Reduction of Organic Nitrites to Nitric Oxide Catalyzed by Xanthine Oxidase: Possible Role in Metabolism of Nitrovasodilators

Doel, Justin J.; Godber, Ben; Goult, Tracey A.; Eisenthal, Robert; Harrison, Roger

doi:10.1006/bbrc.2000.2534

Cited by 47 publications

(30 citation statements)

References 38 publications

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“…Harrison has also shown that nitric oxide formation results from reduction of nitrites, both inorganic [16,31] and organic [32], catalyzed by xanthine oxidoreductase. Activity of xanthine oxidase and xanthine dehydrogenase is increased by nitrite during ischemic conditions, where oxygen and pH are reduced, but not during aerobic conditions.…”

Section: Discussionmentioning

confidence: 99%

Nitrite confers protection against myocardial infarction: Role of xanthine oxidoreductase, NADPH oxidase and KATP channels

Baker

et al. 2007

Journal of Molecular and Cellular Cardiology

120

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Reduction of nitrite to nitric oxide during ischemia protects the heart against injury from ischemia/ reperfusion. However the optimal dose of nitrite and the mechanisms underlying nitrite-induced cardioprotection are not known. We determined the ability of nitrite and nitrate to confer protection against myocardial infarction in two rat models of ischemia/reperfusion injury and the role of xanthine oxidoreductase, NADPH oxidase, nitric oxide synthase and K ATP channels in mediating nitrite-induced cardioprotection. In vivo and in vitro rat models of myocardial ischemia/reperfusion injury were used to cause infarction. Hearts (n=6/group) were treated with nitrite or nitrate for 15 min prior to 30 min regional ischemia and 180 min reperfusion. Xanthine oxidoreductase activity was measured after 15 min aerobic perfusion and 30 min ischemia. Nitrite reduced myocardial necrosis and decline in ventricular function following ischemia/reperfusion in the intact and isolated rat heart in a dose or concentration-dependent manner with an optimal dose of 4 mg/kg in vivo and concentration of 10 μM in vitro. Nitrate had no effect on protection. Reduction in infarction by nitrite was abolished by inhibition of flavoprotein reductases and the molybdenum site of xanthine oxidoreductase, and was associated with an increase in activity of xanthine dehydrogenase and xanthine oxidase during ischemia. Inhibition of nitric oxide synthase had no effect on nitrite-induced cardioprotection. Inhibition of NADPH oxidase and K ATP channels abolished nitrite-induced cardioprotection. Nitrite but not nitrate protects against infarction by a mechanism involving xanthine oxidoreductase, NADPH oxidase and K ATP channels.

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Section: Discussionmentioning

confidence: 99%

Nitrite confers protection against myocardial infarction: Role of xanthine oxidoreductase, NADPH oxidase and KATP channels

Baker

et al. 2007

Journal of Molecular and Cellular Cardiology

120

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“…Nevertheless, several proteins have been shown to mediate the denitration of GTN to generate the biotransformation products 1,2-GDN, 1,3-GDN, and NO 2 Ϫ , including hemoglobin, myoglobin, xanthine oxidoreductase, old yellow enzyme, glutathione S-transferase, cytochromes P450, and cytochrome P450 reductase (Habig et al, 1975;McDonald and Bennett, 1990;McGuire et al, 1998;Doel et al, 2000;Ratz et al, 2000b;Meah et al, 2001). Given the fundamental chemistry underlying these reactions, many other enzymes and proteins containing transition metals or cysteine groups may be involved in nitrate metabolism.…”

Section: Discussionmentioning

confidence: 99%

Role of Mitochondrial Aldehyde Dehydrogenase in Nitrate Tolerance

DiFabio¹,

Ji²,

Vasiliou³

et al. 2003

Mol Pharmacol

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Glyceryl trinitrate (GTN) is used in the treatment of angina pectoris and cardiac failure, but the rapid onset of GTN tolerance limits its clinical utility. Research suggests that a principal cause of tolerance is inhibition of an enzyme responsible for the production of physiologically active concentrations of NO from GTN. This enzyme has not conclusively been identified. However, the mitochondrial aldehyde dehydrogenase (ALDH2) is inhibited in GTN-tolerant tissues and produces NO 2 Ϫ from GTN, which is proposed to be converted to NO within mitochondria. To investigate the role of this enzyme in GTN tolerance, cumulative GTN concentration-response curves were obtained for both GTN-tolerant and -nontolerant rat aortic rings treated with the ALDH inhibitor cyanamide or the ALDH substrate propionaldehyde. Tolerance to GTN was induced using both in vivo and in vitro protocols. The in vivo protocol resulted in almost complete inhibition of ALDH2 activity and GTN biotransformation in hepatic mitochondria, indicating that long-term GTN exposure results in inactivation of the enzyme. Treatment with cyanamide or propionaldehyde caused a dose-dependent increase in the EC 50 value for GTN-induced relaxation of similar magnitude in both tolerant and nontolerant aorta, suggesting that although cyanamide and propionaldehyde inhibit GTN-induced vasodilation, these inhibitors do not affect the enzyme or system involved in tolerance development to GTN. Treatment with cyanamide or propionaldehyde did not significantly inhibit 1,1-diethyl-2-hydroxy-2-nitrosohydrazine-mediated vasodilation in tolerant or nontolerant aorta, indicating that these ALDH inhibitors do not affect the downstream effectors of NO-induced vasodilation. Immunoblot analysis indicated that the majority of vascular ALDH2 is present in the cytoplasm, suggesting that mitochondrial biotransformation of GTN by ALDH2 plays a minor role in the overall vascular biotransformation of GTN by this enzyme.Most current hypotheses on the mechanism of action of organic nitrates consider that these compounds act as prodrugs, in that they undergo mechanism-based biotransformation in vascular smooth muscle cells to an activator of soluble guanylyl cyclase (sGC) (presumed to be NO or a related species) ). The term clearance-based biotransformation has been coined to differentiate pathways that lead to nitrate metabolism without activation of sGC . The biotransformation of glyceryl trinitrate (GTN, nitroglycerin) yields the dinitrate metabolites glyceryl-1,2-dinitrate (1,2-GDN) and glyceryl-1,3-dinitrate (1,3-GDN) as products, and in nitrate-tolerant tissues, the biotransformation of GTN is attenuated. Formation of NO using high concentrations of GTN has been demonstrated in intact and broken cell preparations, but an enzyme in vascular smooth muscle that catalyzes the three-electron reduction of the nitrate ester group of organic nitrates to NO has not been identified (Thatcher and Weldon, 1998). Several enzymes, however, have been identified that are capable of mediating...

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“…63 Interestingly, XOR is able to catalyze the reduction of nitrites to NO under experimental conditions, which has led to the suggestion that XOR may be involved in the vasodilator activity of nitrate drugs, including isosorbide dinitrate and nitroglycerin. 64 However, this has not been demonstrated under physiological conditions. Further cross-talk between these 2 systems is suggested by the observation that NO may regulate XOR activity.…”

Section: Interactions Between Ros and Rnsmentioning

confidence: 96%