碘化N-正丁基氟哌啶醇对大鼠心脏缺血和再灌注室性心律失常的拮抗作用

目的:研究碘化N-正丁基氟哌啶醇(F2)对心肌缺血和再灌注引发的室性心律失常的拮抗作用。方法:采用大鼠Langendorff灌流心脏模型,通过结扎左冠脉前降支缺血20min,解除结扎再灌注,引出室性心律失常。缺血前5min用含不同浓度F2的台氏液灌流,观察其对缺血和再灌注期室性心律失常发生率的影响,同时观察F2对心电图上PR、QT、RR间期的影响。用心房起搏(5Hz)防止心率变慢,观察1μmol/LF2对缺血和再灌注室性心律失常、PR间期的影响。结果:F2可浓度依赖地降低缺血和再灌注期室性心律失常发生率,并减慢心率,延长PR间期。在心房起搏控制心律下,仍具有拮抗缺血和再灌注室性心律失常、延长PR间期的作用。结论:F2对大鼠心脏缺血和再灌注性心律失常具有直接的抑制作用。     

噻苯唑与VC抗大鼠再灌注性心律失常作用的比较研究

比较抗线虫药噻苯唑和VC的抗大鼠再灌注性心律失常作用。用松解结扎的大鼠冠脉致再灌注性心律失常模型,通过记录室速(VT)和室颤(VF)发生率来探讨其抗心律失常作用。结果结扎大鼠冠脉5min后再灌注所致的心律失常中,VT和VF的发生率分别为77％和44％,室速持续时间(DVT)14.8±6min。动力死亡率33％。噻苯唑30mg/kg和大剂量VC300mg/kg均可显著降低VT的发生率,缩短DVT,消除VF,动物存活(P<0.01)。故噻苯唑和大剂量VC均有预防再灌注性心律失常的作用。     

金纳多对大鼠心肌缺血再灌注损伤的保护作用

目的观察金纳多对心肌缺血再灌注损伤的保护作用。方法采用在体大鼠结扎冠状动脉前降支10min后,松扎再灌注30min造成心肌缺血再灌注模型,计算心肌梗死范围(MIS),测定血清磷酸肌酸激酶(CK)、乳酸脱氢酶(LDH)、超氧化物歧化酶(SOD)、丙二醛(MDA)含量,观察心律失常发生情况。结果金纳多对心肌缺血10min再灌注损伤30min大鼠,可明显缩小MIS,降低血清CK、LDH活性和MDA含量,提高SOD活性,降低心律失常的发生率。结论金纳多对大鼠心肌缺血再灌注损伤具有保护作用。     

三七中人参三醇甙对动物缺血性心律失常的影响

三七中人参三醇甙(简称PTS)能明显对抗大鼠结扎冠状动脉诱发的缺血性心律失常及再灌注性心律失常,并可使缺血再灌注引起的心肌梗塞范围明显缩小。对iv CaCl₂-Ach引起的小鼠房颤或房扑也有明显的保护作用。PTS还可明显延长小鼠在常压缺氧条件下的存活时间。     

黄连素对大鼠心肌缺血再灌注所致心肌损伤的保护作用

目的探讨黄连素对缺血再灌注所致心肌损伤的保护作用。方法 60只雄性健康SD大鼠随机分为5组,即对照组、模型组、阳性对照组及黄连素低[75 mg/(kg·d)]、高[150 mg/(kg·d)]剂量组。黄连素连续灌胃给药14 d后,除对照组外,其余各组结扎冠状动脉左前降支建立大鼠心肌缺血再灌注模型,监测心电图,记录心律失常评分;检测血浆中心钠肽(ANP)、脑钠肽(BNP)、心肌肌钙蛋白-I(c Tn-I)浓度;HE染色与Masson染色方法检测心肌机构损伤情况。结果黄连素预防给药可缩短缺血再灌注所致心律失常恢复正常的时间,同时显著抑制血浆中ANP、BNP和c Tn-I水平的上升,改善心肌结构。结论黄连素对缺血再灌注所致的心肌损伤具有保护作用。     

