BY-1949

The effects of BY-1949, a novel dibenzoxazepine derivative, injected into the cerebral ventricle on noxious stimulus-induced responses of regional blood flow in the cortex and neuronal activity in the nucleus basalis of Meynert were studied in male rats. These induced responses were markedly enhanced by administration of BY-1949 (16.4 +/- 0.5 ng/100 g, S.E.M.). These data indicate that BY-1949 acts on the central nervous system to modulate the response to a noxious stimulus of regional cerebral blood flow and neuronal activity in the nucleus basalis of Meynert.

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.