Effect of U88999E on experimental cerebral vasospasm in rabbits.

Abstract

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.

• Authors: S Takahashi, N F Kassell, M Toshima, D A Dougherty, P L Foley, K S Lee
• Journal: Neurosurgery (Neurosurgery) Vol. 32 Issue 2 Pg. 281-8; discussion 288 (Feb 1993) ISSN: 0148-396X [Print] United States
• PMID: 8437666 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Calcium Channel Blockers
• Cycloheptanes
• Piperazines
• U 88999E

Topics

• Animals
• Basilar Artery (drug effects, pathology)
• Calcium Channel Blockers (pharmacology)
• Cycloheptanes (pharmacology)
• Dose-Response Relationship, Drug
• Ischemic Attack, Transient (pathology)
• Lipid Peroxidation (drug effects, physiology)
• Male
• Piperazines (pharmacology)
• Rabbits
• Subarachnoid Hemorrhage (pathology)
• Vascular Resistance (drug effects, physiology)