In a study that could lead to better sickle cell disease treatments with fewer side effects, Michigan State University researchers have determined a new mechanism of action for the drug hydroxyurea (Eur. J. Pharmacol., DOI: 10.1016/j.ejphar.2010.07.012). Hydroxyurea is an approved medication for treating sickle cell disease, a life-span-shortening condition caused by a hemoglobin mutation. But the way the drug works at the molecular level is not clearly understood. A leading hypothesis is that the drug boosts red blood cell production of fetal hemoglobin, which binds oxygen with unusually high affinity and thus alleviates sickle cell symptoms. Michigan State’s Dana M. Spence and coworkers now report using flow-based assays, atomic absorption spectroscopy, electron paramagnetic resonance, and other techniques to determine that hydroxyurea instead stimulates the production of nitric oxide in red blood cells. The boost in NO increases the cells’ ability to release adenosine triphosphate, which in turn improves blood flow. The findings could lead to new or improved sickle cell drugs that target the NO and ATP pathways in blood cells, the researchers note.