Role of Nitric Oxide Synthase in the Infarct-Limiting Effect of Normobaric Hypoxia

Journal of Evolutionary Biochemistry and Physiology - The study was carried out in male Wistar rats. Animals were randomly divided into normoxic control groups and groups exposed to normobaric...     

糖皮质激素对机械通气大鼠肺组织iNOS、NO表达的影响

目的通过观察糖皮质激素对机械通气大鼠肺组织诱导型一氧化氮合酶（iNOS）及一氧化氮（NO）表达的影响,探讨糖皮质激素对呼吸机所致肺损伤（ventilator induced lung injury,VILI）的干预作用。方法 24只雄性Wistar大鼠随机分为对照组、机械通气组、地塞米松（DXM）干预组。用逆转录-聚合酶链反应（RT-PCR）法检测肺组织iNOS mRNA表达,用免疫组织化学染色法检测肺组织iNOS蛋白表达,用硝酸还原酶法测定肺组织和血浆NO含量。结果机械通气组和DXM干预组大鼠肺组织iNOS mRNA及其蛋白表达水平,以及血浆和肺组织NO含量均明显高于对照组（P〈0.01）;DXM干预组上述指标与机械通气组比较均明显降低（P〈0.01）。结论糖皮质激素可通过抑制肺组织iNOS的表达,减少NO的生成,对机械通气大鼠肺组织具有保护作用。     

促炎因子在心脏修复中的作用

肿 瘤 坏死 因 子 TN F)、白介 素 -1(IL-1)、白 介 素 -2(IL-2)以 及 白介 素 -6(IL-6)等 分子 ,叫 作 促 炎细 胞 因 (子 .一 般 认为 它 们不 属于 免 疫系 统,而 只是 与 组织 炎症 的起 始 有关 .促 炎因 子在 心 脏中 也 有表 达,它 的短 期表 达可 以 帮助 心 脏适 应外 界 压力 的损 伤 ,而其 长期 的 表达 却会 引 起明 显的 心 脏代 谢失 常 .主要 就 促炎 因子 在心 脏中 的 作用 作 一综 述 .     

Role of Nitric Oxide Synthase in the Light-Induced Development of Sporangiophores in Phycomyces blakesleeanus

Blue light controls the development of sporangiophores in the zygomycete Phycomyces blakesleeanus Burgeff. Light represses the production of microsporangiophores and enhances the development of macrosporangiophores. Inhibition of the biosynthesis of tetrahydrobiopterin, a cofactor of NO synthase, inhibits this photomorphogenesis. Light induces production of citrulline from arginine in the mycelium and in sporangiophores. The citrulline-forming activity is dependent on NADPH, independent of calcium, and inhibited by NO synthase inhibitors. It is reduced in tetrahydrobiopterin-depleted mycelium. Light induces emission of NO from the developing fungus in the same order of magnitude as citrulline formation from arginine. The NO donor sodium nitroprusside can replace the light effect on sporangiophore development, and inhibitors of NO synthase repress it. We suggest that a fungal NO synthase is involved in sporangiophore development and propose its participation in light signaling.     

致炎细胞因子在骨性关节炎病理生理中的作用

骨性关节炎(OA)是一种退行性病变,表现为关节软骨破坏,关节边缘骨赘形成,并伴有不同程度滑膜炎症,其病因学和发病机制还不是十分清楚。研究表明致炎细胞因子在骨性关节炎病发病的病理生理过程中起着重要的作用。本综述讨论目前关于致炎细胞因子在OA病理生理中的作用机制以及抗致炎细胞因子在治疗OA中的新进展。     

Hunting for Plant Nitric Oxide Synthase Provides New Evidence of a Central Role for Plastids in Nitric Oxide Metabolism

