REACTION AND DIFFUSION OF NITRIC OXIDE IN BIOLOGICAL SYSTEMS

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It has been shown that nitric oxide (NO) is widely synthesized and used as a messenger molecule in the body, but that it also has cytotoxic and mutagenic effects and is a potential cause of cancer. The biological importance of NO notwithstanding, information on the spatial or temporal variations in NO concentrations in the body or in cell culture systems continues to be very limited. This is doubly true for reactive intermediates such as nitrous anhydride and peroxynitrite, which may be mediators of adverse health effects due to the local overproduction of NO. It is not technically feasible to measure the concentrations of these compounds under most conditions of interest, yet such information is needed to correlate levels of toxicity and rates of mutation measured in cell cultures with actual levels of exposure, and to extrapolate those findings to pathological situations in the body. Accordingly, mathematical models will be developed to predict the concentrations of NO and related compounds in aqueous solutions, cell cultures, and tissues. Because the various concentrations are determined by a competition between rates of reaction and diffusion, the models will be based on reaction kinetics and on the physical properties governing diffusion through water, across cell membranes, and within cells. The diffusion and reaction of NO and related compounds will be examined in suspensions of cells or cell-like particles, with an emphasis on the permeability and/or reactivity of the lipid bilayer component of cell membranes. The predictions of the reaction-diffusion models will be tested in cell culture systems. Of particular interest are the interactions between cells which generate large amounts of NO and cells which act as targets for its toxic or mutagenic effects. Methods will be developed for the controlled delivery of peroxynitrite in cell cultures. The objective there is to provide known, near-physiological doses of peroxynitrite for "target" cells by chemical and physical means (i.e., without the need for "generator" cells).