Scavengers of peroxynitrite and selective inhibitors of nitric oxide synthase have been invented and found to have remarkable protective effects as anti-inflammatory agents in experimental models of arthritis, inflammatory bowel disease, allergic encephalomyelitis, endotoxic shock, hemorrhagic shock, and cardiac transplant rejection. Inhibitors of the PARS pathway similarly have been shown to be protective in a variety of inflammatory models. Together these observations formed the basis for the discovery of a novel injury pathway of inflammatory injury in which peroxynitrite-mediated genetic injury triggers PARS activation, resulting in NAD and ATP depletion and cellular dysfunction. The ability of nitric oxide, per se, to induce cellular injury has also been explored, independent of the effects of peroxynitrite. Nitric oxide was found to inactivate aconitase under conditions of hypoxia and acidosis, suggesting that a powerful synergy may be created in circulatory shock whereby ischemia potentiates the toxicity of nitrogen-centered free radicals.
Current approaches using inhaled nitric oxide are cumbersome and potentially toxic.
These compounds owe their selectivity, when administered by an aerosol route, to a charged amino substituent which renders them impermeable to transepithelial flux. Data from various porcine models of pulmonary hypertension, including oleic-acid induced ARDS, demonstrate that these compounds reduce pulmonary hypertension and pulmonary shunt without a corresponding effect on systemic vascular resistance. Current work focuses on expanding the range of compounds of this class, in order to optimize a lead compound which will be a clinically useful pulmonary vasodilator. Serving infants to adolescents, Children's Hospital Medical Center of Cincinnati is an international leader in pediatric healthcare, research and education.