L-精氨酸对创伤性休克大鼠的保护作用研究

目的　探讨左旋精氨酸 (L -Arg)对创伤性休克大鼠的保护作用。方法　通过外力致大鼠双侧后肢骨折 ,制作创伤性休克模型 ,复苏时分别输注L -Arg 10、10 0、30 0mg/kg ,非选择性一氧化氮合成酶 (NOS)抑制剂L -硝基精氨酸甲酯 (L -NAME 10mg/kg) ,诱导型NOS (iNOS)选择性抑制剂氨基胍 (AG 10 0mg/kg)观察存活时间、存活率。结果　L -Arg诸组及AG组大鼠存活时间显著延长 ,存活率提高。结论　L -Arg对创伤性休克大鼠具有保护作用。     

一氧化氮合酶抑制剂、L-精氨酸对创伤性休克时P-选择素的影响

目的 探讨一氧化氮合酶抑制剂、L-精氨酸对创伤性休克鼠血浆中的P—选择素的影响。方法 复制大鼠创伤性休克模型，于复苏时予以左旋—N—位硝基精氨酸甲酯、氨基肌、Ir精氨酸等治疗，采用酶联免疫法(ELISA)测定大鼠动脉血浆中P—选择素的含量。结果 正常大鼠组动脉血浆中的P—选择素的含量较低；休克后30min，动脉血浆中的P—选择素含量较对照组升高，但无明显统计学意义；复苏后60min动脉血浆中的P—选择素含量升高，与对照组比较有显著统计学意义；创伤休克 L-NAME组，复苏后60min动脉血浆中的P—选择素变化含量较创伤休克 盐水组上调；创伤休克 AG组，复苏后60min及复苏后180min动脉血浆中的P-选择素变化不明显；创伤休克 L-Arg组，复苏后60dn动脉血浆中的P—选择素含量较创伤休克 盐水组下调。结论 创伤性休克后体内P—选择素是升高的，这与休克时存在明显的微循环紊乱、内皮功能障碍、再灌流损伤和细菌移位有关；LNAME及L-Arg对P—选择素有调节作用，而AG对P—选择素无调节作用。     

一氧化氮合酶抑制剂对大鼠创伤性休克的治疗作用

目的：评价选择性诱导型一氧化氮合酶(iNOS)抑制剂氨基胍(AG)和非选择性一氧化氮合酶抑制剂L—硝基精氨酸甲酯(L—NAME)对创伤性休克的治疗效果。方法：30只SD大鼠制作创伤性休克动物模型。双侧股骨干砸伤后并经股动脉放血至平均动脉压(MAP)35—45mmHg(1mmHg＝0．133kPa)，维持30min，然后回输失血和等量的林格氏液。随机分为休克组(10只)、AG组(10只，复苏时静脉注射AG8mg／kg)、L—NAME组(10只，复苏时静脉注射L—NAME 8mg／kg)，观察休克前后血浆一氧化氮(NO)浓度的动态变化，观察24h大鼠存活率，24h后留取肺、肝、肾、小肠组织，观察病理改变。结果：大鼠创伤性休克后，血浆NO水平明显高于休克前；AG组动物复苏后血浆NO的水平明显降低，各脏器的病理损害亦显著减轻，存活率明显提高：L—NAME组动物复苏后血浆NO的水平也明显降低，各脏器的病理损害无明显变化，存活率无明显提高。结论：NO在创伤性休克的病理发展过程中起着重要作用，应用AG有助于创伤性休克的纠正，而L—NAME能降低NO的水平，但对休克的预后无明显改善。     

