Nitric Oxide Donor Compounds for the Treatment of Hemolytic Conditions

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DESCRIPTION (provided by applicant): Nitric oxide (NO) is an endothelial derived relaxation factor; it is synthesized in the endothelium surrounding blood vessels and signals to relax smooth muscles and increase blood flow. Hemoglobin (Hb) actively scavenges NO at nearly diffusion-limited rates. In normal physiology, NO scavenging by Hb is reduced due to compartmentalization in red blood cells in the blood. Several diseased conditions including hemolytic anemias such as sickle cell disease and paroxysmal nocturnal hemoglobinuria (PNH), thalassemia intermedia, malaria, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome and cardiopulmonary bypass result in release of Hb into the plasma compartment which efficiently scavenges NO. This increased NO scavenging leads to a host of complications contributing to morbidity and mortality. Administration of NO through inhalation has been shown to restore normal NO responsiveness and shows promise as a treatment for hemolytic conditions. However, NO inhalation is not practical as a means of chronic treatment. The goal of this project is to test (and to some extent synthesize) compounds that can eventually be taken intravenously or orally to treat hemolytic conditions. Unlike many therapeutic compounds, the ones proposed here would be cell-impermeable, acting in the plasma compartment so as to react preferentially with cell-free Hb and thereby inactivate its NO scavenging ability. Lead compounds to be studied include NONOates (NO donors), nitroxyl donors and possibly nitrated lipids and nitrites. A variety of biophysical methods are proposed to test the potential efficacy of the synthesized compounds including absorption and electron paramagnetic resonance spectroscopy and laser diffraction deformability assays. An ideal compound would react preferentially with cell-free (as opposed to red blood cell encapsulated) Hb in a time frame that would allow it to act within its plasma lifetime.