The focus of this grant proposal is to test the hypothesis that exposure to elevated 02 partial pressures, and to hyperbaric oxygen in particular, will increase the steady state concentration of nitric oxide (NO) in vivo.
The specific aims relate to evaluation of the biochemical and physiological events associated with ventilation using elevated partial pressures of 02. Studies will be performed with rats and isolated, perfused rat lung preparations. There are two specific aims for this proposal: (1) Investigate the in vivo potential mechanism(s) for increases in NO production due to O2 exposures by evaluating (a) elevations in stable products of' NO found in blood and he impact of potentially inhibitory pharmacological agents; (b) measuring O2-mediated changes in brain -NO concentration and their relation to blood flow, and (c) determine -NO-mediated inhibition of circulating blood neutrophil adhesion and also markers of oxidative stress. The second specific aim is to evaluate mechanisms for O2-dependent elevations in NO production using isolated, perfused lung preparations. The two sub-aims are: (a) To investigate variations in NO production due to pharmacological agents and changes in perfusion rates, and (b) To evaluate the role of calcium and other molecular mechanisms for alterations in 'NO production. We hypothesize that vasoconstriction mediated by elevated O2 partial pressures increases endothelial shear stress and this is the proximal stimulus for activation of nitric oxide synthase. The research plan is aimed to test this hypothesis and to look for alternative or additional mechanisms that may influence O2-induced responses.
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