Role of vascular nitric oxide in experimental liver cirrhosis

One of the most important features of liver cirrhosis is the splanchnic and systemic arterial vasodilation, related to an increase in vascular capacity and an active vasodilation. This arterial vasodilation seems to be the consequence of the excessive generation of vasodilating substances, which also contributes to a lower than normal pressor response to circulating nervous or humoral substances. The following review analyzes the mechanisms responsible for the vascular hyporesponse to vasoconstrictors observed in the experimental models of liver cirrhosis. It has become increasingly clear that, among the great variety of substances studied, nitric oxide (NO) seems to be one of the main contributors to this vascular alteration, since elimination of the endothelium or inhibition of its synthesis corrects it. The mechanism by which NO interferes with the contractile apparatus in smooth muscle cells seems to be related to a direct effect on calcium entry from the extracellular space and release from the internal stores.     

一氧化氮在顺铂致大鼠肾损害过程中的作用

目的 探讨一氧化氮在顺铂肾毒性氧化应激机制中的作用。方法 采用少量多次给大鼠腹腔注射顺铂（ＣＰ）及经口给予水飞蓟素（ＳＢ）预处理后给予ＣＰ模型,观察血尿素氮（ＢＵＮ）含量、一氧化氮合酶（ＮＯＳ）活性、丙二醛（ＭＤＡ）形成、超氧化物歧化酶（ＳＯＤ）活性等指标的变化。结果 ＣＰ可诱导ＮＯＳ活性增高,使ＮＯ生成量增多;ＢＵＮ含量与ＭＤＡ含量及ＳＯＤ活性的变化并不完全一致,而与ＮＯ含量的时相变化活性增高,     

一氧化氮对大鼠实验性肝纤维化的影响

目的　研究一氧化氮 (NO)在肝纤维化发病中的作用。方法　建立大鼠肝纤维化模型 ,给予NO前体———L 精氨酸 (L Arg)及一氧化氮合酶 (NOS)抑制剂———硝基 L 精氨酸 (L NNA) ,应用病理组织学检查、放免法及生化学方法 ,观察其对肝纤维化程度、透明质酸 (HA)含量、谷 草转氨酶 (AST)及谷 丙转氨酶 (ALT)活性的影响 ,同时测定NO、一氧化氮合酶 (NOS)水平变化。结果　NO能明显降低肝纤维化程度、HA含量、AST及ALT活性。结论　NO对大鼠具有保护肝细胞和抗肝纤维化作用     

实验性糖尿病大鼠血清一氧化氮含量的变化

目的：研究实验性糖尿病大鼠血清一氧化氮（nitric oxide,NO)含量和一氧化氮合成酶（NO synthease,NOS)活力的变化,为糖尿病发生机制的研究提供理论依据。方法：用链脲佐菌素（Streptozotocin,STZ) 复制糖尿病动物模型,用比色法测定其血清NO含量和NOSI知力,结果：糖尿病产血清NO含量和NOS活力,与对照组比较,随病程逐渐增加,在1周内不明显,至第4周时明显升高,结论：在糖尿病晚期,血清NO含量升高,使β细胞损伤加重,糖尿病不易缓解。     

Role of nitric oxide synthase inhibitor in experimental colitis induced by 2,4,6-trinitrobenzene sulphonic acid in rats

1. The present study was designed to investigate the role of nitric oxide (NO) in modulating 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis in rats. 2. Damage scores and NO synthase (NOS) activity were measured. 3. The damage scores and NOS activity reached a peak on the 4th day after administration of TNBS solution (day 0), thereafter gradually decreasing, and were significantly higher than in the group treated with saline throughout the experimental period. 4. Subsequently, we divided the stage of colitis into two groups, one from day 0 to day 3 after induction of colitis, and the other from day 4 onwards. We evaluated the effects of the NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA), on TNBS-hapten-induced colitis and colonic mucosal blood flow. Two different methods of L-NMMA administration, from day 0 to day 3, and from day 4 onwards, were undertaken. 5. The damage score in the early L-NMMA treatment group was significantly higher than in the group without L-NMMA on day 14. In contrast, the damage score in the late L-NMMA treatment group was not significantly different from the group without L-NMMA. Colonic mucosal blood flow in the early L-NMMA treatment group was not significantly different from that in the late L-NMMA treatment group. 6. These data suggest that NO is important for inhibiting inflammation during the early stages.     

