七氟醚预处理对全身缺氧损伤小鼠脑NO含量和NOS活性的影响

目的观察七氟醚(Sev)预处理后全身缺氧损伤小鼠的生存状况,测定脑内一氧化氮(NO)含量及一氧化氮合酶(NOS)活性,探讨七氟醚预处理的保护作用。方法 6~7周龄健康雄性昆明小鼠120只,随机分为3组:Sev 0.5 h组、Sev 24 h组及对照组(P组),每组40只。Sev 0.5 h组吸入1.0%Sev 30 min,在空气中洗脱30 min后放入体积分数5%O2+95%N2环境中持续20 min;Sev 24 h组每天吸入体积分数1.0%Sev30 min,连续2 d,第3天放入体积分数5%O2+95%N2环境中持续20 min;P组不吸入Sev,直接放入体积分数5%O2+95%N2环境中持续20 min。观察小鼠在体积分数5%O2环境中20 min内的生存时间、生存率,测定脑组织NO含量和NOS活性。结果与P组比较,Sev 0.5 h组小鼠生存率提高、生存时间延长(P<0.05),脑组织NO含量降低,NOS活性增高(P<0.05);而Sev 24 h组与P组比较差异无统计学意义(P>0.05)。Sev 0.5 h组与Sev 24 h组比较,生存率提高,生存时间延长(P<0.05),NO含量和NOS活性差异有统计学意义(P<0.05)。结论 Sev预处理能对全身缺氧损伤小鼠产生保护作用,通过即刻效应提高小鼠在低氧环境中的生存率,延长其生存时间,降低脑组织中的NO含量,提高NOS活性,减轻脑组织缺氧损伤。     

N-乙酰半胱氨酸对小鼠免疫性肝损伤的影响

目的研究N-乙酰半胱氨酸(NAC)对卡介苗(BCG)与细菌脂多糖(LPS)引起小鼠免疫性肝损伤的影响。方法建立BCG/LPS引起的小鼠免疫性肝损伤模型。采用两种处理方式给予NAC:方式A,于LPS处理前4h和15min分别经腹腔注射给予NAC(预处理);方式B,于LPS处理后0h和4h分别经腹腔注射NAC(后处理)。LPS处理后8h剖杀动物,取血和肝脏,并检测血清丙氨酸氨基转移酶(ALT)活性与一氧化氮(NO)水平、肝脏组织谷胱甘肽(GSH)与丙二醛(MDA)含量以及肿瘤坏死因子α(TNF-α) mRNA表达水平。结果与模型组比较,NAC预处理组小鼠血清ALT活性下降,肝脏TNF-α mRNA表达明显减少,而体内NO生成和肝脏脂质过氧化水平无改变;NAC后处理组与模型组相比,小鼠死亡率升高,血清NO生成增加,肝脏GSH含量进一步下降,而小鼠血清ALT活性未见明显改变。结论NAC对小鼠免疫性肝损伤有双重效应,NAC预处理对抗BCG/LPS引起的小鼠免疫性肝脏损伤,NAC后处理加重BCG/LPS引起的氧化应激并升高动物死亡率。     

Effects of nitric oxide stimulation on the brain

Nitric oxide (NO) is known as the neurotransmitter responsible for penile erection. Recent experimental studies showed that NO is recognized as an important messenger mediating male copulatory behavior and penile erection in the central nervous system. In this article, the roles of central NO on modulation of male copulatory behavior and penile erection in male rats are reviewed mainly based on our previous experimental results. We focused on two brain areas in the hypothalamus for this purpose: the medial preoptic area (MPOA) and paraventricular nucleus (PVN). Increase in extracellular NO level in the MPOA facilitates copulatory behaviors, while decreases in the NO level reduce them. The altered NO level in the PVN increases frequency of reflexive erections, but does not affect copulatory behavior. Taken together, the current results and previous reports suggest that central NO may modulate male sexual functions and NO in two distinct brain areas and may play different roles through activation of different neurotransmitters. Activities of NO in the hypothalamus are affected by the existence of gonadal steroids. Moreover, our experimental results clearly showed that the extracellular NO level in the MPOA and PVN decreased with aging, and testosterone replacement in aged rats restored NO levels in both brain areas. These results postulate that changes of central NO with aging and following hormone replacement might partly contribute to changes in male rats sexual behavior corresponding to aging and replacement. Moreover, our recent report demonstrated that long-term testosterone replacement in aged rats is more effective for restoration of sexual behavior, which may be partly induced by central NO, than high-dose, short-term replacement.     

