U74389G prevents vasospasm after subarachnoid hemorrhage in dogs

Oxygen-derived free radicals may contribute to vasospasm after rupture of an intracranial aneurysm through direct vasoconstricting effects occurring within the arterial wall or, secondarily, by causing lipid peroxidation in the subarachnoid erythrocytes with secondary induction of vasoconstriction. The compound U74389G is a potent inhibitor of lipid peroxidation and scavenger of oxygen-derived free radicals. This study determined the relative contributions of oxygen-derived free radicals and lipid peroxidation to vasospasm in the double-hemorrhage dog model. Sixteen dogs underwent baseline (Day 0) cerebral angiography and induction of subarachnoid hemorrhage (SAH) by two injections of blood into the cisterna magna 2 days apart. Eight animals were randomized to receive drug vehicle and eight to receive U74389G (3 mg/kg/day) intravenously. Drug administration and endpoint analysis were blinded. The endpoints were angiographic vasospasm as assessed by comparison of angiograms taken before and 7 days after SAH and the levels of malondialdehyde and salicylate hydroxylation products (dihydroxybenzoic acids) in cerebrospinal fluid and of malondialdehyde in subarachnoid blood clots and basilar arteries 7 days posthemorrhage. Comparisons within groups of Day 0 and Day 7 angiograms, and between groups of angiograms at Day 7, showed significant vasospasm in animals in the vehicle group (51 ± 4%, mean ± standard error) but not in those given U74389G (25 ± 11%, p < 0.05, unpaired t-test). High-pressure liquid Chromatographic assays of malondialdehyde and dihydroxybenzoic acids in cerebrospinal fluid, subarachnoid blood clots, and basilar arteries showed no significant differences between groups. The significant prevention of vasospasm by U74389G without change in levels of indicators of free-radical reactions suggests that the effect of the drug is related to other processes occurring in the arterial wall and that cerebrospinal fluid levels of oxygen radicals and lipid peroxides are not useful markers of vasospasm.