Nitric Oxide (NITRIC OXIDE-BIOL CH)

Publications in this journal

• Article: Higher endogenous nitrite levels are associated with superior exercise capacity in highly trained athletes

  Matthias Totzeck, Ulrike B Hendgen-Cotta, Christos Rammos, Lisa-Marie Frommke, Christian Knackstedt, Hans-Georg Predel, Malte Kelm, Tienush Rassaf
  Nitric Oxide 05/2012;
• Article: Dermal application of nitric oxide releasing acidified nitrite-containing liniments significantly reduces blood pressure in humans

  Christian Opländer, Christine M Volkmar, Adnana Paunel-Görgülü, Thomas Fritsch, Ernst E van Faassen, Manfred Mürtz, Gerrit Grieb, Ahmet Bozkurt, Karsten Hemmrich, Joachim Windolf, Christoph V. Suschek
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  ABSTRACT: Vascular ischemic diseases, hypertension, and other systemic hemodynamic and vascular disorders may be the result of impaired bioavailability of nitric oxide (NO). NO but also its active derivates like nitrite or nitroso compounds are important effector and signal molecules with vasodilating properties. Our previous findings point to a therapeutical potential of cutaneous administration of NO in the treatment of systemic hemodynamic disorders. Unfortunately, no reliable data are available on the mechanisms, kinetics and biological responses of dermal application of nitric oxide in humans in vivo. The aim of the study was to close this gap and to explore the therapeutical potential of dermal nitric oxide application. We characterized with human skin in vitro and in vivo the capacity of NO, applied in a NO-releasing acidified form of nitrite-containing liniments, to penetrate the epidermis and to influence local as well as systemic hemodynamic parameters. We found that dermal application of NO led to a very rapid and significant transepidermal translocation of NO into the underlying tissue. Depending on the size of treated skin area, this translocation manifests itself through a significant systemic increase of the NO derivates nitrite and nitroso compounds, respectively. In parallel, this translocation was accompanied by an increased systemic vasodilatation and blood flow as well as reduced blood pressure. We here give evidence that in humans dermal application of NO has a therapeutic potential for systemic hemodynamic disorders that might arise from local or systemic insufficient availability of NO or its bio-active NO derivates, respectively.
  Nitric Oxide 02/2012; 26(2):132-40.
• Article: Dermal application of nitric oxide releasing acidified nitrite-containing liniments significantly reduces blood pressure in humans

  Opländer C, Volkmar CM, Paunel-Görgülü A, Fritsch T, van Faassen EE, Mürtz M, Grieb G, Bozkurt A, Hemmrich K, Windolf J, Suschek CV
  [show abstract] [hide abstract]
  ABSTRACT: Vascular ischemic diseases, hypertension, and other systemic hemodynamic and vascular disorders may be the result of impaired bioavailability of nitric oxide (NO). NO but also its active derivates like nitrite or nitroso compounds are important effector and signal molecules with vasodilating properties. Our previous findings point to a therapeutical potential of cutaneous administration of NO in the treatment of systemic hemodynamic disorders. Unfortunately, no reliable data are available on the mechanisms, kinetics and biological responses of dermal application of nitric oxide in humans in vivo. The aim of the study was to close this gap and to explore the therapeutical potential of dermal nitric oxide application. We characterized with human skin in vitro and in vivo the capacity of NO, applied in a NO-releasing acidified form of nitrite-containing liniments, to penetrate the epidermis and to influence local as well as systemic hemodynamic parameters. We found that dermal application of NO led to a very rapid and significant transepidermal translocation of NO into the underlying tissue. Depending on the size of treated skin area, this translocation manifests itself through a significant systemic increase of the NO derivates nitrite and nitroso compounds, respectively. In parallel, this translocation was accompanied by an increased systemic vasodilatation and blood flow as well as reduced blood pressure. We here give evidence that in humans dermal application of NO has a therapeutic potential for systemic hemodynamic disorders that might arise from local or systemic insufficient availability of NO or its bio-active NO derivates, respectively.
  Nitric Oxide 02/2012; 26(2):132-40.
• Article: Advanced nitric oxide delivery platforms for therapeutic applications

