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-PaCO2 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 greater than or equal to 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-PaCO2 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) F1 alpha (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-PGF1 alpha ratio in vehicle-treated animals was near 2. In animals pretreated with MK-801, at doses of greater than or equal to 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 Ca2+ influx and activate free fatty acid metabolism, leading to probable changes in vascular function and changes in blood-brain barrier permeability.
Stevens
M K
MK
Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota.
Yaksh
T L
TL
D000818:Animals; D001158:Arteries / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D002545:Brain Ischemia / Q000134:cerebrospinal fluid / Q000503:physiopathology*; D002245:Carbon Dioxide / Q000097:blood; D002415:Cats; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D003986:Dibenzocycloheptenes / Q000494:pharmacology*; D016291:Dizocilpine Maleate; D004569:Electroencephalography; D005260:Female; D006863:Hydrogen-Ion Concentration; D008297:Male; D010313:Partial Pressure; D011453:Prostaglandins / Q000134:cerebrospinal fluid; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000187:drug effects*
D003986:Dibenzocycloheptenes; D011453:Prostaglandins; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D002245:Carbon Dioxide; D016291:Dizocilpine Maleate