01 October 2011: Review Article
Reciprocal regulation of cellular nitric oxide formation by nitric oxide synthase and nitrite reductases
George B. Stefano , Richard M. Kream
DOI: 10.12659/MSM.881972
Med Sci Monit 2011; 17(10): RA221-226
Abstract
ABSTRACT: Our mini-review focuses on dual regulation of cellular nitric oxide (NO) signaling pathways by traditionally characterized enzymatic formation from L-arginine via the actions of NO synthases (NOS) and by enzymatic reduction of available cellular nitrite pools by a diverse class of cytosolic and mitochondrial nitrite reductases. Nitrite is a major metabolic product of NO and is found in all cell and tissue types that utilize NO signaling processes. Xanthine oxidoreductase (XOR) has been previously characterized as a housekeeping enzyme responsible for cellular uric acid formation via enzymatic conversion of hypoxanthine and xanthine. It has become apparent that XOR possesses multi-functional enzymatic activities outside the realm of xanthine metabolism and a small but significant literature also established a compelling functional association between administered sodium nitrite, XOR activation, and pharmacologically characterized NO transductive effects in positive cardiovascular function enhanced pulmonary perfusion, and protection against ischemia/reperfusion injury and hypoxic damage and oxidative stress. Similar positive vascular and cellular effects were observed to be functionally associated with mitochondrial aldehyde dehydrogenase and cytochrome c/cytochrome c oxidase. The profound implications of a reciprocal regulatory mechanism responsible for cytosolic and mitochondrial NO production are discussed below.
Keywords: Nitric Oxide Synthase - metabolism, Nitrite Reductases - metabolism, Nitric Oxide - biosynthesis, Myocardial Perfusion Imaging - methods, Models, Biological, Mitochondria - metabolism, Electron Transport Complex IV, Cytosol - metabolism, Arginine, aldehyde dehydrogenase, Signal Transduction - physiology, Xanthine Dehydrogenase - metabolism
Nitric Oxide Synthases and Nitrite Reductases
Over the last two decades, the biological preeminence of cellular nitric oxide (NO) signaling pathways has been intimately linked to many processes and to its regulated enzymatic formation from L-arginine via the actions of NO synthases (NOS) and to secondary activation of soluble guanylate cyclase as a major physiological target/effector system [1–20]. Evolutionary pressure has established a functional diversity in cellular expression of NOS isoenzymes derived from three distinct genes and designated as endothelial (e), neuronal (n) and inducible (i) NOS. E- and n-NOS are constitutively expressed, display Ca2+ dependent activation, and rapidly produce and release NO within spatially defined cellular domains. In contrast, iNOS expression is intimately linked to proinflammatory processes, displays a significant latency period due to transcriptional and translational processing, and effects unregulated Ca2+− independent release of NO for extended periods of time [7,21–28]. Interestingly, a significant body of literature supports the contention that constitutively released NO can attenuate the expression of iNOS in vascular smooth muscle, neutrophils, microglia, astrocytes and hepatocytes [29–35]. Work from our laboratory has demonstrated significant feedback inhibition of NO on constitutively derived NO release [12,14–16,36–41] as well as iNOS derived NO release [27].
Within the past decade, an important body of work has challenged the primacy of NOS/L-arginine derived NO in cellular signaling processes and involves the existence of chemically stable nitrite and nitrite reductase activities in these same cell/tissue types [42–56]. Nitrite is a major metabolic product of NO and is found in all cell and tissue types that utilize NO signaling processes [42–46,52,53,55–67]. Accordingly, the establishment of a parallel and complementary NO signaling pathway utilizing recycled nitrite chemical equivalents, independently expressed from well established NOS/L-arginine signaling pathway, requires the identification and biochemical characterization of key candidate enzymes displaying significant nitrite reductase activities within meaningful biological contexts. Until now, accumulated NO/nitrite reductase literature has focused on xanthine oxidoreductase (XOR) as the major candidate nitrite reductase enzyme linked to cellular NO signaling events [49,51,52,54–58,60–64,68–76]. Other candidate nitrite reductases displaying potentially important biological roles as accessory players in NO signaling events include the mitochondrial enzymes aldehyde dehydrogenase [42,44,50,57], cytochrome c/cytochrome c oxidase [45,47,77], deoxymyoglobin [48,53] and deoxyhemoglobin [57,78].