Nitric oxide (NO) has emerged as a central signaling molecule in plants and animals. However, the long search for a plant NO synthase (NOS) enzyme has only encountered false leads. The first works describing a pathogen-induced NOS-like plant protein were soon retracted. New hope came from the identification of NOS1, an Arabidopsis thaliana protein with an atypical NOS activity that was found to be targeted to mitochondria in roots. Although concerns about the NO-producing activity of this protein were raised (causing the renaming of the protein to NO-associated 1), compelling data on its biological role were missing until recently. Strong evidence is now available that this protein functions as a GTPase that is actually targeted to plastids, where it might be required for ribosome function. These and other results support the argument that the defective NO production in loss-of-function mutants is an indirect effect of interfering with normal plastid functions and that plastids play an important role in regulating NO levels in plant cells.A major revolution in biology took place by the early 1990s after the discovery that nitric oxide (NO), a free radical, was not a toxic by-product of oxidative metabolism but had a fundamental role as a signaling molecule regulating normal physiological processes in animal cells (Culotta and Koshland, 1992). A role of this volatile molecule in plant defense responses was subsequently reported, and it is now well established that NO is also a key player in the regulation of different plant developmental processes, including germination, root growth, vascular differentiation, stomatal closure, and flowering (Lamattina et al., 2003; Wendehenne et al., 2004; Crawford and Guo, 2005). Animal cells synthesize NO primarily by the activity of NO synthase (NOS) enzymes. There are several NOS isoforms, but all of them catalyze the same basic reaction: a NADPH-dependent oxidation of l-Arg to NO and l-citrulline. By contrast, the synthesis of NO in plant cells remains a matter of debate. The first reported mechanism to make NO in plants was the reduction of nitrite to NO catalyzed (with low efficiency) by nitrate reductase (NR), a cytosolic enzyme that normally reduces nitrate to nitrite (Yamasaki et al., 1999). But the contribution of NR to NO synthesis is still controversial.The analysis of the Arabidopsis thaliana nia1 nia2 double mutant, which shows substantially reduced NR activity levels, has shown that such activity is required for NO synthesis during flowering (Seligman et al., 2008), auxin-induced lateral root development (Kolbert et al., 2008), and abscisic acid (ABA)-induced stomatal closure (Desikan et al., 2002; Bright et al., 2006) but not during infection (Zhang et al., 2003), salicylic acid treatment (Zottini et al., 2007), or mechanical stress (Garces et al., 2001). Furthermore, foliar extracts of the mutant show the same capacity to produce NO as wild-type plants when nitrite is exogenously supplied (Modolo et al., 2005). These results indicate that additional mechanisms to reduce nitrite into NO exist in plant cells and that the decreased capability for NO synthesis of mutant plants with defective NR activity might result from their reduced nitrite levels (Modolo et al., 2005). Other enzymatic sources for nitrite-dependent NO synthesis exist in the plasma membrane (Stohr et al., 2001) and mitochondria (Planchet et al., 2005), whereas nonenzymatic production of NO from nitrite has been shown to occur in acidic and reducing environments, such as the apoplasm (Bethke et al., 2004) and plastids (Cooney et al., 1994). The highly reduced levels of l-Arg in the nia1 nia2 mutant (Modolo et al., 2006) might also compromise its ability to produce NO. This amino acid is a substrate for the production of polyamines, compounds that have been proposed to participate in NO synthesis (Tun et al., 2006). Additionally, plants have been found to synthesize NO by an Arg-dependent NOS activity similar to that present in animal cells, as detailed in the next section.     

早期经验对大鼠脑区一氧化氮合酶活性的影响

目的　探讨NO与早期饲养环境所引起脑效应的关系。方法　将断乳大鼠在丰富环境 (EC)和单调环境 (IC)中饲养 30d。环境暴露后通过NADPH -黄递酶组化方法对海马齿状回 (DEN)和大脑皮层NOS活性进行定量测定以及对大鼠进行Morris水迷宫作业训练。结果　EC大鼠与IC大鼠相比 ,海马齿状回 (DEN)和大脑皮层NOS活性明显下降 ,迷宫测试表明EC大鼠的空间认知显著优于IC大鼠。在环境暴露期间隔日注射一氧化氮合酶 (NOS)抑制物L -NAME(50mg/kg) ,未引起EC或IC大鼠认知行为的明显改变 ,但导致DEN和大脑皮层NOS活性的不同改变。结论　NO可能与早期经验脑效应有关。     

Role of Nitric Oxide in Methamphetamine Neurotoxicity: Protection by 7-Nitroindazole, an Inhibitor of Neuronal Nitric Oxide Synthase

