Substantial regional and hemispheric differences in brain nitric oxide synthase (NOS) inhibition following intracerebroventricular administration of N omega-nitro-L-arginine (L-NA) and its methyl ester (L-NAME).
Nitric oxide synthase (NOS) enzyme activity was determined in a comprehensive selection of regions of the rat brain. The effects of lateral ventricular administration of N omega-nitro-L-arginine (L-NA, 30 micrograms) and its methyl ester (L-NAME, 3-100 micrograms) on NOS activity were examined in the ipsilateral and contralateral areas of 4 of these brain regions and in the cerebellum. NOS activity was determined using a new and rapid ex vivo assay method which ensures minimal dissociation of the enzyme-inhibitor complex. Following infusion of L-NAME, NOS activity was rapidly and dose-dependently inhibited in all brain regions studied (cerebral cortex, striatum, hippocampus, cerebellum and thalamus). However, NOS activity of brain regions within the contralateral hemisphere was inhibited significantly less than in ipsilateral regions, with the exception of the thalamus. The degree of NOS inhibition varied markedly between brain regions within each hemisphere and correlated with their ventricular proximity to the site of NOS inhibitor administration. Therefore, NOS in the thalamus was inhibited most effectively and NOS in the cerebral cortex the least. Within the cerebral cortex further regional differences could be observed, with NOS in the frontal/parietal areas inhibited more effectively than NOS in the temporal/occipital areas. Maximal inhibition of NOS was sustained for approx 6 hr after administration of 30 and 100 micrograms L-NAME. No inhibition of NOS was observed 24 hr after administration. Lateral ventricular administration of the metabolite and active moiety of L-NAME, L-NA, resulted in a similar degree of inhibition and time of inhibitory onset. In contrast, when L-NAME was administered i.p., a significant delay in the onset of NOS inhibition was observed in the above brain regions compared to L-NA. However, no regional or hemispheric differences in NOS inhibition were detected following peripheral administration of these inhibitors. These results indicate that central administration of NOS inhibitors yields a complex pattern of NOS inhibition and that data obtained on brain physiology following the i.c.v. administration of NOS inhibitors, or for that matter any other CNS effector, should therefore be interpreted with extreme caution.
Salter
M
M
Wellcome Research Laboratories, Beckenham, Kent, U.K.
Duffy
C
C
Garthwaite
J
J
Strijbos
P J
PJ
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D001921:Brain / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects; D007278:Injections, Spinal; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D019001:Nitric Oxide Synthase / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013788:Thalamus / Q000187:drug effects; D013997:Time Factors
D004791:Enzyme Inhibitors; D001120:Arginine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester