Prevention of cerebral vasospasm by a novel endothelin receptor antagonist, TA-0201.
This study was designed to examine the preventive effect of a novel endothelin (ET)-receptor antagonist TA-0201 on the cerebral vasospasm in a canine double-hemorrhage model. TA-0201 (10(-9)-10(-7) M) inhibited ET-1-induced vasoconstriction in the isolated canine basilar artery without endothelium in a concentration-dependent manner. Its pA2 value was 9.2 (ET(A) antagonism). In a canine double-hemorrhage model, intravenous treatment with TA-0201 (3 mg/kg, twice a day for 7 days) ameliorated the basilar artery narrowing significantly on day 7 compared with that in nontreated dogs. The reductions of the basilar artery diameter were 26.1+/-3.9% and 40.5+/-4.1% with and without TA-0201 treatment, respectively (p<0.05). Histologic study on day 7 indicated that treatment with TA-0201 inhibited vessel-wall damage such as disintegration of endothelium architecture and degeneration of medial smooth-muscle cells. We conclude that intravenous treatment with TA-0201 prevents the development of cerebral vasospasm and accompanying pathologic changes of the vessel wall, probably through blockade of ET(A) receptors.
Kikkawa
K
K
Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd. Toda, Saitama, Japan. kohei-k@tanabe.co.jp
Saito
A
A
Iwasaki
H
H
Ban
Y
Y
Yasoshima
A
A
Yamauchi-Kohno
R
R
Hoshino
T
T
Murata
S
S
D000818:Animals; D001488:Basilar Artery / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors; D004730:Endothelium, Vascular / Q000187:drug effects; D006470:Hemorrhage / Q000150:complications; D008297:Male; D008854:Microscopy, Electron; D011743:Pyrimidines / Q000627:therapeutic use*; D044022:Receptor, Endothelin A; D013449:Sulfonamides / Q000627:therapeutic use*; D014661:Vasoconstriction / Q000187:drug effects; D020301:Vasospasm, Intracranial / Q000209:etiology / Q000517:prevention & control*
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D013449:Sulfonamides; C113972:T 0201