DOCSLIB.ORG

The Noncanonical Pathway for in Vivo Nitric Oxide Generation: the Nitrate-Nitrite-Nitric Oxide Pathway

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Noncanonical Pathway for in Vivo Nitric Oxide Generation: the Nitrate-Nitrite-Nitric Oxide Pathway 1521-0081/72/3/692–766$35.00 https://doi.org/10.1124/pr.120.019240 PHARMACOLOGICAL REVIEWS Pharmacol Rev 72:692–766, July 2020 Copyright © 2020 by The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license. ASSOCIATE EDITOR: CHRISTOPHER J. GARLAND The Noncanonical Pathway for In Vivo Nitric Oxide Generation: The Nitrate-Nitrite-Nitric Oxide Pathway V. Kapil, R. S. Khambata, D. A. Jones, K. Rathod, C. Primus, G. Massimo, J. M. Fukuto, and A. Ahluwalia William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, United Kingdom (V.K., R.S.K., D.A.J., K.R., C.P., G.M., A.A.) and Department of Chemistry, Sonoma State University, Rohnert Park, California (J.M.F.) Abstract ...................................................................................694 Significance Statement. ..................................................................694 I. Introduction . ..............................................................................694 A. Chemistry of ·NO and Its Metabolism to Nitrite and Nitrate . .........................695 II. Inorganic Nitrite and Nitrate . ............................................................697 A. Historical Uses of Inorganic Nitrite.....................................................697 B. Historical Uses of Inorganic Nitrate ....................................................698 III. Sources and Pharmacokinetics of Nitrate . ................................................698 Downloaded from A. Endogenously Derived Nitrate..........................................................698 B. Exogenous Sources of Nitrate ..........................................................699 1. Dietary Intake ......................................................................699 2. Water Supplies . ..................................................................699 C. Pharmacokinetics of Nitrate ............................................................699 by guest on September 28, 2021 D. Enterosalivary Circulation and Oral Reduction of Nitrate ...............................700 E. Nitrate Reductases. ..................................................................702 1. Prokaryotic Nitrate Reductases .....................................................702 2. Mammalian Nitrate Reductase Activity . ..........................................702 IV. Sources and Pharmacokinetics of Nitrite . ................................................703 A. Endogenously Derived Nitrite from the Enterosalivary Circuit . .........................703 B. Endogenously Derived Nitrite from NOS Activity . .....................................704 C. Exogenous Sources of Nitrite ...........................................................704 D. Systemic Nitrite Absorption ............................................................705 V. Mechanisms of Nitrite Bioactivation. ......................................................706 A. Nonenzymatic Nitrite Reduction. ......................................................706 B. Mammalian Nitrite Reductases. ......................................................706 1. Molybdenum-Containing Oxidase Enzymes ..........................................706 a. Xanthine oxidoreductase. ......................................................706 b. Aldehyde oxidase ................................................................708 c. Sulfite oxidase. ..................................................................709 d. Mitochondrial amidoxime reducing component ...................................709 2. Mitochondrial Respiratory Chain Enzymes ..........................................709 3. Globins .............................................................................709 a. Hemoglobin . ..................................................................709 b. Myoglobin .......................................................................710 c. Neuroglobin . ..................................................................710 d. Cytoglobin.......................................................................710 4. Indoleamine 2,3-Dioxygenase 1......................................................711 Address correspondence to: A. Ahluwalia, Centre for Cardiac Medicines and Device Innovation, William Harvey Research Institute, Charterhouse Square, London EC1M 6BQ, UK. E-mail: [email protected] V.K. and D.A.J. were supported by a Barts Charity Programme grant, C.P. by a Derek Willoughby clinical research training fellowship, and K.R. by a National Institute for Health Academic Clinical Lectureship award. https://doi.org/10.1124/pr.120.019240. 