Prevention of subarachnoid hemorrhage-induced cerebral vasospasm by oral administration of endothelin receptor antagonists.
The purpose of this study was to investigate the effectiveness of oral treatment with the endothelin (ET) A/B receptor antagonist Ro 47-0203, 4-tert-butyl-N-[6-(hydroxy- ethoxy)-5-(2-methoxy-phenoxy)-2'-bipyrimidin-4-yl]-benzenesulfonam ide (bosentan), and the ET A receptor antagonist 2-benzo[1,3]dioxol-5-yl-3-benzyl-4-(4-methoxy- phenyl)-4-oxo-but-2-enoic acid monosodium salt (PD155080), in the prevention of subarachnoid hemorrhage (SAH)-induced delayed cerebral vasospasm. Double hemorrhage in the rabbit constricted the basilar artery to 34% if control as determined by angiography. Oral bosentan and PD155080 administration after the initial SAH decreased the magnitude of constriction to 9% and 16% of control, respectively. Plasma and cerebrospinal fluid bosentan levels and plasma PD155808 levels were consistent with concentrations reported to inhibit ET-1 constriction of blood vessels in vitro. These results support the use of oral administration of ET A/B and ET A receptor antagonists as potential specific treatment for vasospasm resulting from SAH in humans.
Zuccarello
M
M
Department of Neurosurgery, University of Cincinnati, Ohio, USA.
Soattin
G B
GB
Lewis
A I
AI
Breu
V
V
Hallak
H
H
Rapoport
R M
RM
D000284:Administration, Oral; D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000503:physiopathology; D000077300:Bosentan; D004149:Dioxoles / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D065128:Endothelin Receptor Antagonists; D002546:Ischemic Attack, Transient / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D011817:Rabbits; D013345:Subarachnoid Hemorrhage / Q000150:complications* / Q000503:physiopathology; D013449:Sulfonamides / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects
D004149:Dioxoles; D065128:Endothelin Receptor Antagonists; C093322:PD 155080; D013449:Sulfonamides; D000077300:Bosentan