血脂康对急性冠脉综合征患者内皮功能的影响

目的观察血脂康对急性冠脉综合征患者血清一氧化氮（NO）及一氧化氮合酶（NOS）的影响。方法随机选择急性冠脉综合征病患者67例．将其随机分为血脂康治疗组35例，阿托伐他汀组32例，并对两组患者治疗前后血清NO及NOS含量水平进行对比分析。结果血脂康和阿托伐他汀均可升高急性冠脉综合征患者血清NO及NOS水平，其作用无明显差异（P〉0．05）。结论血脂康可抑制脂质过氧化反应．保护血管内皮功能，对急性冠脉综合征的防治具有重要意义。     

一氧化氮在肺感染中损伤作用机制探讨

观察４０例肺感染患者血中一气体氮（ＮＯ）及肿瘤坏死因子（ＴＮＦ）、超氧化物歧化酶（ＳＯＤ）、丙二醛（ＭＤＡ）水平变化，并与３０例正常人进行对比，同时对治疗后的１８例患者各指标的变化进行了观察。结果显示：患者血清ＮＯ及ＴＮＦ、ＭＤＡ水平较对照组显著增高（Ｐ〈０．０１），ＳＯＤ则显著降低（Ｐ〈０．０１），治疗后较治疗前血清ＮＯ、ＴＮＦ及ＭＤＡ水平显著降低（Ｐ〈０．０５），而ＳＯＤ活性则显著回升（Ｐ〈０     

一氧化氮合成酶抑制剂的研究进展

一氧化氮（NO）具有广泛的生理功能。哺乳动物体内的NO是由NO合成酶（NOS）氧化L－精氨酸而合成的,合成后的NO迅速跨膜扩散释放。NO合成失调能介导多种疾病产生。特异性NO抑制剂能通过调控NO的合成,对NOS表达相关的各种疾病的防治具有重要的临床意义。本文对近年来NOS抑制剂的研究作一概述。     

呼出气一氧化氮与慢性咳嗽吸入糖皮质激素治疗疗效的关系

【摘要】 目的：探讨呼出气一氧化氮在慢性咳嗽吸入糖皮质激素治疗疗效中的作用。方法：采用回顾性的方法观察2010年1月一2010年12月在我科就诊的慢性咳嗽患者,进行呼出气一氧化氮（FENO）检测以及沙丁胺醇舒张试验,收集相关临床资料,没有临床资料通过电话回访和问卷调查。结果：①共计62名慢性咳嗽患者进入研究,吸入糖皮质激素（ICS）治疗应答和无应答的患者在年龄、性别、体重指数、FEV1%预测值等方面差异无统计学意义;②ICS治疗应答组患者FENO的水平为48.13±15.66ppb,明显高于ICS治疗无应答组患者的24.90±9.26ppb,差异有统计学意义（P<0.05）;③22名呼出气NO正常慢性咳嗽患者,给予ICS治疗,仅有2名患者治疗有效;④判断ICS治疗有无应答的FENO的临界值为34ppb。结论：FENO水平对慢性咳嗽进行ICS治疗有预测作用,高的FENO水平提示慢性咳嗽对ICS治疗有应答,而低FENO提示ICS治疗效果差,这将有助于慢性咳嗽患者的评价和治疗。     

Nitric Oxide Donors Enhance Rectal Absorption of Macromolecules in Rabbits

Purpose. The objective of this investigation is to evaluate the potential of nitric oxide (NO) donors as a new class of absorption enhancers which may act on intestinal epithelial cells through epithelial actions of the chemical mediator, NO. Methods. Suppositories containing NO donors and insulin were administered into the rabbit rectum. After administration of the suppository, blood samples were collected from the auricular vein. The plasma insulin and glucose concentrations were determined. Results. The NO donor S-nitroso-N-acetyl-DL-penicillamine (SNAP, 4 mg) induced a significant increase in the rate of insulin absorption from the rectum. Administration of a suppository containing SNAP without insulin affected neither the plasma insulin nor the plasma glucose concentration. Other NO donors, NOR1 and NOR4, also induced increases in the insulin absorption. The absorption enhancement effect of SNAP was inhibited by coadministration of the NO scavenger carboxy-PTIO. SNAP also enhanced FITC-dextran (MW 4,000) absorption. Little cytotoxicity of SNAP (3.0 mg/ml) as assessed in terms of the rate of lactate dehydrogenase (LDH) release from Caco-2 cells was detected for 2 h of incubation. Conclusions. These findings suggest that NO enhanced macromolecular absorption from the rectum without mucosal cell damage, and that NO donors can act as potent absorption enhancers.     

