The formation of nitric oxide donors from peroxynitrite.
1. Administration of peroxynitrite (ONOO-, 30-300 microM) caused relaxation of rabbit aortic strips superfused in series in a cascade. The compound responsible for this effect had a half-life greater than 20 s and could not therefore be either nitric oxide (NO) or ONOO- which have half-lives in the order of 1-2 s under these conditions. However the relaxation was inhibited by oxyhaemoglobin, suggesting the compound could be converted to NO in the vascular tissues or in the superfusate. 2. The products of the reactions between ONOO- and Krebs buffer containing 11 mM glucose, but not glucose-free Krebs buffer, caused relaxation of the bioassay tissues. These data suggest that stable NO donor(s) were formed from the reaction of ONOO- with glucose. We therefore prepared these NO donor(s) by the reaction of glucose solutions with ONOO- in order to characterize their ability to release NO. 3. These reaction product(s) caused relaxation in the cascade and inhibition of platelet aggregation. Both effects were dependent on the concentration of D-glucose, were equally effective if L-glucose was used as a reactant and were reversed by oxyhaemoglobin. 3. The products of the reaction between ONOO- and glucose or other biological molecules containing an alcohol functional group, such as fructose, glycerol, or glyceraldehyde, released NO in the presence of Cu2+and L-cysteine. 5. These results indicate that ONOO- reacts with sugars or other compounds containing an alcohol functional group(s) to form NO donors with the characteristics of organic nitrate/nitrites. This may represent a further detoxification pathway for ONOO- in vivo.
Moro
M A
MA
Wellcome Research Laboratories, Beckenham, Kent.
Darley-Usmar
V M
VM
Lizasoain
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I
Su
Y
Y
Knowles
R G
RG
Radomski
M W
MW
Moncada
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S
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000737:chemistry / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009566:Nitrates / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D018384:Oxidative Stress; D010108:Oxyhemoglobins / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D011817:Rabbits; D013237:Stereoisomerism
D009566:Nitrates; D010108:Oxyhemoglobins; D010975:Platelet Aggregation Inhibitors; C039642:peroxynitric acid; D009569:Nitric Oxide; D005947:Glucose