Potent Vascular and Anti-inflammatory Effects of Sodium Nitrite: Functional Involvement of Xanthine Oxidoreductase and Accessory Nitrite Reductases
Xanthine oxidoreductase has been previously characterized as a housekeeping enzyme responsible for cellular uric acid formation via enzymatic conversion of hypoxanthine and xanthine [55,56,70,79]. Based on its intrinsic state-dependent biochemical properties to exist as both a dehydrogenase and an oxidase, it became apparent to several investigators that XOR possessed multi-functional enzymatic activities outside the realm of xanthine metabolism [54–56,70,79]. Hallmark positive vascular effects were well established to be mediated by cellular NOS/L-arginine NO signaling pathways [7–11]. A small but significant literature has also established a compelling functional association between administered sodium nitrite, XOR activation, and pharmacologically characterized NO transductive effects in positive cardiovascular function [62,63,75,80–82], enhanced pulmonary perfusion [60,80], and protection against ischemia/reperfusion injury [64,72–75] and hypoxic damage [56,58,83–85] and oxidative stress [63,76]. Similar positive vascular and cellular effects were observed to be functionally associated with mitochondrial aldehyde dehydrogenase [42,44,50,57], cytochrome c/cytochrome c oxidase [45,47,77].
Nitric oxide derived from NOS/L-arginine systems functions not only as a vasodilator but as a general antibacterial and antiviral agent and, counter-intuitively, it can down-regulate proinflammatory events [27,86–92]. Accordingly, significant anti-inflammatory properties of administered sodium nitrite have been attributed to XOR activation via pharmacologically characterized NO transductive effects [58,68].
Microenvironmental Modulation of NO Production: A Putative Role for Xanthine Oxidoreductase and Accessory Nitrite Reductases
Work from our laboratory supports the contention that constitutively derived NO provides a basal or ‘tonal’ level of chemical mediator keeps particular types of cells in a state of inhibition [93]. We have hypothesized that certain classes of cells are always ‘on’, i.e., respond to environmental changes, and that this low basal level of NO [94] provides an organism with a major pathway that functions to dampen microenvironmental “noise” which would otherwise nonspecifically and inappropriately activate them [93]. NO may control the threshold for activation of these cells. This kind of activation really represents a disinhibition process, i.e., an overcoming of the inhibitory influence of NO by changing the balance between basal NO and the levels of excitatory signals.
In support of the hypothesis stated above, there is considerable evidence that constitutively derived NO down-regulates the immunocyte-endothelial interaction [86,93,94]. NO has been shown to inhibit platelet and neutrophil aggregation [90].
Nitric Oxide Regulation of Mitochondrial Respiration and Intermediary Energy Metabolism: Functional Involvement of Xanthine Oxidoreductase and Accessory Nitrite Reductases
It has been well established that mitochondrial respiration linked to homeostasis of intermediary energy metabolism is regulated by NO signaling systems [12,98–104]. For example, pharmacological inhibition of constitutively derived NO has been shown to increase oxygen consumption in many animal species [105–109]. Furthermore, a novel NOS isoform, mtNOS, is present in mitochondria [12,99,110] and appears to modulate local circuit regulatory functions within electron transport complexes. Interestingly, nitrite-derived NO has been shown to potently regulate respiration, reactive oxygen species, and energy metabolism in plant mitochondria [83,111–113]. The apparent redundancy of plant mitochondrial NOS/L-arginine- and nitrite-derived NO signaling systems [83,111–113] provides a compelling platform for further investigation into reciprocal regulatory effects of mtNOS and concerted nitrate reductase actions in mammalian mitochondria (Figure 1) [42–46,53,85,114].
A recent important publication has described local circuit nitrite/NO cycling to produce biologically active NO within liver mitochondria [47]. The investigators have demonstrated that nitrite mediates cellular signaling through its reduction to NO via reactions with the mitochondrial electron carrier cytochrome c. Cytochrome c-mediated nitrite reductase activity is dependent on pentacoordination of the heme iron in the protein and occurs under anoxic and in the presence of nitrite, pentacoordinate cytochrome c generates bioavailable NO that is able to inhibit mitochondrial respiration. An elegant complementary study has demonstrated in yeast that state-dependent hypoxia recruits cytochrome c oxidase as a functionally competent nitrite reductase [77]. The investigators have also evaluated nitrite-dependent NO production by specific isoforms of cytochrome c oxidase in support of a functional role of the enzyme in hypoxic signaling events. Additionally, the study findings suggest a positive feedback mechanism for nitrite-derived mitochondrial NO on selective gene expression of a cytochrome c oxidase subunit that is functionally associated with enhanced production of NO in hypoxic/anoxic cells.
Further Investigation Into the Dual Regulation of Nitric Oxide Production by Nitric Oxide Synthases and Nitrite Reductases
On a functional basis it has become clear that the basal level of NO derived from cNOS in concert with cellular nitrite reduction by XOR within a diverse class of nitrite reductases may serve as a key regulatory mechanism underlying complex, cascading, physiological processes associated with maintaining cellular and organ viability. Further studies are required to probe selective regulatory effects of NOS-derived and nitrite-derived NO on gene expression of their cognate synthetic enzymes. Similar compelling studies are needed to elucidate biologically meaningful cellular coupling of cytosolic XOR and mitochondrial nitrite reductases in normal and pathophysiological states (Figure 1) [68–70,80,115–117]. Finally, holistic pre-clinical and studies to evaluate conversion of dietary nitrate to recycling active cellular nitrite pools hold great promise for improving quality of life in human and animal populations [52,81,118,119].
