Contribution of endothelin-1 to disruption of blood-brain barrier permeability in dogs

We examined the effect of intracisternal application of endothelin-l (ET-1) on the permeability of fluorescein into the cerebrospinal fluid (CSF) in b eagle dogs in order to evaluate its role in disruption of blood-brain barri er (BBB) permeability seen in the subarachnoid hemorrhage animal model. Int racisternal application of their autologous blood for producing a canine tw o-hemorrhage model revealed an enhanced fluorescein permeability into the C SF together with the development of cerebral vasospasm. A single dose of ET -I (40 pmol/animal) significantly increased penetration of fluorescein comp ared with that in normal dogs. Although its magnitude was much less than th at in the two-hemorrhage model after the first administration of ET-I, the second challenge of the same dose of ET-1 with a 48-h interval produced mar ked disruption of BBB permeability similar to those in the animal model. Mo reover, the ET-l-induced enhancement of fluorescein permeability into the C SF was completely prevented by intracisternal pretreatment with an endothel in ETA-receptor selective antagonist, S-0139 (0.03 mg/kg), as were the ET-l -induced cerebral vasoconstriction and behavioral changes as previously rep orted. Thus, we conclude that ET-1 acting on the adventitial site of brain in dogs contributes to the disruption of BBB permeability via endothelin ET A-receptor mediation.