Hydroxyurea-mediated regulation of erythrocyte arg

Abstract

Currently, hydroxyurea (HU), a potent inducer of fetal hemoglobin (Hb F), is the only approved drug for the management of sickle cell disease (SCD).Although the mechanism of induction of Hb F by HU is still unknown, but studies have shown that HU increases Hb F synthesis in response to activation of soluble guanylyl cyclase (sGC), which increases the production of NO. The deficiency in NO due to increased arginase levels may play a role in the pathophysiology of SCD. In this study, we determined the effects of HU on the arginase and nitric oxide synthase (NOS) activities in SCD (N=23) patients and normal control (N = 12) subjects. The results showed that the arginase activity in patients who were on HU therapy were significantly lower than those in SS patients who were not on HU therapy (3.8 ± 1.2 vs 6.6 ± 2.4 U/gHb) and the arginase activity was comparable with those of HbAA volunteers. The NOS activity was higher in patients who were on HU therapy than those who were not on HU therapy (0.72 ± 0.4 vs 0.35 ± 0.15 nmole/ml/min). These data suggest that one of the beneficial effects of HU in vivo may involve the suppression of arginase activity and a concomitant induction of NOS activity, hence an increased production of NO. The outcome of this study may lead to development of improved NO based treatment for SCD.