The molecular design of S-nitrosothiols as photodynamic agents for controlled nitric oxide release

Nitric oxide is a small messenger molecule utilized by nature in cell signalling and the non-specific immune response. At present, nitric oxide releasing prodrugs cannot be efficiently targeted towards a specific body compartment, which restricts their therapeutic applications. To address this limitation, we have designed two photolabile nitric oxide releasing prodrugs, tert-butyl S-nitrosothiol and tert-dodecane S-nitrosothiol, which are based on the S-nitrosothiol functionality. By modulating the prodrugs' hydrophobicity, we postulated that we could increase their stability within the cell by preventing their interaction with hydrophilic thiols and metal ions; processes that are known to inactivate this prodrug class. Our data demonstrate that these prodrugs have improved nitric oxide release kinetics compared to currently available S-nitrosothiols, as they are highly stable in vitro in the absence of irradiation (t(1/2) > 3 h), while their rate of decomposition can be regulated by controlling the intensity or duration of the photostimulus. Nitric oxide release can readily be achieved using non-laser based light sources, which enabled us to characterize photoactivation as a trigger mechanism for nitric oxide release in A549 lung carcinoma cells. Here we confirmed that irradiation induced highly significant increases in cytotoxicity within a therapeutic drug range (1-100 μm), and the utility of this photoactivation switch opens up avenues for exploring the applications of these prodrugs for chemical biology studies and chemotherapy.     

Differential effects of ouabain on the vasodilator actions of nitric oxide and S-nitrosothiols in vivo: relevance to the identity of EDRF/EDHF

OBJECTIVES: This study examined the role of Na+/K+-ATPase in the vasodilator actions of nitric oxide (NO), S-nitrosothiols and the endothelium-dependent agonist, acetylcholine. METHODS: The vasodilator responses elicited by intravenous injections of (i) the NO-donors, sodium nitroprusside and MAHMA NONOate, (ii) the S-nitrosothiols, L-S-nitrosocysteine and S-nitrosocoenzyme A, and (iii) acetylcholine, in urethane-anesthetized rats. RESULTS: The NO-donors, S-nitrosothiols and acetylcholine elicited dose-dependent depressor responses and reductions in hindquarter (HQR) and mesenteric (MR) vascular resistances. The depressor responses and associated reductions in HQR elicited by NO-donors were markedly attenuated after injection of ouabain. In contrast, the depressor responses and reductions in HQR elicited by the S-nitrosothiols and acetylcholine were not affected. The reductions in MR elicited by all vasodilator agents were exaggerated after injection of ouabain. Finally, the decomposition of sodium nitroprusside, MAHMA NONOate, L-S-nitrosocysteine and S-nitrosocoenzyme A to NO upon addition to rat blood or vascular preparations was not affected by ouabain. CONCLUSION: This study demonstrates that ouabain has opposing effects on NO-mediated vasodilation in resistance arteries in the hindquarter and mesenteric beds of the rat. The similarity of effects of ouabain on the vasodilator actions of acetylcholine, L-S-nitrosocysteine and S-nitrosocoenzyme A as opposed to the NO-donors supports the possibility that endothelium-derived relaxing factor released by acetylcholine in resistance arteries is an S-nitrosothiol.     

