Acidosis may augment cerebral ischemic injury by promoting lipid peroxidation. We tested the hypothesis that when
acidosis is augmented by
hyperglycemia, pretreatment with the 21-aminosteroid
tirilazad mesylate (
U74006F), a potent inhibitor of lipid peroxidation in vitro, improves early cerebral metabolic recovery. In a randomized, blinded study, anesthetized dogs received either
tirilazad mesylate (1 mg/kg plus 0.2 mg/kg/h; n = 8) or vehicle (n = 8).
Hyperglycemia (400-500 mg/dl) was produced prior to 30 min of global incomplete
cerebral ischemia. Intracellular pH and high energy
phosphates were measured by
phosphorus magnetic resonance spectroscopy. During
ischemia,
microsphere-determined CBF decreased to 8 +/- 4 ml min-1 100 g-1 and intracellular pH decreased to 5.6 +/- 0.2 in both groups. During the first 20 min of reperfusion,
ATP partially recovered in the vehicle group to 57 +/- 21% of baseline, but then declined progressively in association with
elevated intracranial pressure. By 30 min,
ATP recovery was greater in the
tirilazad group (77 +/- 35 vs. 36 +/- 19%), although postischemic
hyperemia was similar. By 45 min, the
tirilazad group had a higher intracellular pH (6.5 +/- 0.5 vs. 5.9 +/- 0.6) and a lower intracranial pressure (18 +/- 6 vs. 52 +/- 24 mm Hg). By 180 min, blood flow and
ATP were undetectable in seven of eight vehicle-treated dogs, whereas
ATP was > 67% and pH was > 6.7 in six of eight
tirilazad-treated dogs. Thus,
tirilazad acts during early reperfusion to prevent secondary metabolic decay associated with severe acidotic
ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)