Nitric oxide (NO) is produced continuously from the endothelium and plays a pivotal role in the control of vascular tone. Many of the current therapeutic agents that increase blood flow through production of NO have to be taken orally and can produce significant adverse side effects. We now report on some novel NO-donor drugs, based on thiosugars that generate NO spontaneously. From the range of compounds synthesized, D-SNAG (S-nitroso-1-thio-2,3,4,6-tetra-O-acetyl-β-D-glucopyranose) was as effective a vasodilator as any other and, as it was the easiest to synthesize, we undertook a more detailed evaluation to understand the chemistry and mode of action of its vasodilator effect. From the chemical kinetic data, we found that NO release occurred predominantly by thermal decomposition, with a 20-fold increase in decomposition rate between 19 and 37 °C. In the forearm of eight normal male subjects, we found that D-SNAG produced a significant dose-dependent vasodilator effect (P=0.001) with good reproducibility (19%) on repeated testing. We propose that delivery of NO from D-SNAG to the forearm skin microvessels most probably occurs by diffusion across the epidermis. Since such compounds release NO in a non-enzymic manner following topical application, they might produce an attractive therapeutic source of localized NO delivery without inducing systemic side effects.
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November 2003
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Research Article|
November 01 2003
Chemical synthesis and microvascular effects of new nitric oxide donors in humans
Faisel KHAN;
*Vascular Diseases Research Unit, University Department of Medicine, Ninewells Hospital and Medical School, Dundee DD1 9SY, U.K.
Correspondence: Dr Faisel Khan (e-mail [email protected]).
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Russell J. PEARSON;
Russell J. PEARSON
†Centre for Biomolecular Sciences, University of St Andrews, Fife KY16 9ST, U.K.
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David J. NEWTON;
David J. NEWTON
*Vascular Diseases Research Unit, University Department of Medicine, Ninewells Hospital and Medical School, Dundee DD1 9SY, U.K.
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Jill J. F. BELCH;
Jill J. F. BELCH
*Vascular Diseases Research Unit, University Department of Medicine, Ninewells Hospital and Medical School, Dundee DD1 9SY, U.K.
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Anthony R. BUTLER
Anthony R. BUTLER
†Centre for Biomolecular Sciences, University of St Andrews, Fife KY16 9ST, U.K.
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Publisher: Portland Press Ltd
Received:
April 22 2003
Revision Received:
June 19 2003
Accepted:
July 01 2003
Accepted Manuscript online:
July 01 2003
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2003 The Biochemical Society
2003
Clin Sci (Lond) (2003) 105 (5): 577–584.
Article history
Received:
April 22 2003
Revision Received:
June 19 2003
Accepted:
July 01 2003
Accepted Manuscript online:
July 01 2003
Citation
Faisel KHAN, Russell J. PEARSON, David J. NEWTON, Jill J. F. BELCH, Anthony R. BUTLER; Chemical synthesis and microvascular effects of new nitric oxide donors in humans. Clin Sci (Lond) 1 November 2003; 105 (5): 577–584. doi: https://doi.org/10.1042/CS20030144
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