Systematic Studies on the Effects of the NMDA Receptor Antagonist MK-801 on Cerebral Blood Flow and Responsivity,EEG,and Blood-Brain Barrier following Complete Reversible Cerebral Ischemia

The dose-dependent effects of MK-801, a glutamate receptor antagonist, on changes in CBF, CBF-P_a^co₂ responsiveness (¹³³Xe clearance), EEG, and blood-brain barrier (methylene blue) were examined after a 15-min period of reversible complete global ischemia induced in halothane-anesthetized cats by occlusion of the vertebral and carotid arteries. Pretreatment with doses of MK-801 of ≥0.5 mg/kg had no effect on resting CBF measures and produced a dose-dependent slowing of the dominant EEG frequency. In animals receiving this agent, there was an almost immediate return of baseline EEG patterns upon reinstitution of flow, no hypoperfusion after 2 h of reflow, preservation of CBF and CBF-P_a^co₂ responsiveness, and maintenance of blood-brain barrier integrity. In contrast, parallel control animals and animals treated with MK-801 at a dose of 0.1 mg/kg exhibited poor recovery based on the above parameters. MK-801 also diminished in a dose-dependent manner the CSF levels of 6-keto-prostaglandin (PG) F_1α (stable metabolite of PGI₂) and thromboxane (Tx) B₂ (stable metabolite of TxA₂), which were otherwise elevated in vehicle-treated animals 2 h after reflow. Of particular interest, the CSF TxB₂/6-keto-PGF_1α ratio in vehicle-treated animals was near 2. In animals pretreated with MK-801, at doses of ≥0.5 mg/kg, this ratio was nearly 1. These observations are consistent with a possible triggering role of glutamate release in initiating at least part of the acute sequelae of ischemia. Such release in an electrically silent cell would increase C_a²⁺ influx and activate free fatty acid metabolism, leading to probable changes in vascular function and changes in blood-brain barrier permeability.