一氧化氮合酶抑制剂的研究进展

一氧化氮（NO）具有广泛的生理功能,哺乳动物体内的NO是由NO合酶（NOS）氧化L－精氨酸而合成的,合成后的NO迅速跨膜扩散释放,NO合成失调能介导多种疾病产生,特异性NOS抑制剂能通过调控NO的合成,对NOS表达相关的各种疾病的防治具有重要的临床意义,本文对近年来NOS抑制剂的研究作一概述。     

Drug Discovery for Overcoming Chronic Kidney Disease (CKD): The Endothelin ETB Receptor / Nitric Oxide System Functions as a Protective Factor in CKD

Accelerated cardiovascular disease (CVD) is a frequent complication of renal disease. Chronic kidney disease (CKD) develops hypertension and dyslipidemia, which in turn can contribute to the progression of renal failure. There is general agreement that endothelin-1 (ET-1), which acts through the two subtypes of receptor ET_A and ET_B, plays important physiological roles in the regulation of normal cardiovascular function and that excessive ET-1 production is linked to CVD and CKD. Although selective ET_A or nonselective ET_A/ET_B receptor antagonisms have been recognized as a potential strategy for treatment of several cardiovascular disease, it remains unclear which of the antagonisms is suitable for the individuals with CKD because upregulation of the nitric oxide (NO) system via ET_B receptor is responsible for renal function such as natriuresis, diuresis, and glomerular hemodynamics. Our findings clearly indicate that the blockade of ET receptors, in particular ET_A-receptor antagonism, not only produces a potential renoprotective effect in CKD but also reduces the risk of CVD. In contrast, pharmacological blockade or genetic deficiency of ET_B receptor seems to aggravate CKD and CVD in several experimental models of rats. Moreover, preliminary evidence in patients with CKD also suggests that both selective ET_A- and nonselective ET_A/ET_B-receptor blockade decreases blood pressure but that selective ET_A blockade has additional desirable effects on renal hemodynamics. Thus, at least in CKD, these findings support the notion that ET_B receptor– mediated actions produce a renoprotective effect and that nonselective ET_A/ET_B-receptors blockade seem to offer no advantage over selective ET_A antagonism, and if anything may potentially reduce the benefits.     

一氧化氮前体物逆转肺动脉胶原堆积的研究

目的 :研究一氧化氮前体L -精氨酸 (L -Arg)对高肺血流量所致肺动脉高压大鼠肺动脉胶原代谢的干预作用及其机制。方法 :在大鼠行腹主动脉 -下腔静脉分流造成的肺动脉高压模型基础上 ,给予L -Arg灌胃 ,11wk后 ,采用免疫组织化学法检测大鼠肺动脉Ⅰ、Ⅲ型胶原蛋白的表达。结果 :分流组大鼠肺中、小型肺动脉中Ⅰ、Ⅲ型胶原表达与对照组比较明显增加 (P<0 01) ;分流 +L -Arg 组大鼠肺中、小型肺动脉中Ⅰ、Ⅲ型胶原表达较分流组明显降低 (P<0 01)。结论 :L -Arg 对高肺血流量所致胶原堆积具有重要的逆转作用。     

Morphine-induced Neuroimmunomodulation in Murine Visceral Leishmaniasis: The Role(s) of Cytokines and Nitric Oxide

