二苯乙烯苷对大鼠主动脉舒张作用及其一氧化氮含量的影响

目的　研究中药何首乌中有效成分二苯乙烯苷 (2 ,3,5 ,4′ 四羟基二苯乙烯 2 O β D 葡萄糖苷 ,THSG)与结构相似的白黎芦醇 (resveratrol)是否有类似的血管舒张作用。方法　采用血管张力记录法及NO比色法 ,观察THSG对大鼠主动脉环张力及NO含量的影响。结果　①在去氧肾上腺素预收缩的内皮完整及去内皮主动脉环上 ,THSG 0 .1～ 30 .0 μmol·L- 1浓度依赖性舒张主动脉环 ,其Emax分别为 75 %和5 2 % ,EC50 分别为 0 .86和 2 .70 μmol·L- 1。②在内皮完整的血管上 ,THSG 0 .1μmol·L- 1能增强乙酰胆碱1μmol·L- 1依血管内皮的舒张作用。③NO前体物L 精氨酸 1μmol·L- 1可增强THSG 1μmol·L- 1的血管舒张作用 ;而NOS抑制药Nω 硝基L 精氨酸甲酯0 .5 μmol·L- 1可部分削弱之。④鸟苷酸环化酶抑制药亚甲兰 1μmol·L- 1可部分削弱THSG 1μmol·L- 1的血管舒张作用。⑤THSG 30mg·kg- 1,iv ,可短暂降低麻醉大鼠动脉血压 ,但对心率无明显影响。⑥THSG 1μmol·L- 1显著提高大鼠胸主动脉血管组织NO含量。结论　THSG对大鼠主动脉具有舒张作用 ,此作用主要是依血管内皮的 ,并主要由NO介导     

内吗啡肽及其类似物对心血管系统的作用

目的　研究内吗啡肽 (EMs)及其类似物对心血管系统的影响 ,初步探讨其作用机理。方法　测定EMs及其类似物对大鼠平均动脉压和后肢血管阻力、蟾蜍肠系膜微动脉内径、兔离体胸主动脉条张力的影响。结果　EMs及其类似物剂量依赖 ( 10 -9- 10 -6mol·L-1,iv)且Nx敏感地降低麻醉大鼠平均动脉压、后肢血管灌流压和扩张蟾蜍肠系膜微动脉。EMs对去内皮兔离体胸主动脉条张力无影响 ;但剂量依赖地显著降低完整内皮胸主动脉条张力并被Nx和L NNA阻断。结论　EMs及其类似物通过降低外周阻力而显著降低动脉血压 ,其作用与血管内皮细胞释放NO有关     

一氧化氮供体降压活性研究进展

高血压是一种常见的心血管疾病,目前其发病率逐年上升,并有低龄化的趋势.1980年,Furchgott等发现内皮源性舒张因子(EDRF)具有强大舒张血管作用,后经证实EDRF本质即为一氧化氮(NO).大量研究表明,NO作为信使物质和效应分子,参与体内多种生理、病理过程.     

山莨菪碱对乙酰胆碱诱导的猫离体动脉内皮依赖性舒张反应的影响(英文)

目的　观察山莨菪碱对乙酰胆碱 (ACh)诱导的内皮依赖性血管舒张反应的影响。方法　采用猫离体血管功能实验 ,观察山莨菪碱对ACh诱发的内皮依赖性血管舒张反应的影响。结果　在猫肠系膜动脉、肾动脉和股动脉 ,山莨菪碱 0 .0 1～ 1 .0nmol·L-1 能够浓度依赖地抑制ACh诱导的内皮依赖的血管舒张反应。山莨菪碱抑制 1 0 μmol·L-1 ACh所诱导血管舒张的IC50 分别为 0 .2 36 ,0 .72 9和 0 .50 8nmol·L-1 ,山莨菪碱的拮抗作用符合非竞争性拮抗模式。此外 ,1 0nmol·L-1 山莨菪碱能有效拮抗ACh诱导的冠状动脉内皮依赖性舒张反应。结论　山莨菪碱能强效拮抗ACh诱发的内皮依赖性血管舒张反应 ,这种效应具有组织特异性的特点。     