麻醉大鼠再灌注心律失常模型的改良

目的改进和完善大鼠再灌注心律失常在体模型的制作方法。方法将36只雄性Sprague-Dawley大鼠随机分为假手术组(n=8)、模型组(n=20)、胺碘酮组(n=8,3mg·kg~(-1),舌下静脉注射)。麻醉动物后,钝性分离大鼠3、4肋间肌,用自制小拉钩拉开胸腔,"双线法"结扎左冠状动脉前降支,经8min缺血后剪断结扎线,再灌注30min,观察各组死亡率,实验中用PowerLab连续描记心电图,分析再灌注期心电图变化。结果模型组再灌注期100%出现明显室性心律失常,包括心室纤颤、室性心动过速、室性早搏等,恶性心律失常引起的死亡率为55%;胺碘酮可有效控制心律失常,仅发生室性早搏,死亡率为0(P<0.01)。结论改良方法制备的大鼠再灌注心律失常的动物模型的重复性好,成功率高。     

拮抗内源性孤啡肽可通过下调microRNA-1途径抑制大鼠再灌注性心律失常

目的研究内源性孤啡肽(N/OFQ)对大鼠再灌注性心律失常(RA)的影响,以及microRNA-1(miR-1)在其中的作用。方法将SD大鼠随机分为3组,即假手术组(Sham组)、缺血/再灌注组(I/R组)及孤啡肽受体拮抗剂(UFP-101)预处理组(U+I/R组),每组8只。通过结扎左冠状动脉前降支制备大鼠缺血/再灌注模型,记录各组大鼠再灌注期间心律失常的发生情况并对其进行评分;采用qRT-PCR法检测miR-1、GJA1及KCNJ2基因表达水平;采用Western blot法检测Cx43、kir2.1蛋白表达情况。结果拮抗内源性N/OFQ可明显降低大鼠RA及致心律失常评分(P<0.01)。qRT-PCR及Western blot结果提示,与Sham组相比,I/R组miR-1表达增多(P<0.01),而Cx43及其mRNA表达下降(P<0.05),kir2.1表达下降(P<0.01);与I/R组比较,U+I/R组miR-1表达下降(P<0.05),Cx43及kir2.1表达增多(P<0.05)。结论内源性N/OFQ可上调miR-1,使Cx43及kir2. 1蛋白表达受到抑制,从而导致缺血/再灌注性心律失常。     

PB-19对大鼠缺血再灌注心律失常的保护作用

目的观察PB19对离体大鼠心室肌细胞的动作电位(AP)的影响,研究PB19对大鼠冠状动脉缺血再灌注损伤的作用。方法制备大鼠离体心肌模型,记录并观察PB19对离体大鼠正常心肌动作电位的影响;制备在体大鼠心肌缺血及再灌注模型,观察PB19对大鼠缺血性心律失常的保护作用。结果PB19明显延长离体大鼠心室肌细胞复极50%及90%时的动作电位时程(APD50、APD90,P<0.01);大鼠冠脉结扎前后分别给予PB19均缩短VTD(室速持续时间,P<0.05),降低室速(VT)、室颤(VF)发生率和死亡率(P<0.01),并呈剂量依赖性。结论PB19未对Vmax产生影响,但延长了APD。PB19降低了大鼠冠状动脉结扎诱发的室性心律失常和死亡率。这种作用可能与PB19延长动作电位时程有关。     

黄体酮减轻大鼠全脑缺血再灌注损伤

近年来,传统意义上的性激素黄体酮(progesterone,PROG)在神经系统的作用日益受到重视,被称为"神经活性甾体".研究显示,外源性PROG可明显减轻脑挫伤大鼠的脑水肿,促进认知功能的恢复[1].一些学者研究结果表明PROG可减轻大鼠局灶性脑缺血再灌注损伤[2,3].而PROG是否也可减轻大鼠全脑缺血再灌注损伤尚未见文献报道.为此,我们采用大鼠四血管闭塞全脑缺血再灌注模型,观察PROG对大鼠海马神经元和大鼠行为学的影响.     

