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Mechanisms of nitric oxide release from organic nitrates and nitrites: implications on the activation of soluble guanylyl cyclase and inhibition of lipid peroxidation [dissertation]

Domenii publicaţii > Ştiinţe medicale + Tipuri publicaţii > Carte

Autori: Nicolescu A. C

Editorial: National Library of Canada, Ottawa, Queen's University, Theses (Ph.D.), p.293 pp., 2004.


Organic nitrates and nitrites are used in cardiovascular therapy as vasodilators. They are supposedly biotransformed to nitric oxide (NO), which activates soluble guanylyl cyclase (sGC) – the enzyme responsible for their biological activity. Organic nitrites are potential intermediates in the transformation of nitrates to NO. NO appears to have both cytoprotective and cytotoxic properties. In the brain, NO might be cytoprotective by increasing the levels of cyclic guanosine-3′,5′-monophosphate (cGMP), and by scavenging reactive oxygen species (ROS) that initiate lipid peroxidation. The effect of a series of novel nitrates, SS-nitrates, on sGC has been studied and compared to that produced by nitroglycerin (GTN). The oxidation of oxyhemoglobin (oxy-Hb) by SS-nitrates in the presence and absence of cysteine also has been analyzed. The effect of SS-nitrates, simple alkyl nitrites and diazenium diolates (NONOates) on lipid peroxidation has been studied in a variety of systems. The activation of sGC was assessedusing a supernatant fraction of rat aorta homogenate as source for the enzyme. Inhibition of lipid peroxidation was assessed using (i) iron-induced lipid peroxidation in rat cerebrocortical synaptosomes and (ii) azo-initiator induced lipid peroxidation in liposomes and linoleic acid sodium dodecyl sulfate (SDS) micelles. Lipid peroxidation was quantified by thiobarbituric acid-reactive substances (TBARS), spectrofluorometric and oxygen pressure transducer analysis. SS-nitrates released NO in neutral aqueous solution either spontaneously or in the presence of cysteine as assessed by chemiluminescence detection. SS-nitrates activated sGC in the presence and absence of cysteine, demonstrating higher efficacy than GTN. Linear correlations between the Hammett parameter sigma-p and the efficacy of sGC activation and the rates of oxy-Hb oxidation by SS-nitrates in the presence of cysteine were found. These results suggest that SS-nitrates may act via mixed NO-dependent and NO-independent mechanisms. In contrast to GTN, SS-nitrates inhibited lipid peroxidation. NONOates showed a linear correlation between the rates of NO release and the inhibitor potency of lipid peroxidation, which is compatible with an inhibition of lipid peroxidation via NO. For nitrites, no correlation was found between the rates of NO release and their inhibition potency. These results suggest that the inhibition of lipid peroxidation by organic nitrites may occur through mechanisms other than that involving the release of NO. Analysis of the aldehyde products for the reaction of i-amyl nitrite and the peroxyl radical source 2,2′-azobis(2-methylpropionamidine) dihydrochloride by peroxyl radicals.

Cuvinte cheie: Antioxidants, Nitric Oxide, Lipid peroxidation, Reactive Oxygen Species