The University of Southampton
University of Southampton Institutional Repository

On the mechanism of NO release from sydnonimines

Record type: Article

SUMMARY: The vasodilator and antiaggregatory properties of sydnonimines like SIN-1 are thought to be due to their marked stimulatory action on soluble guanylate cyclase. Enzyme activation and consecutive cyclic GMP accumulation is mediated by the liberation of nitric oxide (NO) from the open-ring A forms of sydnonimines. The purpose of the present study was to investigate the mechanism of NO release from sydnonimines in direct comparison to their stimulatory effect at the target enzyme, soluble guanylate cyclase. All sydnonimines tested were found to spontaneously liberate NO, the rate of which closely correlated with the extent of enzyme activation. NO release occurred nonlinearly with time and became maximal at high sydnonimine concentration. The in vitro stability of the A forms neither correlated with the measured rate of NO release nor with enzyme activation, indicating that a direct stimulation of guanylate cyclase by the A forms is rather unlikely. Besides NO, all sydnonimines generated NO2- and NO3- at a nearly equimolar rate. The addition of cysteine induced a marked shift from NO3- to NO2- with a small reduction in NO release, which is paralleled by a weak rightward shift of the EC50 at the guanylate cyclase. All tested sydnonimines were found to consume molecular oxygen at rates that closely corresponded to the measured rates of NO formation. By a molar comparison, the amounts of consumed oxygen are clearly higher, as would be expected for the oxidative conversion of NO to NO2- and NO3-. Oxygen seems to be additionally involved in the induction of NO formation while being converted to superoxide (O2-). In accordance with an autocatalytic processs, O2- further enhances sydnonimine decomposition, since in the presence of superoxide dismutase (SOD) the rate of SIN-1C and NO2-/NO3- formation from SIN-1 A was reduced, whereas the rate of NO liberation seemingly increased. O2- has, however, no influence on the rate of hydrolysis of SIN-1 to SIN-1 A. At the level of guanylate cyclase, the presence of SOD induced a leftward shift of the concentration-response curve to SIN-1, in agreement with an enhancement of efficacy of NO by blocking the NO-scavenging effect of O2-. An additional O2- generation markedly enhanced SIN-1 A decomposition to NO2-/NO3- and reduced the apparent rate of NO formation. We conclude from our results that oxygen plays a key role in the decomposition of sydnonimines and thus in the formation of NO as their pharmacodynamically active principle. Oxygen attack most probably occurs by one-electron abstraction from the A form of the respective sydnonimine compound. Oxygen is thereby converted to O2- while the radical cation of the sydnonimine A form decomposes with the release of NO. Sydnonimines such as SIN-1 thus not only appear to be donors of EDRF by releasing NO but also of EDCF while simultaneously producing O2-, a behavior that has recently been demonstrated for endothelial cells, activated macrophages, and neutrophils.

PDF 1989 Feelisch-SIN-1-JCP.PDF - Other
Download (1MB)

Citation

Feelisch, Martin, Ostrowski, J. and Noack, E. (1989) On the mechanism of NO release from sydnonimines Journal of Cardiovascular Pharmacology, 14, supplement 11, S13-S22. (PMID:2484692).

More information

Published date: 1989
Keywords: nitric oxide (NO EDRF), sydnonimine, SIN-1, oxygen, superoxide (EDCF), guanylate cyclase
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 337920
URI: http://eprints.soton.ac.uk/id/eprint/337920
ISSN: 0160-2446
PURE UUID: 2a611bd0-bac4-47df-9328-fd1dbe07b60e
ORCID for Martin Feelisch: ORCID iD orcid.org/0000-0003-2320-1158

Catalogue record

Date deposited: 17 May 2012 15:02
Last modified: 18 Jul 2017 06:00

Export record

Contributors

Author: Martin Feelisch ORCID iD
Author: J. Ostrowski
Author: E. Noack

University divisions


Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×