Effects of the nonglucocorticoid 21-aminosteroid U74006F on acute cerebral hypoperfusion following experimental subarachnoid hemorrhage.
The ability of the nonglucocorticoid 21-aminosteroid U74006F, a potent inhibitor of iron-dependent lipid peroxidation, to antagonize acute progressive cerebral hypoperfusion following experimental subarachnoid hemorrhage (SAH) was examined in chloralose-anesthetized cats. The SAH was produced by injection of 0.5 ml/kg of unheparinized autologous blood into the cisterna magna after prior withdrawal of an equivalent volume of cerebrospinal fluid. In untreated animals the SAH caused a progressive decline in caudate nuclear blood flow (CNBF) (-51.4% by 3 h) and an increase in intracranial pressure (ICP) (+18.5 mm Hg by 3 h). In comparison, in cats that received a 1 mg/kg iv dose of U74006F at 30 min after SAH, there was a complete prevention of the fall in CNBF and a significant attenuation of the rise in ICP. Furthermore, the drug reduced a concomitant fall in the mean arterial blood pressure and cerebral perfusion pressure. While not as effective as the 1 mg/kg dose, a 0.1 mg/kg dose also significantly attenuated the post-SAH fall in CNBF. These results support a role of lipid peroxidation in the acute pathophysiology of SAH and suggest that U74006F may be useful in the early treatment of this disorder.
Hall
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Central Nervous System Diseases Research Unit, Upjohn Company, Kalamazoo, Michigan 49001.
Travis
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D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002415:Cats; D002421:Caudate Nucleus / Q000098:blood supply; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D005260:Female; D011281:Pregnatrienes / Q000494:pharmacology*; D012039:Regional Blood Flow / Q000187:drug effects; D013345:Subarachnoid Hemorrhage / Q000503:physiopathology*; D014655:Vascular Resistance / Q000187:drug effects
D011281:Pregnatrienes; C053355:tirilazad