新斯的明引起大鼠神经肌接头突触后膜持续性去极化特点

采用大鼠膈肌不均匀牵张肌肉标本,观察可逆性胆碱酯酶抑制剂新斯的明引起神经肌接头突触后膜持续性去极化特点. 结果发现,新斯的明（2.5-5 μmol·L^-1）浴槽内给药引起的持续性去极化（SD）时程比压力给药（1 mmol·L^-1,32 kPa, 2-5 s）时长,结果提示压力给药引起的SD时程仅相当于浴槽内低浓度药物所引起者. 在本实验条件的多数情况下,压力给药引起SD的平台期,复极期以及复极后的一段时间内出现频率显著增高的小终板电位（mEPP）,并且这种高频率的mEPP只伴随SD的产生而出现. 而在浴槽内给予高浓度新斯的明引起的SD过程中,mEPP显著减少. 结果提示,可逆性胆碱酯酶抑制剂新斯的明在低浓度时引起的SD过程中,不仅突触后膜的烟碱受体并没有完全失敏,而且突触前膜自发释放ACh显著增加.     

梭曼引起神经肌接头传递阻断的电生理学机理新探

<正> 梭曼(soman)不可逆地抑制乙酰胆碱酯酶(ACHE),造成突触间隙乙酰胆碱(ACh)大量蓄积,引起神经肌接头传递阻断,但其中毒的单突触电生理学机理尚不十分清楚。本文在接近正常生理水平的不均匀牵张膈肌标本(INSMP)上,以细胞内微电极记录技术,首次观察了梭曼中毒后以终板电位(EPP)消失为特征的突触后膜再生性去极化(regenerative depolarization,RD)现象。 结果表明,在正常情况下,高至1000 Hz的间接串刺激(持续1 s)也不能使串EPPs融合而消失。浴槽给5.5μmol·L~(-1)梭曼10 min后,微终板电位(MEPP)的频率增高,幅度增大,时程加宽;单个EPP幅度增     

新斯的明引起大鼠神经肌接头突触后膜持续性去极化特点

采用大鼠膈肌不均匀牵张肌肉标本 ,观察可逆性胆碱酯酶抑制剂新斯的明引起神经肌接头突触后膜持续性去极化特点 .结果发现 ,新斯的明 ( 2 .5-5μmol· L-1)浴槽内给药引起的持续性去极化( SD)时程比压力给药 ( 1 mmol· L-1,32 k Pa,2 - 5s)时长 ,结果提示压力给药引起的 SD时程仅相当于浴槽内低浓度药物所引起者 .在本实验条件的多数情况下 ,压力给药引起 SD的平台期 ,复极期以及复极后的一段时间内出现频率显著增高的小终板电位 ( m EPP) ,并且这种高频率的 m EPP只伴随 SD的产生而出现 .而在浴槽内给予高浓度新斯的明引起的 SD过程中 ,m EPP显著减少 .结果提示 ,可逆性胆碱酯酶抑制剂新斯的明在低浓度时引起的 SD过程中 ,不仅突触后膜的烟碱受体并没有完全失敏 ,而且突触前膜自发释放 ACh显著增加 .     

在不均匀夸张的大鼠隔肌标本上串终板电位初始段衰减的突触前性质(英文)

在大白鼠离体不均匀牵张膈肌标本(INSMP)上可选择接近神经肌接头正常生理状态的终板,同时记录同一终板的小终板电位(MEPP),终板电位(EPP)和微电泳外源性乙酰胆碱(ACh)产生的乙酰胆碱电位(AChP);以AChP为直接的突触后膜兴奋性大小指标,以量子释放参数:量子含量(M)及二项统计参数为突触前递质释放量大小的指标,研究了串终板电位初始段衰减现象的性质.发现在2,10,50和100 Hz间接刺激下,INSMP上串EPPs都发生初始衰减现象;刺激频率增高,衰减更为明显.50 Hz时,在第1,3,5,7,11,25,50,75和100个EPP后20 ms的AChP幅度与EPP之前的AChP幅度无明显差别.100 Hz时,在产生第25,50,75和100个EPP后10 ms的AChP与EPP之前的AChP幅度也无明显差别.直接证明了在产生串EPPs衰减时无突触后膜兴奋性的改变.刺激频率增高,第1个EPP的量子含量(M_1)无变化,EPPs平台期的量子含量(M_x)减小,即刻可释放的量子贮存(n)无变化,平均量子释放机率(P)减少.表明串EPPs初始段的衰减是正常神经肌接头传递的一种自身调节,它完全由突触前量子释放减少引起的,其大小与刺激频率有关.突触前ACh受体可能参与了这种自身调节.     

梭曼对神经肌肉接头突触前乙酰胆碱释放的影响

<正> 本文研究了至今尚不完全清楚的胆碱酯酶抑制剂梭曼引起肌麻痹的机理。建立了大鼠高体不均匀牵拉的膈肌标本。排除了文献上用箭毒或高镁离子制动的干扰和切压肌肉制动引起的创伤。该标本膜电位正常、终板电位(EPP)高达30-36mV,还可同时记录到频率和幅度正常的小终板电位(MEPP)。此标本用来研究药物对接头的作用优于其他标本。 当给予5.5μM梭曼后,串刺激(50Hz,1.0s)膈神经时,第一个EPP幅度加大,半降期延长。第10个及     

新霉素及链霉素对神经肌肉接头的作用及其对抗梭曼的作用(英文)

