Nitroxyl and Nitric Oxide Producing Reactions of Hydroxyurea and Related Compound

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The long-term goal of the proposed research is to further develop and understand the nitroxyl (HNO) and nitric oxide (NO) producing reactions of hydroxyurea and related compounds. Hydroxyurea has gained clinical approval for treatment of sickle cell disease and exciting work reveals important roles for HNO/NO in both the pathophysiology and treatment of this disease. Previously studies funded by this grant identify C-nitroso species and nitroxyl (HNO) as important components in NO formation from hydroxyurea. The development of new HNO/NO donors based upon C-nitroso compounds will define new structural entities with unique cardiovascular properties. This research goal is based on the hypothesis that C-nitroso compounds act as competent HNO and donors with unique biological effects. The specific research aims in relation to this hypothesis are: i) To determine the reaction of C-nitroso compound-derived HNO with the identified heme-containing proteins catalase, soluble guanylate cyclase and cytochrome P450 by examining the kinetics, reaction products and structural requirements of these reactions as well as the extent of enzyme activation/inhibition; ii) to determine whether C-nitroso compounds act as NO/HNO donors by preparing and characterizing these compounds as NO/HNO donors; and iii) to determine the interaction of these new NO/HNO donors with biological target molecules and tissues, including hemoglobin, soluble guanylate cyclase, catalase, the peroxisomal proliferator-activated receptor gamma (PPAR), pre-constricted blood vessels and cardiac tissue. The achievement of these research goals will be approached through the sequential combination of chemical synthesis and characterization, biochemical and biophysical analysis and physiological study. The results from these studies should enhance our ability to use HNO/NO donors as treatments for sickle cell disease, other anemias and congestive heart failure. .