Competitive and noncompetitive N-methyl-D-aspartate antagonists modify hypoxia-induced membrane potential changes and protect rat hippocampal slices from functional failure: a quantitative comparison.
Hippocampal slice survival after hypoxia was improved by exposure to competitive and noncompetitive N-methyl-D-aspartate (NMDA) antagonists. The rapid blockade and reappearance of synaptic transmission during hypoxia was not altered by these antagonists. However, [(+)-5-methyl-10, 11-dihydro-5H-dibenzo[a,d] cyclohepten-5, 10-imine maleate (MK-801) (50 microM) and 2-amino-5-phosphonopentanoic acid (dl-AP5) (25 microM) delayed the disappearance of these reactivated orthodromic population spikes. Intracellular recordings showed that MK-801 and dl-AP5 delayed the late, but not early, hypoxic depolarization of pyramidal cells, and improved recovery of membrane potential and input resistance (Rin) in many cells after reoxygenation. No untreated cells showed recovery. Thus, both competitive and noncompetitive NMDA antagonists decreased the hypoxia-induced depolarization and Rin. With the return of evoked population spikes as an index for recovery from hypoxia, the ED50 values for dl-AP5, MK-801, phencyclidine and dextromethorphan were 7.7, 4.5, 7.1 and 75 microM, respectively. Thus, in contrast to their higher affinities for the NMDA receptor MK-801 and phencyclidine were not significantly more potent than dl-AP5 in protecting hippocampal slices from hypoxia, and isobolographic analysis revealed dose-additive interactions. The unexpectedly low potency of the noncompetitive NMDA antagonists in protecting against hypoxia is attributed to magnesium in the buffer and the hypoxia-induced membrane depolarization, both of which have been shown to reduce the effectiveness of noncompetitive NMDA antagonists.
Grigg
J J
JJ
Department of Pharmacology, University of Illinois College of Medicine, Chicago.
Anderson
E G
EG
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D001667:Binding, Competitive; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D016291:Dizocilpine Maleate; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D016202:N-Methylaspartate; D010622:Phencyclidine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D003986:Dibenzocycloheptenes; D001224:Aspartic Acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; D008274:Magnesium; D010622:Phencyclidine