褪黑素抑制一氧化氮生成在小鼠免疫性肝损伤中的意义

目的探讨褪黑素（ＭＴ）抑制一氧化氮生成与保护免疫性肝损伤的关系。方法用短小棒状杆菌和脂多糖诱导小鼠免疫性肝损伤模型；分离、培养肝细胞和腹腔巨噬细胞；检测一氧化氮（ＮＯ）、丙氨酸氨基转换酶（ＡＬＴ）、丙二醛（ＭＤＡ）和谷胱甘肽过氧化酶（ＧＳＨ ｐｘ）变化。结果ＭＴ在０１～１０ｍｇ·ｋｇ－１·ｄ－１浓度范围内，明显降低小鼠免疫性肝损伤中ＭＬＴ和ＭＤＡ水平，部分恢复ＧＳＨ ｐｘ活性（Ｐ＜００５～００１），同时血浆ＮＯ水平下降（Ｐ＜００５）。左旋单甲基精氨酸则在显著降低血浆ＮＯ水平（Ｐ＜００１）同时，肝损伤征象加重。体外用ＭＴ对肝细胞和巨噬细胞无明显影响。结论褪黑素抑制体内ＮＯ过度生成，有利于保护免疫性肝损伤。     

Effects of N-acetylcysteine on arginase, ornithine and nitric oxide in renal ischemia-reperfusion injury.

BACKGROUND: Renal ischemia-reperfusion (I/R) is a complex syndrome involving several mechanisms such as renal vasoconstrictions, extensive tubular damage and glomerular injury. N-Acetylcysteine (NAC), a potent antioxidant by itself, may serve as a precursor for glutathione synthesis. The aim of this study was to investigate the possible effects of NAC on liver and kidney tissue arginase activity, ornithine and plasma nitric oxide levels during the I/R injury of kidney. METHODS: Twenty-four female Sprague-Dawley rats divided into three groups: group 1; was given saline intraperitoneally (i.p.). Saline to group 2 and NAC (300 mg kg(-1)) to group 3 were injected i.p. 30 min before induction of ischemia. Groups 2 and 3; subjected to bilateral renal ischemia (60 min) followed by reperfusion (24 h). After the reperfusion period, the rats were sacrificed and liver and kidney tissue arginase activities, ornithine and plasma nitric oxide (NO) levels were determined. RESULTS: NAC had an increasing effect on both of liver and kidney tissue arginase activities and ornithine levels while decreasing plasma NO concentration. CONCLUSION: The stimulatory effect of NAC on arginase activity may result in an inhibition of the plasma NO level. Moreover, it could be possible that one of the protective mechanisms of NAC might be through the stimulation on the both liver and kidney tissue ornithine levels.     

Regulation of nitric oxide synthesis in the liver

Nitric oxide signalling during the past two decades has been one of the most rapidly growing areas in biology. This simple free radical gas can regulate an ever-growing list of biological processes. Here the regulation of NO synthesis in the liver is reviewed. The biogenesis of nitric oxide (NO) is catalysed by nitric oxide synthases (NOS). These enzymes catalyse the oxidation of one of the guanidino nitrogens of l-arginine by molecular oxygen to form NO and citrulline. Three NOS have been identified: two constitutive (cNOS: type 1 or neuronal and type 3 or endothelial) and one inducible (iNOS: type 2). As to the liver, cNOS activity is normally detectable in Kupffer cells, whereas no cNOS is ever encoded in hepatocytes. However, hepatocytes, Kupffer and stellate cells (the three main types of liver cells) are prompted to express an intense iNOS activity once exposed to effective stimuli such as bacterial lipopolysaccharide and cytokines. This review is focused mainly on two aspects: regulation of NOS activity and expression by endogenous and exogenous compounds. Because NO production has beneficial and detrimental effects, understanding the molecular mechanisms that govern NOS is critical to developing strategies to manipulate NO production in liver diseases.     