  Melissa Reynolds, Vinod Damodaran, Jessica Joslin, Kathryn Wold, Jacqueline Harding, Sarah Lantvit, Christopher Nickell, Brittany Barrett
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  ABSTRACT: Nitric oxide (NO) has been identified as a crucial biological signaling molecule in the cardiovascular, nervous, and immune systems. As a result, NO storage and delivery vehicles have been extensively developed to target a range of diseases and to control material-cell interactions. In this presentation, new approaches to store and deliver NO from materials used in therapeutic devices will be discussed. This includes the development of biodegradable and biostable polymers as well as methods to produce NO catalytically from bioavailable sources. The advantages of these systems is that they can tuned to control the NO-loading capacity and then triggered to release NO under various conditions, thereby extending the useful lifetime of currently available NO materials. Further, the delivery platforms have been engineering into a variety of forms including coatings, encapsulated microbeads, and nanofibers. These platforms allow for further tuning of the material properties to maximize control of the bio-interface. Finally, these materials have been extensively characterized for their NO release rates in real-time and under cell culture conditions. These pharmacokinetic profiles have been used to evaluate the physiological effective dosages of NO in cancer, angiogenic, platelet, and infection models.
  Nitric Oxide 01/2012; 27:S33.
• Article: Nitrate reductase activity of bacteria in saliva of term and preterm infants

  Jesica A. Kanady, Wilson Aruni, Janet R. Ninnis, Andrew O. Hopper, Jamie Blood, Luke Byrd, Leighton Holley, Michael Staker, Hansel Fletcher, Gordon G. Power, Arlin B. Blood
  Nitric Oxide 01/2011;
• Article: Neuroprotective effect of s-methylisothiourea in transient focal cerebral ischemia in rat.

  Arunadevi R, Ramteke VD, Kumar S, Shukla MK, Jaganathan S, Kumar D, Sharma AK, Tandan SK
  Nitric Oxide 01/2010; 22:1-10.
• Article: Nitric oxide alleviates arsenic toxicity by reducing oxidative damage in the roots of Oryza sativa (rice).

  Singh HP, Kaur S, Batish DR, Sharma VP, Sharma N, Kohli RK
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  ABSTRACT: Nitric oxide (NO) is a bioactive gaseous, multifunctional molecule playing a central role and mediating a variety of physiological processes and responses to biotic and abiotic stresses including heavy metals. The present study investigated whether NO applied exogenously as sodium nitroprusside (SNP) has any protective role against arsenic (As) toxicity in Oryza sativa (rice). Treatment with 50 lM SNP (a NO donor) significantly ameliorated the As-induced (25 or 50 lM) decrease in root and coleoptile length of rice. Further, As-induced oxidative stress measured in terms of malondialdehyde (MDA), superoxide ion (O��2 ), root oxidizability and H2O2 content was lesser upon supplementation of NO. It indicated a reactive oxygen species (ROS) scavenging activity of NO. NO addition reversed (only partially) the As-induced increase in activities of antioxidant enzymes – superoxide dismutase, ascorbate peroxidase, guaiacol peroxidase, and catalase. The study concludes that exogenous NO provides resistance to rice against As-toxicity and has an ameliorating effect against As-induced stress.
  Nitric Oxide 02/2009; 20(4):289-297.
• Article: Diazeniumdiolate reactivity in model membrane systems.