References
1. Garraza MH, Forneris M, Virginia GL, Oliveros LB, Norepinephrine modulates the effect of neuropeptides in coeliac ganglion on ovarian hormones release: its relationship with ovarian nitric oxide and nerve growth factor: Neuro Endocrinol Lett, 2010; 31; 103-12, pmid: 20150881
2. Jancinova V, Nosal R, Lojek A, Formation of reactive oxygen and nitrogen species in the presence of pinosylvin – an analogue of resveratrol: Neuro Endocrinol Lett, 2010; 31(Suppl 2); 79-83, pmid: 21187828
3. Krejcova D, Pekarova M, Safrankova B, Kubala L, The effect of different molecular weight hyaluronan on macrophage physiology: Neuro Endocrinol Lett, 2009; 30(Suppl 1); 106-11, pmid: 20027154
4. Ozkul A, Ayhan M, Yenisey C, The role of oxidative stress and endothelial injury in diabetic neuropathy and neuropathic pain: Neuro Endocrinol Lett, 2010; 31; 261-64, pmid: 20424576
5. Papezikova I, Pekarova M, Lojek A, Kubala L, The effect of uric acid on homocysteine-induced endothelial dysfunction in bovine aortic endothelial cells: Neuro Endocrinol Lett, 2009; 30(Suppl 1); 112-15, pmid: 20027155
6. Xu J, Xu Q, Chen X, Neuronal expression of inducible nitric oxide synthase in hypothyroid rat: Neuro Endocrinol Lett, 2010; 31; 848-51, pmid: 21196918
7. Moncada S, Palmer RMJ, Higgs EA, Nitric oxide: physiology, pathophysiology, and pharmacology: Pharmacol Rev, 1991; 43; 109-42, pmid: 1852778
8. Moncada S, Higgs A, The L-arginine-nitric oxide pathway: New Eng J Med, 1993; 329; 2002-12, pmid: 7504210
9. Murad F, Nitric oxide signaling: would you believe that a simple free radical could be a second messenger, autacoid, paracrine substance, neurotransmitter, and hormone?: Recent Prog Horm Res, 1998; 53; 43-59, pmid: 9769702
10. Denninger JW, Marletta MA, Guanylate cyclase and the NO/cGMP signaling pathway: Biochimi Biophys Acta, 1999; 1411; 334-50
11. Salvemini D, Regulation of cyclooxygenase enzymes by nitric oxide: Cell Mol Life Sci, 1997; 53; 576-82, pmid: 9312403
12. Kream RM, Stefano GB, Endogenous morphine and nitric oxide coupled regulation of mitochondrial processes: Med Sci Monit, 2009; 15(12); RA263-68, pmid: 19946245
13. Esch T, Stefano GB, The neurobiology of stress management: Neuro Endocrinol Lett, 2010; 31; 19-39, pmid: 20150886
14. Mantione KJ, Kream RM, Stefano GB, Variations in critical morphine biosynthesis genes and their potential to influence human health. REVIEW: Neuro Endocrinol Lett, 2010; 31; 11-18, pmid: 20150871
15. Mantione KJ, Angert R, Cadet P, Identification of a μ. Opiate Receptor Signaling Mechanism in Human Placenta: Med Sci Monit, 2010; 16(11); BR347-52, pmid: 20980951
16. Stefano GB, Esch T, Bilfinger TV, Kream RM, Proinflammation and preconditioning protection are part of a common nitric oxide mediated process: Med Sci Monit, 2010; 16(6); RA125-30, pmid: 20512103
17. Cable DG, Celotto AC, Evora PR, Schaff HV, Asymmetric dimethylarginine endogenous inhibition of nitric oxide synthase causes differential vasculature effects: Med Sci Monit, 2009; 15(9); BR248-53, pmid: 19721392
18. Ilic MD, Ilic S, Lazarevic G, Impact of reversible myocardial ischaemia on nitric oxide and asymmetric dimethylarginine production in patients with high risk for coronary heart disease: Med Sci Monit, 2010; 16(9); CR397-404, pmid: 20802410
19. Kocsis GF, Csont T, Varga-Orvos Z, Expression of genes related to oxidative/nitrosative stress in mouse hearts: effect of preconditioning and cholesterol diet: Med Sci Monit, 2010; 16(1); BR32-39, pmid: 20037483
20. Weerateerangkul P, Chattipakorn S, Chattipakorn N, Roles of the nitric oxide signaling pathway in cardiac ischemic preconditioning against myocardial ischemia-reperfusion injury: Med Sci Monit, 2011; 17(2); RA44-52, pmid: 21278703
21. Faraci FM, Heistad DD, Regulation of the cerebral circulation: role of endothelium and potassium channels: Phys Rev, 1998; 78; 53-97
