzheimer's disease. Accordingly, drugs interfering with APP processing might have an impact on both diseases.     

Phytochemical genistein in the regulation of vascular function: new insights

Genistein, a natural bioactive compound derived from legumes, has drawn wide attention during the last decade because of its potentially beneficial effects on some human degenerative diseases. It has a weak estrogenic effect and is a well-known non-specific tyrosine kinase inhibitor at pharmacological doses. Epidemiological studies show that genistein intake is inversely associated with the risk of cardiovascular diseases. Data from animal and in vitro studies suggest a protective role of genistein in cardiovascular events. However, the mechanisms of the genistein action on vascular protective effects are unclear. Past extensive studies exploring its hypolipidemic effect resulted in contradictory data. Genistein also is a relatively poor antioxidant. However, genistein protects against pro-inflammatory factor-induced vascular endothelial barrier dysfunction and inhibits leukocyte-endothelium interaction, thereby modulating vascular inflammation, a major event in the pathogenesis of atherosclerosis. Recent studies found that genistein exerts a novel non-genomic action by targeting on important signaling molecules in vascular endothelial cells (ECs). Genistein rapidly activates endothelial nitric oxide synthase and production of nitric oxide in ECs. This genistein effect is novel since it is independent of its known effects, but mediated by the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) cascade. Further studies demonstrated that genistein directly stimulates the plasma membrane-associated adenylate cyclases, leading to activation of the cAMP signaling pathway. In addition, genistein activates peroxisome proliferator-activated receptors, ligand-activated nuclear receptors important to normal vascular function. Furthermore, genistein reduces reactive oxygen species (ROS) by attenuating the expression of ROS-producing enzymes. These new findings reveal the novel roles for genistein in the regulation of vascular function and provide a basis for further investigating its therapeutic potential for inflammatory-related vascular disease.     

Paroxetine-induced increase in metabolic end products of nitric oxide

Decreased production of endothelium-derived nitric oxide has been implicated in the pathogenesis of cardiovascular diseases. Metabolic end products of nitric oxide (NO(x)) are often used as markers for endothelial nitric oxide production in humans. Decreased endothelium-derived nitric oxide has been suggested to mediate some of the deleterious effects of conventional cardiovascular risk factors such as hypercholesterolemia, smoking, and physical inactivity. A substantial number of patients with cardiovascular diseases suffer from comorbid major depressive disorder, which is a predictor of a poorer cardiovascular outcome. Paroxetine is a first-line antidepressant and has been reported to decrease plasma NO(x), theoretically suggesting a potential deleterious effect on the cardiovascular system. We assessed the hypothesis that paroxetine would induce a decrease in plasma NO(x) in healthy volunteers. Plasma NO(x) levels were measured by chemiluminescence at baseline, after 8 weeks of paroxetine administration, and at postdiscontinuation. Contrary to our hypothesis, we found that paroxetine administration induced a significant increase in NO(x) that normalized after paroxetine discontinuation. It remains to be demonstrated that the paroxetine-induced increase in NO(x) is associated with a modification of the cardiovascular risk in patients with major depressive disorder.