氨基胍对创伤性休克大鼠血浆一氧化氮及内皮素变化的影响

目的　探讨一氧化氮合酶抑制剂氨基胍对创伤性休克过程中血浆一氧化氮、内皮素及组织氧分压的影响。方法　采用股骨创伤法建立创伤性休克大鼠模型 ,随机分为对照组与处理组。观察两组大鼠创伤前后及复苏后 1、 3、 5、 12h血浆一氧化氮、内皮素及骨骼肌、肝脏、小肠的组织氧分压的动态变化 ,监测血液动力学变化并记录存活时间。结果　两组大鼠休克末及复苏后各时间点血浆一氧化氮、内皮素浓度及组织氧分压较伤前差异有显著性意义 (P <0 0 5 ) ;同对照组相比 ,处理组休克后期一氧化氮及内皮素浓度明显降低 ,差异有显著性意义 (P <0 0 5 ) ,而休克后期肝脏、小肠氧分压明显高于对照组 ,差异有显著性意义 (P <0 0 5 ) ,处理组复苏后血压明显高于对照组 ,其 12、 2 4存活率也明显高于对照组 ,差异有显著性意义 (P <0 0 5 )。结论　氨基胍可降低血浆一氧化氮、内皮素浓度 ,提高血压 ,改善内脏器官的组织氧分压 ,从而改善创伤性休克大鼠的预后     

左旋精氨酸对高脂血症大鼠血清一氧化氮影响的观察

在实验性高脂血症大鼠模型上观察血清一氧化氮（ＮＯ）水平的改变以及左旋精氨酸（ＬＡｒｇ）对其影响，旨在探讨高脂血症与血管内皮细胞合成和释放ＮＯ减少之间的关系，为临床治疗高脂血症和动脉粥样硬化提供有益的线索。１材料与方法１．１动物模型建立与分组：取雄性Ｓ...     

氨基胍对创伤性休克血浆内皮素的影响

目的探讨氨基胍（AG）对创伤性休克大鼠各时间段血浆内皮素（ET）浓度的影响。方法复制SD大鼠创伤性休克模型，将大鼠分为处理组与休克组，处理组在休克末给予AG。测定大鼠在休克末和复苏后1h、3h、5h各时间段血浆ET的浓度。结果创伤性休克大鼠休克末和复苏后各时间段血浆ET浓度显著升高（P〈0．05）。而处理组大鼠由于补充外源性氨基胍，在一定程度上抑制了血浆内皮素ET浓度的升高，改善了创伤性休克的预后。结论休克后血浆ET值显著升高，参与了休克的病理生理损害过程，是有可能造成休克后期机体死亡的原因之一。     

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-精氨酸和氨基胍对大鼠局灶性脑缺血损伤的影响

背景：利用一氧化氮的双重作用，找到治疗脑缺血的最佳药物、最佳给药时间和剂量等一直是研究的热点。目的：观察L-精氨酸和氨基胍对实验性大鼠局灶性脑缺血损伤的治疗作用以及一氧化氮在脑缺血损伤中的作用规律。设计：随机对照实验。地点和材料：实验地点为河北省医学科学院药理研究室。动物：健康雄性SD大鼠，体质量250—300g(由河北省实验动物中心提供)。方法：用线栓法建立大鼠大脑中动脉脑缺血(MCAO)模型后注射L-精氨酸和氨基胍，研究大鼠脑缺血后脑梗死体积变化；脑组织中一氧化氮、丙二醛含量和一氧化氮合酶、超氧化物歧化酶(SOD)活性的变化；缺血脑组织病理变化。主要观察指标：脑梗死体积；脑组织丙二醛含量；SOD活性；脑组织一氧化氮含量；NOS活性。结果：单独给予L-精氨酸[(14．46&;#177;3．59)％]或氨基胍[(14．40&;#177;3．06)％]均可明显缩小脑梗死体积[假手术组为(22．10&;#177;3.98)％]，明显降低缺血脑组织丙二醛含量，增强SOD活性；L-精氨酸还可明显增加缺血脑组织一氧化氮含量，氨基胍可明显抑制缺血脑组织NOS活性；L-精氨酸与氨基胍合用时，上述各项指标与缺血组比较无明显变化。结论：L-精氨酸与氨基胍分别单独应用，对脑缺血性损伤具有治疗作用，两药合用则无明显效果。     