NO在缺血再灌注损伤中的作用

1 NO的基本特性及作用 1980年Furchgott和Zawadzki报告内皮细胞(endothelial cell,EC)可产生一种因子,作用于平滑肌引起血管扩张,并命名为内皮源性舒张因子(endothelial derived relaxing factor,EDRF),进一步的研究表明EDRF就是一氧化氮(nitric oxide,NO)。基础状态下,EC可分别通过NADPH、Ca~(2+)/钙调素依赖的NO合成酶使L-精氨酸(Larginine,L-Arg)氨基端胍基脱氨氧化生成NO和L-瓜氨酸(L-citrulline,L-Cit),并在乙酰胆碱、缓激肽、A_(23187)等作用下通过增加细胞内钙离子浓度进一步增加NO的合成和释放。 EDRF的扩血管作用可能是通过平滑肌细胞(SMC)内环磷酸鸟苷酸(cGMP)含量增加来介导的,即EC释放EDRF,后者弥散到SMC,激活鸟苷酸环化酶,使细胞内cGMP含量升高,再经蛋白激酶G引起蛋白质磷酸化,介导平滑肌的松弛反应。外源性NO合成酶抑制剂N~G-monomethyl-L-arginine(L-NMMA)、N~G-nitro-L-arginine-methylester(L-NAME)可抑制NO的合成和释放,引起平滑肌收缩,补充合成NO所需的底物L-Arg或给予体内生理条件下自发特异形成NO的NO供体——硝普     

靶性一氧化氮用于败血症和脑膜炎治疗

<正> 1980年已证实了从内皮细胞中提取的一种因子能介导动脉血管平滑肌的舒张,这个因子命名为内皮舒张因子(EDRF)。后来又发现它们具有极不稳定性(半衰期大约为3秒),且可被超氧化物所灭活。某些血管扩张药是通过EDRF而起作用的,EDRF又反过来通过活化鸟苷酸环化酶而发挥作用。1986年,R.F Fuchgott等首次提出EDRF就是NO,理由是NO和EDRF半衰期均是为3秒的血管扩张剂,     

高血压病、血管内皮和心血管危险因子

血管内皮在调节血管的渗透选择性,控制止血功能和影响血液细胞成分与非细胞成分问的相互作用方面起着决定性的作用。内皮所释放的扩血管物质有PGI_2(前列环素),血管活性物质有儿茶酚胺类、缓激肽、5-HT和血管紧张素Ⅱ,内皮通过这些物质而调节血管的张力。Furchgott等1980年报告,乙酰胆碱对离体动脉血管平滑肌的松弛作用必须依赖功能完整的血管内皮,他们还将其所释放的因子命名为EDRF(内皮衍生的血管舒张因子)。许多促效剂和机械刺激都能使各种血管床包括肾小球释放EDRF。现已知道,EDRF(至少最重要的EDRF)是一氧化氮(NO),由     

神经肽Y对离体兔脑血管的作用及其内皮依赖关系

神经肽Y对离体兔脑基底动脉的作用表现在:(1)直接收缩;(2)增强组胺的收缩效应;(3)抑制乙酰胆碱和腺苷的舒张效应。作用(1)和(3)不依赖于血管内皮的存在,而作用(2)依赖血管内皮,其机理可能是由于神经肽Y对血管内皮舒张因子(EDRF)的释放或作用具有抑制性影响。     

大豆黄酮血管舒张作用与血管内皮的关系

目的研究植物雌激素大豆黄酮(daidzein,Dai)的舒张血管效应与血管内皮M受体,细胞内、外钙的关系。方法采用家兔离体主动脉环进行等长张力实验。结果Dai(3～100μmol·L-1)对苯肾上腺素(phenylephrine,PHE)依内Ca2+性收缩和依外Ca2+性收缩均具有显著的抑制作用;Dai(10～100μmol·L-1)可使KCl的量效曲线右移,最大效应降低;Dai(10～100μmol·L-1)对ACh引起的血管环的舒张反应有浓度依赖性的增强作用,且在用阿托品阻断M受体后Dai对KCl引起的收缩的舒张效应减弱。结论Dai舒张血管效应与抑制内Ca2+释放和外Ca2+内流有关;Dai对血管环的直接舒张作用与ACh相似,也是通过激动内皮上的M受体释放EDRF等而引起的,且具有内皮依赖性。     

ATP敏感性钾通道SUR2B／Kir6．1亚型选择性开放剂纳他卡林的血管药理学作用特征

目的研究SUR2B／Kir6．1亚型KATP通道开放剂纳他卡林的心血管药理学作用。方法（1）血流动力学测定：戊巴比妥钠腹腔注射麻醉大鼠,从颈总动脉插管至左心室,连接八导生理记录仪记录心功能的变化。（2）制备大鼠离体工作心脏,观察纳他卡林对其心功能的影响。（3）制备大鼠尾动脉血管条,用去甲肾上腺素预收缩后,观察累积给予纳他卡林对血管张力的影响。结果纳他卡林10^-8-10^-4mol&#183;L^-1对大鼠离体工作心脏功能无影响;对大鼠尾动脉血管条具有内皮细胞依赖性舒张作用。麻醉大鼠,纳他卡林0．5、2、8mg&#183;kg^-1静脉注射可剂量依赖性降低血压,纳他卡林8mg&#183;kg^-1抑制心脏的收缩和舒张功能,其效应可被格列苯脲和L-NAME拮抗。结论纳他卡林对心脏无直接作用,可通过舒张血管降低血压;纳他卡林的心血管药理学作用与其选择性开放KATP通道、促进内皮细胞释放NO有关。     