Opioid modulation of host resistance to infectious diseases is well documented; however, not much is known during visceral leishmaniasis (VL). Low doses of morphine, administered subcutaneously in Leishmania donovani-infected BALB/c mice, on days 0 and +15, significantly (p < 0.05) suppressed (1 mg/kg/day) or even sterile-cleared (2 mg/kg/day) the infection; paradoxically, high doses (10 and 30 mg/kg/day) exacerbated the infection. In vitro, low concentration (1 × 10⁻⁹ and 1 × 10⁻¹¹ M) morphine treatment of L. donovani-infected mouse peritoneal macrophages (PM), endowed them with significant (p < 0.05) leishmanicidal activity, whereas a high-concentration (1 × 10⁻⁵ M) treatment augmented intramacrophage parasite growth. Naloxone pre-treatment of infected-mice (4 mg/kg × 2) and of infected-PM (1 × 10⁻⁵ M), blocked only the morphine low dose/concentration-induced protective effect. The splenocytes from protected mice and morphine low concentration-treated infected-PM, elaborated significantly (p < 0.05) enhanced levels of interleukin-12, interferon-γ, tumor necrosis factor-α, granulocyte-macrophage colony-stimulating factor and nitrite in the culture medium; a high dose/concentration suppressed their elaboration. Curiously, only morphine high dose/concentration-treated infected mice splenocytes and infected PM, produced significantly (p < 0.05) increased quantity of transforming growth factor-β1. Aminoguanidine, significantly (p < 0.05) blocked the morphine low dose/concentration-induced protective effect, in vivo and in vitro. This first study demonstrates dose-dependent biphasic modulatory effects of morphine in L. donovani-infected mice and PM, in vitro, apparently via nitric oxide-dependent mechanisms. These results thus demonstrate the implications of opiate abuse on the efficacy assessment of antileishmanial drugs and vaccines, and on the reactivation of latent VL in areas where both drug abuse and VL are rampant. Disclaimers: nil Sources: Senior Research Fellowship to P. S. National Eligibility Test, Senior Research Fellow, The Council of Scientific and Industrial Research, New Delhi, India. Drugs. morphine sulphate (Government Opium and Alkaloid Factory, Ghazipur, India). Meeting presentation. part of the work presented in 12th Society on NeuroImmune Pharmacology Conference, Santa Fe, New Mexico, USA, April 05–9, 2006.     

鼻一氧化氮检测在儿童过敏性鼻炎中的临床意义

目的：了解鼻一氧化氮（nNO）检测对儿童过敏性鼻炎（AR）诊断和管理的价值。方法：选择30例经症状和过敏原特异性IgE检测确诊的AR患儿设为AR组,13例有过敏性鼻炎症状以及过敏史或过敏家族史的患儿设为可疑过敏性鼻炎（SAR）组;12例无鼻部症状、无过敏性疾病家族史的健康儿童设为正常组。使用Sunvou呼出气NO测定系统,应用鼻被动呼气+静音技术检测各组nNO水平。AR组给予鼻用激素丙酸氟替卡松鼻喷剂治疗2周后评估疗效,复查nNO,比较各组间、AR组治疗前后nNO水平。结果：三组患儿性别、年龄比较差异均无统计学意义（P均>0.05）。AR组、SAR组、正常组的nNO水平分别为（842±133）ppb、（569±44）ppb、（289±33）ppb,AR组和SAR组均高于正常组（P均<0.05）。12例（40%）AR患儿经丙酸氟替卡松鼻喷剂治疗后症状改善,治疗后nNO水平低于治疗前（P<0.05）。结论：nNO检测对AR的诊断、随访有一定的临床价值,nNO辅助诊断AR需要综合考虑鼻炎和鼻窦口通畅情况。     

大鼠生后肾内皮型一氧化氮合酶的定量分析

为探讨内皮型一氧化氮合酶在大鼠生后肾发育中的作用,采用SD大鼠按生后年龄随机分为6组,即新生组、生后3天组、5天组、7天组、14天组和成年组,用免疫印记技术和光密度分析法对各组大鼠生后肾内皮型一氧化氮合酶进行定量检测,以测得的一氧化氮合酶最大量为1(100%),计算蛋白相对含量,SPSS10.0统计软件包统计分析。结果显示,新生组酶含量最高为1,随年龄增长酶含量逐渐减少,至第7天达到最少为44.60±2.41%,以后又增高至14天达成年水平为71.55±4.35%。提示大鼠生后不同年龄组肾内皮型一氧化氮合酶有明显的变化规律,NO可能在肾脏的成熟与发育中起重要作用。     

Macrophage receptors of polysaccharide isolated from a marine filamentous fungus Phoma herbarum YS4108

