Effects of a synthetic allosteric modifier of hemoglobin oxygen affinity on outcome from global cerebral ischemia in the rat.
OBJECTIVE
Neuronal injury results from an insufficient supply of oxygen to the brain. This experiment examined whether a pharmacologically induced rightward shift of the partial pressure of oxygen at which 50% of hemoglobin is saturated (P50) would improve outcome from either incomplete and/or near-complete forebrain ischemia-induced hypoxia in the rat.


METHODS
For incomplete ischemia (attenuated electroencephalogram), fasted rats (n = 17 to 19 per group) were given a synthetic allosteric modifier of hemoglobin affinity for oxygen (RSR13; 150 mg/kg IV) before or immediately after 20 minutes of bilateral carotid occlusion combined with a decrease in mean arterial pressure to 40 mm Hg. For near-complete ischemia (isoelectric electroencephalogram), rats (n = 15 per group) were given RSR13 (150 mg/kg) at onset of reperfusion after 10 minutes of bilateral carotid occlusion combined with a decrease in mean arterial pressure to 30 mm Hg. In both experiments, control rats were given vehicle (0.9% NaCl IV) only. Outcome (defined as percent dead hippocampal CA1 neurons) was determined at 5 days after ischemia.


RESULTS
RSR13 (150 mg/kg) produced a 68% rightward shift of P50 (34+/-3 to 57+/-8 mm Hg). RSR13 reduced CA1 damage resulting from incomplete ischemia by 28% (P=0.02), but only when administered at the onset of reperfusion. RSR13 had no effect on outcome from near-complete ischemia.


CONCLUSIONS
A postischemic pharmacologically induced increase in P50 may improve outcome from incomplete global cerebral ischemia. More severe (near-complete) ischemia negates this benefit.
Department of Anesthesiology, Duke University Medical Center, Durham, NC 27705, USA. h.grocott@duke.edu
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Grocott
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Bart
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Sheng
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Miura
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Steffen
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Pearlstein
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Warner
D000494:Allosteric Regulation; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D000986:Antisickling Agents / Q000494:pharmacology*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D010100:Oxygen / Q000097:blood*; D010108:Oxyhemoglobins / Q000737:chemistry / Q000378:metabolism*; D011422:Propionates / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism; D016896:Treatment Outcome
D000814:Aniline Compounds; D000986:Antisickling Agents; D003432:Cross-Linking Reagents; D010108:Oxyhemoglobins; D011422:Propionates; C067396:efaproxiral; D010100:Oxygen