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 ≤ 0.01). Regional CBF was depressed significantly in ischemic controls compared to sham-ischemic animals (p ≤ 0.01 in all regions except for p ≤ 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 ≤ 0.05).