Contribution of endothelin-1 to disruption of blood-brain barrier permeability in dogs.
We examined the effect of intracisternal application of endothelin-1 (ET-1) on the permeability of fluorescein into the cerebrospinal fluid (CSF) in beagle dogs in order to evaluate its role in disruption of blood-brain barrier (BBB) permeability seen in the subarachnoid hemorrhage animal model. Intracisternal application of their autologous blood for producing a canine two-hemorrhage model revealed an enhanced fluorescein permeability into the CSF together with the development of cerebral vasospasm. A single dose of ET-1 (40 pmol/animal) significantly increased penetration of fluorescein compared with that in normal dogs. Although its magnitude was much less than that in the two-hemorrhage model after the first administration of ET-1, the second challenge of the same dose of ET-1 with a 48-h interval produced marked disruption of BBB permeability similar to those in the animal model. Moreover, the ET-1-induced enhancement of fluorescein permeability into the CSF was completely prevented by intracisternal pretreatment with an endothelin ET(A)-receptor selective antagonist, S-0139 (0.03 mg/kg), as were the ET-1-induced cerebral vasoconstriction and behavioral changes as previously reported. 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.
Narushima
I
I
Department of Pharmacology, Nara Medical University, Kashihara, Japan.
Kita
T
T
Kubo
K
K
Yonetani
Y
Y
Momochi
C
C
Yoshikawa
I
I
Shimada
K
K
Nakashima
T
T
D000704:Analysis of Variance; D000818:Animals; D001769:Blood / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000502:physiology; D002109:Caffeic Acids / Q000008:administration & dosage; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D002946:Cisterna Magna; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000008:administration & dosage* / Q000378:metabolism*; D005260:Female; D019793:Fluorescein / Q000032:analysis*; D007276:Injections, Intraventricular; D008297:Male; D009828:Oleanolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D044022:Receptor, Endothelin A; D013345:Subarachnoid Hemorrhage / Q000097:blood / Q000134:cerebrospinal fluid / Q000503:physiopathology*
D002109:Caffeic Acids; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D044022:Receptor, Endothelin A; C086421:S 0139; D009828:Oleanolic Acid; D019793:Fluorescein