22. Kinoshita H, Tsutsui M, Milstien S, Katusic ZS, Tetrahydrobiopterin, nitric oxide and regulation of cerebral arterial tone: Prog Neurobiol, 1997; 52; 295-302, pmid: 9247967
23. Cooke JP, Dzau VJ, Nitric oxide synthase: role in the genesis of vascular disease: Ann Rev Med, 1997; 48; 489-509, pmid: 9046979
24. Moncada S, Palmer RM, Higgs EA, The discovery of nitric oxide as the endogenous nitrovasodilator: Hypertension, 1988; 12; 365-72, pmid: 3049340
25. Stefano GB, Scharrer B, Smith EM, Opioid and opiate immunoregulatory processes: Crit Rev in Immunol, 1996; 16; 109-44, pmid: 8879941
26. Fimiani C, Mattocks DW, Cavani F, Morphine and anandamide stimulate intracellular calcium transients in human arterial endothelial endothelial cells: coupling to nitric oxide release: Cellular Signaling, 1999; 11; 189-93
27. Stefano GB, Salzet M, Magazine HI, Bilfinger TV, Antagonist of LPS and IFN-g induction of iNOS in human saphenous vein endothelium by morphine and anandamide by nitric oxide inhibition of adenylate cyclase: J Cardiovasc Pharmacol, 1998; 31; 813-20, pmid: 9641464
28. Prevot V, Croix D, Rialas CM, Estradiol coupling to endothelial nitric oxide production stimulates GnRH release from rat median eminence: Endocrinol, 1999; 140; 652-59
29. Mariotto S, Cuzzolin L, Adami A, Inhibition by sodium nitroprusside of the expression of inducible nitric oxide synthase in rat neutrophils: Br J Pharmacol, 1995; 114; 1105-6, pmid: 7542530
30. Colasanti M, Persichini T, Menegazzi M, Induction of nitric oxide synthase mRNA expression. Suppression by exogenous nitric oxide: J Biol Chem, 1995; 270; 26731-33, pmid: 7592903
31. Park SK, Lin HL, Murphy S, Nitric oxide regulates nitric oxide synthase-2 gene expression by inhibiting NF-kappa B binding to DNA: Biochem J, 1997; 322; 609-13, pmid: 9065784
32. Taylor BS, Kim YM, Wang Q, Nitric oxide down-regulates hepatocyte-inducible nitric oxide synthase gene expression: Arch Surg, 1997; 132; 1177-83, pmid: 9366709
33. Togashi H, Sasaki M, Frohman E, Neuronal (type 1) nitric oxide synthase regulates nuclear factor kappa B activity and immunologic (type II) nitric oxide synthase expression: Proc Natl Acad Sci USA, 1997; 94; 2676-80, pmid: 9122255
34. Katsuyama K, Shichiri M, Marumo F, Hirata Y, NO inhibits cytokine-induced iNOS expression and NF-kappaB activation by interfering with phosphorylation and degradation of IkappaB-alpha: Arterioscler Thromb Vasc Biol, 1998; 18; 1796-802, pmid: 9812920
35. Park SK, Lin HL, Murphy S, Nitric oxide limits transcriptional induction of nitric oxide synthase in CNS glial cells: Biochem Biophys Res Commun, 1994; 201; 762-68, pmid: 7516158
36. Magazine HI, Detection of endothelial cell-derived nitric oxide: current trends and future directions: Adv Neuroimmunol, 1995; 5; 479-85, pmid: 8746518
37. Esch T, Stefano GB, The neurobiological link between compassion and love: Med Sci Monit, 2011; 17(3); RA65-75, pmid: 21358615
38. Stefano GB, Kream RM, Mantione KJ, Ptacek R, Endogenous morphine, stress and psychiatric disorders – review of actual findings: J Czech Psychol, 2011 In Press
39. Atmanene C, Laux A, Glattard E, Characterization of human and bovine phosphatidylethanolamine-binding protein (PEBP/RKIP) interactions with morphine and morphine-glucuronides determined by noncovalent mass spectrometry: Med Sci Monit, 2009; 15(7); BR178-187, pmid: 19564817
40. Stefano GB, Esch T, Kream RM, Xenobiotic perturbation of endogenous morphine signaling: paradoxical opiate hyperalgesia: Med Sci Monit, 2009; 15(5); RA107-10, pmid: 19396050
41. Stefano GB, Kream RM, Esch T, Revisiting tolerance from the endogenous morphine perspective: Med Sci Monit, 2009; 15(9); RA189-98, pmid: 19721410
42. Chen Z, Stamler JS, Bioactivation of nitroglycerin by the mitochondrial aldehyde dehydrogenase: Trends Cardiovasc Med, 2006; 16; 259-65, pmid: 17055381
43. Nohl H, Staniek K, Kozlov AV, The existence and significance of a mitochondrial nitrite reductase: Redox Rep, 2005; 10; 281-86, pmid: 16438799