YCP, a novel （1,4）-α-D-glucan, was isolated from the mycelium of the marine filamentous fungus Phoma herbarum YS4108. In this work, we investigated a YCP-binding cellular receptor expressed by macrophages and the intracellular signal transduction pathways involved in YCP-induced macrophage activation.
Methods： Fluorescence-labeled YCP （fl-YCP） was prepared using the CDAP-activation method. Fluorescence confocal laser microscopy and fluorescence-activated cell sorting （FACS） were used to analyze the effect of fl-YCP on macrophages. To characterize the properties of the YCP receptor, carbohydrates and antibodies were used to inhibit the binding of fl-YCP to macrophages. Moreover, we investigated the role of membrane receptors Toll-like receptor 2 （TLR2）, Toll-like receptor 4 （TLR4）, Toll-like receptor 6 （TLR6） and complement receptor 3 （CR3）. We also examined the role of the p38 kinase pathway in mediating nitric oxide （NO） production.
Results： YCP had an in vitro stimulatory effect on the release of NO in macrophage, and fI-YCP can bind directly to receptors on the surface of macrophages in a time- and dose-dependent manner. Competition studies show that LPS, laminarin, anti-TLR4 antibody and anti-CD11b （CR3） antibody could inhibit fl-YCP binding to macrophages. Conversely, mannose, anti-TLR2 and anti-TLR6 antibody could not. Treatment of RAW264.7 cells with YCP resulted in significant activation of p38 in a time-dependent manner. The specific p38 inhibitor SB203580 abrogated YCP-induced NO generation. Treatment of RAW264.7 cells with anti-TLR4 antibody and anti-CR3 antibody significantly reduced YCP-induced NO production and p38 activation.
Conclusion： We have demonstrated that YCP-induced NO production occurs through the TLR4 and CR3 membrane receptors in a p38 kinase-dependent manner in macrophages.     

Inhibition of Nitric Oxide Synthesis Reduces Intravenous Cocaine Self-administration in the Rat

The effects of a blockade of nitric oxide synthesis were studied in rats trained to self-administer cocaine intravenously. Pretreatment with Ng-nitro-1-arginine methyl ester (l-NAME; 10–50 mg/kg, intraperitoneally, twice daily for 4 days), significantly and dose-dependently suppressed the maintenance of intravenous cocaine self-administration and the absolute reward magnitude of cocaine. These results suggest that nitric oxide may play a role in cocaine abuse and dependence. © 1997 Elsevier Science Ltd. All rights reserved.     

Endothelium-Derived Nitric Oxide: Pharmacology and Relationship to the Actions of Organic Nitrate Esters

Vascular smooth muscle relaxation elicited by various endogenous substances results from their interaction with vascular endothelial cells to trigger the formation of endothelium-derived relaxing factor (EDRF). EDRF from pulmonary and peripheral arteries and veins and from cultured and freshly harvested aortic endothelial cells has been identified pharmacologically and chemically as nitric oxide (NO) or a labile nitroso compound. Endothelium-derived NO (EDNO) and authentic NO activate the cytoplasmic form of guanylate cyclase by heme-dependent mechanisms and thereby stimulate intra-cellular cyclic GMP accumulation in cells including vascular smooth muscle and platelets. Cyclic GMP functions as a second messenger to cause vascular smooth muscle relaxation and inhibition of platelet aggregation and adhesion to vascular endothelial surfaces. EDNO is synthesized from L-arginine and perhaps arginine-containing peptides by an unidentified calcium-requiring process coupled to the occupation of extracellular endothelial receptors. The biological actions of EDNO are terminated by spontaneous oxidation to NO₂ ^– and NO₃ ^–. The biological half-life of the very lipophilic EDNO is only 3–5 sec and this allows EDNO to function locally as an autacoid. Nitroglycerin and other organic nitrate esters elicit endothelium-independent relaxation after entering vascular smooth muscle cells and undergoing denitration and formation of NO. The pharmacological actions of nitroglycerin are therefore essentially the same as those of EDNO, and the endogenous NO receptor is the heme group bound to soluble guanylate cyclase. EDNO may serve a biological role to modulate local blood flow and platelet function.     

先天性小肠闭锁肠壁内一氧化氮合酶的分布

目的：了解一氧化氮合酶（NOS）在小肠闭锁中分布的临床意义。方法：应用免疫组化技术检测15例先天性小肠闭锁患儿肠壁内NOS表达情况，并以10例正常小肠标本作为对照。结果：肠闭锁组肌间神经丛NOS阳性神经元低于正常对照组（P〈0．05）。结论：先天性小肠闭锁的近端肠壁内一氧化氮产生的减少，可能会影响闭锁区域肠道的功能。     