一氧化氮合酶抑制剂对严重烧伤大鼠的作用研究

目的 :研究一氧化氮合酶 (NOS)抑制剂对严重烧伤大鼠体内一氧化氮 (NO)含量及 NOS表达的影响及其与预后的关系。方法 :复制大鼠重症烧伤模型 ,检测应用非选择性 NOS抑制剂 N 硝基 L 精氨酸甲酯(L NAME)和选择性诱生型 NOS(i NOS)抑制剂氨基胍 (AG)后大鼠血液中 NO代谢产物 (NO- 2 /NO- 3 )以及肺和十二指肠组织中神经型 NOS(n NOS) m RNA的表达水平 ,同时统计各组大鼠的存活率。结果 :烧伤后大鼠血液中 NO- 2 /NO- 3 含量明显增高 ,L NAME和 AG都能抑制 NO2 /NO- 3 的升高 ,L NAME作用更为明显 ;烧伤后 n NOS的 m RNA表达在肺和十二指肠中均有不同程度升高 ,AG和 L NAME使 n NOS表达增加 ,AG作用更为明显 ;L NAME组动物存活时间较对照组显著缩短 ,AG组动物存活时间明显延长。结论 :结构型NOS(c NOS)与 i NOS在烧伤休克病理生理过程中的作用明显不同 ,i NOS活性过度增高与烧伤休克发病关系密切     

内毒素休克血浆一氧化氮的变化及其意义

为了探讨一氧比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-哨基左旋精氨酸治疗,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NO浓度升高,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,值得进一步研究.     

Therapeutic administration of nitric oxide synthase inhibitors reverses hyperalgesia but not inflammation in a rat model of polyarthritis

Nitric oxide (NO) has been postulated to play a role in pain as well as in inflammation. In the present studies, the effects of NO synthase (NOS) inhibitors on both pain and inflammation were examined in a rat model of polyarthritis. Female Lewis rats were injected intraperitoneally (i.p.) with peptidoglycan/polysaccharide (PG/PS) or saline to induce arthritis. Hind paw volume, response latency to thermal nociceptive stimulus and mechanical threshold were measured daily for the next 35 days. Paw inflammation, thermal hyperalgesia and mechanical allodynia developed in all rats that received PG/PS compared to saline. On day 19 (chronic inflammation phase), rats were given either N(G)-nitro-L-arginine methyl ester (L-NAME, non-selective NOS inhibitor, 100 mg/l), L-N (6)-(1-iminoethyl) lysine (L-NIL, selective inducible NOS inhibitor, 10 mg/l) or no drug in drinking water. By day 21, L-NAME treatment reversed the thermal hyperalgesia completely and this effect remained until day 35. Similarly, L-NIL treatment reversed thermal hyperalgesia from days 24 to 34. Neither treatment affected mechanical allodynia. Paw volume was not different between PG/PS treated and PG/PS plus L-NAME treated rats. However, the PG/PS plus L-NIL treatment produced an increase in paw volume greater than did PG/PS alone. Other rats were treated with PG/PS plus the antiinflammatory agent indomethacin (days 19-35). Indomethacin treatment reversed all the measured parameters, although the reversal of mechanical allodynia was only partial. These results suggest that NO is involved in thermal, but not mechanical sensory pathways and that the selective inhibition of inducible NOS activity exacerbates established inflammation.     

Effects of inducible nitric oxide synthase inhibition or norepinephrine on the neurovascular coupling in an endotoxic rat shock model

Introduction  

The inducible nitric oxide synthase (iNOS) plays a crucial role in early sepsis-related microcirculatory dysfunction. Compared to a catecholamine therapy we tested effects of a specific iNOS-inhibitor (1400W) on the microcirculatory function in the brain.     

大鼠创伤性脑水肿一氧化氮及其合成酶的变化

目的：探讨脑损伤后一氧化氮（ＮＯ）及一氧化氮合酶（ＮＯＳ）与脑水肿的关系。方法：建立大鼠创伤性脑水肿模型,按不同时间点处死动物,测定其脑含水量及静脉血ＮＯ 和脑组织中ＮＯＳ。结果：脑创伤后脑含水量随静脉血ＮＯ的增加而增加,组织ＮＯＳ则随ＮＯ 的增加而下降。结论：创伤性脑水肿与血ＮＯ 有密切相关性,组织中ＮＯＳ则是该过程的可能催化剂     

