NO synthase inhibition modulates NMDA-induced changes in cerebral blood flow and EEG activity.
The effects of nitric oxide synthase (NOS) inhibition on the cerebral blood flow (CBF) and electroencephalographic (EEG) changes accompanying intravenous administration of the excitatory amino acid receptor agonist, N-methyl-D-aspartate (NMDA), were examined in anesthetized rats. Two NOS inhibition strategies were used: chronic N omega-nitro-L-arginine (L-NNA) administration (100 mg.kg-1.day-1 ip, over 4 days) and acute L-NNA administration (100 mg/kg iv infused over 1 h). In both cases, cortical CBF was continuously monitored on study days using laser-Doppler flowmetry, and EEG was recorded, along with measurements of total EEG power. In all rats, the NMDA was given as a 1-min intravenous infusion (20 mg/kg). During all experiments, arterial pressure was controlled within the autoregulatory range. We compared the results from rats treated chronically with L-NNA or its enantiomer. N omega-nitro-D-arginine. In the acute treatment group, two NMDA infusions were given, separated by 90 min, interposed by a 1-h L-NNA infusion. Control rats received saline in place of the L-NNA. Both L-NNA treatment protocols significantly increased the duration of NMDA-induced alterations in EEG activity, relative to controls. NMDA induced a transient 40-100% increase in cortical CBF that was blocked by acute but not chronic L-NNA administration. These results indicate that 1) under normal circumstances nitric oxide is the principal mediator of NMDA-induced cerebrovasodilation; 2) with chronic NOS inhibition, NMDA-induced vasodilation returns to normal, implying replacement of nitric oxide by other factors; and 3) nitric oxide acts as a negative feedback modulator of NMDA-induced changes in brain activity.
Pelligrino
D A
DA
Department of Anesthesiology, College of Medicine, University of Illinois, Chicago 60612, USA.
Gay
R L
RL
Baughman
V L
VL
Wang
Q
Q
D000818:Animals; D001921:Brain / Q000187:drug effects*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004569:Electroencephalography; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019335:Nitroarginine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
D004791:Enzyme Inhibitors; D019335:Nitroarginine; D016202:N-Methylaspartate; D019001:Nitric Oxide Synthase