Influence of nitric oxide derived from neuronal nitric oxide synthase on glomerular filtration

The neuronal isoform of nitric oxide synthase (nNOS) has been localized to specific regions of the kidney, including the thick ascending limb of the loop of Henle and the macula densa. Because of this discrete localization in the renal cortex, nitric oxide (NO) produced by nNOS has been suggested to play an important role in the regulation of macula densa-mediated arteriole tone and therefore could play an important role in the regulation of whole-kidney glomerular filtration rate (GFR). We hypothesized that selective blockade of nNOS would decrease GFR. Renal hemodynamics were measured before and after acute selective blockade of nNOS by 50 mg/kg 7-nitroindazole (7-NI) in anesthetized rats. Administration of 7-NI had no significant effect on basal blood pressure (from 105 +/- 3 to 101 +/- 2 mm Hg), renal blood flow [from 6.08 +/- 0.39 to 6.31 +/- 0.33 ml/min/gram of kidney weight (gkw)], or total renal vascular resistance (from 18.1 +/- 1.6 to 16.4 +/- 1.0 mm Hg/ml/min/gkw) but decreased GFR by 26% (from 1.36 +/- 0.15 to 1.00 +/- 0.13 ml/min/gkw; p < 0.02), urinary flow rate by 28% (from 24.7 +/- 1.8 to 17.8 +/- 2.2 microl/min; p < 0.05), and sodium excretion by 22% (from 5.55 +/- 0.53 to 4.30 +/- 0.52 microEq/min; p < 0.05). However, fractional sodium excretion was not changed by nNOS inhibition. There were no such changes in vehicle-treated time controls. We conclude that, in the renal cortex, NO produced by nNOS plays an important role in the regulation of whole-kidney GFR and excretion in normal, sodium-replete rats.     

Cocaine-induced liver injury in mice is mediated by nitric oxide and reactive oxygen species

The modulating effects of nitric oxide (NO) and reactive oxygen species on cocaine-induced hepatotoxicity were examined by measuring plasma alanine aminotransferase activity and by carrying out histological studies. Liver injury was induced by a single injection of cocaine in adult male ICR mice. Pretreatment with aminoguanidine (an inhibitor of NO synthase), N-methyl-d-glucamine dithiocarbamate complex with iron ion (II) (Fe²⁺(MGD)₂, a trapping reagent of NO) or deferoxamine complex with iron ion (III) (Fe³⁺-deferoxamine, a scavenger of NO) produced a marked inhibition of the hepatotoxicity induced by cocaine. In addition, pretreatment with allopurinol (an inhibitor of xanthine oxidase) and 1,3-dimethylthiourea (a scavenger of hydroxyl radical) also produced a potent inhibition. These findings suggest that a hydroxyl radical produced by the reaction of NO and superoxide anion (O₂⁻) via peroxynitrite may be involved in the pathogenesis of cocaine hepatotoxicity.     

Febrigenic signaling to the brain does not involve nitric oxide

1. The involvement of peripheral nitric oxide (NO) in febrigenic signaling to the brain has been proposed because peripherally administered NO synthase (NOS) inhibitors attenuate lipopolysaccharide (LPS)-induced fever in rodents. However, how the unstable molecule of NO can reach the brain to trigger fever is unclear. It is also unclear whether NOS inhibitors attenuate fever by blocking febrigenic signaling or, alternatively, by suppressing thermogenesis in brown fat. 2. Male Wistar rats were chronically implanted with jugular catheters; their colonic and tail skin temperatures (T(c) and T(sk)) were monitored. 3. Study 1 was designed to determine whether the relatively stable, physiologically relevant forms of NO, that is, S-nitrosoalbumin (SNA) and S-nitrosoglutathione (SNG), are pyrogenic and whether they enhance LPS fever. At a neutral ambient temperature (T(a)) of 31 degrees C, afebrile or LPS (1 microg kg(-1), i.v.)-treated rats were infused i.v. with SNA (0.34 or 4.1 micromol kg(-1); the controls received NaNO(2) and albumin) or SNG (10 or 60 micromol kg(-1); the controls received glutathione). T(c) of SNA- or SNG-treated rats never exceeded that of the controls. 4. In Study 2, we tested whether the known fever-attenuating effect of the NOS inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) at a subneutral T(a) (when fever is brought about by thermogenesis) also occurs at a neutral T(a) (when fever is brought about by skin vasoconstriction). At a subneutral T(a) of 24 degrees C, L-NAME (2.5 mg kg(-1), i.v.) attenuated LPS (10 microg kg(-1), i.v.) fever, presumably by inhibiting thermogenesis. At 31 degrees C, L-NAME enhanced LPS fever by augmenting skin vasoconstriction (T(sk) fall). 5. In summary, both SNA and SNG had no pyrogenic effect of their own and failed to enhance LPS fever; peripheral L-NAME attenuated only fever brought about by increased thermogenesis. It is concluded that NO is uninvolved in febrigenic signaling to the brain.     

