Chemical synthesis and microvascular effects of new nitric oxide donors in humans.
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-beta-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 degrees 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.
Khan
Faisel
F
Vascular Diseases Research Unit, University Department of Medicine, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. f.khan@dundee.ac.uk
Pearson
Russell J
RJ
Newton
David J
DJ
Belch
Jill J F
JJ
Butler
Anthony R
AR
D000328:Adult; D000704:Analysis of Variance; D004305:Dose-Response Relationship, Drug; D005542:Forearm / Q000098:blood supply; D006358:Hot Temperature; D006801:Humans; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D020030:Nitric Oxide Donors / Q000138:chemical synthesis* / Q000494:pharmacology*; D012039:Regional Blood Flow / Q000187:drug effects; D013863:Thioglucosides / Q000138:chemical synthesis* / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000138:chemical synthesis* / Q000494:pharmacology*
D020030:Nitric Oxide Donors; C481163:S-nitroso-1-thio-2,3,4,6-tetra-O-acetyl-beta-D-glucopyranose; D013863:Thioglucosides; D014665:Vasodilator Agents