Thromboxane synthetase inhibition with imidazole increases blood flow in ischemic penumbra.
Previous studies have indicated that the regional distribution of the arachidonic acid metabolites around a focal ischemic lesion may be important in the pathogenesis of cerebral ischemia. To determine the functional significance of this regionalization, we examined the effect of imidazole (a thromboxane synthetase inhibitor) on the distribution of the vasoconstrictor thromboxane and the vasodilators prostacyclin and prostaglandin E2 (PGE2) and on the distribution of cerebral blood flow (CBF) around a focal ischemic lesion, middle cerebral artery (MCA) occlusion in the cat. The study was conducted in two phases. The first phase examined regional distribution of tissue arachidonic acid metabolites and the effect of imidazole treatment on that distribution. The second phase examined the effect of imidazole treatment on the distribution of blood flow about the focal ischemic lesion as well as on electrocortical function and edema production. MCA occlusion resulted in increased thromboxane, prostacyclin, and PGE2 levels in the ipsilateral hemisphere. These increases were greatest in the region of marginal ischemia and were present both 3 and 6 hours after occlusion. Imidazole pretreatment (50 mg/kg i.p.) significantly inhibited thromboxane production, but augmented production of prostacyclin and PGE2. In the blood flow studies, imidazole was without effect on regions of dense cerebral ischemia (CBF less than 20 ml/minute/100 g for more than 12 of 24 postocclusion hours). In regions of marginal ischemia (20 less than CBF less than 30 ml/minute/100 g for more than 12 of 24 postocclusion hours), imidazole pretreatment significantly increased blood flow in both gray and white matter compared with saline-treated controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Roy
M W
MW
Department of Surgery, University of Kentucky Medical Center, Lexington.
Dempsey
R J
RJ
Cowen
D E
DE
Donaldson
D L
DL
Young
A B
AB
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D001929:Brain Edema / Q000139:chemically induced; D002415:Cats; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D015232:Dinoprostone; D005073:Evoked Potentials, Somatosensory / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D002546:Ischemic Attack, Transient / Q000378:metabolism / Q000503:physiopathology*; D011458:Prostaglandins E / Q000378:metabolism; D013929:Thromboxane B2 / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D007093:Imidazoles; D011458:Prostaglandins E; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; C029899:imidazole; D013930:Thromboxane-A Synthase; D015232:Dinoprostone