一氧化氮与内毒素休克关系的实验研究

为了评价一氧化氮（NO）在内毒素休克中的作用，应用脂多糖建立兔内毒素休克模型，然后分别应用N-硝基主旋精氨酸（L-NNA）和生理盐水静注治疗，分别测量治疗前后血压、血浆NO、环磷酸鸟苷（cGMP）和心钠素（ANF）。结果发现，内毒素休克时，血压下降，血浆NO、cGMP浓度升高，静注L-NNA（20mg／kg）治疗后休克大白兔血压升高，血浆NO、CGMP浓度下降。说明内毒素休克时机体内NO和cGMP产生增加，并与低血压有关，其机理是NO通过激活可溶性鸟苷酸环化酶，使cGMP增高所致，并提示L-NNA具有治疗内毒素休克的价值。     

内毒素休克血浆一氧化氮的变化及其意义

为了探讨一氧化氮与内毒素休克的关系，应用脂多糖建立兔内毒素休克模型，然后应用Ｎ－硝基左旋精氨酸治疗，分别观察治疗前后血压，血浆ＮＯ的变化，结果发现内毒素休克时，血浆ＮＯ２升高，静注Ｌ－ＮＮＡ后，休克大白兔血压升高，血浆ＮＯ下降。提示内毒素休克时，机体内ＮＯ产生增加并与低血压有关，Ｌ－ＮＮＡ可能具有治疗内毒素休克的意义，值得进一步的研究。     

L-精氨酸和氨基胍在失血性休克中的治疗作用

目的：研究L-精氨酸（L-NNA）和氨基胍（AG）在失血性休克中的治疗效果。方法：大鼠40例随机分为休克组、L-NNA组、AG组和对照组，每组各10例。观察休克前后血浆内毒素（ET）、肿瘤坏死因子（TNF）-α、白介素（IL）-6、IL-8、一氧化氮（NO）的变化。以及动物12h、24h、48h的存活率。结果：大鼠失血休克后，血浆ET、TNF-a、IL-6、IL-8、NO水平明显升高；复苏后，L-NNA组、AG组动物血浆中上述物质水平明显低于休克组，该两组动物存活率高于休克组，而L-NNA和AG组间存活率无明显差异。结论：内毒素、TNF-α、IL-6、IL-8、NO在失血性休克的发展过程中起重要的作用，L-NNA和AG作为一氧化氮合酶（NOS）抑制剂，有助于改善失血性休克的预后。     

美蓝对感染性休克作用的初步实验观察

为了观察美蓝对内毒素性休克血压的影响，作者通过动物实验后发现，对照组大白兔静注生理盐水前后，平均动脉压、血浆环磷酸鸟着、心钠素均无差异（P＞0．05）；而实验组休克大白兔经静注美蓝前后比较，平均动脉压升高（P＜0．01），血浆环磷酸写音（P＜0.05）；并且实验组与对照组相比较，平均动脉压和血浆环磷酸鸟着水平亦有显著差异（P＜0．01）。提示血浆环磷酸鸟普值升高与内毒素性休克时的低血压、低循环阻力有关，提示美蓝的应用可有效地抑制体内可溶性鸟音酸环化酶，使休克的大白兔血浆环磷酸鸟着值下降，血压上升，并具有桔抗一氧化氮的作用，结果提示美蓝有可能作为感染性休克的治疗药物。     

牛珀至宝微丸对内毒素休克时蛋白激酶C调控一氧化氮生成的影响

目的：研究牛珀至宝微丸对蛋白激酶C调控内毒素休克时一氧化氮（NO）生成的影响。方法：以内毒素制成休克大鼠模型，用硝酸还原酶法检测血浆中NO；用免疫组织化学，Westernblot法检测诱生型一氧化氮合酶（iNOS)的表达，用同位素标记法检测其活性；观察牛珀至宝微丸对蛋白激酶C抑制剂H7及激动剂佛波脂（PMA）的影响。结果：牛珀至宝微丸可增强H7对iNOS表达的调控而使血压回升和NO浓度下降，其作用可部分被PMA逆转。结论：牛珀至宝微丸可经蛋白激酶C通路抑制内毒素诱导的NO合成而调节血压。     