Role of nitric oxide in catalepsy and hyperthermia in morphine-dependent rats

The possible involvement of nitric oxide (NO) in morphine-induced catalepsy and hyperthermia was studied in morphine-dependent rats. Four days repeated injection regimen was used to induce morphine dependence, which was assessed by naloxone challenge (0.5 mg x kg(-1), s.c.). Pretreatment of rats with the NO synthase inhibitor, N(G)-nitro-L-arginine (L-NA, 8 mg x kg(-1) twice daily, i.p.) potentiated the cataleptic response of morphine as shown by a rightward shift in the morphine-log dose-response curve. Prior treatment of rats with the NO precursor, L-arginine (200 mg x kg(-1), twice daily, i.p.) abolished the potent effect of L-NA and restored the cataleptic scores to levels similar to those of morphine-dependent rats. The same dose of L-NA significantly blocked morphine-induced hyperthermia at the dose levels of morphine (15-105 mg x kg(-1)) and this effect was reversed by L-arginine. These data provide the first experimental evidence that NO is involved in morphine induced catalepsy and hyperthermia and demonstrated that blockade of NO synthesis may suggest a dangerous interaction with opioids in the control of motor function.     

Role of nitric oxide in amphetamine-induced sensitization of schedule-induced polydipsic rats

Rationale  

Repeated injections of amphetamine (AMPH) can progressively augment behavioral responses, a phenomenon known as behavioral sensitization. AMPH-induced behavioral sensitization can be demonstrated in a rat model of schedule-induced polydipsia (SIP).     

Role of nitric oxide in hypodipsia of rats with obstructive cholestasis

Cholestasis is associated with the overproduction of nitric oxide (NO), and NO acts as an inhibitory mechanism when thirst is stimulated by water deprivation or by angiotensin II. Due to the presence of hypodipsia in the cholestatic condition, we have compared the rate of water intake between bile duct-ligated (cholestatic) and sham-operated rats. We have evaluated the effect of NO synthesis inhibition by N(G)-nitro-L-arginine (L-NNA, 10 mg kg(-1)/day) on the rate of water intake in cholestatic rats. The results showed that plasma alkaline phosphatase activity (a marker of liver damage) increased after bile-duct ligation, and that its elevation was partially (but significantly) prevented by treatment with L-arginine. A two-week bile-duct obstruction induced a significant decrease in the rate of water intake compared with sham-operated animals (35.87 +/- 1.45 vs 42.37 +/- 1.99 mL/day, P < 0.05). This effect was corrected by the daily administration of L-NNA. Surprisingly, L-arginine (200 mg kg(-1)/day) showed similar activity as L-NNA in cholestatic rats and increased water intake, but not in control animals. Systemic NO synthesis inhibition corrected the decrease in water intake observed in cholestatic rats. This suggests an important role for NO in the pathophysiology of hypodipsia in cholestatic subjects. The effect of chronic L-arginine administration observed in cholestatic rats but not seen in the control rats could be explained theoretically by the amelioration of cholestasis-induced liver damage by chronic L-arginine administration in bile duct-ligated rats.     

Role of nitric oxide in electroshock and pentylenetetrazole seizure threshold in rats

There are contradictory reports on whether nitric oxide (NO) is a proconvulsant or anticonvulsant. Hence a study was designed to investigate the effect of NO donor l-Arginine and NO synthesis inhibitor N omega-nitro-L-arginine (NOARG) on electroshock- and pentylenetetrazole (PTZ)-induced seizure threshold in rats. L-arginine was tested in three doses (75, 150 and 300 mg/kg), and NOARG was administered in doses of 4, 8 and 16 mg/kg. L-Arginine increased the intensity of current required to produce a threshold seizure, whereas NOARG had the opposite effect. In PTZ-induced seizures, L-arginine significantly decreased the dose of PTZ required to produce a threshold seizure, while NOARG increased it. Hence, it was concluded that NO synthase inhibition had the opposite effect in electroshock- and PTZ-induced seizures, meriting further studies on the mechanism of effect.     

