s-0139 and Subarachnoid-Hemorrhage

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.

Topics: Analysis of Variance; Animals; Blood; Blood-Brain Barrier; Caffeic Acids; Cell Membrane Permeability; Cisterna Magna; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Female; Fluorescein; Injections, Intraventricular; Male; Oleanolic Acid; Receptor, Endothelin A; Subarachnoid Hemorrhage

We examined the prophylactic effect of a novel nonpeptide endothelin (ET) A-receptor selective antagonist, S-0139, using a canine two-hemorrhage model and an ET-1-induced cerebral vasospasm model. The agent markedly prevented cerebral vasospasm in the canine two-hemorrhage model when given intracisternally or intravenously by continuous daily dosing. An efficacious intravenous method was to apply a relatively high initial dose followed by daily sustaining administration at a much lower dose, which alone would have been ineffective. The need for sustaining dosing may imply daily successive attacks of ETs in the cerebral vessel compartment after the introduction of autologous blood into the subarachnoid space. A small amount of S-0139 was detected from the cerebrospinal fluid (CSF) with an apparent lag time after its disappearance from the plasma following intravenous dosing of 0.83 mg/kg/min for 12 min, however, cerebral vasoconstriction induced by ET-1 dosing from the adventitial side was clearly inhibited during such a lag period. Moreover, its movement into the CSF was greatly enhanced after the application of autologous blood to the animals. From these results, we conclude that ET-1 play a major role in producing delayed cerebral vasospasm in this canine two-hemorrhage model, and S-0139 effectively antagonizes the action of ET-1 even by intravenous treatment because it moves easily into the cerebral vessel compartment from plasma.

Topics: Animals; Basilar Artery; Caffeic Acids; Disease Models, Animal; Dogs; Endothelin Receptor Antagonists; Female; Infusions, Intravenous; Ischemic Attack, Transient; Male; Oleanolic Acid; Spine; Subarachnoid Hemorrhage