U74389G PREVENTS VASOSPASM AFTER SUBARACHNOID HEMORRHAGE IN DOGS

OBJECTIVE: Oxygen-derived free radicals may contribute to vasospasm af ter the rupture of an intracranial aneurysm through direct vasoconstri cting effects occurring within the arterial wall or, secondarily, by c ausing lipid peroxidation in the subarachnoid erythrocytes with second ary induction of vasoconstriction. U74389G is a potent inhibitor of li pid peroxidation and a scavenger of oxygen-derived free radicals. This study determined the relative contributions of oxygen-derived free ra dicals and lipid peroxidation to vasospasm in the double-hemorrhage do g model. METHODS: Sixteen dogs underwent baseline (Day 0) cerebral ang iography and induction of subarachnoid hemorrhage by two injections of blood into the cisterna magna 2 days apart. They were randomized to r eceive drug vehicle (n = 8) or U74389G (n = 8, 3 mg/kg of body weight/ d) intravenously. Drug administration and end point analysis were blin ded. The end points were angiographic vasospasm, as assessed by compar ison of angiograms obtained before and 7 days after subarachnoid hemor rhage, and the levels of malondialdehyde and salicylate hydroxylation products (dihydroxybenzoic acids) in cerebrospinal fluid and of malond ialdehyde in subarachnoid blood clots and basilar arteries 7 days afte r hemorrhage. RESULTS: Comparisons within groups of Day 0 and Day 7 an giograms and between groups of angiograms obtained at Day 7, showed si gnificant vasospasm in animals in the vehicle group (mean +/- standard error, 51% +/- 4) but not in the U74389G group (25% +/- 11, P < 0.05, unpaired t test). High-pressure liquid chromatographic assays of malo ndialdehyde and dihydroxybenzoic acids in cerebrospinal fluid, subarac hnoid blood clots, and basilar arteries showed no significant differen ces between groups. CONCLUSION: The significant prevention of vasospas m by U74389C without change in levels of indicators of free radical re actions suggests that the effect of the drug is related to other proce sses occurring in the arterial wall and that cerebrospinal fluid level s of oxygen radicals and lipid peroxides are not useful markers of vas ospasm.