Glutamate-induced disruption of the blood-brain barrier in rats. Role of nitric oxide.
OBJECTIVE
The first goal of this study was to determine the effect of glutamate on permeability and reactivity of the cerebral microcirculation. The second goal of this study was to determine a possible role for nitric oxide in the effects of glutamate on the cerebral microcirculation.


METHODS
We examined the pial microcirculation in rats with intravital microscopy. Permeability of the blood-brain barrier was quantified by the clearance of fluorescent-labeled dextran (molecular weight, 10 000 D; FITC-dextran-10K) before and during application of glutamate (0.1 and 1.0 mmol/L). In addition, we examined the permeability of the blood-brain barrier during application of a nitric oxide donor, S-nitroso-acetyl-penicillamine (SNAP; 10 mumol/L). Diameter of pial arterioles was measured before and during application of glutamate or SNAP. To determine a potential role for nitric oxide in glutamate-induced effects on the cerebral microcirculation, we examined the effects of NG-monomethyl-L-arginine (10 mumol/L).


RESULTS
In control rats, clearance of FITC-dextran-10K from pial vessels was minimal, and the diameter of pial arterioles remained constant during the experimental period. Topical application of glutamate (0.1 and 1.0 mmol/L) and SNAP (10 mumol/L) produced an increase in clearance of FITC-dextran-10K and in diameter of pial arterioles. In addition, NG-monomethyl-L-arginine (10 mumol) attenuated glutamate-induced increases in permeability of the blood brain barrier and glutamate-induced dilatation of cerebral arterioles.


CONCLUSIONS
The findings of the present study suggest that glutamate, a major neurotransmitter in the brain, increases permeability of the blood-brain barrier to low-molecular-weight molecules and dilates cerebral arterioles via a nitric oxide-dependent mechanism.
Mayhan
W G
WG
Department of Physiology and Biophysics, University of Nebraska Medical Center, Omaha 68198-4575, USA.
Didion
S P
SP
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001160:Arterioles / Q000187:drug effects / Q000502:physiology; D001812:Blood-Brain Barrier / Q000187:drug effects*; D003911:Dextrans; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives; D018698:Glutamic Acid / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010841:Pia Mater / Q000098:blood supply*; D051381:Rats; D011920:Rats, Inbred WF; D012016:Reference Values; D026423:S-Nitroso-N-Acetylpenicillamine; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology*; D019323:omega-N-Methylarginine
D003911:Dextrans; D014665:Vasodilator Agents; C015219:fluorescein isothiocyanate dextran; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D018698:Glutamic Acid; D026423:S-Nitroso-N-Acetylpenicillamine; D001120:Arginine; D010396:Penicillamine; D016650:Fluorescein-5-isothiocyanate