The Role of nitric oxide in convulsions induced by lindane in rats

Lindane is an organochloride pesticide and scabicide. It evokes convulsions mainly trough the blockage of GABA_A receptors. Nitric oxide (NO), gaseous neurotransmitter, has contradictor role in epileptogenesis due to opposite effects of l-arginine, precursor of NO syntheses (NOS), and L-NAME (NOS inhibitor) observed in different epilepsy models. The aim of the current study was to determine the effects of NO on the behavioral and EEG characteristics of lindane-induced epilepsy in male Wistar albino rats.The administration of l-arginine (600, 800 and 1000 mg/kg, i.p.) in dose-dependent manner significantly increased convulsion incidence and severity and shortened latency time to first convulsion elicited by lower lindane dose (4 mg/kg, i.p.). On the contrary, pretreatment with L-NAME (500, 700 and 900 mg/kg, i.p.) decreased convulsion incidence and severity and prolonged latency time to convulsion following injection with a convulsive dose of lindane (8 mg/kg, i.p.). EEG analyses showed increase of number and duration of ictal periods in EEG of rats receiving l-arginine prior to lindane and decrease of this number in rats pretreated with L-NAME.These results support the conclusion that NO plays a role of endogenous convulsant in rat model of lindane seizures.     

Role of nitric oxide in gastric injury induced by hemorrhagic shock in rats

The aim of this study was to investigate the effect of nitric oxide (NO) on the gastric injury induced by hemorrhagic shock. Hemorrhagic shock was created by withdrawing 3 ml blood/200 g body weight of the rats. Before the hemorrhage, N(G)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg i.v. bolus), D-NAME (10 mg/kg i.v. bolus), or L-arginine (100 mg/kg i.v. bolus and 10 mg/kg/min infusion) + L-NAME were administered. At the end of the 1-hour hypovolemic shock period, histological analysis, gastric ulcer index, gastric myeloperoxidase (MPO) activity, and gastric protein oxidation (PO) levels were determined. In histological analysis a destructive effect of L-NAME (NO synthase inhibitor) was demonstrated. L-NAME treatment increased gastric MPO activity, L-arginine reversed this effect and D-NAME had no effect. Tissue PO activity was found to be increased in L-NAME-treated rats; L-arginine treatment reversed this activity. It is concluded that gastric barrier function is altered after hemorrhagic shock, and L-arginine (NO precursor) can prevent mucosal injury in the stomach. This effect of NO may be on gastric blood flow and can be mediated by tissue neutrophils.     

Role of nitric oxide in inflammatory diseases

Nitric oxide (NO) is a signaling molecule that plays a key role in the pathogenesis of inflammation. It gives an anti-inflammatory effect under normal physiological conditions. On the other hand, NO is considered as a pro-inflammatory mediator that induces inflammation due to over production in abnormal situations. NO is synthesized and released into the endothelial cells by the help of NOSs that convert arginine into citrulline producing NO in the process. Oxygen and NADPH are necessary co-factors in such conversion. NO is believed to induce vasodilatation in cardiovascular system and furthermore, it involves in immune responses by cytokine-activated macrophages, which release NO in high concentrations. In addition, NO is a potent neurotransmitter at the neuron synapses and contributes to the regulation of apoptosis. NO is involved in the pathogenesis of inflammatory disorders of the joint, gut and lungs. Therefore, NO inhibitors represent important therapeutic advance in the management of inflammatory diseases. Selective NO biosynthesis inhibitors and synthetic arginine analogues are proved to be used for the treatment of NO-induced inflammation. Finally, the undesired effects of NO are due to its impaired production, including in short: vasoconstriction, inflammation and tissue damage. Received 12 December 2006; revised 7 March 2007; accepted 15 April 2007     

