I. Physiological chemistry of nitric oxide and its metabolites: implications in inflammation.

The role of nitric oxide (NO) in inflammation represents one of the most studied yet controversial subjects in physiology. A number of reports have demonstrated that NO possesses potent anti-inflammatory properties, whereas an equally impressive number of studies suggest that NO may promote inflammation-induced cell and tissue dysfunction. The reasons for these apparent paradoxical observations are not entirely clear; however, we propose that understanding the physiological chemistry of NO and its metabolites will provide a blueprint by which one may distinguish the regulatory/anti-inflammatory properties of NO from its deleterious/proinflammatory effects. The physiological chemistry of NO is complex and encompasses numerous potential reactions. In an attempt to simplify the understanding of this chemistry, the physiological aspects of NO chemistry may be categorized into direct and indirect effects. This type of classification allows for consideration of timing, location, and rate of production of NO and the relevant targets likely to be affected. Direct effects are those reactions in which NO interacts directly with a biological molecule or target and are thought to occur under normal physiological conditions when the rates of NO production are low. Generally, these types of reactions may serve regulatory and/or anti-inflammatory functions. Indirect effects, on the other hand, are those reactions mediated by NO-derived intermediates such as reactive nitrogen oxide species derived from the reaction of NO with oxygen or superoxide and are produced when fluxes of NO are enhanced. We postulate that these types of reactions may predominate during times of active inflammation. Consideration of the physiological chemistry of NO and its metabolites will hopefully allow one to identify which of the many NO-dependent reactions are important in modulating the inflammatory response and may help in the design of new therapeutic strategies for the treatment of inflammatory tissue injury.