BY-1949 elicits vasodilatation via preferential elevation of cyclic GMP levels within the cerebral artery: possible involvement of endothelium-mediated mechanisms

Abstract

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) F 2α, endothelin and phorbol-12,13-diacetate (PDA), respectively, to the same extent. In addition, pretreatment of the artery with methylene blue suppressed the vasodilating effect of BY-1949. BY-1949 also dose dependently suppressed contractions of the basilar artery induced by CaCl 2 (Ca 2+) in a non-competitive manner. Biochemical studies disclosed that BY-1949 significantly increased cyclic GMP without 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.