Correction of ischaemic brain acidosis with SQ29,548/1-benzylimidazole.
Thromboxane A2 (TXA2) is a proaggregatory vasoconstrictor that is synthesized and released during reperfusion of ischaemic brain. We administered a TXA2 receptor antagonist, SQ29,548, and a thromboxane A synthase inhibitor, 1-benzylimidazole (1-BI), to rats subjected to 30 min of reversible forebrain ischaemia. Cerebral thromboxane B2 (TXB2), the stable metabolite of TXA2, measured after 60 min of reperfusion was 0.37 +/- 0.08 ng/mg brain protein in animals treated with SQ29,548/1-BI compared with 1.20 +/- 0.16 in ischaemic controls (p < 0.05). Cerebral pH determined by 31P magnetic resonance spectroscopy was higher in treated animals, 7.06 +/- 0.04, than in ischaemic controls, 6.5 +/- 0.01, after 20 min of reperfusion (p < or = 0.01). The significant elevation of cerebral pH in treated animals persisted at 30 (7.17 +/- 0.05 vs. 6.5 +/- 0.01; p < or = 0.01), 35 (7.17 +/- 0.05 vs. 6.44 +/- 0.04; p < or = 0.01), and 40 min of reperfusion (7.06 +/- 0.06 vs. 6.37 +/- 0.01; p < or = 0.05). We conclude that SQ29,548/1-BI reduces thromboxane levels and promotes resolution of tissue acidosis in ischaemic brain. The combination of a TXA2 receptor antagonist with a thromboxane A synthase inhibitor deserves further study as a potential treatment for acute cerebral infarction.
Pettigrew
L C
LC
Sanders-Brown Center of Excellence in Aging, University of Kentucky College of Medicine and Medical Center, Lexington 40536-0230.
Hazle
J D
JD
Gutierrez
G
G
Smith
C D
CD
Ogletree
M L
ML
D000138:Acidosis / Q000188:drug therapy* / Q000209:etiology; D000818:Animals; D002545:Brain Ischemia / Q000150:complications*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004359:Drug Therapy, Combination; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D008297:Male; D016548:Prosencephalon / Q000098:blood supply; D051381:Rats; D017208:Rats, Wistar; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D015427:Reperfusion Injury / Q000517:prevention & control; D013928:Thromboxane A2 / Q000378:metabolism*; 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; D013928:Thromboxane A2; C045749:SQ 29548; D013930:Thromboxane-A Synthase