Pharmacological treatment of COVID-19: an opinion paper

The precocity and efficacy of the vaccines developed so far against COVID-19 has been the most significant and saving advance against the pandemic. The development of vaccines has not prevented, during the whole period of the pandemic, the constant search for therapeutic medicines, both among existing drugs with different indications and in the development of new drugs. The Scientific Committee of the COVID-19 of the Illustrious College of Physicians of Madrid wanted to offer an early, simplified and critical approach to these new drugs, to new developments in immunotherapy and to what has been learned from the immune response modulators already known and which have proven effective against the virus, in order to help understand the current situation.     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

---

Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

Lung disease and PKCs

The lung offers a rich opportunity for development of therapeutic strategies focused on isozymes of protein kinase C (PKCs). PKCs are important in many cellular responses in the lung, and existing therapies for pulmonary disorders are inadequate. The lung poses unique challenges as it interfaces with air and blood, contains a pulmonary and systemic circulation, and consists of many cell types. Key structures are bronchial and pulmonary vessels, branching airways, and distal air sacs defined by alveolar walls containing capillaries and interstitial space. The cellular composition of each vessel, airway, and alveolar wall is heterogeneous. Injurious environmental stimuli signal through PKCs and cause a variety of disorders. Edema formation and pulmonary hypertension (PHTN) result from derangements in endothelial, smooth muscle (SM), and/or adventitial fibroblast cell phenotype. Asthma, chronic obstructive pulmonary disease (COPD), and lung cancer are characterized by distinctive pathological changes in airway epithelial, SM, and mucous-generating cells. Acute and chronic pneumonitis and fibrosis occur in the alveolar space and interstitium with type 2 pneumocytes and interstitial fibroblasts/myofibroblasts playing a prominent role. At each site, inflammatory, immune, and vascular progenitor cells contribute to the injury and repair process. Many strategies have been used to investigate PKCs in lung injury. Isolated organ preparations and whole animal studies are powerful approaches especially when genetically engineered mice are used. More analysis of PKC isozymes in normal and diseased human lung tissue and cells is needed to complement this work. Since opposing or counter-regulatory effects of selected PKCs in the same cell or tissue have been found, it may be desirable to target more than one PKC isozyme and potentially in different directions. Because multiple signaling pathways contribute to the key cellular responses important in lung biology, therapeutic strategies targeting PKCs may be more effective if combined with inhibitors of other pathways for additive or synergistic effect. Mechanisms that regulate PKC activity, including phosphorylation and interaction with isozyme-specific binding proteins, are also potential therapeutic targets. Key isotypes of PKC involved in lung pathophysiology are summarized and current and evolving therapeutic approaches to target them are identified.     

In vitro studies on sterically stabilized liposomes (SL) as enzyme carriers in organophosphorus (OP) antagonism

This study describes a new approach for organophosphorous (OP) antidotal treatment by encapsulating an OP hydrolyzing enzyme, OPA anhydrolase (OPAA), within sterically stabilized liposomes. The recombinant OPAA enzyme was derived from Alteromonas strain JD6. It has broad substrate specificity to a wide range of OP compounds: DFP and the nerve agents, soman and sarin. Liposomes encapsulating OPAA (SL)* were made by mechanical dispersion method. Hydrolysis of DFP by (SL)* was measured by following an increase of fluoride ion concentration using a fluoride ion selective electrode. OPAA entrapped in the carrier liposomes rapidly hydrolyze DFP, with the rate of DFP hydrolysis directly proportional to the amount of (SL)* added to the solution. Liposomal carriers containing no enzyme did not hydrolyze DFP. The reaction was linear and the rate of hydrolysis was first order in the substrate. This enzyme carrier system serves as a biodegradable protective environment for the recombinant OP-metabolizing enzyme, OPAA, resulting in prolongation of enzymatic concentration in the body. These studies suggest that the protection of OP intoxication can be strikingly enhanced by adding OPAA encapsulated within (SL)* to pralidoxime and atropine.