人工肝支持系统治疗肝肾综合征前后肿瘤坏死因子-α一氧化氮和内毒素水平的变化研究

目的 探讨人工肝支持系统治疗中血浆置换(plasma exchange,PE)联合连续性血液透析滤过(continuous hemodiafiltration,CHDF)治疗严重肝硬化合并肝肾综合征(hepatorenal syndrome,HRS)的疗效及治疗前后血浆一氧化氮(NO)、肿瘤坏死因子(TNF)-α和内毒素变化水平,揭示其可能的致病机制.方法 研究分两组,肝硬化合并HRS组32例,均采取PE联合CHDF治疗,治疗前后自身对照;肝硬化无HRS组25例,与治疗组前后做两两对比.应用ELISA双抗体夹心法测定TNF-α,亚硝酸还原法测定血浆NO,采用鲎试验检测血浆内毒素.分析血浆内毒素与NO、TNF-α的相关性.结果 血浆NO、TNF-α、内毒素水平在肝硬化合并HRS组治疗前后差异有统计学意义(P<0.01),HRS组治疗前较单纯肝硬化组差异有统计学意义(P<0.01),HRS组治疗后与单纯肝硬化组无统计学意义(P>0.05).肝硬化合并HRS患者血浆内毒素与NO、TNF-α存在直线正相关,相关系数分别为0.927和0.857(P<0.01).结论 肝硬化内毒素血症刺激机体产生过量的NO、TNF-α,是HRS重要的发病机制,人工肝支持系统PE和CHDF治疗后可有效地降低血浆NO、TNF-α及内毒素水平,是治疗HRS的一种有效安全的方法.     

失血性休克复苏时心肌损伤和一氧化氮的变化及灵芝多糖的干预作用

目的 :探讨失血性休克和复苏再灌注过程中心肌损伤和一氧化氮 (NO)浓度的变化及灵芝多糖的干预作用。方法 :复制家兔失血性休克再灌注模型 ,随机分成假手术组、生理盐水再灌注组和质量分数为 1%的灵芝多糖再灌注组 ;观察 3组动物平均动脉血压 (MAP)、心功能、血浆 NO浓度及心肌 NO含量和一氧化氮合酶(NOS)活性的变化。结果 :两个再灌注组动物在失血性休克 4 0 m in时左心室舒张末压 (L VEDP)比休克前及假手术组略有升高 ,但差异不显著 (P均 >0 .0 5 ) ,左心室内压最大变化速率 (± dp/dt max)则明显降低 (P均 <0 .0 5 ) ,血浆 NO浓度则显著升高 (P均 <0 .0 5 )。生理盐水再灌注组动物再灌注 4 0 min时 ,心功能较休克 4 0 m in时进一步降低 (P<0 .0 5 ) ,血浆 NO浓度进一步升高 ,心肌 NOS活性和 NO含量明显高于假手术组 (P均 <0 .0 5 )。灵芝多糖组再灌注 4 0 min时较生理盐水再灌注组、心功能明显改善 ,血浆 NO浓度、心肌 NO含量和心肌 NOS活性均明显降低 (P均 <0 .0 5 )。结论 :失血性休克再灌注过程中心肌 NOS活性、血浆 NO浓度、心肌NO含量均升高 ,而心功能降低 ,提示 NO在失血性休克再灌注心肌损伤中起重要作用 ;而灵芝多糖可通过抑制 NOS活性、降低 NO浓度对失血性休克再灌注心肌损伤起保护作用。     

肝硬化患者血浆内毒素、一氧化氮和内皮素水平变化

目的：研究内毒素、一氧化氮（NO）和内皮素（ET）在肝硬化中的变化及意义。方法：用鲎试验定量检验法测定61例肝硬化患者血浆的内毒素；用比色法测定61例肝硬化患者血浆的NO；用ELISA法测定61例肝硬化患者血浆的ET。结果：内毒素、NO和ET在肝硬化中均显著升高，肝功能越差，升高越明显；NO、ET与内毒素水平呈显著正相关，内毒素、NO和ET水平与门、脾静脉宽度呈显著正相关。结论：内毒素、NO、ET与肝硬化门脉高压的形成密切相关。     

电刺激迷走神经对感染性休克大鼠血浆肿瘤坏死因子α、一氧化氮合酶及一氧化氮的影响

目的 研究电刺激迷走神经对感染性休克大鼠血浆肿瘤坏死因子α(TNF-a)、一氧化氮合酶(NOS)及一氧化氮(NO)水平的影响.方法 成年雄性SD大鼠40只,采用盲肠结扎穿孔法(CLP)复制感染性休克模型,随机分为5组:假CLP组、CLP组、迷切组、电刺激左侧迷走神经组、电刺激右侧迷走神经组.各组动物均行颈总动脉置管连续监测平均动脉压,ELISA法检测血浆 TNF-α,生化法检测血浆中NOS活性和NO水平.结果 CLP组术后平均动脉血压进行性下降,2 h时血浆TNF-α、NOS及NO水平显著升高;与CLP组比较,电刺激组动物平均动脉压下降幅度减轻,血浆TNF-α、NOS及NO水平显著降低.结论 电刺激左、右迷走神经均可能缓解CLP致感染性休克大鼠的进行性血压下降,降低血浆TNF-α、NOS及NO水平,有助于抗休克.     

