Hydroxyurea effects on blood vessels. Hydroxyurea oxidizes oxy- and deoxy-hemoglobin to methemoglobin (metHb), which may react directly with other molecules of hydroxurea (or via hydroxylamine) to form nitrosylhemoglobin (HbNO), which can slowly release NO. Hydroxyurea may also chemically or enzymatically (peroxidase, urease, catalase) decompose to NO, as well as directly effect intracellular levels of cations, production of VCAM-1, and red-cell adhesion, among others. Our data show that hydroxyurea also stimulates the phosphorylation and thus activation of endothelial NOS (eNOS) with resultant production of NO. This effect is modulated by increased intracellular calcium levels and increases in cAMP, which stimulates phosphorylation at Ser1177 by PKA. NO production is regulated by both PKA and PKB/Akt. The increase in eNOS activity presumably leads to increases in cGMP in endothelial and surrounding cells; this increase results in many of the pleiotropic effects of endothelial-produced NO. SM indicates smooth muscle cells; E, endothelial cells.