THE ROLE OF CGMP IN THE ANTI-AGGREGATING PROPERTIES OF BY-1949, A NOVEL DIBENZOXAZEPINE DERIVATIVE

The anti-aggregatory activity of a novel agent, BY-1949, 3-methoxy-11-methyldibenz (b,f) (1,4) oxazepine-8-carboxylic acid, was examined using rabbit platelets. Oral administration of BY-1949 (10 or 30 mg/kg) inhibited platelet aggregation induced by ADP, collagen, and arachidonate in a dose-related fashion. In in vitro studies, however, neither BY-1949 nor its major metabolites inhibited platelet aggregation, even at a concentration similar to that attained in plasma in vivo. With regard to the anti-aggregatory action of BY-1949, biochemical analysis revealed that BY-1949 preferentially augmented cyclic GMP (cGMP) formation, via inhibition of phosphodiesterase activity, without altering cyclic AMP (cAMP) formation. Furthermore, the in vitro anti-aggregatory activity was significantly enhanced when the platelets were concomitantly treated with nitric oxide (NO). Based on these results, it is suggested that the in vivo anti-aggregatory effects of BY-1949 are at least partly elicited via platelet/endothelium interactions, in which cGMP plays a pivotal role.