捕食应激对大鼠海马一氧化氮及神经型一氧化氮合酶的影响

目的探讨一氧化氮(NO)在创伤后应激障碍(PTSD)样行为异常大鼠的变化规律,以进一步揭示PTSD的神经生物学机制。方法将144只Wistar大鼠随机分组为捕食应激组(n=72)及正常对照组(n=72),在大鼠捕食应激PTSD动物模型基础上,动态检测大鼠海马、额叶皮层组织匀浆NO、一氧化氮合酶(NOS)含量及神经元型NOS(nNOS)表达。结果应激大鼠海马NO含量于捕食应激后即刻明显高于对照组犤(2.8±0.8)μmol/g,F=23.112,P=0.000犦,12h达高峰(3.9±1.1)μmol/g,与对照组比较,F=56.616,P=0.000;与同组其他时相比较,F=14.917,P<0.05,24h时仍明显增多犤(2.6±0.7)μmol/g,F=23.094,P=0.000犦;海马nNOS表达亦同步增高(应激后即刻,12及24h,F=14.228,21.772,18.500,P<0.01),而海马总NOS活性仅在应激后12h内增高犤应激后即刻及12hNOS分别为(9.8±2.5)mmol/(s·kg),F=32.812,P=0.000及(10.2±2.7)mmol/(s·kg),F=31.395,P=0.000犦。结论严重心理/生理应激所致海马nNOS持续性高表达与NO释放明显增多,在实验大鼠持续性PTSD样行为异常中可能有重要作用。     

亚低温对急性创伤性脑水肿大鼠一氧化氮及其合成酶变化的影响

目的：探讨亚低温疗法对急性创伤性脑水肿后一氧化氮及其合成酶变化的影响机制。方法：建立大鼠创伤性脑水肿模型,测定伤后不同时间点常温下及亚低温后颈内静脉血一氧化氮、脑组织一氧化氮合成酶和脑含水量。结果：致伤后３０分钟大鼠即出现脑水肿,伤后８小时达高峰（从伤前７７．６３％±０．２１％升至７９．８３％±０．４１％）;一氧化氮具有同步效应〔从伤前（２．４４±０．１２）μｍｏｌ／Ｌ升至（７．８３±０．２７）μｍｏｌ／Ｌ〕;一氧化氮合成酶伤后３０分钟达高峰〔从伤前（３８．８９±４１．３０）μｍｏｌ·ｍｉｎ－１·ｇ－１升至（１０６．５８±５２．４６）μｍｏｌ·ｍｎ－１·ｇ－１〕,以后逐渐下降,伤后８小时〔（５８．２９±１９．４２）μｍｏｌ·ｍｉｎ－１·ｇ－１〕仍高于假手术组。而亚低温（３２～３３℃）能明显减轻脑水肿,减少一氧化氮含量及一氧化氮合成酶的表达〔伤后８小时分别为７９．５６％±０．２７％,（６．８４±０．３７）μｍｏｌ／Ｌ,（５１．０２±２４．５１）μｍｏｌ·ｍｉｎ－１·ｇ－１〕。结论：一氧化氮在创伤性脑水肿发生发展中起作用,而亚低温可能抑制一氧化氮合成酶的表达,减少一氧化氮含量,对创伤性脑水肿有一定保护作用。     

Aminoethyl-isothiourea, a nitric oxide synthase inhibitor and oxygen radical scavenger, improves survival and counteracts hemodynamic deterioration in a porcine model of streptococcal shock

