Application of MB as a therapeutic strategy showed a strong effect inhibiting constitutive NOS activity and nNOS expression. Histochemical and immunohistochemical studies support these results, with nNOS localization in ganglionar and amacrine cells. CTL with a significant 60% reduction in PA+MB vs. This was correlated with a 28% significant increment in nNOS expression in PA vs. A significant increase of nNOS activity was observed in retinas of 30 day-old animals subjected to PA compared to CTL (PA=10,8☐,4 CTL=9,1☐,3 pmol/min/mg protein, p<0,05), while PA+MB animals showed no Constitutive NOS enzymatic activity, NADPH diaphorase histochemical method, immunohistochemistry and Western-blot assay for nNOS were used to evaluate retinas. We used 30 days-old male Spregue-Dawley rats (n=5/group) obteined as follows: 1) PA were animals exposed to perinatal asphyxia (20min, at 37☌), 2) PA+MB were animals born from pregnant to term female rats treated with MB (2mg/kg) 30 and 5min before delivery and subjected to PA induction during 20min at 37☌, 3) CTL were born to term animals. We hypothetize the participation of nitric oxide (NO) through the neuronal isoform of the enzyme nitric oxide synthase (nNOS) as trigger of the previously observed structural and molecular alterations, and analyze the application of methylene blue (MB), a NOS inhibitor, as a therapeutic strategy. Furthermore we have identified the involvement of the nitrergic system in this physiopathology. Previously we have demonstrated in this model retinal neurodegeneration, gliosis, and neovascularization, which are compatible with retinopathy of prematuriry (ROP). We conclude that endogenous opioids inhibit the vasoconstriction of these vascular beds during fetal asphyxia.Perinatal asphyxia is able to induce retinal lesions, generating ischemic proliferative retinopathy (IPR) resulting, in severe cases, in blindness. In contrast, kidney and carcass blood flows decreased, and their vascular resistances increased. Heart, brain, and adrenal blood flows increased due to the increase in blood pressure, with no changes in their vascular resistances. Asphyxia caused hypertension, and the fetal arterial blood pressure further increased when asphyxiated fetuses received naloxone. Naloxone solution or the solvent alone was added for the last 20 min. Fetal asphyxia was induced by reducing the uterine blood flow with an inflatable occluder around the common internal iliac artery to approximately 50% of control for 40 min. Thirteen fetal sheep (0.8-0.9 of gestation) were chronically catheterized. We examined the hypothesis that endogenous opioids modify the cardiac output distribution during asphyxia due to changes in the vascular resistance of some fetal organs. Intravenous administration of the opioid receptor antagonist naloxone to asphyxiated fetal sheep increases the arterial blood pressure.
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