Pre- and postischemic effects of the NMDA receptor antagonist dizocilpine maleate (MK-801) on collateral cerebral blood flow.
The authors studied the effects of pre- and postischemic administration of dizocilpine maleate (MK-801) on collateral and regional cerebral blood flow (CBF). The ischemic penumbra appears to benefit most from the neuroprotective effects of MK-801. The precise mechanism by which MK-801 provides this neuroprotection remains controversial. Alterations in CBF have been demonstrated with MK-801 administration, but whether the response is an increase or decrease in flow has remained unclear. A left-sided craniectomy was performed in 20 dogs. A branch of the middle cerebral artery (MCA) was cannulated and collateral blood supply-dependent tissue (CDT) was identified using the "shadow flow" technique. Regional CBF was measured using radiolabeled microspheres. Six dogs received MK-801 (1 mg/kg administered intravenously) before they underwent MCA branch occlusion; the remaining 14 dogs received MK-801 after they underwent MCA occlusion. Cerebral blood flow and vascular pressures were measured 30 and 60 minutes after MK-801 administration. In animals that received MK-801 before MCA occlusion, CBF did not change significantly from baseline values before or after occlusion. In contrast, in animals that received MK-801 after MCA occlusion, CBF was significantly reduced in all regions of the brain, including the CDT. Collateral blood supply-dependent tissue showed a 51.7% reduction in flow, whereas normal CBF was reduced by 29.7%. The MK-801 induced cerebral vasoconstriction in both groups. The neuroprotective effects of MK-801 do not appear to be caused by the augmentation of collateral or global cerebral circulation and, in fact, may block the glutamate-mediated vasodilation that occurs during ischemia.
Robertson
S C
SC
Division of Neurosurgery, University of Iowa College of Medicine, Iowa City 52242, USA.
Wetjen
N M
NM
Beer
B J
BJ
Loftus
C M
CM
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002545:Brain Ischemia / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D002536:Cerebral Arteries / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D003097:Collateral Circulation / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000627:therapeutic use*; D004285:Dogs; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D007275:Injections, Intravenous; D008863:Microspheres; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D014655:Vascular Resistance / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000627:therapeutic use; D014664:Vasodilation / Q000187:drug effects
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D019275:Radiopharmaceuticals; D016194:Receptors, N-Methyl-D-Aspartate; D014662:Vasoconstrictor Agents; D016291:Dizocilpine Maleate