脑复合剂对创伤性脑损伤模型大鼠脑内NO、nNOS活性及表达的影响

目的:探讨脑复合剂治疗对创伤性脑损伤(traumatic brain injury,TBI)模型大鼠脑保护作用可能的分子机制.方法:用自由落体打击(Feeney法)建立TBI模型,分别设立假手术组、TBI模型组及中药治疗组.中药治疗组给予脑复合剂10 g· kg-1·d-1,假手术组及TBI模型组给予同等剂量的等渗盐水...     

Comparison of the pharmacological profile of S-nitrosothiols, nitric oxide and the nitrergic neurotransmitter in the canine ileocolonic junction.

1. In organ bath experiments, hydroquinone (30-100 microM) and hydroxocobalamin (30-100 microM) concentration-dependently inhibited the relaxations induced by NO (0.3-30 microM) but not those by nitroglycerin (GTN, 1 microM) in the canine ileocolonic junction (ICJ). Hydroxocobalamin reduced the relaxation to low frequency (2 Hz) stimulation of the non-adrenergic, non-cholinergic (NANC) nerves, whereas hydroquinone only reduced the NANC nerve-mediated relaxations to electrical stimulation at 16 Hz, 0.5 ms. 2. Relaxations to S-nitroso-L-cysteine (CysNO, 1-30 microM), or S-nitroso-N-acetyl-D,L-penicillamine (SNAP, 1-30 microM) were not inhibited by hydroquinone (30-100 microM), hydroxocobalamin (30-100 microM), pyrogallol (30-100 microM) or L-cysteine (1-3 microM). Hydroquinone (100 microM) only reduced the relaxation to 10 microM CysNO. Hydroxocobalamin, but not hydroquinone, pyrogallol or L-cysteine, potentiated the relaxations to the lowest concentration (1 microM) of S-nitrosoglutathione (GSNO, 1-30 microM). 3. In the superfusion bioassay, hydroquinone (100 microM) and hydroxocobalamin (1 microM) concentration-dependently inhibited the biological activity of authentic NO (1-4 pmol) to the same extent as that of the transferable nitrergic factor, released from the canine ICJ in response to NANC nerve stimulation (8-16 Hz, 2 ms). Responses to GTN (10 pmol) or adenosine 5'-triphosphate (10 nmol) were not affected. 4. In conclusion, the nitrosothiols CysNO, SNAP and GSNO relax the canine ileocolonic junction, but these relaxations, pharmacologically, behave differently from the NANC nerve-mediated relaxations.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of nitric oxide agents in the dorsal hippocampus of mice on anxiogenic-like effect induced by histamine

Histaminergic receptors and neuronal nitric oxide synthase (nNOS) are co-expressed at high levels in the hippocampal neurons and alter anxiety-like behaviors in rodents. Since the dorsal hippocampus may be involved in modulation of anxiety-like behaviors, the aim of the present study was to assess whether the nitric oxide (NO) system in the dorsal hippocampus affects anxiety-like behaviors induced by histaminergic agents in mice. The effects of the NO precursor, L-arginine and NOS inhibitor, L-nitro-amino-methyl-ester (L-NAME) on histamine, pyrilamine and ranitidine responses in elevated plus maze (E.P.M.) in mice were investigated. Intra-CA1 microinjection of histamine (9 μg/mouse) or H1 receptor antagonist, pyrilamine (3, 6 and 9 μg/mouse), but not H2 receptor antagonist, ranitidine decreased the percentage of open arm time (%OAT) and open arm entries (%OAE), without affecting locomotor activity, suggesting an anxiogenic-like response. Both L-arginine (0.4 and 0.8 μg/mouse) and L-NAME (40 ng/mouse) when injected into the dorsal hippocampus induced anxiety-like behaviors, but the drugs reversed the anxiogenic response induced by the effective dose of histamine (9 μg/mouse) or pyrilamine (9 μg/mouse). Our results also indicated that intra-CA1 administration of L-arginine and L-NAME, in the presence or absence of ranitidine, exerted an anxiogenic effect. The results may indicate a modulatory role for NO in the dorsal hippocampus in the anxiogenic-like response induced by histamine or pyrilamine.     