c-Jun氨基末端激酶通路在内毒素休克大鼠生物喋呤诱生中的信号机制

目的 观察c-Jun氨基末端激酶(JNK)信号通路抑制剂——curcumin对内毒素休克大鼠生物喋呤(BH4)及一氧化氮(NO)表达的影响，并探讨JNK途径在生物喋呤诱生中的信号转导机制。方法建立内毒素休克模型，60只大鼠随机分为正常对照组(n=8)、内毒素休克组(n=32)和curcumin拮抗组(n=20)。采用逆转录多聚酶链式反应测定肝、肺、肾组织三磷酸鸟苷环水解酶Ⅰ(GTP-CHI)与诱生型一氧化氮合酶(iNOS)mRNA表达水平，分别采用反相高效液相色谱法和Griess比色法测定血浆与组织中BH4、NO水平的变化。结果与正常对照组相比，内毒素使动物肝、肺、肾组织GTP-CHI基因表达和BH4水平明显升高，至伤后24h仍持续于较高水平；与之相应，组织iNOS基因表达和NO水平亦明显升高。curcumin处理可明显下调肝、肺、肾组织GTP-CHI mRNA表达水平，并且肝组织6～24h时、肺组织12h时BH4水平显著降低；各组织iNOS mRNA表达及NO水平亦显著降低。结论抑制JNK信号通路能明显抑制内毒素休克鼠多器官生物喋呤／NO系统的表达，JNK途径参与了生物喋呤诱生的信号转导过程。     

盐酸戊乙奎醚对内毒素休克兔器官的保护作用

目的观察不同剂量盐酸戊乙奎醚(长托宁)对内毒素休克兔血压及重要器官形态学的影响。方法35只健康新西兰大白兔随机分成正常对照组、休克组、长托宁低剂量组(0．05 mg/kg)、长托宁中剂量组(0．15 mg/kg)和长托宁高剂量组(0．45 mg/kg)。采用静脉注射大肠杆菌脂多糖制作内毒素休克模型。长托宁各组分别于静注脂多糖后立即静注不同剂量长托宁。连续监测给药后动物平均动脉压;光学显微镜下观察各组动物心、肺、肝、肾的形态学变化。结果给药后90 min,中剂量组动物血压较休克组明显改善,低、高剂量组改善不明显。长托宁低、中、高剂量组动物各组织病变不同程度较休克组减轻,中剂量组病变减轻更明显。结论长托宁能改善内毒素休克兔的血压,减轻内毒素休克引起的重要器官的组织损伤;相对于低、高剂量长托宁,中剂量在改善血压及减轻组织损伤方面效果更为显著。     

Effects of MCI-154, a calcium sensitizer, on cardiac dysfunction in endotoxic shock in rabbits

This study was designed to observe the effects of MCI-154, a calcium sensitizer, on cardiac dysfunction after endotoxic shock in rabbits. Ten hours after the rabbits were given injection of 1.0 mg/kg endotoxin (Escherichia coli, O111:B4) via marginal ear veins, 0.1 mg/kg MCI-154 was injected intravenously and then 50 mL/kg normal saline (NS) + 0.1 mg/kg MCI-154 was infused continuously at a rate of 0.7 mL/min. During this process, the parameters of cardiac function were measured. It was found that 10 h after the endotoxin injection, heart rate (HR) was increased significantly while the mean arterial blood pressure (MAP), left ventricular systolic pressure (LVSP), isovolumetric pressure (IP), myocardial contractility (MC), and the area of p-dp/dt(max) vector loop (Lo) all were markedly decreased. Treatment with 50 mL/kg NS alone had slight effects on these parameters. On the contrary, LVSP, IP, MC, and Lo all were increased significantly while HR was not obviously changed and left ventricular end-diastolic pressure (LVEDP) was reduced remarkably following MCI-154 administration in endotoxic shock rabbits. The parameters of myocardial contractility were improved nearly to the values in sham shock group and were markedly higher than that in NS alone-treated group. It can be concluded that MCI-154 can exert significant therapeutic effects on cardiac dysfunction after endotoxic shock, for it improves cardiac function, dilates peripheral blood vessels, and slightly affects HR.     

