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 delayed 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 (ascorbic acid and U74389F) that have antioxidant but not iron-chelating capacity. For the systemic application of drugs in 23 rats, whole blood encased in a silastic cuff was applied to the right femoral artery of each rat; whole-blood serum (lacking erythrocytes) was similarly applied 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 was administered three times daily by intraperitoneal injection for 7 days. After exposure to whole blood, arteries treated with intraperitoneal vehicle showed an 85% reduction in the lumen, compared with vessels exposed to erythrocyte-free serum (P < 0.001). Intraperitoneal ascorbic acid and U74389F produced moderate amelioration in arterial narrowing (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 by the perivascular application of drugs, whole blood was applied to both 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) were directly applied to the perivascular thrombus surrounding the femoral 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 mg of deferoxamine (41% reduction, P < 0.05) significantly inhibited arterial narrowing, compared with vehicle. The application of U74389F at a dose of 15 or 30 mg directly into the perivascular thrombus produced nonsignificant reduction in arterial narrowing. These data suggest that mechanisms other than direct iron toxicity, such as generation of cytotoxic free radicals, may play an important role in cerebral vasospasm. In addition, the route of administration and concentration of drugs in the perivascular region adjacent to the thrombus may be critical to their efficacy.
Luo
Z
Z
Department of Neurological Surgery, University of Washington, Seattle, USA.
Harada
T
T
London
S
S
Gajdusek
C
C
Mayberg
M R
MR
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005263:Femoral Artery / Q000473:pathology; D005609:Free Radicals; D007501:Iron / Q000633:toxicity; D007502:Iron Chelating Agents / Q000494:pharmacology*; D002546:Ischemic Attack, Transient / Q000473:pathology*; D008297:Male; D011281:Pregnatrienes / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013927:Thrombosis / Q000473:pathology; D014655:Vascular Resistance / Q000187:drug effects
D000975:Antioxidants; D005609:Free Radicals; D007502:Iron Chelating Agents; D011281:Pregnatrienes; C074965:U 74389F; D007501:Iron; D003676:Deferoxamine; D001205:Ascorbic Acid