丹金合剂对大鼠心肌缺血再灌注损伤的保护作用

目的:探讨丹金合剂对大鼠心肌缺血再灌注损伤的保护作用。方法:通过结扎大鼠冠状动脉左前降支(LAD)制成心肌缺血再灌注损伤模型,观察丹金合剂在心肌缺血再灌注状态下对心功能及心肌组织酶的影响。结果:丹金合剂能显著的升高大鼠心肌缺血再灌注引起的左室内压(LVSP)、左室内压最大上升与下降速率(dp/dtmax);降低心肌丙二醛(MDA)含量,增高超氧化物歧化酶(SOD)、Na 、K -ATPase,Ca2 、Mg2 -ATPase的活力。结论:丹金合剂对大鼠心肌缺血再灌注损伤具有保护作用。     

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.

     

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.     

2-(Acetoxyphenyl)-(Z)-styryl sulfides as cyclooxygenase inhibitors

2-(Acetoxyphenyl)-(Z)-styryl sulfides are described as selective cyclooxygenase-2 (COX-2) inhibitors, useful for treating inflammation and COX-2-mediated disorders including neoplasia. 2-(Acetoxyphenyl)-(Z)-styryl sulfide is claimed to be the most potent COX inhibitor in the series with a COX-2 selectivity ratio of 33. This compound is also claimed to be superior to celecoxib (Celebrex^®, Pfizer) in inhibiting cell growth of colorectal carcinoma cells. In this evaluation, the COX inhibitory activity of this compound is compared to that previously disclosed for diarylheterocycles and 2-(acetoxyphenyl)alkyl sulfides. The validity of the DLD-1 cell line in the growth inhibition studies is questioned based on recent literature reports indicating the lack of COX-2 expression in this cell line.     

Sleep-disordered breathing with chronic opioid use

Chronic opioid use for pain relief or as substitution therapy for illicit drug abuse is prevalent in our societies. In the US, retail distribution of methadone and oxycodone has increased by 824 and 660%, respectively, between 1997 and 2003. μ-Opioids depress respiration and deaths related to illicit and non illicit chronic opioid use are not uncommon. Since 2001 there has been an emerging literature that suggests that chronic opioid use is related to central sleep apnoea of both periodic and non-periodic breathing types, and occurs in ～ 30% of these subjects. The clinical significance of these sleep-related abnormalities are unknown. This review addresses the present knowledge of control of ventilation mechanisms during wakefulness and sleep, the effects of opioids on ventilatory control mechanisms, the sleep-disordered breathing found with chronic opioid use and a discussion regarding the future research directions in this area.     

Drug targets for cognitive enhancement in neuropsychiatric disorders

The investigation of novel drug targets for treating cognitive impairments associated with neurological and psychiatric disorders remains a primary focus of study in central nervous system (CNS) research. Many promising new therapies are progressing through preclinical and clinical development, and offer the potential of improved treatment options for neurodegenerative diseases such as Alzheimer's disease (AD) as well as other disorders that have not been particularly well treated to date like the cognitive impairments associated with schizophrenia (CIAS). Among targets under investigation, cholinergic receptors have received much attention with several nicotinic agonists (α7 and α4β2) actively in clinical trials for the treatment of AD, CIAS and attention deficit hyperactivity disorder (ADHD). Both glutamatergic and serotonergic (5-HT) agonists and antagonists have profound effects on neurotransmission and improve cognitive function in preclinical experiments with animals; some of these compounds are now in proof-of-concept studies in humans. Several histamine H3 receptor antagonists are in clinical development not only for cognitive enhancement, but also for the treatment of narcolepsy and cognitive deficits due to sleep deprivation because of their expression in brain sleep centers. Compounds that dampen inhibitory tone (e.g., GABA_A α5 inverse agonists) or elevate excitatory tone (e.g., glycine transporter inhibitors) offer novel approaches for treating diseases such as schizophrenia, AD and Down syndrome. In addition to cell surface receptors, intracellular drug targets such as the phosphodiesterases (PDEs) are known to impact signaling pathways that affect long-term memory formation and working memory. Overall, there is a genuine need to treat cognitive deficits associated with many neuropsychiatric conditions as well as an increasingly aging population.