INHIBITION OF AGGREGATION OF HUMAN PLATELETS BY A NEW CLASS OF SOLUBLE GUANYLATE-CYCLASE ACTIVATORS GENERATING NITRIC-OXIDE

Derivatives of diazetidine di-N-oxides are a novel class of compounds capable of generating nitric oxide (NO) by a new, nonenzymatic mechanism: the compounds are degraded to release NO under experimental conditions. We studied the effects of synthesized compounds on the activity of human platelet soluble guanylate cyclase and on ADP-induced platelet aggregation. Among seven derivatives of diazetidine di-N-oxides tested, four compounds displayed full correspondence between the intensity of activation of platelet guanylate cyclase and inhibition of platelet aggregation. The compounds also accelerated platelet disaggregation. They are degraded under the experimental conditions with the release of NO. The amounts of NO generated in this reaction were shown to correlate with the intensity of activation of guanylate cyclase by these compounds. Taken together, the data suggest that the antiaggregatory and disaggregation-facilitating properties of these compounds are mediated by a NO-dependent mechanism which activates guanylate cyclase and increases cGMP levels in platelets. Therefore, the derivatives of 1,2-diazetidine-1,2-di-N-oxide can be considered as a novel class of antiaggregatory compounds.