nitroarginine and Retinal-Degeneration

To investigate if retinal blood flow decreases with progression of the disease in Abyssinian cats with progressive retinal atrophy (PRA), to examine if the choroidal blood flow was affected by the disease, and to determine the uptake of glucose and formation of lactate in the outer retina.. Local blood flow in different parts of the eye was determined with radioactive microspheres, in 9 normal cats and in 10 cats at different stages of PRA. Three blood flow determinations were made in each animal, during control conditions, after IV administration of indomethacin and after subsequent administration of N(omega)-nitro-L-arginine (L-NA). Blood samples from a choroidal vein and a femoral artery were collected to determine the retinal formation of lactate and uptake of glucose.. In Abyssinian cats with PRA (n = 10), the retinal blood flow was significantly (P < or = 0.01) lower than in normal cats (n = 9) during control conditions, 6.4 +/- 1.7 compared with 14.1 +/- 1.9 g min(-1) x (100 g)(-1). The vascular resistance in the iris and ciliary body was significantly higher in the cats at a late stage of PRA, both compared with normal cats and to cats at an early stage of the disease, whereas the choroidal vascular resistance was not significantly affected. Indomethacin had no effect on ocular blood flows in normal cats, but in cats with PRA, iridal blood flow was more than doubled after indomethacin. The retinal formation of lactate was significantly (P < or = 0.001) lower in cats with PRA than in normal cats, 0.111 +/- 0.035 (n = 8) compared with 0.318 +/- 0.024 (n = 8) micromol x min(-1). The uptake of glucose was not significantly different in cats with PRA.. Retinal blood flow is severely decreased in Abyssinian cats at a late stage of retinal degeneration, whereas the choroidal microcirculation is not significantly affected by the disease. At a late stage of retinal degeneration, vascular resistance in the iris is significantly increased, which at least in part could be caused by cyxlooxygenase products.

Topics: Animals; Blood Flow Velocity; Blood Glucose; Cardiovascular Agents; Cats; Choroid; Disease Models, Animal; Disease Progression; Enzyme Inhibitors; Female; Heart Rate; Indomethacin; Lactic Acid; Male; Nitroarginine; Regional Blood Flow; Retina; Retinal Degeneration; Retinal Vessels

The inherited retinal dystrophy observed in Royal College of Surgeons (RCS) rats is a widely used model for the study of the photoreceptor degeneration that occurs in retinitis pigmentosa and macular degeneration. The visual cell degeneration is accompanied by an abnormal accumulation of microglial cells in the retina of RCS rats presenting the dystrophy. In the present study, we show that combined stimulation of RCS dystrophic retinal Müller glial (RMG) cells with interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS) induced the release in culture supernatants of significantly higher amounts of tumor necrosis factor (TNF) and nitric oxide (NO) compared to nondystrophic congenic controls. In contrast, the levels of TNF and NO found in the supernatants from microglial cells were not significantly different in both strains. Interestingly, as shown by thymidine incorporation, microglial cells from RCS dystrophic rats have a prominent capacity of proliferation in culture medium compared to microglia isolated from RCS non dystrophic controls. Incubation of RMG cells and microglia with the stereoselective inhibitor of NOS, NG-monomethyl-L-arginine (L-NMMA), inhibited nitrite release in LPS + IFN-gamma-stimulated RMG cells and microglia. The addition of TGF-beta with LPS + IFN-gamma clearly inhibited TNF release in supernatants from both dystrophic and control rat RMG cells and microglia. While TGF-beta significantly inhibited nitrite synthesis in RMG cells, the effect on nitrite synthesis by microglia was very low. The retinal dystrophy observed in RCS dystrophic rats could result from an abnormal reactivity of RMG and microglial cells to release TNF and NO in response to stimulants. The immunomodulatory cytokine TGF-beta and inhibitors of NOS could be negative regulators in the cytokine network and nitrite synthesis thus interfering with the development of photoreceptor cell death.

Topics: Animals; Cell Culture Techniques; Cell Division; Enzyme Inhibitors; Interferon-gamma; Lipopolysaccharides; Neuroglia; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Rats; Rats, Mutant Strains; Recombinant Proteins; Retina; Retinal Degeneration; Salmonella typhimurium; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha