NO problem for nitroglycerin: organic nitrate chemistry and therapy

Thatcher, Gregory R. J.

doi:10.1039/a827331z

Cited by 70 publications

(86 citation statements)

References 32 publications

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“…It has been accepted by many that nitrovasodilators, including the organic nitrates like nitroglycerin (GTN), cause vasodilation by their biotransformation to NO. Although many pathways invoking a variety of enzymes and different intermediates have been proposed to be involved in the biotransformation of GTN to NO, none have conclusively described the mechanism of action of GTN (10,11). Even the evidence for NO production from GTN is confounded by assays not sufficiently specific for NO (12)(13)(14).…”

mentioning

confidence: 99%

Effects of Nitroglycerin on Soluble Guanylate Cyclase

Artz¹,

Schmidt²,

McCracken³

et al. 2002

Journal of Biological Chemistry

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Soluble guanylate cyclase (sGC) is a heterodimeric hemoprotein that catalyzes the conversion of GTP to cGMP. Upon binding NO to its heme cofactor, purified sGC was activated 300-fold. sGC was only activated 67-fold by nitroglycerin (GTN) and Cys; and in the absence of Cys, GTN did not activate sGC. Electronic absorption spectroscopy studies showed that upon NO binding, the Soret of ferrous sGC shifted from 431 to 399 nm. The data also revealed that activation of sGC by GTN/Cys was not via the expected ferrous heme-NO species as indicated by the absence of the 399 nm heme Soret. Furthermore, EPR studies of the reaction of GTN/Cys with sGC confirmed that no ferrous heme-NO species was formed but that there was heme oxidation. Potassium ferricyanide is known to oxidize ferrous sGC to the ferric oxidation state. Spectroscopic and activity data for the reactions of sGC with GTN alone or with K 3 Fe(CN) 6 were indistinguishable. These data suggest the following: 1) GTN/Cys do not activate sGC via GTN biotransformation to NO in vitro, and 2) in the absence of added thiol, GTN oxidizes sGC.

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mentioning

confidence: 99%

Effects of Nitroglycerin on Soluble Guanylate Cyclase

Artz¹,

Schmidt²,

McCracken³

et al. 2002

Journal of Biological Chemistry

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“…Al though only disulfide R´S-SR´ and NO 2 -were found as the reaction products of nitrate RO-NO 2 with thiols R´SH, it has been suggested that the reaction proceeds via intermediate cysteine thionitrate R´S-NO 2 . 9, 10 In the present study, we demonstrated that this reaction does proceed in two steps via intermediate cysteine thionitrate.…”

Section: Resultsmentioning

confidence: 93%

“…(10) In the review, 10 the possibility of the production of NO from sulfenyl nitrite through homolytic decomposi tion was discussed. In some cases (most likely, this is associated with a decrease in pH to values lower than neutral pH or in the case of tert butyl nitrate), a small amount of NO was detected in the reaction of nitrates with thiols.…”

Section: R´s-no 2 + Hbmentioning

confidence: 99%

Reduction of nitrates, the no donors, by hemoglobin in the presence of cysteine

et al. 2007

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Hemoglobin (Hb) reduces 3,3 bis(nitroxymethyl)oxetane (NMO) only in the presence of cysteine (Cys) via intermediate cysteine thionitrate. The kinetics of the reaction of NMO with Cys and the kinetics and mechanism of formation of NO in the ternary system Hb-NMO-Cys were studied. The formation rate of Hb-NO in the ternary system is higher than that of Hb-NO in the reaction of Hb only with NO 2 -generated in the binary system NMO-Cys. The second order rate constants of the main reaction steps in the system Hb-NMO-Cys were estimated by simulating the kinetics of the reactions with a system of equations taking into account equilibria between all components of the reaction mixture. Hemoglobin reduces cysteine thionitrate, the intermediate in the reaction of NMO with Cys, to NO.

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“…Organic nitrates containing a sulfur atom at β-position to a nitrate group were originally termed as "SS-nitrates," 20) and they were designed to prove the hypothesized sulfhydryl-dependent mechanism of NO release from organic nitrates such as glyceryl trinitrate (GTN). 21,22) Such 'SS-nitrates' exhibited good stability in neutral aqueous solution but released significant amounts of NO in aqueous medium at biologically relevant pH on addition of sulfhydryl-containing compounds. 20) By partly adopting this "SS-nitrate" feature into our disulfide-linker containing prodrug strategy, 7) we have designed, synthesized and evaluated NO-NSAID prodrugs that contain a NO-releasing nitrate moiety at β-position to the disulfide group, which is, in turn, covalently bonded through "CH 2 CH 2 " chain to the carboxyl group of parent NSAIDs via linkages such as an ester (compounds 9-16), a double ester (compounds 17-24), an imide (compounds 25-30) or an amide (compounds 31-33) as shown in Fig.…”

Section: No-nsaid Designmentioning

confidence: 99%