44. Kollau A, Hofer A, Russwurm M, Contribution of aldehyde dehydrogenase to mitochondrial bioactivation of nitroglycerin: evidence for the activation of purified soluble guanylate cyclase through direct formation of nitric oxide: Biochem J, 2005; 385; 769-77, pmid: 15377279
45. Sarti P, Giuffre A, Barone MC, Nitric oxide and cytochrome oxidase: reaction mechanisms from the enzyme to the cell: Free Radic Biol Med, 2003; 34; 509-20, pmid: 12614840
46. Kozlov AV, Staniek K, Nohl H, Nitrite reductase activity is a novel function of mammalian mitochondria: FEBS Lett, 1999; 454; 127-30, pmid: 10413109
47. Basu S, Azarova NA, Font MD, Nitrite reductase activity of cytochrome c: J Biol Chem, 2008; 283; 32590-97, pmid: 18820338
48. Hendgen-Cotta UB, Merx MW, Shiva S, Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury: Proc Natl Acad Sci USA, 2008; 105; 10256-61, pmid: 18632562
49. Maia LB, Moura JJ, Nitrite reduction by xanthine oxidase family enzymes: a new class of nitrite reductases: J Biol Inorg Chem, 2011; 16; 443-60, pmid: 21170563
50. Badejo AM, Hodnette C, Dhaliwal JS, Mitochondrial aldehyde dehydrogenase mediates vasodilator responses of glyceryl trinitrate and sodium nitrite in the pulmonary vascular bed of the rat: Am J Physiol Heart Circ Physiol, 2010; 299; H819-26, pmid: 20543077
51. Huang L, Borniquel S, Lundberg JO, Enhanced xanthine oxidoreductase expression and tissue nitrate reduction in germ free mice: Nitric Oxide, 2010; 22; 191-95, pmid: 20142047
52. Jansson EA, Huang L, Malkey R, A mammalian functional nitrate reductase that regulates nitrite and nitric oxide homeostasis: Nat Chem Biol, 2008; 4; 411-17, pmid: 18516050
53. Shiva S, Huang Z, Grubina R, Deoxymyoglobin is a nitrite reductase that generates nitric oxide and regulates mitochondrial respiration: Circ Res, 2007; 100; 654-61, pmid: 17293481
54. Li H, Samouilov A, Liu X, Zweier JL, Characterization of the magnitude and kinetics of xanthine oxidase-catalyzed nitrate reduction: evaluation of its role in nitrite and nitric oxide generation in anoxic tissues: Biochemistry, 2003; 42; 1150-59, pmid: 12549937
55. Godber BL, Doel JJ, Sapkota GP, Reduction of nitrite to nitric oxide catalyzed by xanthine oxidoreductase: J Biol Chem, 2000; 275; 7757-63, pmid: 10713088
56. Millar TM, Stevens CR, Benjamin N, Xanthine oxidoreductase catalyses the reduction of nitrates and nitrite to nitric oxide under hypoxic conditions: FEBS Lett, 1998; 427; 225-28, pmid: 9607316
57. Golwala NH, Hodenette C, Murthy SN, Vascular responses to nitrite are mediated by xanthine oxidoreductase and mitochondrial aldehyde dehydrogenase in the rat: Can J Physiol Pharmacol, 2009; 87; 1095-101, pmid: 20029546
58. Zuckerbraun BS, Shiva S, Ifedigbo E, Nitrite potently inhibits hypoxic and inflammatory pulmonary arterial hypertension and smooth muscle proliferation via xanthine oxidoreductase-dependent nitric oxide generation: Circulation, 2010; 121; 98-109, pmid: 20026772
59. Isenberg JS, Shiva S, Gladwin M, Thrombospondin-1-CD47 blockade and exogenous nitrite enhance ischemic tissue survival, blood flow and angiogenesis via coupled NO-cGMP pathway activation: Nitric Oxide, 2009; 21; 52-62, pmid: 19481167
60. Casey DB, Badejo AM, Dhaliwal JS, Pulmonary vasodilator responses to sodium nitrite are mediated by an allopurinol-sensitive mechanism in the rat: Am J Physiol Heart Circ Physiol, 2009; 296; H524-33, pmid: 19074675
61. McNulty PH, Scott S, Kehoe V, Nitrite consumption in ischemic rat heart catalyzed by distinct blood-borne and tissue factors: Am J Physiol Heart Circ Physiol, 2008; 295; H2143-48, pmid: 18820031
62. Baker JE, Su J, Fu X, Nitrite confers protection against myocardial infarction: role of xanthine oxidoreductase, NADPH oxidase and K(ATP) channels: J Mol Cell Cardiol, 2007; 43; 437-44, pmid: 17765919
