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Oral presentation

There is mounting evidence to believe that only part of the actions of nitric oxide (NO) is mediated via stimulation of soluble guanylyl cyclase and formation of the second messenger, cyclic GMP, and that direct interactions of NO with heme and thiol-containing cellular targets may play a more important role in cell signalling than hitherto assumed. In vitro, the exposure of numerous biomolecules to rather high fluxes of NO and related species has been shown to lead to transient nitrosation or nitrosylation that often is associated with a change in protein function and/or enzyme activity. Whether those reactions, however, occur under basal, non-inflammatory conditions in vivo is unclear. Using the rat as an animal model, we sought to investigate to what extent nitros(yl)ated products are physiologically present in blood and various organs, and whether their concentrations are affected by changes in tissue oxygenation. We find that, besides nitrite and nitrate, endogenous nitroso and nitrosyl species exist not only in blood, but prevail throughout the entire organ system. In addition to the ubiquitous occurrence of S-nitrosothiols (RSNO) and N-nitrosamines (RNNO), nitrosyl-heme species are found in erythrocytes, brain, heart, liver and kidney. Systemic inhibition of constitutive NOS activity over 0.5-3 hours leads to differential depletion of tissue nitroso and nitrosyl species, suggesting that the in vivo half-life of most of these NO-derived products is on the order of minutes to hours. Intraperitoneal application of lipopolysaccharide produced a systemic inflammation that was accompanied by differential increases in nitrosation levels, suggesting that endogenous nitroso/nitrosyl products may represent sensitive markers of local nitrosative stress. The rapid decreases in tissue concentrations during the initial phase of global hypoxia in unstimulated animals are consistent with a possible regulatory role of these products in hypoxic vasodilatation, whereas their gradual elevation above baseline during prolonged hypoxic periods suggests involvement in the protective effects of ischemic preconditioning.

This work has been funded in part by NIH grant HL69029 (to MF).

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