  Bach T Dinh, Stacy E Price, Amr Majul, Mazen El-Hajj, Victor Morozov, Joseph A Hrabie, Keith M Davies
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  ABSTRACT: The effect of small unilamellar phospholipid vesicles on the acid-catalyzed dissociation of nitric oxide from diazeniumdiolate ions, R(1)R(2)N[N(O)NO](-), [1: R(1)=H(2)N(CH(2))(3)-, R(2)=H(2)N(CH(2))(3)NH(CH(2))(4)-; 2: R(1)=R(2)=H(2)N(CH(2))(3)-; 3: R(1)=n-butyl-, R(2)=n-butyl-NH2+(CH(2))(6)-; 4: R(1)=R(2)=nPr-] has been examined at pH 7.4 and 37 degrees C. NO release was catalyzed by anionic liposomes (DPPG, DOPG, DMPS, POPS and DOPA) and by mixed phosphatidylglycerol/phosphatidylcholine (DPPG/DPPC and DOPG/DPPC) covesicles, while cationic liposomes derived from 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and the zwitterionic liposome DMPC did not significantly affect the dissociation rates of the substrates examined. Enhancement of the dissociation rate constant in DPPG liposome media (0.010M phosphate buffer, pH 7.4, 37 degrees C) at 10mM phosphoglycerol levels, ranged from 37 for 1 to 1.2 for the anionic diazeniumdiolate 4, while DOPA effected the greatest rate enhancement, achieving 49-fold rate increases with 1 under similar conditions. The observed catalysis decreases with increase in the bulk concentration of electrolytes in the reaction media. Quantitative analysis of catalytic effects has been obtained through the application of pseudo-phase kinetic models and equilibrium binding constants at different liposome interfaces are compared. The stoichiometry of nitric oxide release from 1 and 2 in DPPG/DPPC liposome media has been obtained through oxyhemoglobin assay. DPPG=1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)], DOPG=1,2-dioleoyl-sn-glycero-3-[phospho-rac-(1-glycerol)], DMPS=1,2-dimyristoyl-sn-glycero-3-[phospho-l-serine], POPS=1-palmitoyl-2-oleoyl-sn-glycero-3-[phospho-l-serine], DOPA=1,2-dioleoyl-sn-glycero-3-phosphate; DPPC=1,2-dipalmitoyl-sn-glycero-3-phosphocholine, DMPC=1,2-dimyristoyl-sn-glycero-3-phosphocholine, DOTAP=1,2-dioleoyl-3-trimethylammonium-propane.
  Nitric Oxide 04/2008; 18(2):113-21.
• Article: Proteasome inhibition: an early or late event in nitric oxide-induced neuronal death?

  Zhao Feng Peng, Minghui Jessica Chen, Yann Wan Yap, Jayapal Manikandan, Alirio J Melendez, Meng Shyan Choy, Philip K Moore, Nam Sang Cheung
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  ABSTRACT: Nitric oxide (NO), ubiquitously expressed in the central nervous system, has been perceived to be a potential neuromodulator. Employing cultured murine primary cortical neurons, NO resulted in an inhibition of the ubiquitin-proteasome system (UPS) with a dose- and time-dependent decrease in cell viability. This is consistent with a previous study that reported a dysfunction of UPS with consequential apoptotic death in macrophage cell with NO treatment. However, it cannot be unclear if the drop in UPS efficiency is directly imposed on by NO. Therefore by using microarray analysis, our study revealed an early down-regulation or non-significant differential expression of genes encoding UPS proteins in NOC-18 (NO donor)-treated neurons as compared to an observed elevation of corresponding gene expression genes in lactacystin (classical proteasome inhibitor)-treated neurons (conducted earlier). Furthermore, time-course analysis of proteasome activity in NOC-18-treated neurons demonstrated a late onset of reduction. This is intriguing as it is well established that in an exclusive proteasome dysfunction-induced cell death, a compensatory feedback mechanism will be activated with an initial and concerted up-regulation of genes encoding proteins involved in UPS as seen when neurons were treated with lactacystin. Thus, it is highly suggestive that NO-triggered neuronal death takes on a different signaling cascade from that of a classical proteasome inhibitor, and that the late reduction of proteasome activity is a downstream event following the activation of apoptotic cellular signaling cascade. In intracellular condition, the proteasome is not NO preferred primary target responsible for the trigger of the cell death machinery. In conclusion, we presented novel findings that shed light into NO-induced cell death signaling cascade, which would be important in understanding the pathogenesis of neurodegenerative disorders such as Parkinson's disease.
  Nitric Oxide 04/2008; 18(2):136-45.
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  Available from: thu.edu.tw

