Development of cyclooxygenase and lipoxygenase metabolites of arachidonic acid after transient cerebral ischemia.

Vasoactive arachidonic acid metabolites are postulated to play a role in the pathogenesis of cerebral ischemia. In order to characterize the local generation of cyclooxygenase and lipoxygenase metabolites of arachidonic acid in transient ischemia with reperfusion, Mongolian gerbils were studied for regional cerebral blood flow (CBF), using the hydrogen clearance technique, and for cerebral levels of the thromboxane metabolite TXB2, and prostaglandins 6-keto-PGF1 alpha and PGE2, as well as the leukotriene LTB4. The gerbils were anesthetized with pentobarbital, and half of the animals were pretreated with the cyclooxygenase inhibitor indomethacin. All received 10 or 20 minutes of dense forebrain ischemia followed by reperfusion of 10 minutes, 50 minutes, or 100 minutes. A separate control group received no ischemic lesion. Regional CBF decreased significantly from 23.7 +/- 2.6 to 4.3 +/- 1.7 cc/100 gm/min during ischemia (p less than 0.01). Reperfusion resulted in initially normal flows (22.5 +/- 5.1 cc/100 gm/min) followed by a progressive hypoperfusion (11.3 +/- 2.7 cc/100 gm/min). All metabolites showed parallel significant (p less than 0.05) increases after transient ischemia and reperfusion compared to baseline levels (values (in pg/mg protein) were: TXB2 45.5 +/- 7.1 vs 23.3 +/- 3.6; 6-keto-PGF1 alpha 262.8 +/- 47.9 vs 175.8 +/- 26.8; PGE2 256.5 +/- 35.6 vs 112.5 +/- 11.2; and LTB4 37.8 +/- 4.6 vs 24.6 +/- 6). These levels were all significantly decreased (p less than 0.05) by pretreatment with indomethacin except for the leukotriene LTB4, which was increased. Transient cerebral ischemia results in a reperfusion abnormality and the local generation of cyclooxygenase products, which are reduced by pretreatment with indomethacin; however, cyclooxygenase inhibition may result in increased substrate availability for the lipoxygenase system. Studies of such an interaction may lead to new understandings of the pharmacological modification of detrimental vascular changes after transient cerebral ischemia.