N-acetylcysteine attenuates lipopolysaccharide-induced apoptotic liver damage in D-galactosamine-sensitized mice

Aim： To investigate the effects of N-acetylcysteine on D-galactosamine （GAIN）/ lipopolysaccharide （LPS）-induced apoptotic liver injury in mice. Methods： When given together with a low dose of LPS, GaIN highly sensitizes animals to produce apoptotic liver injury with severe hepatic congestion, resulting in rapid death. In the GalN/LPS model, TNF-α is the major mediator leading to apoptotic liver injury. Reactive oxygen species （ROS） are involved in GaiN-induced sensitization to TNF-α-evoked hepatocyte apoptosis. N-acetylcysteine （NAC） is an antioxidant and a glutathione （GSH） precursor. In this study, we investigated the effects of NAC on LPS-induced apoptotic liver injury in GaiN-sensitized mice. Results： Pretreatment with NAC significantly reduced GalN/LPS-induced elevation of serum alanine aminotransferase levels. In parallel, GalN/LPS-induced hepatic necrosis and congestion were obviously improved by NAC. Furthermore, NAC pretreatment significantly alleviated GalN/LPS-induced hepatic apoptosis, measured by the inhibition of hepatic caspase-3 activity and attenuation of DNA laddering. NAC pretreatment had no effect on LPS-evoked nitric oxide production in GaiN-sensitized mice. Increases in serum TNF-α concentration, which were observed in GalN/LPS-treated mice, were not significantly reduced by NAC. Although NAC pretreatment significantly alleviated LPS-induced hepatic GSH depletion, DL-buthionine-（SR）-sulfoximine, an inhibitor of GSH synthesis, did not influence the protective effect of NAC on GalN/LPS-induced apoptotic liver injury. Conclusion： NAC attenuates GalN/LPS-induced apoptotic liver injury via its strong ROS scavenging and anti-apoptotic effects.     

Up-regulated neuronal nitric oxide synthase compensates coronary flow response to bradykinin in endothelial nitric oxide synthase-deficient mice

It has been reported that endothelium-dependent relaxations are preserved in isolated coronary arteries of endothelial nitric oxide synthase-deficient (eNOS-/-) mice with a possible involvement of nNOS. However, it remains to be examined whether nNOS compensates coronary flow response in a beating heart of eNOS-/- mice and if so, whether and where nNOS is up-regulated. Coronary flow response to bradykinin was examined in Langendorff-perfused hearts from WT and eNOS-/- mice. Bradykinin-induced coronary flow was greater in eNOS-/- mice than in WT mice, and indomethacin had no inhibitory effect on it. Bradykinin receptor antagonist HOE-140 abolished the bradykinin response in both strains. Non-selective NOSs inhibitor L-NNA inhibited the bradykinin-induced coronary flow in both strains, whereas specific inhibitors of nNOS, SMTC, and 7-NI, significantly attenuated the coronary flow response only in eNOS-/- mice. A guanylate cyclase inhibitor ODQ also attenuated the bradykinin response in eNOS-/- mice. Immunohistochemistry revealed the presence of nNOS mainly in coronary vascular smooth muscle cells (VSMCs) in both strains and Western blot analysis demonstrated a marked increase in cardiac nNOS expression in eNOS-/- mice. These results indicate that nNOS compensates coronary flow response to bradykinin in eNOS-/- mice, for which up-regulation of nNOS in VSMCs may be involved.     