  Article: AH23848 accelerates inducible nitric oxide synthase degradation through attenuation of cAMP signaling in glomerular mesangial cells.

  Yu-Sheng Lin, Mingli Hsieh, Yi-Ju Lee, Kai-Li Liu, Ting-Hui Lin
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  ABSTRACT: Excessive release of nitric oxide (NO) by mesangial cells contributes to the pathogenesis of glomerulonephritis. Prostaglandin E(2) (PGE(2)) produced at inflammatory sites regulates the release of NO through its downstream signaling. In glomerular mesangial cells (MES-13 cells), PGE(2) modulated NO production mainly through EP4 receptor in a cAMP-dependent manner. Lipopolysaccharide and interferon-gamma (LPS+IFNgamma)-induced NO production, inducible nitric oxide synthase (iNOS) gene and protein expression were greatly inhibited by AH23848, an EP4 antagonist. Further investigation indicated that AH23848 attenuated endogenous cAMP accumulation in MES-13 cells and modulated NO production through declination of iNOS gene expression and acceleration of iNOS protein degradation. AH23848 downregulated the iNOS protein in MES-13 cells through protein kinase A (PKA) since KT5720, a PKA-specific inhibitor, reduced iNOS protein stability. A short exposure of activated MES-13 cells to okadaic acid augmented iNOS activity. AH23848 and KT5720 attenuated serine/threonine phosphorylation of iNOS protein in LPS + IFNgamma-stimulated MES-13 cells. The results of this study led us to speculate that cAMP might regulate iNOS-stimulated NO synthesis through posttranslational mechanisms. Attenuation of cAMP signaling and the phosphorylation status of the iNOS protein may account for the effect of AH23848 in accelerating iNOS protein degradation in MES-13 cells.
  Nitric Oxide 04/2008; 18(2):93-104.
• Article: Edaravone prevents iNOS expression by inhibiting its promoter transactivation and mRNA stability in cytokine-stimulated hepatocytes.

  Hideyuki Yoshida, A-Hon Kwon, Masaki Kaibori, Katsushige Tsuji, Kozo Habara, Masanori Yamada, Yasuo Kamiyama, Mikio Nishizawa, Seiji Ito, Tadayoshi Okumura
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  ABSTRACT: Edaravone has an anti-inflammatory effect in experimental models of various organ injuries. We reported that edaravone reduces the induction of inducible nitric oxide synthase (iNOS) as well as pro-inflammatory cytokines in endotoxin-treated rats with partial hepatectomy, leading to the prevention of liver injury. Studies were performed to investigate the mechanisms involved in the inhibition of iNOS expression by edaravone in hepatocytes. Primary cultured rat hepatocytes were treated with interleukin (IL)-1beta in the presence or absence of edaravone, and iNOS and its signal were analyzed. Edaravone decreased the expression of iNOS mRNA and its protein stimulated by IL-1beta, resulting in the reduction of NO production. Edaravone inhibited the activation of transcription factor NF-kappaB through IkappaB degradation and the up-regulation of type I IL-1 receptor through PI3K/Akt activation, which are essential signals for iNOS induction. Further transfection experiments with iNOS promoter-luciferase construct having iNOS 3'-UTR revealed that edaravone decreased the stability of iNOS mRNA. In support of this observation, edaravone decreased the expression of iNOS antisense-transcript, which stabilizes iNOS mRNA by interacting with its 3'-UTR and RNA-binding protein. Edaravone may inhibit the induction of iNOS gene expression at steps of promoter transactivation and mRNA stabilization in cytokine-stimulated hepatocytes.
  Nitric Oxide 04/2008; 18(2):105-12.
• Article: Interactions of nitrosylhemoglobin and carboxyhemoglobin with erythrocyte.

