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 mechani sm: the compounds are degraded to release NO under experimental condit ions. We studied the effects of synthesized compounds on the activity of human platelet soluble guanylate cyclase and on ADP-induced platele t aggregation. Among seven derivatives of diazetidine di-N-oxides test ed, four compounds displayed full correspondence between the intensity of activation of platelet guanylate cyclase and inhibition of platele t 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 corr elate with the intensity of activation of guanylate cyclase by these c ompounds. Taken together, the data suggest that the antiaggregatory an d disaggregation-facilitating properties of these compounds are mediat ed by a NO-dependent mechanism which activates guanylate cyclase and i ncreases cGMP levels in platelets. Therefore, the derivatives of 1,2-d iazetidine-1,2-di-N-oxide can be considered as a novel class of antiag gregatory compounds.