Intracameral muramyl dipeptide-induced paracellular permeability associated with decreased glutamate transporter and gamma -glutamyltranspeptidase activities.
Muramyl dipeptide (MDP) (N -acetylmuramyl- L -alanyl- D - isoglutamine) was injected intracamerally to test if MDP applied to the aqueous side of the blood-aqueous barrier would increase paracellular permeability in association with diminished uptake of glutamate. The symptoms of anterior uveitis, i.e., increase in vascular dilatation, could be detected as early as 30 min post MDP injection while aqueous protein concentration did not increase at this time suggesting an initial dissociation between the circulatory and epithelial barrier responses. However, at 45 min, the aqueous protein concentration increased 10-fold (201+/-174 to 2094+/-1835 micrograms ml-1;P<0.001) rising progressively to 20-fold above the control eye at 60 min post injection (254+/-194 vs. 5038+/-2514 micrograms ml-1;P<0.001). Epithelial cell barrier paracellular permeability increased at 45 min as evidenced by the enhanced efflux of radiolabelled L -glucose out of the aqueous (8% and 13% faster than control at 45 and 60 min post MDP injection, respectively), coinciding with the accelerated protein influx. A near 50% reduction in efflux of both radiolabelled glutamate and D -aspartate was consistent with reduced glutamate uptake by the transport system X-AG. In addition, a 24% decline in aqueous glutamate, but not aspartate, was detected in the aqueous of the MDP-treated eyes in association with a 54% decrease in iris/ciliary body gamma-glutamyltranspeptidase activity consistent with reduced de novo glutamate formation from glutamine. The aqueous of MDP injected eyes also had 6-fold and 34-fold higher prostaglandin E2and F2alphaconcentrations, respectively (P</=0.03) as well as reduced AH bicarbonate concentration. These results suggest that increased paracellular permeability is associated with diminished gamma-glutamyltranspepidase-mediated glutamate production, X-AGtransport activity, and cellular acidosis in the MDP-induced prostaglandin-mediated inflammation.
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology*; D027322:Amino Acid Transport System X-AG; D000818:Animals; D001082:Aqueous Humor / Q000187:drug effects*; D001639:Bicarbonates / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D018916:Blood-Aqueous Barrier / Q000187:drug effects*; D015237:Dinoprost / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D005136:Eye Proteins / Q000378:metabolism; D005947:Glucose / Q000493:pharmacokinetics; D007429:Intraocular Pressure / Q000187:drug effects; D010539:Permeability; D011817:Rabbits; D014606:Uveitis, Anterior / Q000139:chemically induced*; D005723:gamma-Glutamyltransferase / Q000378:metabolism