Thromboxane receptor antagonism and synthase inhibition in cerebral ischemia.
Thromboxane A2 (TXA2) is a proaggregatory vasoconstrictor that may suppress regional cerebral blood flow (rCBF) during postischemic hypoperfusion. This study was undertaken to determine if rCBF could be elevated by postischemic treatment with a TXA2 receptor antagonist, SQ29,548, given alone or in combination with 1-benzylimidazole (1-BI), a thromboxane synthase inhibitor. Wistar rats were subjected to 30 min of reversible forebrain ischemia and treated with SQ29,548 or an SQ29,548/1-BI combination during 60 min of reperfusion. Cerebral TXB2, the stable metabolite of TXA2, was 1.33 +/- 0.91 ng mg brain protein-1 in animals treated with SQ29,548 and exposed to ischemia, compared to 1.15 +/- 0.32 in ischemic controls (p = NS). Administration of SQ29,548/20 mg kg-1 1-BI reduced cerebral TXB2 to 0.20 +/- 0.25 (p < or = 0.01). Regional CBF was depressed significantly in ischemic controls compared to sham-ischemic animals (p < or = 0.01 in all regions except for p < or = 0.05 in diencephalon) and was not altered by treatment with SQ29,548. Rats given the SQ29,548/1-BI combination showed an overall increase in rCBF that did not reach statistical significance when compared to ischemic controls. However, rCBF in hippocampus and diencephalon of animals given the drug combination was significantly greater than in rats treated with SQ29,548 alone (p < or = 0.05).
Pettigrew
L C
LC
Department of Statistics, University of Kentucky College of Medicine, Lexington 40536-0230.
Kryscio
R J
RJ
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004357:Drug Synergism; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines / Q000008:administration & dosage / Q000627:therapeutic use; D007093:Imidazoles / Q000008:administration & dosage / Q000627:therapeutic use; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D012039:Regional Blood Flow / Q000187:drug effects; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D007093:Imidazoles; D017482:Receptors, Thromboxane; C017062:1-benzylimidazole; C045749:SQ 29548; D013930:Thromboxane-A Synthase