Hyperglycemic damage to mitochondrial membranes during cerebral ischemia: amelioration by platelet-activating factor antagonist BN 50739.
The Pulsinelli-Brierley four-vessel occlusion model was used to study the consequences of hyperglycemic ischemia and reperfusion. Rats were subjected to either 30 min of normo- or hyperglycemic ischemia or 30 min of normo- or hyperglycemic ischemia followed by 60 min of reperfusion. In some animals, 2 mg/kg BN 50739, a platelet-activating factor receptor antagonist, was administered intraarterially either before or after the ischemic insult. The changes in mitochondrial membrane free fatty acid levels, phosphatidylcholine fatty acyl composition, and thiobarbituric acid-reactive material (TBAR) content plus the mitochondrial respiratory control ratio (RCR) were monitored. When the platelet-activating factor antagonist was present during normoglycemia, (a) the mitochondrial free fatty acid release both during and after ischemia was slowed, (b) reacylation of phosphatidylcholine following ischemia was promoted, and (c) TBAR accumulation during and following ischemia was decreased. The detrimental effects of hyperglycemia were muted when BN 50739 was present during ischemia. The RCR was preserved and phosphatidylcholine hydrolysis during ischemia was decreased. TBAR levels were consistently higher in hyperglycemic brain mitochondria both during and after ischemia. The RCR correlated directly with mitochondrial phosphatidylcholine polyunsaturated fatty acid content during ischemia and reperfusion. BN 50739 protection of mitochondrial membranes in brain may be influenced by tissue pH.
Kintner
D B
DB
Department of Neurological Surgery, University of Wisconsin Medical School, Madison 53706-1532, U.S.A.
Fitzpatrick
J H
JH
Gilboe
D D
DD
D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D001794:Blood Pressure; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004569:Electroencephalography / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D005263:Femoral Artery; D006943:Hyperglycemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002546:Ischemic Attack, Transient / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008563:Membrane Lipids / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010101:Oxygen Consumption / Q000187:drug effects; D010743:Phospholipids / Q000378:metabolism; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D015424:Reperfusion; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D013997:Time Factors; D014230:Triazoles / Q000494:pharmacology*
D001381:Azepines; D005230:Fatty Acids, Nonesterified; D005231:Fatty Acids, Unsaturated; D008563:Membrane Lipids; D010743:Phospholipids; D010972:Platelet Activating Factor; D017392:Thiobarbituric Acid Reactive Substances; D014230:Triazoles; C064509:BN 50739