Abstract: The role of nitric oxide (NO^•) in the neurotoxic effects of methamphetamine (METH) was evaluated using 7-nitroindazole (7-NI), a potent inhibitor of neuronal nitric oxide synthase. Treatment of mice with 7-NI (50 mg/kg) almost completely counteracted the loss of dopamine, 3,4-dihydroxyphenylacetic acid, and tyrosine hydroxylase immunoreactivity observed 5 days after four injections of 10 or 7.5 mg/kg METH. With the higher dose of METH, this protection at 5 days occurred despite the fact that combined administration of METH and 7-NI significantly increased lethality and exacerbated METH-induced dopamine release (as indicated by a greater dopamine depletion at 90 min and 1 day). Combined treatment with 4 × 10 mg/kg METH and 7-NI also slightly increased the body temperature of mice as compared with METH alone. Thus, the neuroprotective effects of 7-NI are independent from lethality, are not likely to be related to a reduction of METH-induced dopamine release, and are not due to a decrease in body temperature. These results indicate that NO^• formation is an important step leading to METH neurotoxicity, and suggest that the cytotoxic properties of NO^• may be directly involved in dopaminergic terminal damage.     

Effect of 7-Nitroindazole Sodium on the Cellular Distribution of Neuronal Nitric Oxide Synthase in the Cerebral Cortex of Hypoxic Newborn Piglets

Cerebral hypoxia results in generation of nitric oxide (NO) free radicals by Ca⁺⁺-dependent activation of neuronal nitric oxide synthase (nNOS). The present study tests the hypothesis that the hypoxia-induced increased expression of nNOS in cortical neurons is mediated by NO. To test this hypothesis the cellular distribution of nNOS was determined immunohistochemically in the cerebral cortex of hypoxic newborn piglets with and without prior exposure to the selective nNOS inhibitor 7-nitroindazole sodium (7-NINA). Studies were conducted in newborn piglets, divided into normoxic (n = 6), normoxic treated with 7-NINA (n = 6), hypoxic (n = 6) and hypoxic pretreated with 7-NINA (n = 6). Hypoxia was induced by lowering the FiO₂ to 0.05–0.07 for 1 h. Cerebral tissue hypoxia was documented by decrease of ATP and phosphocreatine levels in both the hypoxic and 7-NINA pretreated hypoxic groups (P < 0.01). An increase in the number of nNOS immunoreactive neurons was observed in the frontal and parietal cortex of the hypoxic as compared to the normoxic groups (P < 0.05) which was attenuated by pretreatment with 7-NINA (P < 0.05 versus hypoxic). 7-NINA affected neither the cerebral energy metabolism nor the cellular distribution of nNOS in the cerebral cortex of normoxic animals. We conclude that nNOS expression in cortical neurons of hypoxic newborn piglets is NO-mediated. We speculate that nNOS inhibition by 7-NINA will protect against hypoxia-induced NO-mediated neuronal death.     

Effects of Respiratory Burst Inhibitors on Nitric Oxide Production by Human Neutrophils

Human neutrophils (PMN) activated by N-formyl-methionyl-leucyl-phenylalanine (fMLP) simultaneously release nitric oxide (.NO), superoxide anion (O₂-) and its dismutation product, hydrogen peroxide (H₂O₂). To assess whether NO production shares common steps with the activation of the NADPH oxidase, PMN were treated with inhibitors and antagonists of intracellular signaling pathways and subsequently stimulated either with fMLP or with a phorbol ester (PMA). The G-protein inhibitor, pertussis toxin (1-10 μg/ml) decreased H₂O₂ yield without significantly changing. NO production in fMLP-stimulated neutrophils; no effects were observed in PMA-activated cells. The inhibition of tyrosine kinases by genistein (1-25 μg/ml) completely abolished H₂O₂ release by fMLP-activated neutrophils; conversely, NO production increased about 1.5- and 3-fold with fMLP and PMA, respectively. Accordingly, orthovanadate, an inhibitor of phosphotyrosine phosphatase, markedly decreased -NO production and increased O_2;^- release. On the other hand, inhibition of protein kinase C with staurosporine and the use of burst antagonists like adenosine, cholera toxin or dibutyryl-cAMP diminished both H₂O₂ and NO production. The results suggest that the activation of the tyrosine kinase pathway in stimulated human neutrophils controls positively O₂^- and H₂O₂ generation and simultaneously maintains -NO production in low levels. In contrast, activation of protein kinase C is a positive modulator for O_2;^-and *NO production.     

