Effect of the 21-aminosteroid tirilazad on cerebral pH and somatosensory evoked potentials after incomplete ischemia.
OBJECTIVE
Postischemic evoked potential recovery correlates with acidosis during ischemia and early reperfusion. Acidosis promotes lipid peroxidation in vitro. We tested the hypothesis that the 21-aminosteroid tirilazad mesylate (U74006F), an inhibitor of lipid peroxidation in vitro, ameliorates somatosensory evoked potential recovery and acidosis during reperfusion after severe incomplete cerebral ischemia.


METHODS
Cerebral perfusion pressure was reduced to 11 +/- 1 mm Hg (+/- SEM) for 30 minutes by cerebral ventricular fluid infusion in anesthetized dogs. Cerebral intracellular pH and high-energy phosphates were measured by magnetic resonance spectroscopy. Dogs were randomized to receive vehicle (citrate buffer; n = 8) or tirilazad (1 mg/kg; n = 8) before ischemia in a blinded study.


RESULTS
Cerebral blood flow was reduced to 6 +/- 1 mL/min per 100 g during ischemia, resulting in nearly complete loss of high-energy phosphates and an intracellular pH of 6.0-6.1 in both groups. Initial postischemic hyperemia was similar between groups but lasted longer in the vehicle group. Tirilazad accelerated mean recovery time of intracellular pH from 31 +/- 5 to 15 +/- 3 minutes and of inorganic phosphate from 13 +/- 2 to 6 +/- 1 minutes. Recovery of somatosensory evoked potential amplitude was greater with tirilazad (49 +/- 3%) than vehicle (33 +/- 6%). Fractional cortical water content was less with tirilazad (0.819 +/- 0.003) than vehicle (0.831 +/- 0.002).


CONCLUSIONS
Tirilazad attenuates cerebral edema and improves somatosensory evoked potential recovery after incomplete ischemia associated with severe acidosis. Accelerated pH and inorganic phosphate recovery indicates that this antioxidant acts during the early minutes of reperfusion.
Maruki
Y
Y
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, Md.
Koehler
R C
RC
Kirsch
J R
JR
Blizzard
K K
KK
Traystman
R J
RJ
D000138:Acidosis / Q000188:drug therapy; D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D001639:Bicarbonates / Q000032:analysis; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D001929:Brain Edema / Q000188:drug therapy*; D002545:Brain Ischemia / Q000188:drug therapy*; D003593:Cytoplasm / Q000737:chemistry; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005073:Evoked Potentials, Somatosensory / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D008297:Male; D010725:Phosphocreatine / Q000032:analysis; D011281:Pregnatrienes / Q000494:pharmacology*; D017382:Reactive Oxygen Species; D015427:Reperfusion Injury / Q000517:prevention & control*
D001639:Bicarbonates; D011281:Pregnatrienes; D017382:Reactive Oxygen Species; D010725:Phosphocreatine; D000255:Adenosine Triphosphate; C053355:tirilazad