692 Nitrate-Nitrite-Nitric Oxide Pathway 693 5. Nitric Oxide Synthase . ............................................................711 6. Carbonic Anhydrase ................................................................711 VI. Functional Effects of the Noncanonical ·NO Pathway and Clinical Translation . .............712 A. Nitrite, Nitrate, and the CV System ....................................................712 1. Vasodilation ........................................................................712 2. Blood Pressure . ..................................................................714 3. Enterosalivary Generation of Nitrite Regulates Basal BP . .........................719 4. Endothelial Dysfunction ............................................................720 5. Arterial Stiffness . ..................................................................720 6. Cerebral Blood Flow ................................................................721 B. Nitrite and Nitrate in Exercise and Muscle Biology .....................................721 1. Nitrate and Exercise Performance on Moderately Trained Athletes ..................722 a. Mechanisms for enhanced exercise performance after nitrate supplementation . 723 2. Nitrate and Exercise Performance in Patient Populations. .........................724 3. Cardiac Muscle Function and Heart Failure .........................................725 a. ·NO as an inotrope . ............................................................725 b. Cardiac hypertrophy and ·NO....................................................727 c. Positive inotropic and antihypertrophic effects of nitrite and nitrate . .............727 d. Preclinical studies: cardiac dysfunction, nitrite, and nitrate.......................727 e. Clinical translation . ............................................................730 C. Nitrite and Nitrate in Inflammation ....................................................731 1. Thrombosis . ........................................................................735 2. Peripheral Arterial Disease . ......................................................737 3. Atherosclerosis . ..................................................................737 D. Nitrite and Nitrate in the Respiratory System ..........................................738 1. Pulmonary Hypertension............................................................739 2. Chronic Obstructive Pulmonary Disease . ..........................................740 3. Sleep-Disordered Breathing . ......................................................740 4. Toxic Lung Injury. ..................................................................741 E. Nitrite and Nitrate in the GI System . ................................................741 F. Nitrite and Nitrate in Metabolic Diseases...............................................742 G. Nitrite and Nitrate in I/R Injury. ......................................................743 1. Cytoprotection ......................................................................743 2. Potential Mechanisms for Nitrite-Induced Reduction in I/R Injury ...................743 3. Potential Mechanisms for Nitrite-Induced Cytoprotection in I/R Injury . .............744 a. Improved mitochondrial function. ................................................744 b. Antiplatelet effects . ............................................................745 ABBREVIATIONS: ABP, ambulatory blood pressure; ADI, acceptable daily intake; AMI, acute myocardial infarction; AMPK, AMP- activated protein kinase; AO, aldehyde oxidase; ApoE, apolipoprotein E; BNP, brain natriuretic peptide; BP, blood pressure; CABG, coronary artery bypass grafting; CCL2, chemokine (C-C motif) ligand 2; cGMP, cyclic GMP; COPD, chronic obstructive pulmonary disease; C-PTIO, 2- (4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; CV, cardiovascular; CVD, cardiovascular disease; CXCL2, chemokine (C-X-C motif) ligand 2; DASH, Dietary Approaches to Stop Hypertension; DBP, diastolic blood pressure; deoxyHb, deoxyhemoglobin; deoxyMb, deoxymyoglobin; dP/dt, rate of change of pressure; DOCA, deoxycorticosterone acetate; EDRF, endothelium-derived relaxing factor; eNOS, endothelial nitric oxide synthase; Fe(II), ferrous; Fe(III), ferric; FMD, flow-mediated dilation; GAG, glycosaminoglycan; GC-1, soluble guanylyl cyclase; GI, gastrointestinal; GTN, glyceryl trinitrate; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; ICAM-1, intercellular adhesion molecule-1; IDO1, indoleamine 2,3-dioxygenase 1; IL, interleukin; iNO, 1 inhaled·NO; iNOS, inducible nitric oxide synthase; I/R, ischemia/reperfusion; KATP, ATP-sensitive K ; KO, knockout; L-NAME, N(g)--nitro-L- arginine methyl ester; LV, left ventricular; LVEF, left ventricular ejection fraction; MAP, mean