63. Saraiva RM, Minhas KM, Zheng M, Reduced neuronal nitric oxide synthase expression contributes to cardiac oxidative stress and nitroso-redox imbalance in ob/ob mice: Nitric Oxide, 2007; 16; 331-38, pmid: 17307368
64. Tripatara P, Patel NS, Webb A: J Am Soc Nephrol, 2007; 18; 570-80, pmid: 17202421
65. Fujita K, Wada K, Nozaki Y, Serum nitric oxide metabolite as a biomarker of visceral fat accumulation: clinical significance of measurement for nitrate/nitrite: Med Sci Monit, 2011; 17(3); CR123-31, pmid: 21358598
66. Kucukatay V, Hacioglu G, Ozkaya G, The effect of diabetes mellitus on active avoidance learning in rats: the role of nitric oxide: Med Sci Monit, 2009; 15(3); BR88-93, pmid: 19247238
67. Lobo SM, Soriano FG, Barbeiro DF, Effects of dobutamine on gut mucosal nitric oxide production during endotoxic shock in rabbits: Med Sci Monit, 2009; 15(2); BR37-42, pmid: 19179959
68. Klocke R, Mani AR, Moore KP, Inactivation of xanthine oxidoreductase is associated with increased joint swelling and nitrotyrosine formation in acute antigen-induced arthritis: Clin Exp Rheumatol, 2005; 23; 345-50, pmid: 15971422
69. Kelley EE, Batthyany CI, Hundley NJ, Nitro-oleic acid, a novel and irreversible inhibitor of xanthine oxidoreductase: J Biol Chem, 2008; 283; 36176-84, pmid: 18974051
70. Godber BL, Doel JJ, Durgan J, A new route to peroxynitrite: a role for xanthine oxidoreductase: FEBS Lett, 2000; 475; 93-96, pmid: 10858495
71. Webb AJ, Patel N, Loukogeorgakis S, Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite: Hypertension, 2008; 51; 784-90, pmid: 18250365
72. Lu P, Liu F, Yao Z, Nitrite-derived nitric oxide by xanthine oxidoreductase protects the liver against ischemia-reperfusion injury: Hepatobiliary Pancreat Dis Int, 2005; 4; 350-55, pmid: 16109514
73. Duranski MR, Greer JJ, Dejam A: J Clin Invest, 2005; 115; 1232-40, pmid: 15841216
74. Webb A, Bond R, McLean P, Reduction of nitrite to nitric oxide during ischemia protects against myocardial ischemia-reperfusion damage: Proc Natl Acad Sci USA, 2004; 101; 13683-88, pmid: 15347817
75. Berry CE, Hare JM, Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications: J Physiol, 2004; 555; 589-606, pmid: 14694147
76. Aliciguzel Y, Ozen I, Aslan M, Karayalcin U, Activities of xanthine oxidoreductase and antioxidant enzymes in different tissues of diabetic rats: J Lab Clin Med, 2003; 142; 172-77, pmid: 14532905
77. Castello PR, Woo DK, Ball K, Oxygen-regulated isoforms of cytochrome c oxidase have differential effects on its nitric oxide production and on hypoxic signaling: Proc Natl Acad Sci USA, 2008; 105; 8203-8, pmid: 18388202
78. Shiva S, Rassaf T, Patel RP, Gladwin MT, The detection of the nitrite reductase and NO-generating properties of haemoglobin by mitochondrial inhibition: Cardiovasc Res, 2011; 89; 566-73, pmid: 20952414
79. Godber BL, Doel JJ, Goult TA, Suicide inactivation of xanthine oxidoreductase during reduction of inorganic nitrite to nitric oxide: Biochem J, 2001; 358; 325-33, pmid: 11513730
80. Zuckerbraun BS, George P, Gladwin MT, Nitrite in pulmonary arterial hypertension: therapeutic avenues in the setting of dysregulated arginine/nitric oxide synthase signalling: Cardiovasc Res, 2011; 89; 542-52, pmid: 21177703
81. Nossaman VE, Nossaman BD, Kadowitz PJ, Nitrates and nitrites in the treatment of ischemic cardiac disease: Cardiol Rev, 2010; 18; 190-97, pmid: 20539102
82. Tota B, Quintieri AM, Angelone T, The emerging role of nitrite as an endogenous modulator and therapeutic agent of cardiovascular function: Curr Med Chem, 2010; 17; 1915-25, pmid: 20377513
83. Gupta KJ, Igamberdiev AU, Kaiser WM, New insights into the mitochondrial nitric oxide production pathways: Plant Signal Behav, 2010; 5; 999-1001, pmid: 20699641
84. Feelisch M, Fernandez BO, Bryan NS, Tissue processing of nitrite in hypoxia: an intricate interplay of nitric oxide-generating and -scavenging systems: J Biol Chem, 2008; 283; 33927-34, pmid: 18835812
