Profiles of an intravenously available endothelin A-receptor antagonist, S-0139, for preventing cerebral vasospasm in a canine two-hemorrhage model.
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.
Department of Pharmacology, Nara Medical University, Kashihara, Japan.
T
T
Kita
K
K
Kubo
K
K
Hiramatsu
T
T
Sakaki
Y
Y
Yonetani
S
S
Sato
M
M
Fujimoto
T
T
Nakashima
D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000503:physiopathology; D002109:Caffeic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D005260:Female; D007262:Infusions, Intravenous; D002546:Ischemic Attack, Transient / Q000150:complications / Q000517:prevention & control*; D008297:Male; D009828:Oleanolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D013131:Spine / Q000098:blood supply; D013345:Subarachnoid Hemorrhage / Q000150:complications*
D002109:Caffeic Acids; D065128:Endothelin Receptor Antagonists; C086421:S 0139; D009828:Oleanolic Acid