Load more

Recommended publications
  • Cytochrome C Nitrite Reductase (Ccnir) Does Not Disproportionate Hydroxylamine to Ammonia and Nitrite, Despite a Strongly Favorable Driving Force
    Marquette University e-Publications@Marquette Physics Faculty Research and Publications Physics, Department of 4-2014 Shewanella oneidensis Cytochrome c Nitrite Reductase (ccNiR) Does Not Disproportionate Hydroxylamine to Ammonia and Nitrite, Despite a Strongly Favorable Driving Force Matthew Youngblut University of Wisconsin - Milwaukee Daniel J. Pauly University of Wisconsin - Milwaukee Natalia Stein University of Wisconsin - Milwaukee Daniel Walters University of Wisconsin - Milwaukee John A. Conrad University of Wisconsin - Milwaukee See next page for additional authors Follow this and additional works at: https://epublications.marquette.edu/physics_fac Part of the Physics Commons Recommended Citation Youngblut, Matthew; Pauly, Daniel J.; Stein, Natalia; Walters, Daniel; Conrad, John A.; Moran, Graham R.; Bennett, Brian; and Pacheco, A. Andrew, "Shewanella oneidensis Cytochrome c Nitrite Reductase (ccNiR) Does Not Disproportionate Hydroxylamine to Ammonia and Nitrite, Despite a Strongly Favorable Driving Force" (2014). Physics Faculty Research and Publications. 7. https://epublications.marquette.edu/physics_fac/7 Authors Matthew Youngblut, Daniel J. Pauly, Natalia Stein, Daniel Walters, John A. Conrad, Graham R. Moran, Brian Bennett, and A. Andrew Pacheco This article is available at e-Publications@Marquette: https://epublications.marquette.edu/physics_fac/7 Marquette University e-Publications@Marquette Physics Faculty Research and Publications/College of Arts and Sciences This paper is NOT THE PUBLISHED VERSION; but the author’s final, peer-reviewed manuscript. The published version may be accessed by following the link in the citation below. Biochemistry, Vol. 53, No. 13 (8 April 2014): 2136–2144. DOI. This article is © American Chemical Society Publications and permission has been granted for this version to appear in e- Publications@Marquette. American Chemical Society Publications does not grant permission for this article to be further copied/distributed or hosted elsewhere without the express permission from American Chemical Society Publications.
    [Show full text]
  • Nitrate Reductase-Dependent Nitric Oxide Synthesis in the Defense Response of Arabidopsis Thaliana Against Pseudomonas Syringae
    Tropical Plant Pathology, vol. 35, 2, 104-107 (2010) Copyright by the Brazilian Phytopathological Society. Printed in Brazil www.sbfito.com.br SHORT COMMUNICATION / COMUNICAÇÃO Nitrate reductase-dependent nitric oxide synthesis in the defense response of Arabidopsis thaliana against Pseudomonas syringae Halley C. Oliveira, Elzira E. Saviani, Jusceley F. P. Oliveira & Ione Salgado Departamento de Biologia Vegetal, Instituto de Biologia, Universidade Estadual de Campinas - UNICAMP, 13083-970, Campinas, SP, Brazil Author for correspondence: Ione Salgado, e-mail: [email protected] ABSTRACT Nitrate reductase (NR) was recently shown to play an important role during phytopathogenic interactions by providing substrates for the synthesis of nitric oxide (NO), a key signal for plant defense responses. In order to give additional support to this hypothesis, we compared NO-mediated defense responses of wild-type and NR double-deficient (nia1 nia2) Arabidopsis thaliana plants inoculated with the IBSBF-1115 (ibs) strain of Pseudomonas syringae pv. maculicola (Psm) and with genetically characterized avirulent (avr) or virulent (vir) strains of Psm. Inoculation of wild-type leaves with avr or ibs, but not vir, stimulated NO emission, as measured by the indicator 4,5-diaminofluorescein. NO emission induced by avr was higher than that induced by ibs. Wild-type plants displayed the hypersensitive response (HR) when infiltrated with the strains avr or ibs, although a stronger HR was induced by avr. The vir strain did not induce HR in wild-type plants, and leaves developed severe infection symptoms. nia1 nia2 plants did not show significantly increased NO emission nor did they develop HR to any of the analyzed strains of Psm, but displayed clorotic lesions and higher bacterial growth in their leaves.
