Amelioration of impaired cerebral metabolism after severe acidotic ischemia by tirilazad posttreatment in dogs.
OBJECTIVE
Acidosis may contribute to ischemic injury by mobilizing iron because the iron chelator deferoxamine improves early metabolic recovery from hyperglycermic ischemia. Mobilized iron may then promote oxygen radical-induced lipid peroxidative injury during reperfusion. We tested the hypothesis that administration of the antioxidant tirilazad at the start of reperfusion improves early metabolic recovery after severe acidotic ischemia and ameliorates depletion of the endogenous antioxidant glutathione.


METHODS
In anesthetized dogs, arterial glucose concentration was increased to 500 to 600 mg/dL and global incomplete cerebral ischemia was produced for 30 minutes by ventricular fluid infusion to reduce perfusion pressure to 10 to 12 mm Hg. Metabolic recovery and intracellular pH were measured by phosphorus MR spectroscopy. In the first experiment, four groups of eight dogs each received either vehicle or 0.25, 1, or 2.5 mg/kg of tirilizad mesylate at reperfusion. Cerebral blood flow was measured with microspheres. In the second experiment, two groups of eight dogs each each received either vehicle or 2.5 mg/kg of tirilazad at reperfusion, and cortical glutathione was measured at 3 hours of reperfusion.


RESULTS
Cerebral blood flow decreased to approximately 6 mL/min per 100 g and intracellular pH decreased to approximately 5.6 during ischemia in all groups. In the vehicle group, ATP recovery was transient and pH remained less than 6.0. Cerebral blood flow, O2 consumption, and ATP eventually declined to near-zero levels by 3 hours. Recovery was improved by tirilazad posttreatment in a dose-dependent fashion. At the highest dose, cerebral blood flow and O2 consumption were sustained near preischemic levels, and five of eight dogs had recovery of ATP greater than 50% and of pH greater than 6.7. Recovery of ATP and phosphocreatine became significantly greater than that in the vehicle group by 17 minutes of reperfusion despite similar levels of early hyperemia, indicating that the drug was acting before the onset of hypoperfusion. Cortical glutathione concentration in the vehicle group was 27% less than that in the tirilazad group and 34% less than that in nonischemic controls.


CONCLUSIONS
Decreased depletion of the endogenous antioxidant glutathione is consistent with tirilazad acting as an antioxidant in vivo. Improvement in high-energy phosphate recovery 17 minutes after starting tirilazad infusion during reperfusion is consistent with an early onset of a functionally significant oxygen radical injury. Thus, severe acidosis appears to contribute to early ischemic injury through an oxygen radical mechanism sufficient to impede metabolic recovery.
Kim
H
H
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, Md 21287-4961, USA.
Koehler
R C
RC
Hurn
P D
PD
Hall
E D
ED
Traystman
R J
RJ
D000138:Acidosis / Q000188:drug therapy* / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000627:therapeutic use*; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D006940:Hyperemia / Q000150:complications / Q000378:metabolism; D006943:Hyperglycemia / Q000150:complications / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010101:Oxygen Consumption / Q000187:drug effects; D010725:Phosphocreatine / Q000378:metabolism; D010758:Phosphorus; D011281:Pregnatrienes / Q000008:administration & dosage / Q000627:therapeutic use*; D015424:Reperfusion
D000975:Antioxidants; D016166:Free Radical Scavengers; D011281:Pregnatrienes; D010725:Phosphocreatine; D010758:Phosphorus; D000255:Adenosine Triphosphate; D007501:Iron; D005978:Glutathione; C053355:tirilazad