The Search for the Mechanism of Nitric Oxide Release in Hydroxyurea Therapy

Abstract

Hydroxyurea (HU) is an FDA approved drug that has shown promise in the treatment of sickle cell anemia. Increases in the production of nitric oxide metabolites (iron nitrosyl hemoglobin (HbNO), nitrite, and nitrate) have been reported in sickle cell disease patients receiving HU therapy. The exact mechanism by which HU produces HbNO in vivo is still not completely understood. The purpose of this research was to further investigate the reactions of NO and NO-producing compounds on blood and other blood constituents. The kinetics of polymerization and solubility effects of HU and NO were studied for the reaction of sickle cell hemoglobin (HbS) with HU. While HU and NO prolonged the delay time of polymerization for HbS in buffers of high phosphate concentration, NO had no solubilizing effect on HbS under physiological conditions. Experiments involving HU, NO, and hydroxylamine (HA) were conducted to determine the kinetics and products of their respective reactions with blood and blood constituents, as well as to determine how these NO-producing compounds alleviate some of the symptoms of sickle cell disease.