    [Show full text]
  • The Availability of Organic Nitrates from Intravenous Administration Systems
    THE AVAILABILITY OF ORGANIC NITRATES FROM INTRAVENOUS ADMINISTRATION SYSTEMS by Paul Adrian Cossum B.Sc., M.P.S. submitted in partial fulfilment of the requirements for the degree of Master of Pharmacy UNIVERSITY OF TASMANIA - HOBART JUNE 1981 SUMMARY Nitroglycerin aind isosorbide dinitrate are two drugs which are infused intravenously during the treatment of ischaemic heart disease. The availability of these two drugs in solutions infused from plastic infusion bags or glass infusion bottles through plastic giving sets has been investigated. During simulated infusions the concentration of nitroglycerin and isosorbide dinitrate appearing in the effluent of the • giving set tubing was found to be much less than the concentration of the drug solution initially contained in the plastic infusion bag or glass infusion bottle. It was found that each component of the plastic infusion equipment sorbed the drugs to a significant extent and that the rate of disappearance of drugs from solutions stored in each component was in the rank order: giving set tubing > giving set burette > plastic infusion bag. There was no significant loss of either drug from solutions stored in glass bottles. The influence of formulation factors and storage conditions on the sorption of nitroglycerin, isosorbide dinitrate and another organic nitrate compound., ethylene glycol dinitrate, by plastic infusion equipment was studied. The extent of loss during simulated infusions was also found to be dependent on flow rate of drug solution through the giving set. The sorption of nitroglycerin and isosorbide dinitrate has clinical and pharmacokinetic significance. Losses of nitroglycerin and isosorbide dinitrate associated with their infusion through plastic Lnfusion equipment were minimised by infusing drug solutions from a glass syringe through high density polyethylene tubing.
    [Show full text]
  • Nitric Oxide Signaling in Plants
    plants Editorial Nitric Oxide Signaling in Plants John T. Hancock Department of Applied Sciences, University of the West of England, Bristol BS16 1QY, UK; [email protected]; Tel.: +44-(0)117-328-2475 Received: 3 November 2020; Accepted: 10 November 2020; Published: 12 November 2020 Abstract: Nitric oxide (NO) is an integral part of cell signaling mechanisms in animals and plants. In plants, its enzymatic generation is still controversial. Evidence points to nitrate reductase being important, but the presence of a nitric oxide synthase-like enzyme is still contested. Regardless, NO has been shown to mediate many developmental stages in plants, and to be involved in a range of physiological responses, from stress management to stomatal aperture closure. Downstream from its generation are alterations of the actions of many cell signaling components, with post-translational modifications of proteins often being key. Here, a collection of papers embraces the differing aspects of NO metabolism in plants. Keywords: nitrate reductase; nitration; nitric oxide; reactive oxygen species; stress responses; S-nitrosation; S-nitrosylation; SNO-reductase; thiol modification 1. Introduction Nitric oxide (NO) is now well acknowledged as an instrumental signaling molecule in both plants and animals [1]. First recognized as important as a signal in the control of vascular tone [2], its role in plants came to prominence in the late 1990s [3–5]. The forty years of research into NO in plants has just been highlighted by a review by Kolbert et al. [6]. In plants, NO has been found to be involved in a wide range of developmental stages and physiological responses.
    [Show full text]
  • Protein Disulfide Isomerase May Facilitate the Efflux
    Redox Biology 1 (2013) 373–380 Contents lists available at SciVerse ScienceDirect Redox Biology journal homepage: www.elsevier.com/locate/redox Protein disulfide isomerase may facilitate the efflux of nitrite derived S-nitrosothiols from red blood cells$ Vasantha Madhuri Kallakunta a, Anny Slama-Schwok b, Bulent Mutus a,n a Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario, Canada N9B 3P4 b INRA UR892, Domaine de Vilvert, 78352 Jouy-en-Josas, France article info abstract Article history: Protein disulfide isomerase (PDI) is an abundant protein primarily found in the endoplasmic reticulum Received 20 June 2013 and also secreted into the blood by a variety of vascular cells. The evidence obtained here, suggests that Received in revised form PDI could directly participate in the efflux of NO+ from red blood cells (RBC). PDI was detected both in 8 July 2013 RBC membranes and in the cytosol. PDI was S-nitrosylated when RBCs were exposed to nitrite under Accepted 9 July 2013 ∼50% oxygen saturation but not under ∼100% oxygen saturation. Furthermore, it was observed that hemoglobin (Hb) could promote PDI S-nitrosylation in the presence of ∼600 nM nitrite. In addition, three Keywords: lines of evidence were obtained for PDI–Hb interactions: (1) Hb co-immunoprecipitated with PDI; (2) Hb Nitrite reductase quenched the intrinsic PDI fluorescence in a saturable manner; and (3) Hb–Fe(II)–NO absorption S-nitrosohemoglobin spectrum decreased in a [PDI]-dependent manner. Finally, PDI was detected on the surface RBC under Hypoxic vasodilation ∼100% oxygen saturation and released as soluble under ∼50% oxygen saturation.