OBJECTIVE: To test the effect of a continuous infusion of the nitric oxide (NO) synthase (S) inhibitor aminoethyl-isothiourea (AE-ITU) on survival time, hemodynamics, and oxygen transport in a porcine model of live group A streptococcal (GAS) sepsis. Furthermore, to examine the role of endothelin-1, histamine, and reactive oxygen species (ROS) in streptococcal shock. DESIGN: Prospective, randomized trial. SETTING: Laboratory at a university hospital. SUBJECTS: Twenty-eight pigs with an average weight of 25 kg. INTERVENTIONS: Sixteen animals received a continuous infusion of live Streptococcus pyogenes 1.3 x 10(10) colony forming units/hr: eight received fluids only, and the other eight received an intravenous infusion of AE-ITU 10 mg/kg/hr starting 30 mins before the GAS challenge. Six control pigs received AE-ITU 10 mg/kg/hr iv for 5 hrs. Another six animals received half the dose of GAS over 5 hrs. MEASUREMENTS AND MAIN RESULTS: GAS infusion caused a rapid increase in pulmonary, hepatic, and systemic vascular resistance, followed by hypotension with a 90% lethality at 4 hrs. Treatment with AE-ITU increased 4-hr survival in septic animals from 1/8 to 8/8 and 5-hr survival from 0/8 to 5/8, prevented hypotension, and increased urine output. AE-ITU attenuated the decrease in cardiac output, liver blood flow, and oxygen delivery, and hepatic arterial blood flow as a fraction of cardiac output increased (all p < .05). Plasma nitrate/nitrite levels decreased in all animals. Inducible NOS and endothelial constitutive NOS activities in liver, gut, and lung were not increased during sepsis, nor were they decreased after AE-ITU. Plasma levels of endothelin-1 and methylhistamine increased in all septic animals and were not modified by AE-ITU. AE-ITU prevented the increase in monocyte ROS production caused by GAS. In control animals, AE-ITU caused an increase in mean arterial pressure, liver blood flow, and oxygen delivery. CONCLUSIONS: In this model of porcine GAS-induced septic shock, which was not associated with enhanced NO production, infusion of the NOS inhibitor AE-ITU prolonged survival, prevented hypotension, and improved cardiac contractility, organ perfusion, and tissue oxygenation. These beneficial effects of AE-ITU might be a result of the combined effect of ROS scavenging and modulation of local NO production, thus improving the balance of vasodilator and vasoconstrictor forces and reducing oxidative stress.     

Androstenetriol improves survival in a rodent model of traumatic shock

Trauma results in activation of the hypothalamic-pituitary-adrenal axis to mediate a cascade of neurohormonal changes as a defensive mechanism. Its prolongation, however, leads to a hypermetabolic, hypoperfused, and immunosuppressed state, setting the stage for subsequent sepsis and organ failure. Androstenetriol (5-androstene-3beta, 7beta, 17betatriol - AET), a metabolite of dehydroepiandrosterone, up-regulates the host immune response markedly, prevents immune suppression and controls inflammation, leading to improved survival after lethal infections by several diverse pathogens and lethal radiation. Such actions may be useful in improving survival from traumatic shock. HYPOTHESIS: The neurosteroid AET will increase survival following traumatic shock. METHODS: A combat relevant model of traumatic shock was used. Male Sprague-Dawley rats were anesthetized, catheterized and subjected to soft tissue injury (laparotomy). Animals were allowed to regain consciousness over the next 0.5 h and then bled 40% of their blood volume over 15 min. Forty-five minutes after the onset of hemorrhage animals were randomized to receive either a single subcutaneous dose of AET (40 mg/kg, sc) or vehicle (methylcellulose). Volume resuscitation consisted of l-lactated Ringer's (three times the shed blood volume), followed by packed red blood cells (one-third shed red cell volume). Animals were observed for three days. RESULTS: A total of 24 animals were studied. Of the 12 animals randomized to receive AET, all (100%) survived compared to 9 of 12 animals (75%) randomized to receive the vehicle (p < 0.05). CONCLUSION: AET significantly improved survival when administered subcutaneously in a single dose in this rodent model of traumatic shock. Further survival and mechanism studies are warranted.     

Prolactin secretion in hypothyroid endotoxemic rats: involvement of L-arginine and nitric oxide synthase

The identification of nitric oxide (NO) within the hypothalamus and pituitary gland has suggested its role as modulator of the activity on hypothalamic-pituitary axis. Hypothalamic NO synthase (NOS) is known to be regulated by thyroid hormones. We investigated the effects of previous injection of N-nitro-L-arginine methyl ester (L-NAME), a NOS inhibitor, and L-arginine (L-Arg), the substrate for NO synthesis, on prolactin (PRL) secretion, through the lipopolysaccharide (LPS)-induced inflammatory response in thyroidectomized (TX) rats. TX or sham-operated (N) rats were intraperitoneally (i.p.) injected with L-NAME (10 mg kg) or L-Arg (200 mg kg) or the same volume of vehicle (saline solution) 30 min before endotoxemia-induction with LPS at 250 mug (100 g body weight), i.p.. In N rats, NO increased PRL release in response to endotoxemia, whereas in hypothyroid rats, NO appeared to have the opposite effect. Our data support the hypothesis that NO exerts a modulatory influence on PRL secretion after LPS-induced inflammatory response.