藻酸双脂钠联合辛伐他汀对青年混合型高脂血症患者血管内皮功能的影响

目的探讨藻酸双脂钠联合辛伐他汀对青年混合型高脂血症患者血管活性物质及其对内皮依赖的舒张功能的影响。方法给予45例青年混合型高脂血症患者辛伐他汀20mg,每晚顿服,藻酸双脂钠0．1g静脉滴注,每天1次,连用2周。比较治疗前后患者血清中一氧化氮（N0）和血管内皮生长因子（VEGF）浓度的变化。结果青年混合型高脂血症患者治疗后血清NO及VEGF均明显升高。结论青年混合型高脂血症可影响NO及VEGF的分泌,藻酸双脂钠联合辛伐他汀对防止和延缓动脉粥样硬化的形成有一定作用。     

Exposure-Based Safety Evaluation of Recombinant Human Macrophage Colony-Stimulating Factor (M-CSF) in Cynomolgus Monkeys

The safety of M-CSF was assessed in cynomolgus monkeys in anintravenous dosing regimen. Exposure (AUC_0–24) multiples(monkey vs human) were calculated using the no observable adverseeffect level (NOAEL) observed in this study and correlated withknown M-CSF-induced toxicities in a previous continuous intravenousinfusion (civ) study in monkeys. M-CSF was administered by dailyintravenous infusion (2 h) to cynomolgus monkeys (2/sex/ group)at 0.1, 0.3,0.7, and 1.0 mg/kg/day, for 28 consecutive days.Control animals (2/sex) received placebo. The 0.7 mg/kg/daygroup was held for an additional 4-week recovery period. Criteriaevaluated included physical observations, ophthalmoscopy, elec-trocardiography,body weight, food consumption, clinical pathology, antibodyformation, pharmacokinetics, necropsy, organ weights, and histopathology.The only effect previously seen in monkeys after intravenouslyadministered M-CSF occurred in animals in the 0.7 and 1.0 mg/kg/daygroups. They exhibited a slight decrease in platelets betweendays 4 and 12 with subsequent recovery. No effects related toM-CSF administration were evident in macroscopic or microscopicevaluations and there was no evidence of anti-M-CSF antibodyproduction. M-CSF at all dose levels was completely eliminatedwithin each dosing interval with no accumulation. Clearanceof M-CSF was enhanced during the first week of dosing, but returnedto baseline clearance levels by day 27. This dosing regimenwas shown to be remarkably free of toxicities noted in a previousmonkey study where M-CSF was given by civ at similar daily doses.At the high dose, which was considered to be the NOAEL, theAUC_0–24 was 40-fold greater than the AUC_0–24 inclinical trials where 2.0 mg/m² was administered by a daily2-h infusion.     

一氧化氮在脑缺血预处理中的作用及其机制

作为一个重要的信号分子，一氧化氮可调节大脑血流量和局部大脑灌注时的新陈代谢活性。在脑缺血预处理中，一氧化氮水平发生变化，其通过调控下游信号通路，产生神经保护效应。综述一氧化氮在脑缺血预处理中的作用及其机制。     

胰岛素对平滑肌细胞产生一氧化氮的影响

目的：探讨胰岛素和血管紧张素Ⅱ（AngⅡ）对人脐动脉平滑肌细胞产生一氧化氮（NO）和超氧阴离子（O^-2）的影响.方法：不同浓度的AngⅡ和胰岛素加入体外培养的人脐动脉平滑肌细胞,分别测定细胞培养液中一氧化氮合酶（NOS）、超氧化物歧化酶（SOD）活性,NO、环鸟苷磷酸（cGMP）和O^-2浓度.结果：胰岛素（10,100,1 000mU/L）使平滑肌细胞NOS活性升高,NO、cGMP产生增加,对SOD活性和O^-2无影响;1.0 nmol/LAngⅡ使NOS活性下降,NO、cGMP产生减少;0.1,0.5,1.0 nmol/L AngⅡ使SOD活性下降,O^-2水平升高;胰岛素和AngⅡ同时存在时NOS活性下降,NO和cGMP产生减少,SOD活性下降,O^-2水平升高;氯沙坦（losartan）可以改善AngⅡ引起的NOS、SOD活性下降,NO、cGMP产生减少,O^-2水平升高.结论：胰岛素使平滑肌细胞NO产生增加,高浓度AngⅡ使NO产生减少,O^-2水平升高,且可以被Losartan阻断,胰岛素和AngⅡ同时存在时平滑肌细胞NO产生减少,O^-2水平升高.