cyclic-gmp and 3-methoxy-11-methyldibenz(b-f)oxazepine-8-carboxylate

The pharmacological mechanisms by which BY-1949, a novel dibenzoxazepine derivative, increases in regional cerebral blood flow, were investigated using the canine basilar artery in vitro. BY-1949 inhibited contractions elicited by serotonin (5-HT), prostaglandin (PG) F2 alpha, endothelin and phorbol-12,13-diacetate (PDA), respectively, to the same extent. In addition, pretreatment of the artery with methylene blue significantly suppressed the vasodilating effect of BY-1949. BY-1949 also dose dependently suppressed contractions of the basilar artery induced by CaCl2 (Ca2+) in a non-competitive manner. Biochemical studies disclosed that BY-1949 significantly increased cyclic GMP without causing any apparent change in cyclic AMP. These increases in cyclic GMP were virtually abolished after the endothelial cells were removed. These results strongly suggest that the increased regional cerebral blood flow induced by BY-1949 is explicable, at least partly, in terms of a preferential elevation of cyclic GMP within the cerebral vasculature, where the endothelium plays a pivotal role.

Topics: Animals; Basilar Artery; Calcium; Cerebral Arteries; Cyclic AMP; Cyclic GMP; Dibenzoxazepines; Dogs; Endothelium, Vascular; In Vitro Techniques; Methylene Blue; Muscle Contraction; Muscle, Smooth, Vascular; Vasodilator Agents

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.

Topics: Animals; Blood Platelets; Chromatography, High Pressure Liquid; Cyclic AMP; Cyclic GMP; Dibenzoxazepines; Endothelium, Vascular; In Vitro Techniques; Male; Nitric Oxide; Platelet Aggregation Inhibitors; Rabbits