INDUCTION OF CEREBRAL THROMBOSIS WITH PHENYTOIN IN RATS

Background and Purpose This study was conducted to explore whether int ra-arterial infusion of phenytoin causes cerebral ischemia and to exam ine the mechanism of cerebral ischemia induced by phenytoin. Methods T en rats were infused with phenytoin (150 mu L, 3.75 mg) retrogradely f rom the left external carotid artery, followed by perfusion of carbon black transcardially. The removed brain was photographed from above, a nd the nonperfused area was compared with control rats (n=10) with the use of an image analyzer. Eight animals with or without phenytoin tre atment were perfusion-fixed for transmission electron microscopic anal yses of cerebral vasculature. To determine the effect of tissue plasmi nogen activator (TPA) on phenytoin-infused rat cerebrum, 20 rats were treated with or without TPA (120 000 IU) 5 minutes after the phenytoin infusion (n=10 each). Results All rats suffered from respiratory dist ress 25 to 40 minutes after the injection and received carbon black tr anscardially. The nonperfused area was seen in the territory of the le ft internal carotid artery. Thrombi were observed from arterioles to c apillaries. Under electron microscopy, endothelial cells were partiall y exfoliated, and the vascular lumen was obstructed by thrombi predomi nantly consisting of platelets, Eight rats with TPA survived more than 60 minutes, whereas only 2 rats survived without the treatment (P<.00 5). Nonperfused areas were 7+/-5% and 50+/-11% of cerebral surface are a in rats with and without TPA treatment, respectively (P<.001). Concl usions Intra-arterial infusion of phenytoin results in a nonperfused a rea in rat cerebrum primarily due to thrombosis of arterioles and capi llaries.