Augmented photoplethysmographic low frequency waves at the onset of endotoxic shock in rabbits

A rabbit model of endotoxaemia was employed to study the regional changes in photoplethysmogram (PPG) waveform and its low frequency fluctuations, and how they are related to the physiological events during the time course of endotoxic shock. Endotoxin (1 mg kg(-1) lipopolysaccharide) was injected into eight anaesthetized and mechanically ventilated rabbits. The 90 min monitoring period was divided into six stages, with the onset of hypotension separating the first three (EDTX1-3) and last three (HYPO1-3) stages. The most significant finding was a substantial but transient elevation in sympathetic-related toe PPG variability (PPGV) spectral power in EDTX3 and HYPO1 (P < 0.01 versus EDTX1). The group average response showed that the rapid rise started 15 min before and peaked at the onset of hypotension, which indicated a surge in sympathetic vasomotor activity that preceded the decompensatory blood pressure fall. Ear skin vasoconstriction was evident by a marked and sustained fall in ear PPG amplitude along with a decrease in ear skin temperature at the onset of hypotension, during which the sympathetic-related ear PPGV spectral power was elevated (P < 0.01, HYPO1 versus EDTX1). The results demonstrate the value of PPGV in characterizing regional vascular control and provide important insights into the physiological mechanisms of endotoxic shock.     

血管加压素在内毒素休克兔中抗休克作用的探讨

目的:探讨血管加压素(vasopressin,VP)在内毒素休克中的抗休克作用及其对肾脏功能的影响。方法:将24只兔随机分为两组,每组12只,用注射大肠杆菌类毒素(LPS)的方法制作内毒素休克兔模型。对照组不采取复苏措施,VP组以VP复苏。分时段监测血压,测定血NO、肌酐等。并取肾脏标本行病理检查。结果:VP除了有收缩血管、升高血压的作用外,还能抑制NO的生成,起到抗休克的作用,对肾功能影响较小。结论:VP在感染性休克的治疗中具有较好的抗休克作用。     

THE ROLE OF THE RETICULO-ENDOTHELIAL SYSTEM IN HEMORRHAGIC SHOCK

"Blockade" of the RES by thorotrast so lowered the tolerance of hemorrhagic shock in rabbits and dogs that a reversible degree of hemorrhagic shock became irreversible. This was true not only in normal rabbits, but in rabbits made resistant to hemorrhagic shock by producing resistance to endotoxins. Rabbits which had been pretreated with thorotrast and then subjected to hemorrhagic shock displayed at death the hemorrhagic lesions and the renal cortical necrosis characteristic of the Shwartzman reaction, in addition to the intramural hemorrhages in the gut which are characteristic of animals dying of hemorrhagic or of endotoxic shock. Elimination of the Shwartzman reaction by the prior administration of nitrogen mustard did not prevent the endotoxemia or the death in shock. Rabbits made more resistant to thorotrast than normal rabbits by prior repeated administration of this substance were also more resistant than normal rabbits to endotoxin, and survived an ordinarily lethal exposure to hemorrhagic shock. During the first few hours after its administration thorotrast induced excessive vulnerability not only to endotoxin and to hemorrhagic shock, but also to an additional small dose of thorotrast. Moreover, a non-absorbable antibiotic given by gavage shortly after thorotrast produced the same lesions as these other agents; i.e. endotoxic shock, the Shwartzman reaction, and death. These data indicate that the lesions induced by thorotrast are produced by endotoxins which the injured or blockaded RES cannot inactivate. The presence of endotoxins in the blood of these rabbits was indicated by the lethal effect of this blood in test recipients. The foregoing observations did not apply to rabbits with an intestinal flora free of coliform bacteria. Over 80 per cent of such rabbits were resistant to an ordinarily lethal exposure to hemorrhagic shock, and they escaped the damage caused by the usual doses of thorotrast. They did, however, develop endotoxic shock and die if given a large dose of thorotrast. These data were taken to indicate that coliform-free rabbits are not entirely free of endotoxins. (In the ordinary environment animals cannot avoid swallowing endotoxin and coliform bacteria.) The absence of the Shwartzman reaction in the coliform-free rabbits is taken to signify that this reaction requires the participation of the endotoxins derived from the intraintestinal bacteria. The absence of endotoxic shock in the coliform-free rabbits is taken to signify that the endotoxins of the coliform bacteria are involved in the shock and death of the coliform-bearing rabbits. Finally the prevention by dibenamine of both the Shwartzman reaction and endotoxic shock and death in rabbits with a normal flora demonstrates that adrenergic activity plays an indispensable role in both phenomena. The foregoing data provide strong support for the thesis that when the RES is severely disabled by any agent, endotoxins which normally and continuously enter the circulation from the gut will produce endotoxic shock and death.     

