resonance decreased when nitrite was reduced to NO under acidic conditions. Consistent with these findings, increasing gastric pH with omeprazole (30 mg/kg; p.o.) attenuated the hypotensive responses to nitrite and blunted the enhancement in plasma nitrite concentrations and hypotensive effects induced by TEMPOL. Nitrite-derived NO formation in vivo was confirmed by using the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (C-PTIO), which blunted the responses to oral nitrite. Our results showed that TEMPOL promotes nitrite reduction to NO in the stomach and enhanced plasma nitrite concentrations and the hypotensive effects of oral sodium nitrite through mechanisms critically dependent on gastric pH. Interestingly, the effects of TEMPOL on nitrite-mediated hypotension cannot be explained by increased NO formation in the stomach alone, but rather appear more directly related to increased plasma nitrite levels and reduced nitrate levels during TEMPOL treatment. This may relate to enhanced nitrite uptake or reduced nitrate formation from NO or nitrite.

Effects of a Novel Thiol Antioxidant, N-Acetylcysteine Amide (NACA), on Reversing Sodium Selenite-Induced Cataracts in Wistar Rats Shakila Tobwala1, Sri Krishna Yasaswi Maddirala1, and Nuran Ercal1 1Missouri University of Science and Technology, United States Cataract, the opacification of an eye lens, is a common pathological abnormality of the lens accounting for approximately 50% of all blindness. Age is often considered to be the biggest risk factor for cataracts. the lens depends on a balanced redox state for maintaining its transparency, and a high content of glutathione (GSH) in the lens is believed to play a key role in doing so. Oxidative damage is a prominent feature of age-related cataracts and, therefore, the present study was sought to evaluate the efficacy of a novel thiol antioxidant, N-acetylcysteine amide (NACA), in preventing selenite-induced cataractogenesis. in the present study, Wistar rat pups were divided into a control group, a NACA-only group, a sodium-selenite-induced cataract group, and a NACA-treated cataract group. the rat lenses in both the control and the NACA-only groups were clear, whereas 75% of the pups within the sodium-selenite-induced group developed Grade 4 cataracts. It was found that treatment with NACA eye drops for 9 weeks reversed Grade 4 cataracts to Grades 3 or 2 in all the rats (0% Grade 4) by increasing the GSH/GSSG ratio and glutathione reductase enzyme activity, and decreasing lipid peroxidation. These results suggest that application of NACA eye drops is able to significantly retard selenite-induced cataractogenesis and may be developed into a potential therapeutic agent for the prevention and cure of age-related cataracts.

We Have Come a Long Way with Mn Porphyrins: from Superoxide Dismutation to H2O2-Driven Pathways Artak Tovmasyan1, Tin Weitner1, Melba Jaramillo2, Rudolf Wedmann3, Emily R. H. Roberts1, Kam W. Leong1, Milos Filipovic3, Ivana Ivanovic-Burmazovic3, Ludmil Benov4, Margaret E. Tome2, and Ines Batinic-Haberle1 1Duke University, United States, 2University of Arizona, United States, 3Friedrich-Alexander University, Erlangen-Nurnberg, Germany, 4Kuwait University, Kuwait

Recent findings indicate that the mechanism of Mn porphyrin (MnP)-based SOD mimics may be both anti- and pro-oxidative. the nature of in vivo behavior would be dominated by the redox status of their microenvironment. Deduced from aqueous chemistry data (with related rate constants) and in vitro and in vivo studies, we report herein the possible cellular pathways that could contribute to H2O2 production by MnPs (A) and subsequent coupling with H2O2 in catalyzing the oxidation of vital cellular components (D). However, if H2O2 is produced in an environment abundant with H2O2-removing systems (C), no consequential oxidative events would occur due to MnP/H2O2 cycling. Catalases and peroxidases could even be upregulated as a result of an adaptive response, such as the scenario simulated by treatment of E. coli with MnP/ascorbate or rats with MnP/thiol in a kidney I/R model. Yet, with insufficient levels/activity of H2O2-removing enzymes and/or H2O2 generation above the threshold that cells could metabolize, apoptosis would occur, as shown with bacterial and mammalian cells. MnPs may also utilize H2O2 to deplete NADPH/NADH and GSH pools. the latter reaction leads to thiyl radical formation and glutathionylation of protein thiols, e.g. p65 subunit of NF- B and complexes I, III and IV of electron transport chain, which in turn suppresses the ATP production. MnPs could also induce lipid oxidation and peroxidation when coupled with H2O2. Due to the ability of radiation and certain chemotherapeutics to produce peroxide in situ, we have hypothesized and demonstrated the radio- and chemosensitizing effects of MnPs in animal models (B). Support: NIH U19AI067798; W.H. Coulter Foundation.

doi: 10.1016/j.freeradbiomed.2013.10.729

doi: 10.1016/j.freeradbiomed.2013.10.730

doi: 10.1016/j.freeradbiomed.2013.10.731