Role of Nitric Oxide and Hydrogen Peroxide During the Salt Resistance Response

Ion homeostasis is essential for plant cell resistance to salt stress. Under salt stress, to avoid cellular damage and nutrient deficiency, plant cells need to maintain adequate K nutrition and a favorable K to Na ratio in the cytosol. Recent observations revealed that both nitric oxide (NO) and hydrogen peroxide (H₂O₂) act as signaling molecules to regulate K to Na ratio in calluses from Populus euphratica under salt stress. Evidence indicated that NO mediating H₂O₂ causes salt resistance via the action of plasma membrane H⁺-ATPase but that activity of plasma membrane NADPH oxidase is dependent on NO. Our study demonstrated the signaling transduction pathway. In this addendum, we proposed a testable hypothesis for NO function in regulation of H₂O₂ mediating salt resistance.Key Words: hydrogen peroxide, nitric oxide, signaling molecule, salt resistanceUnder salinity conditions, tolerant plant cells achieve ion homeostasis by extruding Na to the external medium and/or compartmentalizing into vacuoles, maintaining K uptake and high K and low Na in the cytosol.^1,2 Control of Na movement across the plasma membrane (PM) and tonoplast in order to maintain a low Na concentration in the cytoplasm is a key factor of cellular adaptation to salt stress.^3,4 Na transport across the PM is dependent on the electrochemical gradient created by the PM H⁺-ATPase.^5,6 It has been proven that the activity of the PM H⁺-ATPase is a key index of plant adaptation to salt stress.⁷ Therefore, the regulation of expression of the PM H⁺-ATPase may represent an important cellular mechanism for salt resistance. In contrast to our understanding of the regulation of PM H⁺-ATPase by other factors, the roles of NO and H₂O₂ act as signals under salt stress have been less known.Previous studies have shown that both NO and H₂O₂ function as stress signals in plants, mediating a range of resistance mechanisms in plants under stress conditions.^8–10 We have previously shown that NO serves as a signal in inducing salt resistance by increasing the K to Na ratio, which is dependent on the increased PM H⁺-ATPase activity in calluses from reed.¹¹ Although NO acts as a signal molecule under salt stress and induces salt resistance by increasing PM H⁺-ATPase activity, our research results also indicated NO can not activate purified PM H⁺-ATPase activity, at least in vitro. Subsequently, we set out to find the other signal molecules and factors between NO and PM H⁺-ATPase activity. Since our studies have indicated that NO can not induce salt resistance directly, what roles dose it play in salt resistance in tolerant cells under salt stress? We initially hypothesized ABA or H₂O₂ might be downstream signal molecules to regulate the activity of PM H⁺-ATPase. Further results indicated H₂O₂ content increased greatly under salt stress. Since H₂O₂ might be the candidate downstream signal molecule, we tested PM H⁺-ATPase activity and K to Na ratio in calluses by adding H₂O₂. The results suggested that H₂O₂ inducing an increased PM H⁺-ATPase activity resulted in an increased K to Na ratio. Summing up this new assay that allows us to speculate NO maybe regulate the H₂O₂ generation.Since H₂O₂ is involved in downstream signal molecule of NO, PM NADPH oxidase, the main source of H₂O₂ production, might be the regulated target of NO. We took a pharmacological approach to examine the speculation. The results indicated that PM NADPH oxidase is required for H₂O₂ accumulation and PM NADPH oxidase activity could attribute to NO in calluses under salt stress. These results also raised another question regarding what concentrations of NO can induce such effects. In our experiments, NO content was induced 1.6 times higher than the control values under salt treatment. We speculated there exists an effective balance point in NO signal system similar to previous reports by Delledonne et al.¹² in disease resistance.Further research work is required to decipher the mechanism through which NO and H₂O₂ acts and how K and Na elements uptake might be connected with salt resistance. We would like to propose a simple testable model that accounts for the results reported in this paper (Fig. 1). According to our model, H₂O₂ rather than NO is the major signaling molecular that mediated directly PM H⁺-ATPase under salt stress. Normally, NO generated from nitric oxide synthase (NOS) acts as a signal molecule to regulate other mechanisms. Under salt stress, accumulated NO activates PM NADPH oxidase activity. Then, a number of H₂O₂ is produced from PM NADPH oxidase. The PM H⁺-ATPase is activated greatly by the accumulated H₂O₂. Eventually, the transmembrane electrochemical gradient is created and K to Na ratio increases. The model we have proposed here is testable and should provide further insights into salt resistance mechanism regulated by NO and H₂O₂ signal molecules.Open in a separate windowFigure 1Hypothetical model for the potential function of NO and H₂O₂ as signaling molecules in inducing salt resistance. Salt stress activates a signal transduction cascade that leads to the increased activity of PM H⁺-ATPase, whose expression produces salt resistance. NO is generated by NOS, and H₂O₂ is produced by NADPH oxidase attributed to NO. The activity of PM H⁺-ATPase is regulated by H₂O₂ directly under salt stress. The model is based on the recent results in calluses from P. euphratica¹² and those previously reported on the NO function in reed.¹¹Research on roles of NO and H₂O₂ under stress conditions in plant is advancing rapidly. Further analysis of salt resistance mechanism with novel technology will certainly increase our knowledge in this field.     