在不均匀牵拉的离体大鼠膈肌标本上观察了氨基甙类抗菌素新霉素和链霉对终板电位(EPP)和微终板电位(MEPP)的影响和对不可逆胆碱酯酶抑制剂索曼的对抗作用。新霉素减低EPP量子含量,抑制MEPP幅度和减慢MEPP放电频率的浓度相应为0.03,0.1和0.32 mmol/L。链霉素抑制EPP和MEPP相应比新霉素强50和30倍。不影响量子含量的阈下剂量的新霉素(0.015mmol/L)和链霉素(0.8 mmol/L)能部分预防梭曼减少量子含量的作用。再增加此两药的浓度不能提高它们对抗梭曼的效用.同样,不影响MEPP频率的阈下剂量的新霉素和链霉素能完全预防梭曼加快MEPP频率的作用。认为新霉素和链霉素对神经肌接头抑制作用的主要作用部位是突触前递质诱发释放系统。其机理可能是它们竞争性地减少梭曼引起的向突触前膜内Ca~(2+)内流的增加。它们预防梭曼增加MEPP频率的机理也可能是如此。     

梭曼引起大鼠膈肌终板区持续性去极化

在大鼠离休不均匀牵张膈肌标本（ＩＮＳＭＰ）上,选择接近正常电生理学状态的神经肌肉接头,研究了梭曼引起的串终板电位（ＴＥＰＰ）变化,观察到．梭曼浓度在５．５ｎｍｏｌ·Ｌ１到５５μｍｏｌ。Ｌ１范围内,间接串刺激时除在少数标本上出现ＴＥＰＰ幅度降低的第一种反应外,在大多数标本上出现持续性去极化（ＳＤ）．ＳＤ过程中,终板电位（ＥＰＰ）完全消失,ＳＤ－旦出现,持续时间相对稳定,具有“全或无”性质,梭曼浓度在５５ｎｍｏｌ·Ｌ到５５μｍｏｌ·Ｌ范围内,反应以ＳＤ为主（＞８０％）大鼠一个致死量梭曼中毒（０,１ｍｇ·ｋｇ１ｉｍ）后制备ＩＮＳＭＰ,间接串刺激时也产生这两种反应,仍以ＳＤ为主（９１％）冲洗掉残余梭曼,对ＳＤ各参数无影响,再加入高浓度梭曼（５５μｍｏｌ·Ｌ１）时,４５％标本上ＳＤ转化为第一种反应,另５５％标本上ＳＤ的７０％时程缩短至４２％,再冲洗梭曼后１００％标本上ＳＤ恢复。结果表明,ＳＤ与第一种反应有质的区别．ＳＤ是梭曼抑酶作用的结果,高浓度梭曼可能对神经肌肉接头有直接作用,但不是梭曼中毒的主要因素,ＳＤ是梭曼中毒后,间接串刺激时ＴＥＰＰ的主要变化,是在突触电位水平上梭曼等胆碱酯酶抑制剂中毒致神经肌肉传递阻断的?     

在不均匀牵拉的离体大鼠膈肌标本上梭曼的突触前和突触后作用

在离体大鼠膈肌上制备了一种不均匀牵拉肌肉以制动,便于用微电极记录终板电位(EPP)的标本(INSMP),避免了常规制动方法带来的制动药物、台氏液Ca~(2+),Mg~(2+)浓度改变或钳压肌肉导致膜电位(MP)下降的种种干扰。INSMP的MP和小终板电位(MEPP)正常,EPP幅度高达30mV以上,是研究药物对接头作用的较好标本。在INSMP上,梭曼(5.5μM)使MEPP频率加快,串刺激(50Hz)诱发的平均串EPPs幅度及其平均ACh 量子含量减少80％和77％。小剂量三碘季铵酚和六烃季铵可部分对抗梭曼的作用。梭曼引起强直收缩抑制主要原因为终板区蓄积的ACh作用于突触前N受体、负反馈地抑制ACh 量子释放;次要原因为作用突触后N受体、使其对ACh敏感性降低。     

离体大鼠膈肌标本上梭曼引起终板区持续性去极化的机理分析

在离休大鼠膈肌标本上，细胞内记录终板区微电泳给乙酰胆碱（ＡＣｈ）的电位，以ＡＣｈ电位幅度为突触后反应性指标，观察了梭曼中毒后间接串刺激产生终板区持续性去极化反应的性质并分析了其产生的机理。持续性去极化过程中不仅串终板电位消失，ＡＣｈ电位也消失，持续性去极化之后ＡＣｈ逐渐恢复。在正常大鼠和肉毒毒素Ａ中毒大鼠膈肌标本上，梭曼中毒后，串ＡＣｈ电位（５－１０Ｈｚ）也可诱发与持续性去极化性质相同的去极化反应，结果表明，持续性去极化主要是突触后Ｎ型ＡＣｈ受体对高浓度ＡＣｈ的一种反应，不支持突触前ＡＣｈ“再生性”释放的假说。     

金环蛇毒的分离及组分Ⅸ的初步研究

从金环蛇毒中分离到一个神经毒—组分Ⅸ。该组分阻断小鸡颈二腹肌神经肌肉接头传递;阻断标本对乙酰胆碱的反应,标本对直接电刺激以及对高浓度钾离子的反应性仍然存在;组分Ⅸ使蛙缝匠肌终板电位,微终板电位振幅逐渐减小,最后完全消失;但不影响微终板电位的发放频率,也不影响肌纤维的静息膜电位。实验表明组分Ⅸ是作用于突触后膜的神经毒。     

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.

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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.

     

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.     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.     

Steroidal sapogenin contents in some domestic plants

In order to find out the values of the steroid resources for the future use. the compositions and contents of steroidal sapogenins from 13 domestic plants have been investigated. As a result,Dioscorea nipponica, D. quinqueloba andSmilax china were found to have large amount of diosgenin. And pennogenin inTrillium kamtschaticum andParis verticillata, yuccagenin inAllium fistulosum, hecogenin inAgave americana and neochlorogenin inSolanum nigum were appeared to be major steroidal sapogenins.