ANTIOXIDANT AND IRON-CHELATING AGENTS IN CEREBRAL VASOSPASM

PRIOR WORK IN our laboratory showed that the perivascular application of deferoxamine (an antioxidant and iron-chelating agent) inhibited de layed arterial narrowing after chronic blood exposure in a rat femoral artery model of vasospasm. To determine which of these mechanisms was operant in vasospasm, we compared deferoxamine with two agents (ascor bic acid and U74389F) that have antioxidant but not iron-chelating cap acity. For the systemic application of drugs in 23 rats, whole blood e ncased in a silastic cuff was applied to the right femoral artery of e ach rat; whole-blood serum (lacking erythrocytes) was similarly applie d to the left femoral artery. Deferoxamine (30 mg/kg/d), ascorbic acid (1000 mg/kg/d), U74389F (30 mg/kg/d), or pH-matched control vehicle w as administered three times daily by intraperitoneal injection for 7 d ays. After exposure to whole blood, arteries treated with intraperiton eal vehicle showed an 85% reduction in the lumen, compared with vessel s exposed to erythrocyte-free serum (P < 0.001). Intraperitoneal ascor bic acid and U74389F produced moderate amelioration in arterial narrow ing (53 and 61% decrease, respectively, in the lumen versus controls; P < 0.05 versus vehicle); deferoxamine had no significant effect when administered intraperitoneally. To test the efficacy of these agents b y the perivascular application of drugs, whole blood was applied to bo th femoral arteries in each of 25 rats. Solutions of deferoxamine (10 mg/ml), ascorbic acid (50 or 100 mg/ml), or U74389F (15 or 30 mg/ml) w ere directly applied to the perivascular thrombus surrounding the femo ral arteries, compared with vehicle applied to contralateral vessels. The perivascular application of 50 mg of ascorbic acid (36% reduction, P < 0.05), 100 mg of ascorbic acid (31% reduction, P < 0.01), or 10 m g of deferoxamine (41% reduction, P < 0.05) significantly inhibited ar terial narrowing, compared with vehicle, The application of U74389F at a dose of 15 or 30 mg directly into the perivascular thrombus produce d nonsignificant reduction in arterial narrowing. These data suggest t hat mechanisms other than direct iron toxicity, such as generation of cytotoxic free radicals, may play an important role in cerebral vasosp asm. In addition, the route of administration and concentration of dru gs in the perivascular region adjacent to the thrombus may be critical to their efficacy.