血管加压素对内毒素休克抗休克作用的探讨

【摘 要】 目的 探讨血管加压素（Vasopressin，VP）在内毒素休克中的抗休克作用，及对肾脏功能的影响。 方法 将24只兔随机分为两组，每组12只，用注射大肠杆菌类毒素（LPS）的方法制作内毒素休克兔模型。对照组（A组）不采取复苏措施；血管加压素组（B组）以血管加压素复苏。分时段监测血压，测定血NO、BUN、Cr等。并取肾脏标本行病理检查。 结果 血管加压素除了收缩血管，升高血压的作用外，能抑制一氧化氮的生成，起到抗休克的作用，对肾功能影响较小。 结论 血管加压素在感染性休克的治疗中具有较好的抗休克作用。     

The nitric oxide synthase inhibitor N(G)-nitro-L-arginine decreases defibrillation-induced free radical generation

OBJECTIVES: To demonstrate that nitric oxide (NO) contributes to free radical generation after epicardial shocks and to determine the effect of a nitric oxide synthase (NOS) inhibitor, N(G)-nitro-L-arginine (L-NNA), on free radical generation. BACKGROUND: Free radicals are generated by direct current shocks for defibrillation. NO reacts with the superoxide (O(2).(-)) radical to form peroxynitrite (O=NOO(-)), which is toxic and initiates additional free radical generation. The contribution of NO to free radical generation after defibrillation is not fully defined. METHODS AND RESULTS: Fourteen open chest dogs were studied. In the initial eight dogs, 40 J damped sinusoidal monophasic epicardial shocks was administered. Using electron paramagnetic resonance, we monitored the coronary sinus concentration of ascorbate free radical (Ascz.(-)), a measure of free radical generation (total oxidative flux). Epicardial shocks were repeated after L-NNA, 5 mg/kg IV. In six additional dogs, immunohistochemical staining was done to identify nitrotyrosine, a marker of reactive nitrogen species-mediated injury, in post-shock myocardial tissue. Three of these dogs received L-NNA pre-shock. After the initial 40 J shock, Ascz.(-) rose 39+/-2.5% from baseline. After L-NNA infusion, a similar 40 J shock caused Ascz.(-) to increase only 2+/-3% from baseline (P<0.05, post-L-NNA shock versus initial shock). Nitrotyrosine staining was more prominent in control animals than dogs receiving L-NNA, suggesting prevention of O=NOO(-) formation. CONCLUSIONS: NO contributes to free radical generation and nitrosative injury after epicardial shocks; NOS inhibitors decrease radical generation by inhibiting the production of O=NOO(-).     

Endotoxin-induced pulmonary dysfunction is prevented by C1-esterase inhibitor.

In septic shock, hypotension, disseminated intravascular coagulation, and neutrophil activation are related to the activation of the blood coagulation contact system. This study evaluates in dogs the effect of the C1-esterase inhibitor (C1-INH), a main inhibitor of the blood coagulation contact system, on the cardiovascular and respiratory dysfunction associated with endotoxic shock. Two groups were included: controls, which received Escherichia coli endotoxin, and a C1-INH group in which C1-INH was infused before E. coli endotoxin administration. In both groups, endotoxin produced hypodynamic shock; however, the decrease in the systolic index and the ventricular systolic work indexes were greater in controls than the C1-INH group. In controls, the arterial O2 partial pressure decreased by 30% and the alveolo-arterial O2 difference increased by 625%, these parameters remained unchanged in the C1-INH group. Hypoxemia was associated with increased intrapulmonary shunt, decreased blood coagulation contact factors, and decreased C3c. In contrast, C1-INH administration prevented endotoxin-induced hypoxemia, the increase in intrapulmonary shunt, and the decrease in blood coagulation contact factors. This study shows that, in dogs with endotoxic shock, pulmonary dysfunction is associated with an activation of the blood coagulation contact phase system. An inhibition of this system by C1-INH prevented the hypoxemia induced by endotoxic shock.