Induction of cerebral thrombosis with phenytoin in rats.

Abstract

This study was conducted to explore whether intra-arterial infusion of phenytoin causes cerebral ischemia and to examine the mechanism of cerebral ischemia induced by phenytoin. Ten rats were infused with phenytoin (150 microL, 3.75 mg) retrogradely from the left external carotid artery, followed by perfusion of carbon black transcardially. The removed brain was photographed from above, and the nonperfused area was compared with control rats (n = 10) with the use of an image analyzer. Eight animals with or without phenytoin treatment were perfusion-fixed for transmission electron microscopic analyses of cerebral vasculature. To determine the effect of tissue plasminogen 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). All rats suffered from respiratory distress 25 to 40 minutes after the injection and received carbon black transcardially. The nonperfused area was seen in the territory of the left internal carotid artery. Thrombi were observed from arterioles to capillaries. Under electron microscopy, endothelial cells were partially exfoliated, and the vascular lumen was obstructed by thrombi predominantly consisting of platelets. Eight rats with TPA survived more than 60 minutes, whereas only 2 rats survived without the treatment (P < .005). Nonperfused areas were 7 +/- 5% and 50 +/- 11% of cerebral surface area in rats with and without TPA treatment, respectively (P < .001). Intra-arterial infusion of phenytoin results in a nonperfused area in rat cerebrum primarily due to thrombosis of arterioles and capillaries.