    [Show full text]
  • Dietary Nitrates, Nitrites, and Food Safety: Risks Versus Benefits
    Acta Scientific NUTRITIONAL HEALTH (ISSN:2582-1423) Volume 5 Issue 6 June 2021 Review Article Dietary Nitrates, Nitrites, and Food Safety: Risks Versus Benefits Keith R Martin* Received: April 08, 2021 Center for Nutraceutical and Dietary Supplement Research, College of Health Sci- Published: May 26, 2021 ences, University of Memphis, Memphis, USA © All rights are reserved by Keith R Martin. *Corresponding Author: Keith R Martin, Center for Nutraceutical and Dietary Supplement Research, College of Health Sciences, University of Memphis, Memphis, USA. Abstract Nitrates, as a result, are intermediates in the movement of atmospheric nitrogen into the food chain with rich dietary sources includ- Atmospheric nitrogen, via the environmental nitrogen cycle, is captured, or fixed, by symbiotic bacteria interacting with plants. ing red spinach, beetroot, etc. Nitrate-rich fertilizers may further increase nitrogen content of plants. Other sources include potable water, dietary supplements and food additives. Although prevalent in the diet, nitrates have been viewed negatively because they chemically form carcinogenic nitrosamines in acidic environments, e.g. stomach, purportedly leading to gastric cancer as well as neoplasia of the intestine, brain, pancreas, and contributing to Non-Hodgkin’s lymphoma. Other reports indicate associations with hyperthyroidism and diabetes mellitus. A second major concern with dietary nitrate consumption is the development of methemo- - globinemia particularly in infants caused by increases in methemoglobin where
    [Show full text]
  • ATSDR Case Studies in Environmental Medicine Nitrate/Nitrite Toxicity
    ATSDR Case Studies in Environmental Medicine Nitrate/Nitrite Toxicity Agency for Toxic Substances and Disease Registry Case Studies in Environmental Medicine (CSEM) Nitrate/Nitrite Toxicity Course: WB2342 CE Original Date: December 5, 2013 CE Renewal Date: December 5, 2015 CE Expiration Date: December 5, 2017 Key • Nitrate toxicity is a preventable cause of Concepts methemoglobinemia. • Infants younger than 4 months of age are at particular risk of nitrate toxicity from contaminated well water. • The widespread use of nitrate fertilizers increases the risk of well-water contamination in rural areas. About This and This educational case study document is one in a series of Other Case self-instructional modules designed to increase the Studies in primary care provider’s knowledge of hazardous Environmental substances in the environment and to promote the Medicine adoption of medical practices that aid in the evaluation and care of potentially exposed patients. The complete series of Case Studies in Environmental Medicine is located on the ATSDR Web site at URL: http://www.atsdr.cdc.gov/csem/csem.html In addition, the downloadable PDF version of this educational series and other environmental medicine materials provides content in an electronic, printable format. Acknowledgements We gratefully acknowledge the work of the medical writers, editors, and reviewers in producing this educational resource. Contributors to this version of the Case Study in Environmental Medicine are listed below. Please Note: Each content expert for this case study has indicated that there is no conflict of interest that would bias the case study content. CDC/ATSDR Author(s): Kim Gehle MD, MPH CDC/ATSDR Planners: Charlton Coles, Ph.D.; Kimberly Gehle, MD; Sharon L.
    [Show full text]
  • Analysis of Nitrogen Utilization Capability During the Proliferation and Maturation Phases of Norway Spruce (Picea Abies (L.) H.Karst.) Somatic Embryogenesis
    Article Analysis of Nitrogen Utilization Capability during the Proliferation and Maturation Phases of Norway Spruce (Picea abies (L.) H.Karst.) Somatic Embryogenesis Julia Dahrendorf 1, David Clapham 2 and Ulrika Egertsdotter 1,3,* 1 Umeå Plant Science Centre, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, SE-901 83 Umeå, Sweden; [email protected] 2 BioCentre, Swedish University of Agricultural Sciences, SE-750 07 Uppsala, Sweden; [email protected] 3 G.W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA * Correspondence: [email protected]; Tel.: +1-404-663-6950 Received: 1 April 2018; Accepted: 22 May 2018; Published: 24 May 2018 Abstract: Somatic embryogenesis (SE) is a laboratory-based method that allows for cost-effective production of large numbers of clonal copies of plants, of particular interest for conifers where other clonal propagation methods are mostly unavailable. In this study, the effect of L-glutamine as an organic nitrogen source was evaluated for three contrasted media (containing NH4 + NO3 without glutamine, or glutamine + NO3, or glutamine without inorganic nitrogen) during proliferation and maturation of Norway spruce somatic embryos through analyses of activities of the key enzymes of nitrogen metabolism: nitrate reductase (NR), glutamine synthetase (GS) and arginase. A major change in nitrogen metabolism was indicated by the increased activity of GS from zero in the proliferation stage through maturation to high activity in somatic embryo-derived plantlets; furthermore, NR activity increased from zero at the proliferation stage to high activity in maturing embryos and somatic-embryo derived plantlets.
