Formation of Reactive Oxygen Species in Various Vascular Cells During Glyceryltrinitrate Metabolism

Dikalov, Sergey; Fink, Bruno; Skatchkov, M.; Sommer, Olaf; Bassenge, E.

doi:10.1177/107424849800300107

Cited by 38 publications

(24 citation statements)

References 58 publications

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“…Local redox poise might be another factor. Tissue antioxidant content has been shown to influence constitutive nitroso͞nitrosyl levels (15), and GTN biotransformation can stimulate the production of superoxide anions, whose avid reactivity with NO is believed to contribute to nitrovasodilator tolerance and pathological NO insufficiency (39). Evaluation of the extent to which these and other factors govern the tissue-specific dynamics of the GTN NObonome awaits further study.…”

Section: Discussionmentioning

confidence: 99%

Differential nitros(yl)ation of blood and tissue constituents during glyceryl trinitrate biotransformation in vivo

Janero

Bryan

Saijo

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Nitric oxide (NO)-derived products may modify tissue constituents, forming S-and N-nitroso adducts and metal nitrosyls implicated in NO signaling. Nitrovasodilator drugs have been in widespread use for more than a century, yet their biotransformation pathways to NO and their effects as NO donors across tissues remain ill defined. By using a metabonomics approach (termed ''NObonomics'') for detailing the global NO-related metabolism of the cornerstone nitrovasodilator, glyceryl trinitrate (GTN; 0.1-100 mg͞kg), in the rat in vivo, we find that GTN biotransformation elicits extensive tissue nitros(yl)ation throughout all major organ systems. The corresponding reaction products remained detectable hours after administration, and vascular tissue was not a major nitros(yl)ation site. Extensive heart and liver modifications involved both S-and N-nitrosation, and RBC S-nitrosothiol formation emerged as a sensitive indicator of organic nitrate metabolism. The dynamics of GTN-derived oxidative NO metabolites in blood did not reflect the nitros(yl)ation patterns in the circulation or in tissues, casting doubt on the usefulness of plasma nitrite͞nitrate as an index of NO͞NO-donor biodynamics. Target-tissue NO metabolites varied in amount and type with GTN dose, suggesting a dose-sensitive shift in the prevailing routes of GTN biotransformation (''metabolic shunting'') from thiol nitrosation to heme nitrosylation. We further demonstrate that GTN-induced nitros(yl)ation is modulated by a complex, tissue-selective interplay of enzyme-catalyzed pathways. These findings provide insight into the global in vivo metabolism of GTN at pharmacologically relevant doses and offer an additional experimental paradigm for the NObonomic analysis of NO-donor metabolism and signaling.nitric oxide ͉ nitrosylheme ͉ nitrosothiols ͉ metabonomics N itric oxide (NO) regulates diverse aspects of mammalian physiology by enhancing cGMP production through soluble guanylyl cyclase activation (1). This classic signal transduction mechanism notwithstanding, NO's highly reactive, diffusible nature fosters an extensive chemical biology in vivo that influences gene expression, mitochondrial respiration, and drug metabolism; induces posttranslational protein modification; and generates numerous NO-derived metabolites (2, 3) (collectively referred to herein as the NO metabonome or ''NObonome'').¶ Some of these metabolites have been implicated in NO's beneficial and pathological effects (2, 3). Recent demonstration that constitutive thiol, amine, and heme nitros(yl)ation in mammalian tissues generates, respectively, S-nitrosothiols (RSNOs), N-nitroso compounds (RNNOs), and nitrosylheme (NO-heme) species suggests new signaling pathways through which nitrogen oxides might influence cell physiology by covalently modifying tissue biomolecules (3,5). Given the mounting evidence that thiol nitrosation modulates cell function (6), it is a matter of great interest to identify the biological targets of NO-dependent modification, the mechanism(s) responsible, and the dis...

