BY-1949 elicits vasodilation via preferential elevation of cyclic GMP levels within the cerebral artery: possible involvement of endothelium-mediated mechanisms.
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.
Sugawa
M
M
Department of Pharmacology, Chugai Pharmaceutical Company Ltd., Shizuoka, Japan.
Koide
T
T
Takato
M
M
D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D002118:Calcium / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002536:Cerebral Arteries / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D003989:Dibenzoxazepines / Q000494:pharmacology*; D004285:Dogs; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D066298:In Vitro Techniques; D008751:Methylene Blue / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*
D003989:Dibenzoxazepines; D014665:Vasodilator Agents; C058844:3-methoxy-11-methyldibenz(b,f)oxazepine-8-carboxylate; D000242:Cyclic AMP; D006152:Cyclic GMP; D002118:Calcium; D008751:Methylene Blue