Nitric Oxide Synthase and Breast Cancer: Role of TIMP-1 in NO-mediated Akt Activation

Prediction of therapeutic response and cancer patient survival can be improved by the identification of molecular markers including tumor Akt status. A direct correlation between NOS2 expression and elevated Akt phosphorylation status has been observed in breast tumors. Tissue inhibitor matrix metalloproteinase-1 (TIMP-1) has been proposed to exert oncogenic properties through CD63 cell surface receptor pathway initiation of pro-survival PI3k/Akt signaling. We employed immunohistochemistry to examine the influence of TIMP-1 on the functional relationship between NOS2 and phosphorylated Akt in breast tumors and found that NOS2-associated Akt phosphorylation was significantly increased in tumors expressing high TIMP-1, indicating that TIMP-1 may further enhance NO-induced Akt pathway activation. Moreover, TIMP-1 silencing by antisense technology blocked NO-induced PI3k/Akt/BAD phosphorylation in cultured MDA-MB-231 human breast cancer cells. TIMP-1 protein nitration and TIMP-1/CD63 co-immunoprecipitation was observed at NO concentrations that induced PI3k/Akt/BAD pro-survival signaling. In the survival analysis, elevated tumor TIMP-1 predicted poor patient survival. This association appears to be mainly restricted to tumors with high NOS2 protein. In contrast, TIMP-1 did not predict poor survival in patient tumors with low NOS2 expression. In summary, our findings suggest that tumors with high TIMP-1 and NOS2 behave more aggressively by mechanisms that favor Akt pathway activation.     

Role of Different Isoforms of Nitric Oxide Synthase in Development of Tumor Mutants in Drosophila melanogaster

We studied the role of nitric oxide synthase during tumor growth in oncovirus-induced tumor mutants of Drosophila melanogaster. The lines with different capacity for malignancy differed reliably in the level of enzymatic activity. It was shown using specific inhibitors of neuronal and inducible isoforms that the neuronal isoform was not involved in tumor formation, while the inducible one appears to play an important role in tumor growth inhibition. This isoform was identified with the help of immunoblotting and monoclonal antibodies against inducible nitric oxide synthase.     

Protective Vascular and Cardiac Effects of Inducible Nitric Oxide Synthase in Mice with Hyperhomocysteinemia

Diet-induced hyperhomocysteinemia produces endothelial and cardiac dysfunction and promotes thrombosis through a mechanism proposed to involve oxidative stress. Inducible nitric oxide synthase (iNOS) is upregulated in hyperhomocysteinemia and can generate superoxide. We therefore tested the hypothesis that iNOS mediates the adverse oxidative, vascular, thrombotic, and cardiac effects of hyperhomocysteinemia. Mice deficient in iNOS (Nos2−/−) and their wild-type (Nos2+/+) littermates were fed a high methionine/low folate (HM/LF) diet to induce mild hyperhomocysteinemia, with a 2-fold increase in plasma total homocysteine (P<0.001 vs. control diet). Hyperhomocysteinemic Nos2+/+ mice exhibited endothelial dysfunction in cerebral arterioles, with impaired dilatation to acetylcholine but not nitroprusside, and enhanced susceptibility to carotid artery thrombosis, with shortened times to occlusion following photochemical injury (P<0.05 vs. control diet). Nos2−/− mice had decreased rather than increased dilatation responses to acetylcholine (P<0.05 vs. Nos2+/+ mice). Nos2−/− mice fed control diet also exhibited shortened times to thrombotic occlusion (P<0.05 vs. Nos2+/+ mice), and iNOS deficiency failed to protect from endothelial dysfunction or accelerated thrombosis in mice with hyperhomocysteinemia. Deficiency of iNOS did not alter myocardial infarct size in mice fed the control diet but significantly increased infarct size and cardiac superoxide production in mice fed the HM/LF diet (P<0.05 vs. Nos2+/+ mice). These findings suggest that endogenous iNOS protects from, rather than exacerbates, endothelial dysfunction, thrombosis, and hyperhomocysteinemia-associated myocardial ischemia-reperfusion injury. In the setting of mild hyperhomocysteinemia, iNOS functions to blunt cardiac oxidative stress rather than functioning as a source of superoxide.     