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Section: Discussionmentioning

confidence: 99%

Differential nitros(yl)ation of blood and tissue constituents during glyceryl trinitrate biotransformation in vivo

Janero

Bryan

Saijo

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…An unavoidable superoxide source may be GTN itself, which was shown to trigger superoxide formation in blood vessels, thereby limiting vascular NO bioavailability (33)(34)(35). In addition, we found that DTT, which was present to minimize mechanism-based oxidative ALDH inactivation, caused rapid consumption of authentic (DEA/NO-derived) NO that was prevented by superoxide dismutase.…”

Section: Discussionmentioning

confidence: 99%

Bioactivation of Nitroglycerin by Purified Mitochondrial and Cytosolic Aldehyde Dehydrogenases

Beretta

Gruber

Kollau

et al. 2008

Journal of Biological Chemistry

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Metabolism of nitroglycerin (GTN) to 1,2-glycerol dinitrate (GDN) and nitrite by mitochondrial aldehyde dehydrogenase (ALDH2) is essentially involved in GTN bioactivation resulting in cyclic GMP-mediated vascular relaxation. The link between nitrite formation and activation of soluble guanylate cyclase (sGC) is still unclear. To test the hypothesis that the ALDH2 reaction is sufficient for GTN bioactivation, we measured GTNinduced formation of cGMP by purified sGC in the presence of purified ALDH2 and used a Clark-type electrode to probe for nitric oxide (NO) formation. In addition, we studied whether GTN bioactivation is a specific feature of ALDH2 or is also catalyzed by the cytosolic isoform (ALDH1). Purified ALDH1 and ALDH2 metabolized GTN to 1,2-and 1,3-GDN with predominant formation of the 1,2-isomer that was inhibited by chloral hydrate (ALDH1 and ALDH2) and daidzin (ALDH2). GTN had no effect on sGC activity in the presence of bovine serum albumin but caused pronounced cGMP accumulation in the presence of ALDH1 or ALDH2. The effects of the ALDH isoforms were dependent on the amount of added protein and, like 1,2-GDN formation, were sensitive to ALDH inhibitors. GTN caused biphasic sGC activation with apparent EC 50 values of 42 ؎ 2.9 and 3.1 ؎ 0.4 M in the presence of ALDH1 and ALDH2, respectively. Incubation of ALDH1 or ALDH2 with GTN resulted in sustained, chloral hydrate-sensitive formation of NO. These data may explain the coupling of ALDH2-catalyzed GTN metabolism to sGC activation in vascular smooth muscle.

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“…While the means by which ascorbate prevents tolerance remain to be determined, others have suggested that Vit-C could ( a ) directly affect superoxide production by the NADPH oxidoreductase; ( b ) scavenge superoxide directly, and thereby decrease nitric oxide inactivation; ( c ) increase ni- trosothiol formation by protecting plasma thiols from oxidation; and ( d ) suppress peroxynitrite-mediated inactivation of target enzymes (4,7,(13)(14)(15)(16)(17)(27)(28)(29). Other factors, including possible effects on GTN biotransformation, the neurohumoral axis, prostacyclin generation, leukocyte aggregation, oxidized LDL generation, or platelet-activating factor mimetics, cannot be ruled out (30)(31)(32)(33)(34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

Dietary supplement with vitamin C prevents nitrate tolerance.

Bassenge¹,

Fink²,

Skatchkov³

et al. 1998

J. Clin. Invest.

129

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Enhanced formation of superoxide radicals has been proposed to play a major role in the development of nitrate tolerance in humans. We tested the effects of vitamin C (Vit-C) supplementation on glyceroltrinitrate (GTN)-induced hemodynamic effects during 3-d nonintermittent transdermal administration of GTN (0.4 mg/h) in nine healthy subjects. Tolerance development was monitored by changes in arterial pressure, dicrotic digital pulse pressure, and heart rate. Studies with GTN, Vit-C, or GTN/Vit-C were successively carried out at random in three different series in the same subjects. GTN treatment caused an immediate rise in arterial conductivity (a/b ratio of dicrotic pulse), but within 2 d of initiating GTN, the a/b ratio progressively decreased and reached basal levels. In addition, there was a progressive loss of the orthostatic decrease in blood pressure. However, coadministration of Vit-C and GTN fully maintained the GTN-induced changes in the orthostatic blood pressure, and the rise of a/b ratio was augmented by 310% for the duration of the test period. Changes in vascular tolerance in GTN-treated subjects were paralleled by upregulation of the activity of isolated platelets, which was also reversed by

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Formation of Reactive Oxygen Species in Various Vascular Cells During Glyceryltrinitrate Metabolism

Cited by 38 publications

References 58 publications

Differential nitros(yl)ation of blood and tissue constituents during glyceryl trinitrate biotransformation in vivo

Differential nitros(yl)ation of blood and tissue constituents during glyceryl trinitrate biotransformation in vivo

Bioactivation of Nitroglycerin by Purified Mitochondrial and Cytosolic Aldehyde Dehydrogenases

Dietary supplement with vitamin C prevents nitrate tolerance.

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