    [Show full text]
  • Inhibitory Effects of Sildenafil and Tadalafil on Inflammation, Oxidative
    Pharmacological Reports 71 (2019) 517–521 Contents lists available at ScienceDirect Pharmacological Reports journal homepage: www.elsevier.com/locate/pharep Original article Inhibitory effects of sildenafil and tadalafil on inflammation, oxidative stress and nitrosative stress in animal model of bronchial asthma a a, a b b Vijaya Laxmi , Rachna Gupta *, Swapan K. Bhattacharya , Arunabha Ray , Kavita Gulati a Department of Pharmacology, University College of Medical Sciences and GTB Hospital, New Delhi, India b Vallabhbhai Patel Chest Institute, New Delhi, India A R T I C L E I N F O A B S T R A C T Article history: Background: Cyclic neucleotides are involved in many cellular functions including smooth muscle Received 9 June 2018 relaxation, inflammation, and signal transduction. Sildenafil and tadalafil are phosphodiesterase-5 Received in revised form 22 January 2019 0 0 (PDE-5) inhibitors which prevent the degradation of cyclic neucleotide i.e. guanosine 3 ,5 cyclic Accepted 14 February 2019 monophosphate (cGMP) and increase the levels of cGMP. In this study sildenafil and tadalafil were Available online 15 February 2019 evaluated for their anti-inflammatory, anti-oxidative and anti-nitrosative stress potential in animal model of bronchial asthma. Keywords: Methods: Wistar rats were sensitized with 10 mg intraperitoneal (ip) ovalbumin adsorbed to 10 mg of Bronchial asthma aluminum hydroxide on day 0. Animals were given sildenafil (1 and 3 mg/kg ip) and tadalafil (1 and Inflammation 3 mg/kg ip) from day 1 to day 14. Also, on day 14 animals were challenged with ovalbumin (1 mg ip). After Oxidative stress Ovalbumin 24 h, samples were collected to analyze interleukin-4 (IL-4) and tumour necrosis factor-α (TNF-α), in Sildenafil serum and bronchoalveolar lavage fluid (BALF).
    [Show full text]
  • Possible Modes of Cytotoxicity of High Energy Aliphatic Nitroesters and N-Nitramines for Mouse Splenocytes
    CHEMIJA. 2012. Vol. 23. No. 2. P. 141–146 © Lietuvos mokslų akademija, 2012 Possible modes of cytotoxicity of high energy aliphatic nitroesters and N-nitramines for mouse splenocytes Valė Miliukienė, In this work, we report for the first time the cytotoxicity data of a large number of struc- turally diverse high energy aliphatic nitrate esters and N-nitramines (n = 20) to mouse Jonas Šarlauskas, splenocyte cells. Their concentrations causing 50% cell death (cL50) vary from 18 µM (N-nitro-diethanolamine dinitrate) to >250 µM (octahydro-1,3,5,7-tetranitro-1,3,5,7- Kastis Krikštopaitis, tetrazocine, ethylene glycol dinitrate). The log cL50 of compounds does not depend on the calculated heats of their hydride adduct formation, or voltammetric reduction peak poten- Algirdas Šaikūnas, tials, or lipophilicity. The cytotoxicity of compounds is not oxidative stress-dependent. On the other hand, their cytotoxicity is partly decreased by an inhibitor of aldehyde dehydro- Narimantas Čėnas* genase (EC 1.2.1.10), tetraethylthiuram disulfide. It shows an involvement of this enzyme in bioreductive activation of nitrate esters and N-nitramines with the liberation of nitrite, Institute of Biochemistry which is further converted to NO. of Vilnius University, Mokslininkų 12, Key words: organic nitrate ester, N-nitramine, cytotoxicity, aldehyde dehydrogenase LT-08662 Vilnius, Lithuania Abbreviations: cL50 – compound concentration causing 50% cell death, ∆Hf – heat of for- mation, Ep(7) – voltammetric reduction peak potential at pH 7.0, P – octanol / water partition coefficient, GTN – glycerol trinitrate, PETN – pentaerythritol tetranitrate, RDX – hexahy- dro-1,3,5-trinitro-1,3,5-triazine, HMX – octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine, TNT – 2,4,6-trinitrotoluene, P-450R – NADPH: cytochrome P-450 reductase, ADH – alde- hyde dehydrogenase.