Role of inducible nitric oxide synthase-derived nitric oxide in lipopolysaccharide plus interferon-gamma-induced pulmonary inflammation

Exposure of mice to lipopolysaccharide (LPS) plus interferon-gamma (IFN-gamma) increases nitric oxide (NO) production, which is proposed to play a role in the resulting pulmonary damage and inflammation. To determine the role of inducible nitric oxide synthase (iNOS)-induced NO in this lung reaction, the responses of inducible nitric oxide synthase knockout (iNOS KO) versus C57BL/6J wild-type (WT) mice to aspirated LPS + IFN-gamma were compared. Male mice (8-10 weeks) were exposed to LPS (1.2 mg/kg) + IFN-gamma (5000 U/mouse) or saline. At 24 or 72 h postexposure, lungs were lavaged with saline and the acellular fluid from the first bronchoalveolar lavage (BAL) was analyzed for total antioxidant capacity (TAC), lactate dehydrogenase (LDH) activity, albumin, tumor necrosis factor-alpha (TNF-alpha), and macrophage inflammatory protein-2 (MIP-2). The cellular fraction of the total BAL was used to determine alveolar macrophage (AM) and polymorphonuclear leukocyte (PMN) counts, and AM zymosan-stimulated chemiluminescence (AM-CL). Pulmonary responses 24 h postexposure to LPS + IFN-gamma were characterized by significantly decreased TAC, increased BAL AMs and PMNs, LDH, albumin, TNF-alpha, and MIP-2, and enhanced AM-CL to the same extent in both WT and iNOS KO mice. Responses 72 h postexposure were similar; however, significant differences were found between WT and iNOS KO mice. iNOS KO mice demonstrated a greater decline in total antioxidant capacity, greater BAL PMNs, LDH, albumin, TNF-alpha, and MIP-2, and an enhanced AM-CL compared to the WT. These data suggest that the role of iNOS-derived NO in the pulmonary response to LPS + IFN-gamma is anti-inflammatory, and this becomes evident over time.     

Role of inducible nitric oxide synthase-derived nitric oxide in silica-induced pulmonary inflammation and fibrosis

Inhalation of crystalline silica can produce lung inflammation and fibrosis. Inducible nitric oxide synthase (iNOS)-derived nitric oxide (NO) is believed to be involved in silica-induced lung disease. To investigate the role of iNOS-derived NO in this disease, the responses of iNOS knockout (KO) versus C57Bl/6J wild-type (WT) mice to silica were compared. Male mice (8-10 wk old, mean body weight 24.0 g) were anesthetized and exposed, by aspiration, to silica (40 mg/kg) or saline. At 24 h and 42 d postexposure, lungs were lavaged with saline. The first bronchoalveolar lavage (BAL) fluid supernatant was analyzed for lactate dehydrogenase (LDH) activity, levels of albumin, tumor necrosis factor-alpha (TNF-alpha), and macrophage inflammatory protein-2 (MIP-2), as well as total antioxidant capacity (TAC). The cellular fraction of the total BAL was used to determine alveolar macrophage (AM) and polymorphonuclear leukocyte (PMN) counts, and zymosanstimulated AM chemiluminescence (AM-CL). In separate mice, lung histopathological changes were evaluated 42 d postexposure. Acute (24-h) silica exposure decreased AMs, increased PMNs, increased LDH activity and levels of albumin, TNF-alpha, and MIP-2 in BAL fluid, and enhanced AM-CL in both iNOS KO and WT mice. However, iNOS KO mice exhibited less AM activation (defined as increased AM-CL and decreased AM yield) than WT. Furthermore, TAC following acute silica decreased in WT but was maintained in iNOS KO mice. Pulmonary reactions to subchronic (42 d) silica exposure were similar to acute. However, histopathological and BAL fluid indices of lung damage and inflammation, AM activation, and lung hydroxyproline levels were significantly less in iNOS KO compared to WT mice. These results suggest that iNOS-derived NO contributes to the pathogenesis of silica-induced lung disease in this mouse model.     