  Katherine J Chou, Joanna Dodd, James C Liao
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  ABSTRACT: Nitrosylhemoglobin (HbFe(II)NO) has been detected in vivo, and its role in NO transport and preservation has been discussed. To gain insight into the potential role of HbFe(II)NO, we performed in vitro experiments to determine the effect of oxygenated red blood cells (RBCs) on the dissociation of cell-free HbFe(II)NO, using carboxyhemoglobin (HbFe(II)CO) as a comparison. Results show that the apparent half-life of the cell-free HbFe(II)CO was reduced significantly in the presence of RBCs at 1% hematocrit. In contrast, RBC did not change the apparent half-life of extracellular HbFe(II)NO, but caused a shift in the HbFe(II)NO dissociation product from methemoglobin (metHbFe(III)) to oxyhemoglobin (HbFe(II)O(2)). Extracellular hemoglobin was able to extract CO from HbFe(II)CO-containing RBC, but not NO from HbFe(II)NO-containing RBC. Although these results appear to suggest some unusual interactions between HbFe(II)NO and RBC, the data are explainable by simple HbFe(II)NO dissociation and hemoglobin oxidation with known rate constants. A kinetic model consisting of these reactions shows that (i) deoxyhemoglobin is an intermediate in the reaction of HbFe(II)NO oxidation to metHbFe(III), (ii) the rate-limiting step of HbFe(II)NO decay is the dissociation of NO from HbFe(II)NO, (iii) the magnitude of NO diffusion rate constant into RBC is estimated to be approximately 10(4)M(-1)s(-1), consistent with previous results determined from a competition assay, and (iv) no additional chemical reactions are required to explain these data.
  Nitric Oxide 04/2008; 18(2):122-35.
• Article: Oxidation of 5-thio-2-nitrobenzoic acid, by the biologically relevant oxidants peroxynitrite anion, hydrogen peroxide and hypochlorous acid.

  Lisa M Landino, Catherine B Mall, Joshua J Nicklay, Sarah K Dutcher, Katherine L Moynihan
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  ABSTRACT: The modification of protein and non-protein thiols by oxidants including hydrogen peroxide (H(2)O(2)), peroxynitrite anion (ONOO(-)) and hypochlorous acid (HOCl) is well documented. Using an aromatic thiol, 5-thio-2-nitrobenzoic acid, and biologically relevant oxidants, we have identified higher oxidation states of sulfur including the sulfonic acid derivative and the disulfide S-oxide, a thiosulfinate, by HPLC and mass spectrometry. The initial reaction of ONOO(-) with 5-thio-2-nitrobenzoic acid yielded a transient red intermediate, the sulfenate anion. The red intermediate was observed when ONOO(-) and H(2)O(2) were used to oxidize 5-thio-2-nitrobenzoic acid and it persisted for several seconds at pH 7. HOCl oxidized the disulfide, 5,5'dithiobis(2-nitrobenzoic acid) to the corresponding sulfonic acid and no additional products were detected. Using this system, we can directly compare the thiol-oxidizing abilities of several oxidants. Because 5-thio-2-nitrobenzoic acid is the product of the reaction of Ellman's reagent with protein thiols, a detailed study of its stability in biological matrices where oxidants may be generated is warranted.
  Nitric Oxide 03/2008; 18(1):11-8.
• Article: Pitavastatin up-regulates the induction of iNOS through enhanced stabilization of its mRNA in pro-inflammatory cytokine-stimulated hepatocytes.