85. Benamar A, Rolletschek H, Borisjuk L, Nitrite-nitric oxide control of mitochondrial respiration at the frontier of anoxia: Biochim Biophys Acta, 2008; 1777; 1268-75, pmid: 18602886
86. Stefano GB, Autoimmunovascular regulation: Morphine and anandamide stimulated nitric oxide release: J Neuroimmunol, 1998; 83; 70-76, pmid: 9610675
87. Stefano GB, Salzet M, Rialas C, Macrophage behavior associated with acute and chronic exposure to HIV GP120, morphine and anandamide: Endothelial implications: Int J Cardiol, 1998; 64; S3-S13, pmid: 9687087
88. Kubes P, Granger DN, Nitric oxide modulates microvascular permeability: Am J Physiol, 1992; 262; H611-15, pmid: 1539722
89. Kubes P, Kanwar S, Niu XF, Nitric oxide synthesis inhibition induces leukocyte adhesion via superoxide and mast cells: FASEB J, 1993; 7; 1293-99, pmid: 8405815
90. Kubes P, Suzuki MM, Granger DN, Nitric oxide an endogenous modulator of leukocyte adhesion: Proc Natl Acad Sci USA, 1991; 88; 4651-55, pmid: 1675786
91. Kurose I, Kubes P, Wolf R, Inhibition of nitric oxide production: Mechanisms of vascular albumin leakage: Circ Res, 1993; 73; 164-71, pmid: 7685251
92. Niu XF, Smith CW, Kubes P, Intracellular oxidative stress induced by nitric oxide synthesis inhibition increases endothelial cell adhesion to neutrophils: Circ Res, 1995; 74; 1133-40, pmid: 7910528
93. Stefano GB, Goumon Y, Bilfinger TV, Basal nitric oxide limits immune, nervous and cardiovascular excitation: Human endothelia express a mu opiate receptor: Progress in Neurobiology, 2000; 60; 513-30, pmid: 10739087
94. Bilfinger TV, Hartman A, Liu Y, Cryopreserved veins in myocardial revascularization: Possible mechanism for their increased failure: Ann Thorac Surg, 1997; 63; 1063-69, pmid: 9124906
95. Bath PMW, Hasall DG, Gladwin AM: Arterioscler Thromb, 1991; 11; 254-60, pmid: 1847823
96. Stefano GB, Salzet M, Bilfinger TV, Long-term exposure of human blood vessels to HIV gp120, morphine and anandamide increases endothelial adhesion of monocytes: Uncoupling of Nitric Oxide: J Cardiovasc Pharmacol, 1998; 31; 862-68, pmid: 9641470
97. Magazine HI, Liu Y, Bilfinger TV, Morphine-induced conformational changes in human monocytes, granulocytes, and endothelial cells and in invertebrate immunocytes and microglia are mediated by nitric oxide: J Immunol, 1996; 156; 4845-50, pmid: 8648133
98. Brown GC, Cooper CE, Nanomolar concentrations of nitric oxide reversibly inhibit synaptosomal respiration by competing with oxygen at cytochrome oxidase: FEBS Letters, 1994; 356; 295-98, pmid: 7805858
99. Brown GC, Nitric oxide and mitochondrial respiration: Biochim Biophys Acta, 1999; 1411; 351-69, pmid: 10320668
100. Ockaili R, Emani VR, Okubo S, Opening of mitochondrial KATP channel induces early and delayed cardioprotective effect: role of nitric oxide: Am J Physiol, 1999; 277; H2425-34, pmid: 10600865
101. Cleeter MW, Cooper JM, Darley-Usmar VM, Reversible inhibition of cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain, by nitric oxide. Implications for neurodegenerative diseases: FEBS Letters, 1994; 345; 50-54, pmid: 8194600
102. Schweizer M, Richter C, Nitric oxide potently and reversibly deenergizes mitochondria at low oxygen tension: Biochem Biophys Res Commun, 1994; 204; 169-75, pmid: 7945356
103. Takehara Y, Kanno T, Yoshioka T, Oxygen-dependent regulation of mitochondrial energy metabolism by nitric oxide: Arch Biochem Biophys, 1995; 323; 27-32, pmid: 7487069
104. Nishikawa M, Sato EF, Kuroki T, Inoue M, Role of glutathione and nitric oxide in the energy metabolism of rat liver mitochondria: FEBS Letters, 1997; 415; 341-45, pmid: 9357996
105. Shen W, Hintze TH, Wolin MS, Nitric oxide. An important signaling mechanism between vascular endothelium and parenchymal cells in the regulation of oxygen consumption: Circulation, 1995; 92; 3505-12, pmid: 8521573
106. Shen W, Xu X, Ochoa M, Role of nitric oxide in the regulation of oxygen consumption in conscious dogs: Circulation Research, 1994; 75; 1086-95, pmid: 7525103