    [Show full text]
  • The Nitric Oxide System in Peripheral Artery Disease: Connection with Oxidative Stress and Biopterins
    antioxidants Article The Nitric Oxide System in Peripheral Artery Disease: Connection with Oxidative Stress and Biopterins Ahmed Ismaeel 1, Evlampia Papoutsi 1, Dimitrios Miserlis 2 , Ramon Lavado 3 , Gleb Haynatzki 4, George P. Casale 5, William T. Bohannon 6, Robert S. Smith 6, Jack Leigh Eidson 6, Robert Brumberg 7, Aaron Hayson 7, Jeffrey S. Kirk 8, Carlos Castro 8, Ian Sawicki 6, Charalambos Konstantinou 9 , Luke P. Brewster 10, Iraklis I. Pipinos 5,11 and Panagiotis Koutakis 1,* 1 Department of Nutrition, Food and Exercise Sciences, Florida State University, Tallahassee, FL 32304, USA; [email protected] (A.I.); [email protected] (E.P.) 2 Department of Surgery, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA; [email protected] 3 Department of Environmental Science, Baylor University, Waco, TX 76798, USA; [email protected] 4 Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE 68198, USA; [email protected] 5 Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198, USA; [email protected] (G.P.C.); [email protected] (I.I.P.) 6 Department of Surgery, Baylor Scott & White Medical Center, Temple, TX 76508, USA; [email protected] (W.T.B.); [email protected] (R.S.S.); [email protected] (J.L.E.); [email protected] (I.S.) 7 Vascular Surgery Associates, Tallahassee, FL 32308, USA; rbrumberg@vsafl.com (R.B.); [email protected] (A.H.) 8 Department of Vascular Surgery, Capital Regional Medical Center, Tallahassee, FL 32308,
    [Show full text]
  • AFRICA CARDIOVASCULAR JOURNAL of AFRICA • Volume 28, No 6, November/December 2017 389
    AFRICA CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 6, November/December 2017 389 The effect of iloprost and sildenafil, alone and in combination, on myocardial ischaemia and nitric oxide and irisin levels Suna Aydin, Tuncay Kuloglu, Suleyman Aydin, Meltem Yardim, Davut Azboy, Zeki Temizturk, Ali Kemal Kalkan, Mehmet Nesimi Eren Abstract sacrificed after 24 hours, and their heart, liver and kidney tissues and blood samples were collected for analyses. An Aim: Insufficient oxygen supply to organs and tissues due to immunohistochemical method was used to measure the change reduced arterial or venous blood flow results in ischaemia, in irisin levels, the ELISA method to quantify blood irisin during which, although ATP production stops, AMP and levels, and Griess’ assay to determine nitric oxide (NO) levels adenosine continue to be produced from ATP. The fate of in the serum and tissue. Myocardial ischaemia was confirmed irisin, which causes the production of heat instead of ATP based on the results of Masson’s trichrome staining, as well as during ischaemia, is unknown. Iloprost and sildenafil are levels of troponin and creatine kinase MB. two pharmaceutical agents that mediate the resumption of Results: Irisin levels in biological tissue and serum dropped reperfusion (blood supply) via vasodilatation during ischae- statistically significantly in the ischaemic group (MI), but mic conditions. Our study aimed to explore the effects of were restored with ILO and SIL administration. Individual iloprost and sildenafil on irisin levels in the heart, liver and SIL administration was more potently restorative than indi- kidney tissues and whether these pharmaceutical agents had vidual ILO administration or the combined administration any impact on serum irisin and nitric oxide levels in rats with of the two agents.
    [Show full text]