Nitroglycerin-patch induced tolerance is associated with reduced ability of nitroglycerin to increase exhaled nitric oxide

Nitroglycerin (GTN), used in the treatment of ischemic heart disease, acts through the liberation of nitric oxide (NO). However, its clinical use is limited due to tolerance development. Expired NO was used as an indicator of GTN-bioactivation and was measured together with plasma nitrite and mean arterial pressure (MAP) during GTN indicator infusions. The model was applied in rabbits subjected to various time periods of low-dose GTN pretreatment by patch application for 1, 24 and 72 h. Pretreatment with GTN-patch resulted in significant attenuation of expired NO from the GTN indicator infusion in the 24 h and 72 h pretreatment groups compared to placebo (72 h). Dose-response curves with increasing GTN infusions after 24 h GTN-patch pretreatment revealed a significant attenuation of the MAP decrease compared to placebo. GTN-induced changes in plasma nitrite correlated to increases in expired NO and decreases in MAP. This indicates that expired NO could serve as an indicator of NO generation from GTN in the vascular system. We conclude that GTN tolerance is associated with reduced capacity to generate NO from GTN. Care should be taken in using MAP-reduction to evaluate tolerance since high indicator doses could liberate sufficient amounts of NO to elicit maximal MAP decrease even in tolerant animals.     

Mechanisms of nitric oxide generation from nitroglycerin and endogenous sources during hypoxia in vivo

Nitroglycerin (GTN), often used in conditions of cardiovascular ischaemia, acts through the liberation of nitric oxide (NO) and the local concentration of NO in the tissue is responsible for any biological effect. However, little is known about the way in which the concentration of NO from GTN and other NO-donors is influenced by low oxygen tension in the target tissues. To evaluate the impact of changes in oxygen tension in the metabolism of NO-donors we measured exhaled NO in anaesthetized rabbits in vivo and expired NO and perfusate nitrite (NO(2)(-)) in buffer-perfused lungs in situ. The impact of acute hypoxia on NO formation from GTN, isosorbide-5-mononitrate (ISMN), dissolved authentic NO, NO(2)(-) and NO generated from endogenous NO-synthase (NOS) was studied in either model. Acute hypoxia drastically increased exhaled NO concentrations from all NO-donors studied, both in vivo and in the perfused lung. During similar conditions endogenous NO generation from NOS was strongly inhibited. The effects were most pronounced at less than 3% inspired oxygen. The mechanisms for the increased NO-formation during hypoxia seems to differ between GTN- and NO(2)(-)-derived NO. The former phenomenon is likely due to diminished breakdown of NO. In conclusion, hypoxic conditions preserve very high local NO concentrations generated from organic nitrates in vivo and we suggest that this might benefit preferential vasodilation in ischaemic tissue regions. Our findings point out the necessity to consider the influence of oxygen tension when studying the action of NO-donors.     

Nicotine modulates nitric oxide in rat brain

Nicotine exerts its central actions by regulating cationic fluxes through nicotinic acetylcholine receptors (nAChRs). By this effect, the drug likely also modifies events occurring beyond the nAChR, including the regulation of nitric oxide (NO) synthesis. The present study was undertaken to assess the effects of acute and chronic nicotine administration (0.4 mg/kg, s.c.) on levels of NO⁻₂+NO⁻₃, stable metabolites of NO, in brain regions of male and female rats. Nicotine increased levels of the metabolites, and therefore presumably of NO, with sex differences in the degree of stimulation, the brain regions affected, and the variance between the effects of acute and chronic administration. Prior inhibition of NO synthase eliminated the effect of nicotine in all regions studied. While nicotine appeared to increase NO indirectly via glutamate receptors in the cortex and hippocampus, this was not true of the corpus striatum, where blocking NMDA-type glutamate receptors with MK-801 had no effect. The findings support the view that NO is likely involved in some of the central effects of nicotine.