107. Laycock SK, Vogel T, Forfia PR, Role of nitric oxide in the control of renal oxygen consumption and the regulation of chemical work in the kidney: Circulation Research, 1998; 82; 1263-71, pmid: 9648722
108. King CE, Melinyshyn MJ, Mewburn JD, Canine hindlimb blood flow and O2 uptake after inhibition of EDRF/NO synthesis: J Appl Physiol, 1994; 76; 1166-71, pmid: 7516323
109. Ishibashi Y, Duncker DJ, Zhang J, Bache RJ, ATP-sensitive K+ channels, adenosine, and nitric oxide-mediated mechanisms account for coronary vasodilation during exercise: Circulation Research, 1998; 82; 346-59, pmid: 9486663
110. Bates TE, Loesch A, Burnstock G, Clark JB, Mitochondrial nitric oxide synthase: a ubiquitous regulator of oxidative phosphorylation?: Biochem Biophys Res Comm, 1996; 218; 40-44, pmid: 8573169
111. Blokhina O, Fagerstedt KV, Reactive oxygen species and nitric oxide in plant mitochondria: origin and redundant regulatory systems: Physiol Plant, 2010; 138; 447-62, pmid: 20059731
112. Igamberdiev AU, Hill RD, Plant mitochondrial function during anaerobiosis: Ann Bot, 2009; 103; 259-68, pmid: 18586697
113. Stoimenova M, Igamberdiev AU, Gupta KJ, Hill RD, Nitrite-driven anaerobic ATP synthesis in barley and rice root mitochondria: Planta, 2007; 226; 465-74, pmid: 17333252
114. Kollau A, Beretta M, Russwurm M, Mitochondrial nitrite reduction coupled to soluble guanylate cyclase activation: lack of evidence for a role in the bioactivation of nitroglycerin: Nitric Oxide, 2009; 20; 53-60, pmid: 18951990
115. Wright RM, McManaman JL, Repine JE, Alcohol-induced breast cancer: a proposed mechanism: Free Radic Biol Med, 1999; 26; 348-54, pmid: 9895226
116. Maciel ME, Castro GD, Castro JA, Inhibition of the rat breast cytosolic bioactivation of ethanol to acetaldehyde by some plant polyphenols and folic acid: Nutr Cancer, 2004; 49; 94-99, pmid: 15456641
117. Alef MJ, Vallabhaneni R, Carchman E, Nitrite-generated NO circumvents dysregulated arginine/NOS signaling to protect against intimal hyperplasia in Sprague-Dawley rats: J Clin Invest, 2011; 121; 1646-56, pmid: 21436585
118. Cooke JP, Ghebremariam YT, Dietary nitrate, nitric oxide, and restenosis: J Clin Invest, 2011; 121; 1258-60, pmid: 21436578
119. Larsen FJ, Schiffer TA, Borniquel S, Dietary inorganic nitrate improves mitochondrial efficiency in humans: Cell Metab, 2011; 13; 149-59, pmid: 21284982
In Press
Clinical Research
Institutional and Regional Variations in Access to Clinical Trials and Next-Generation Sequencing in Turkis...Med Sci Monit In Press; DOI: 10.12659/MSM.951027
Clinical Research
Low-Intensity Blood Flow-Restricted Multi-Joint Exercise Improves Muscle Function in Patients With Patellof...Med Sci Monit In Press; DOI: 10.12659/MSM.950516
Review article
Musculoskeletal Ultrasound and MRI in the Evaluation of Chemotherapy-Induced Peripheral Neuropathy: A ReviewMed Sci Monit In Press; DOI: 10.12659/MSM.951283
Clinical Research
Sensory Processing, Dissociation, and Affective Symptoms in Misophonia: A Cross-Sectional Study of 35 AdultsMed Sci Monit In Press; DOI: 10.12659/MSM.950938
Most Viewed Current Articles
17 Jan 2024 : Review article 10,187,196
Vaccination Guidelines for Pregnant Women: Addressing COVID-19 and the Omicron VariantDOI :10.12659/MSM.942799
Med Sci Monit 2024; 30:e942799
13 Nov 2021 : Clinical Research 3,708,487
Acceptance of COVID-19 Vaccination and Its Associated Factors Among Cancer Patients Attending the Oncology ...DOI :10.12659/MSM.932788
Med Sci Monit 2021; 27:e932788
14 Dec 2022 : Clinical Research 2,341,643
Prevalence and Variability of Allergen-Specific Immunoglobulin E in Patients with Elevated Tryptase LevelsDOI :10.12659/MSM.937990
Med Sci Monit 2022; 28:e937990
16 May 2023 : Clinical Research 706,524
Electrophysiological Testing for an Auditory Processing Disorder and Reading Performance in 54 School Stude...DOI :10.12659/MSM.940387
Med Sci Monit 2023; 29:e940387