dinoprost and peroxynitric-acid

The choroid is the main source of oxygen to the retina. In contrast to the adult, the absence of autoregulation of choroidal blood flow in the newborn leads to hyperoxygenation of the retina. In the immature retina which contains relatively low levels of antioxidants this hyperoxygenation favors peroxidation including the generation of biologically active isoprostanes, and results in vasoconstriction and vascular cytotoxicity leading to ischemia, which predisposes to the development of a vasoproliferative retinopathy, commonly termed retinopathy of prematurity. During frequently encountered oxidative stress to the perinate, the combined absence of vascular autoregulation and excessive oxygen delivery to the eyes of the developing subject is largely the result of a complex epigenetic and genetic interplay between prostanoids and nitric oxide (NO) systems on vasomotor regulation. The effects of certain prostaglandins are NO-dependent; conversely, those of NO have also been found to be largely prostaglandin I(2)-mediated in the eye; and NO synthase expression seems to be significantly regulated by other prostaglandins apparently through activation of functional perinuclear prostanoid receptors which affect gene transcription. The increased production of both prostaglandins and NO in the perinate augment ocular blood flow and as a result oxygen delivery to an immature retina partly devoid of antioxidant defenses. The ensuing peroxidation results in impaired circulation (partly thromboxane A(2)-dependent) and vascular integrity, leading to ischemia which predisposes to abnormal preretinal neovascularization, a major feature of ischemic retinopathy. Because tissue oxygenation is largely dependent upon circulation and critical in the generation of reactive oxygen species, and since the latter exert a major contribution in the pathogenesis of retinopathy of prematurity, it is important to understand the mechanisms that govern ocular blood flow. In this review we focus on the important and complex interaction between prostanoid, NO and peroxidation products on circulatory control of the immature retina.

Topics: Choroid; Dinoprost; Endothelial Growth Factors; Free Radicals; Humans; Infant, Newborn; Infant, Premature; Ischemia; Lipid Peroxidation; Lymphokines; Neovascularization, Pathologic; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Oxygen; Receptors, Prostaglandin E; Retina; Retinal Vessels; Retinopathy of Prematurity; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Peroxynitrite is formed by the reaction of nitric oxide (NO) and superoxide. Since widespread peroxynitrite activity was observed during experimental allergic encephalomyelitis (EAE), the effect of this strong lipid-peroxidizing agent on myelin integrity was examined. Incubation of myelin suspensions with the peroxynitrite donor 3-morpholinosydnonimine (SIN-1) resulted in the formation of the lipid peroxidation product, malondialdehyde (MDA). MDA formation was inhibited in the presence of butylated hydroxytoluene, which interrupts the progression of the lipid peroxidation chain reaction. Superoxide dismutase inhibited the effect of SIN-1, which indicates a role for superoxide, and contradicts a role for its dismutation product, hydrogen peroxide. The latter was confirmed by the failure of the catalase to inhibit MDA formation. Neither NO nor superoxide alone induced significant MDA formation in myelin, indicating that peroxynitrite formation is required for myelin-lipid peroxidation. Interestingly, NO actually inhibited lipid peroxidation in myelin, as demonstrated using simple NO donors. On the other hand, the simultaneous production of superoxide, as achieved with the NO-donor SIN-1, negated the inhibitory effect of NO. Finally, the production of isoprostanes, novel products generated during lipid peroxidation, was examined. Peroxynitrite-induced peroxidation of myelin resulted in isoprostane formation. Furthermore, increased levels of F2-isoprostanes and neuroprostanes were observed in spinal cords of mice during early progressive stages of autoimmune encephalomyelitis.

Topics: Animals; Central Nervous System; Dinoprost; Encephalomyelitis, Autoimmune, Experimental; F2-Isoprostanes; Lipid Peroxidation; Mice; Molsidomine; Myelin Proteins; Myelin Sheath; Nitrates; Nitric Oxide; Nitric Oxide Donors; Oxidants; Penicillamine

Lipid peroxidation is a component of various pathologies associated with nitric oxide (NO). It has been suggested that in vivo production of peroxynitrite (ONOO-) is responsible for the detrimental effects of pathologies associated with NO. To investigate the role of NO and ONOO- in the formation of specific lipid peroxidation products, liposomes of phosphatidylcholine were incubated at 37 degrees C for 1 h with various NO sources [NO, diethylamine NONOate (DEA/NO)] or ONOO-sources [3-morpholinosydnonimine-HCl (Sin-1), ONOO-]. Gas chromatography-mass spectrometry was used to quantify the formation of hydroperoxy- and hydroxyeicosatetraenoic acids (HETEs) and F2-isoprostanes. Peroxynitrite (0.5 mm) caused significant oxidation of phosphatidylcholine liposomes as measured by the increased formation of HETEs and F2-isoprostanes. NO, either added directly to the liposomes as a bolus or delivered by slow diffusion or via the donor compound DEA/NO, caused no lipid peroxidation itself and significantly inhibited both iron- and ONOO--induced lipid peroxidation. Sin-l (1 mM), which releases both NO and superoxide, resulted in minor increases in peroxidation and did not inhibit iron-induced HETE formation. We conclude that peroxynitrite but not nitric oxide can directly cause lipid peroxidation and that NO can act as an antioxidant by terminating lipid radical chain propagation reactions.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Animals; Cattle; Dinoprost; Gas Chromatography-Mass Spectrometry; Hydroxyeicosatetraenoic Acids; Lipid Peroxidation; Liposomes; Liver; Nitrates; Nitric Oxide; Oxidation-Reduction; Phosphatidylcholines

Topics: Arachidonic Acids; Dinoprost; Humans; Kinetics; Lipoproteins, LDL; Molsidomine; Nitrates; Oxidation-Reduction; Platelet Aggregation Inhibitors