Up-regulation of renal and vascular nitric oxide synthase in iron-deficiency anemia

Anemia is frequently associated with increased cardiac output and reduced vascular resistance. The latter has been attributed to reduced inactivation of nitric oxide (NO) by hemoglobin. We hypothesized that in addition to reducing NO inactivation, anemia may up-regulate NO production. To test this hypothesis, male Sprague-Dawley rats with chronic iron-deficiency anemia (produced by multiple phlebotomies and an iron-free diet) were studied. The results were compared with those obtained in a group of normal control animals. The anemic group showed marked increases in urinary excretion, plasma concentration, and renal and aorta tissue contents of NO metabolites (total nitrates and nitrites, NOx). This was accompanied by a significant rise in urinary excretion of cGMP, the second messenger for NO. In addition, NO synthase (NOS) activity and endothelial constitutive (ecNOS) and inducible NOS (iNOS) proteins of the thoracic aorta were markedly increased in the anemic group. Likewise, renal tissue ecNOS and iNOS proteins were greatly increased in the anemic animals. NOS activity and protein values were inversely related to hematocrit and directly related to plasma, tissue and urinary NOx. The constellation of these findings points to an increased NOS expression and NO production as opposed to the mere reduction of NO inactivation in iron-deficiency anemia. Further studies are planned to determine the mechanism of NOS up-regulation in iron-deficiency anemia.