A novel endothelin ETA receptor antagonist, BQ-485, and its preventive effect on experimental cerebral vasospasm in dogs.
Because endothelin-1 has a potent and long-lasting vasoconstrictive action, it has been proposed that it plays some important roles in the pathogenesis of delayed cerebral vasospasm following subarachnoid hemorrhage. We examined the preventive effect of a novel ETA receptor antagonist, BQ-485, on experimental vasospasm using canine two-hemorrhage model of subarachnoid hemorrhage. The IC50 value of BQ-485 on [125I]endothelin-1 binding was 3.4 x 10(-9) M for ETA receptor and 26 x 10(-6) M for ETB receptor. Systemic continuous administration of 120 mg/day of the agent inhibited the narrowing of canine basilar artery on day 7 following experimental subarachnoid hemorrhage (75.0% vs 59.9% (control), p < 0.01). The present results suggest that endothelin-1 and ETA receptor participate in the pathogenesis of delayed cerebral vasospasm.
Itoh
S
S
Department of Neurosurgery, Faculty of Medicine, University of Tokyo, Japan.
Sasaki
T
T
Ide
K
K
Ishikawa
K
K
Nishikibe
M
M
Yano
M
M
D000818:Animals; D001011:Aorta / Q000378:metabolism; D001381:Azepines / Q000097:blood / Q000494:pharmacology*; D001667:Binding, Competitive; D002462:Cell Membrane / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism*; D002543:Cerebral Hemorrhage / Q000503:physiopathology; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology*; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000517:prevention & control*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009842:Oligopeptides / Q000097:blood / Q000494:pharmacology*; D017466:Receptors, Endothelin / Q000378:metabolism; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D001381:Azepines; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D009842:Oligopeptides; D017466:Receptors, Endothelin; D014662:Vasoconstrictor Agents; C083116:BQ 485