眼镜蛇毒对大鼠延髓一氧化氮合酶表达的影响

目的 探讨眼镜蛇毒对大鼠延髓某些核团一氧化氮合酶(NOS)表达的影响。方法 采用还原型尼克酰胺腺嘌呤二核苷酸脱氢酶(NADPH-d)方法,观察大鼠延髓某些核团NOS阳性神经元在眼镜蛇毒中毒组、生理盐水组、正常对照组的变化。结果 蛇毒组大鼠延髓的中缝大核,外侧网状核NOS阳性神经元比对照组表达增强。结论 眼镜蛇毒对延髓的NOS阳性神经元表达有上调作用。     

Effects of Chronic Nitric Oxide Inhibition on the Renal Excretory Response to Leptin

Objective: Previous investigations have demonstrated that leptin promotes natriuresis with a renal tubular effect. However, the mechanisms involved in this response are unclear. The present study was designed to examine the hypothesis that the natriuretic response to leptin in normotensive Sprague‐Dawley rats is regulated by nitric oxide (NO). Research Methods and Procedures: The hemodynamic and renal excretory effects of intravenous bolus administration of pharmacological doses of synthetic murine leptin were examined in groups of control Sprague‐Dawley rats (n = 8), Sprague‐Dawley rats treated for 4 days with the NO synthase inhibitor Nω‐nitro‐l‐arginine methyl ester (l‐NAME) (n = 8), and Sprague‐Dawley rats treated for 4 days with l‐NAME followed by acute treatment with sodium nitroprusside (n = 8). Results: In the control group (n = 8), an intravenous bolus of leptin, 400 μg/kg body weight, increased urinary sodium excretion 4‐ to 6‐fold. In the Sprague‐Dawley rats chronically administered l‐NAME (n = 8), an intravenous bolus of 400 μg/kg of leptin did not increase sodium excretion. Acute sodium nitroprusside infusion to Sprague‐Dawley rats chronically treated with l‐NAME (n = 8) was associated with partial restoration of the sodium excretory response to leptin administration. Discussion: Collectively, these results are interpreted to suggest that the natriuretic and diuretic responses to leptin observed in the Sprague‐Dawley rat require a functional NO system.     

Influence of Hyperthyroidism on the Activity of Liver Nitric Oxide Synthase in the Rat

Hyperthyroidism enhances the prooxidant activity of the liver by elevating superoxide radical and/or hydrogen peroxide generation in microsomal, mitochondrial, and peroxisomal fractions, with an increased respiratory burst of Kupffer cells. In this study, the influence of daily doses of 0.1 mg 3,3′,5-triiodothyronine (T₃)/kg for three consecutive days on liver nitric oxide (NO) synthase (NOS) was assessed, as a possible contributory mechanism to T₃-induced liver prooxidant activity. Thyroid calorigenesis was paralleled by a progressive increment in the rate of NO generation, with significant increases after 2 (47%) and 3 days (70%) of T₃treatment, and a net 45% (P< 0.05) enhancement in theN^G-methyl-l-arginine-sensitive NO production, compared to control values. These enhancement effects were reversed to control levels after 3 days of hormone withdrawal, concomitantly with the normalization of hepatic respiration. Enhancement of liver NOS activity in hyperthyroid animals was diminished by 27% (P< 0.05) by the selectivein vivoinactivation of Kupffer cells by gadolinium chloride (GdCl₃), without direct actions of GdCl₃on the enzyme. These data demonstrate that hyperthyroidism leads to a significant and reversible enhancement in rat liver NOS activity, an effect that is exerted at hepatocyte and Kupffer cell levels, thus representing an additional source of prooxidants to those of reactive oxygen species.