Effect of U88999E on experimental cerebral vasospasm in rabbits.
U88999E, 7-[4,(4, 4'-difluorobenzhydryl)piperazino-1-methyl]-4- isopropyl-2-methoxy-2,4,6-cycloheptatrien-1-one hydrochloride, is a recently developed tropolone derivative that inhibits lipid peroxidation and also acts as a calcium antagonist. The effects of U88999E on basilar artery tone were examined in two model systems: 1) an in vitro preparation of arterial rings that measures isometric tension, and 2) an in vivo model of cerebral vasospasm measuring arterial diameter. U88999E elicited dose-dependent relaxation of preconstricted arterial rings maintained in vitro. Ring preparations were preconstricted using elevated potassium (40 mmol/L), uridine triphosphate (10(-3) mol/L), or endothelin-1 (10(-8) mol/L); U88999E reversed these constrictions across a concentration range of 10(-8) to 10(-5) mol/L. The potency of U88999E for relaxing preconstricted vessels was slightly less than that observed for flunarizine or diltiazem. A dose-dependent, relaxing effect of U88999E on potassium-induced contractions was observed in the presence of calcium concentrations ranging from 0.03 to 20 mmol/L. Vasospasm of basilar arteries after subarachnoid hemorrhage was inhibited in a dose-dependent and significant manner by intravenous injections of U88999E. Animals receiving intraperitoneal injections of U88999E also exhibited a tendency for reduced vasospasm; however, this effect did not achieve statistical significance. These findings suggest that U88999E may be useful in the prevention of cerebral vasospasm after subarachnoid hemorrhage.
Takahashi
S
S
Department of Neurological Surgery, University of Virginia Health Sciences Center, Charlottesville.
Kassell
N F
NF
Toshima
M
M
Dougherty
D A
DA
Foley
P L
PL
Lee
K S
KS
D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000473:pathology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003508:Cycloheptanes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D002546:Ischemic Attack, Transient / Q000473:pathology*; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D011817:Rabbits; D013345:Subarachnoid Hemorrhage / Q000473:pathology; D014655:Vascular Resistance / Q000187:drug effects* / Q000502:physiology
D002121:Calcium Channel Blockers; D003508:Cycloheptanes; D010879:Piperazines; C079797:U 88999E