  Kozo Habara, Yoshinori Hamada, Masanori Yamada, Katsuji Tokuhara, Hironori Tanaka, Masaki Kaibori, Yasuo Kamiyama, Mikio Nishizawa, Seiji Ito, Tadayoshi Okumura
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  ABSTRACT: Studies have indicated that protective effects of statins (HMG-CoA reductase inhibitor) are associated with the regulation of endothelial nitric oxide synthase (eNOS) or inducible NOS (iNOS) in heart and liver diseases. Statins have been reported to enhance hepatic NO production and decrease the vascular tone in patients with cirrhosis. However, it is unclear which NOS contributes to the increased NO production. We hypothesized that statins are involved in the up-regulation of iNOS in inflammatory liver, resulting in decreased hepatic resistance. Primary cultured rat hepatocytes were treated with pro-inflammatory cytokine interleukin (IL)-1beta in the presence or absence of pitavastatin. Pretreatment of cells with pitavastatin resulted in up-regulation of iNOS induction by IL-1beta, followed by increased NO production. Pitavastatin had no effects on the degradation of IkappaB or activation of NF-kappaB. However, pitavastatin super-induced the up-regulation of type I IL-1 receptor (IL-1RI), which is essential for iNOS induction in addition to the IkappaB/NF-kappaB pathway. Mevalonate and geranylgeranylpyrophosphate blocked the stimulatory effects of pitavastatin on iNOS and IL-1RI induction. Transfection experiments revealed that pitavastatin increased the stability of iNOS mRNA rather than its promoter transactivation. In support of this observation, pitavastatin increased the antisense-transcript corresponding to the 3'-UTR of iNOS mRNA, which stabilizes iNOS mRNA by interacting with the 3'-UTR- and RNA-binding proteins. These findings demonstrate that pitavastatin up-regulates iNOS by the stabilization of its mRNA, presumably through the super-induction of IL-1RI and antisense-transcript. This implies that statins may contribute to a novel potentiated treatment in liver injuries including cirrhosis.
  Nitric Oxide 03/2008; 18(1):19-27.
• Article: Nitric oxide-deficiency regulates hepatic heme oxygenase-1.

  Alexander Hoetzel, Armin Welle, René Schmidt, Torsten Loop, Matjaz Humar, Stefan W Ryter, Klaus K Geiger, Augustine M K Choi, Benedikt H J Pannen
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  ABSTRACT: Nitric oxide plays a crucial role in the maintenance of liver function and integrity. During stress, the inducible heme oxygenase-1 protein and its reaction products, including carbon monoxide, also exert potent hepatoprotective effects. We investigated a potential relationship between endogenous nitric oxide synthesis and the hepatic regulation of heme oxygenase-1. Inhibition of nitric oxide synthesis in vivo by injection of l-NAME led to a dose-dependent induction of heme oxygenase-1 mRNA, protein and activity in the rat liver, whereas did not affect the expression of other heat shock proteins. The effect of l-NAME was demonstrated by hemodynamic changes within the liver circulation as measured by ultrasonic flow probes. Inhibition of nitric oxide synthase led to a decline in hepatic arterial and portal venous blood flow, and subsequently caused liver cell damage. In contrast, the combined administration of l-NAME and the nitric oxide-independent intestinal vasodilator dihydralazine completely restored portal venous flow, abolished the liver cell damage, and prevented the upregulation of heme oxygenase-1, despite inhibition of nitric oxide production. In conclusion, nitric oxide deficiency upregulates hepatic heme oxygenase-1, which is reversible by maintaining hepatic blood flow. This interdependence has important implications for the development of therapeutic strategies aimed at modulating the activity of these hepatoprotective mediator systems.
  Nitric Oxide 03/2008; 18(1):61-9.
• Article: Differential NOS expression in freshwater and aestivating Protopterus dolloi (lungfish): heart vs kidney readjustments.

