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.
Aono
J
J
Department of Pharmacology, Chugai Pharmaceutical Company, Ltd., Shizuoka, Japan.
Sugawa
M
M
Koide
T
T
Takato
M
M
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000096:biosynthesis / Q000502:physiology*; D003989:Dibenzoxazepines / Q000378:metabolism / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011817:Rabbits
D003989:Dibenzoxazepines; D010975:Platelet Aggregation Inhibitors; D009569:Nitric Oxide; C058844:3-methoxy-11-methyldibenz(b,f)oxazepine-8-carboxylate; D000242:Cyclic AMP; D006152:Cyclic GMP