Role of endothelial nitric oxide in cerebrovascular regulation

Endothelial nitric oxide (NO) plays important roles in the vascular system. Animal models that show vascular dysfunction demonstrate the protective role of endothelial NO dependent pathways. This review focuses on the role of endothelial NO in the regulation of cerebral blood flow and vascular tone. We will discuss the importance of NO in cerebrovascular function using animal models with altered endothelial NO production under normal, ischemic and reperfusion conditions, as well as in hyperoxia. Pharmacological and genetic manipulations of the endothelial NO system demonstrate the essential roles of endothelial NO synthase in maintenance of vascular tone and cerebral perfusion under normal and pathological conditions.     

Role of nitric oxide and mucus in ischemia/reperfusion-induced gastric mucosal injury in rats

The present study aims at investigating the role of nitric oxide (NO) on the oxidative damage in gastric mucosa of rats which received ischemia/reperfusion (I/R) and its relation to mucus. NO synthesis modulators such as L-arginine and N(G)-nitro-L-arginine methyl ester (L-NAME) were injected intraperitoneally to the rats 30 min prior to I/R which was induced by clamping the celiac artery and the superior mesenteric artery for 30 min and reperfusion for 1 h. As a result, I/R increased lipid peroxide production and decreased the contents of glutathione (GSH), cGMP and mucus as well as GSH peroxidase activities of gastric mucosa. I/R decreased the activity and protein of NO synthase (NOS) in gastric mucosa. Pretreatment of L-arginine, a substrate for NOS, prevented I/R-induced alterations of gastric mucosa. However, L-NAME, an NOS inhibitor, deteriorated oxidative damage induced by I/R. In conclusion, NO has an antioxidant defensive role on gastric mucosa by maintaining mucus, GSH and GSH peroxidase, which were related to preservation of cGMP and NOS in gastric mucosa.     

Role of endogenous nitric oxide in the nitric oxide donor-induced plasma extravasation of mouse skin.

The role of endogenous nitric oxide (NO) and prostanoids in the increase in microvascular permeability induced by NO donors was investigated in the mouse skin by a dye leakage method. Subcutaneous (s.c.) injection of 1-hydroxy-2-oxo-3-(3-aminopropyl)-3-isopropyl-1-triazene (NOC 5), 1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene (NOC 18) and sodium nitroprusside dose-dependently increased local dye leakage. While indomethacin inhibited the dye leakage elicited by these NO donors, N(G)-nitro-L-arginine methyl ester (L-NAME) inhibited the effect of NOC 5 and NOC 18 but not of sodium nitroprusside. These results suggest that endogenous NO, in addition to the prostanoid biosynthesis, is involved in the dermal microvascular permeability increase induced by the NOC series NO donors.     

Role of nitric oxide in benzodiazepines-induced antinociception in mice

The influence of nitric oxide (NO) on antinociceptive activity of diazepam (DZ), chlordiazepoxide (CDP) and clonazepam (CZ) was examined using the writhing test in mice. The effect of DZ was also studied in mice using hot plate and tail flick tests. DZ (1.25, 2.5 and 5 mg/kg), CDP (1.25, 2.5, 5, 10 and 20 mg/kg) and CZ (0.075, 0.3125, 0.625, 1.25 and 2.5 mg/kg) produced significant, dose-dependent (DZ, CDP) antinociception in mice. The benzodiazepines (BZs)-induced antinociception was antagonized by flumazenil (5 mg/kg) and was not changed by naloxone (2.5, 5 and 10 mg/kg), except that of CZ, which was reversed by 5 mg/kg of naloxone. NG-nitro-L-arginine methyl ester hydrochloride (L-NAME) as well as 7-nitroindazole (7-NI) intensified antinociceptive activity of BZs. The antinociceptive effect resulting from co-administration of L-NAME with CZ and 7-NI with CDP was reversed by L-arginine. Methylene blue (MB) increased, whereas L-arginine (but not D-arginine) decreased antinociceptive effects of the studied BZs. These results suggest that the NO-cGMP pathway is involved in the mechanism of BZs-induced antinociception in the writhing test in mice.