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Thiol-mediated generation of nitric oxide accounts for the vasodilator action of furoxans

Record type: Article

Furoxans (1,2,5-oxadiazole-2-oxides) are widely used in organic chemistry as intermediate compounds for the synthesis of various heterocycles. Despite the fact that some furoxans have been found to possess remarkable biological activities, up to now no systematic study on their mode of action has been reported. The aim of the present study was to investigate the molecular mode of the vasodilator action of furoxans. Furoxans, but not the corresponding furazans, concentration-dependently increased coronary flow in an isolated working rat heart preparation. This effect was blunted upon coinfusion with methylene blue. All tested furoxans were demonstrated to increase potently the activity of soluble guanylate cyclase. Enzyme stimulation was found to be mediated by the generation of nitric oxide (NO) following chemical reaction of the furoxans with sulfhydryl groups of low molecular weight thiols and proteins. Furoxans are thus prodrugs which increase the level of cyclic GMP via formation of NO and may therefore be classified as nitrovasodilators. Along with the generation of NO, nitrite and nitrate ions and S-nitrosothiols were formed. The rates of formation of these metabolites, however, did not appear to be related to enzyme stimulation. A tentative reaction scheme that fits the obtained experimental data is proposed. Recently reported cytotoxic, mutagenic, immunosuppressive and anticancer effects of furoxans are discussed in the light of their ability to release NO upon reaction with thiols.

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Citation

Feelisch, Martin, Schönafingeri, Karl and Noack, Eike (1992) Thiol-mediated generation of nitric oxide accounts for the vasodilator action of furoxans Biochemical Pharmacology, 44, (6), pp. 1149-1157. (doi:10.1016/0006-2952(92)90379-w). (PMID:1358072).

More information

Published date: 25 September 1992
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 337912
URI: http://eprints.soton.ac.uk/id/eprint/337912
ISSN: 0006-2952
PURE UUID: fe8e3c21-df73-44af-9a1c-dcc17ac7125d
ORCID for Martin Feelisch: ORCID iD orcid.org/0000-0003-2320-1158

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Date deposited: 20 Jun 2012 11:58
Last modified: 18 Jul 2017 06:00

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Contributors

Author: Martin Feelisch ORCID iD
Author: Karl Schönafingeri
Author: Eike Noack

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