  Daniela Amelio, Filippo Garofalo, Elvira Brunelli, Ai May Loong, Wai Peng Wong, Yuen Kwong Ip, Bruno Tota, Maria Carmela Cerra
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  ABSTRACT: African lungfish Protopterus dolloi is an obligatory air-breather, which aestivates in a cocoon during the dry season. Aestivation associates with functional modifications in many tissues and organs, including heart and kidney. Due to its pleiotropic modulatory effects, nitric oxide (NO), generated by nitric oxide synthases (NOSs), may coordinate organ rearrangement, allowing adaptive adjustments under stressful environmental conditions. By immunofluorescence, Western blotting and NADPH-diaphorase, we examined cardiac and renal localization and activity of NOSs isoforms in both freshwater (FW) and aestivating [6 days (6DA) and 40 days (40DA) of estivation] P. dolloi. In heart and kidney endothelial NOS (eNOS) is the major isoform with respect to inducible and neuronal NOS (iNOS and nNOS, respectively). Cardiac eNOS locates in the epicardium, the trabecular endothelial endocardium, and myocardiocytes of both FW and aestivating fish. Western blotting revealed that cardiac eNOS expression increases in 6DA, but decreases in 40DA fish. In FW fish kidney eNOS is present in vascular endothelial cells and in podocytes of renal corpuscles. In tubular epithelial cells it is restricted to the apical pole. With aestivation, both renal localization and expression of eNOS increase. NADPH-diaphorase revealed an enhancement of cardiac and renal NOS activities during aestivation. Results suggest that in P. dolloi NO contributes, in an autocrine-paracrine fashion, to cardiac and renal readjustments during aestivation. Our findings are of evolutionary interest, since they document for the first time the presence of a NOS system in a ancestral fish, indicative of deep phylogenetic roots of NO bio-synthesis.
  Nitric Oxide 03/2008; 18(1):1-10.
• Article: Rebamipide, anti-gastric ulcer drug, up-regulates the induction of iNOS in proinflammatory cytokine-stimulated hepatocytes.

  Katsuji Tokuhara, Yoshinori Hamada, Hironori Tanaka, Masanori Yamada, Takashi Ozaki, Kosuke Matsui, Yasuo Kamiyama, Mikio Nishizawa, Seiji Ito, Tadayoshi Okumura
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  ABSTRACT: Nitric oxide (NO) generated from inducible NO synthase (iNOS) during hepatic injury has been reported to contribute to cytoprotection or cellular damage. Rebamipide, anti-gastric ulcer drug, has protective effects in a variety of tissue and organ injury. However, it remains unknown whether rebamipide is involved in the regulation of iNOS gene expression under pathological conditions. We examined whether rebamipide influences the induction of iNOS in hepatocytes exposed to pro-inflammatory cytokine. Primary cultured rat hepatocytes were treated with interleukin (IL)-1beta in the presence or absence of rebamipide. Pretreatment of cells with rebamipide resulted in up-regulation of iNOS induction by IL-1beta, followed by increased NO production. Rebamipide enhanced the degradation of IkappaBalpha and the activation of NF-kappaB. Further, rebamipide super-induced the up-regulation of type I IL-1 receptor (IL-1RI), which is essential for iNOS induction in addition to the IkappaB/NF-kappaB pathway. Transfection experiments revealed that rebamipide increased the transactivation of iNOS promoter and the stability of iNOS mRNA. In the latter, rebamipide increased the antisense-transcript corresponding to the 3'-UTR of iNOS mRNA, which stabilizes iNOS mRNA by interacting with the 3'-UTR and RNA-binding proteins. These findings demonstrate that rebamipide up-regulates iNOS by iNOS promoter activation through NF-kappaB, and by its mRNA stabilization presumably through the super-induction of IL-1RI and antisense-transcript. Rebamipide may contribute to a novel potentiated treatment in liver injuries.
  Nitric Oxide 03/2008; 18(1):28-36.