The metabolites of nitric oxide in sickle‐cell disease

Abstract

Plasma NOx concentrations were raised in 22 acute painful crises in SCD. We have measured blood concentrations of nitric oxide metabolites (NOx) in sickle-cell disease (SCD), and shown that they are increased compared with healthy controls (P = 0.002), and haemoglobin E/beta-thalassaemic controls (P = 0.05). Concentrations in steady-state SCD were also higher than in healthy controls (P = 0.04) but not significantly different from the concentrations at the beginning of painful crises (P = 0.34). Importantly, in 12 regularly exchanged sicklers, the mean pre-transfusion NOx concentration did not differ significantly from the control population (P = 0.52), suggesting that the changes in NO metabolism can be reversed. It is unlikely that the increased concentrations of NOx in SCD result from anaemia or haemolysis as the untransfused haemoglobin E/beta-thalassaemics did not show increased levels.

Nitric Oxide-dependent Generation of Reactive Species in Sickle Cell Disease

“…Moreover, NOS2 can serve as a locus for tissue O 2 . production during conditions of low arginine substrate availability, as observed in SCD (22,23). This setting favors the generation of peroxynitrite (ONOO Ϫ ), the nitrating and oxidizing species produced by the radical-radical reaction of O 2 .…”

Oxygen radical inhibition of nitric oxide-dependent vascular function in sickle cell disease

“…For example, vascular production of ⅐ NO seems to be chronically activated to maintain vasodilation, as indicated by low baseline blood pressure (13) and decreased plasma arginine levels (14). Also, decreased pressor responses to angiotensin II (15), renal hyperfiltration (16), a tendency for priapism (17), and elevated plasma nitrite and nitrate (NO 2 Ϫ ϩ NO 3 Ϫ ) levels occur in SCD (18). During vaso-occlusive crisis, an increased metabolic demand for arginine and an inverse relationship between subjective pain scores and plasma NO 2 Ϫ ϩ NO 3 Ϫ levels has been reported (18,19).…”

“…Also, decreased pressor responses to angiotensin II (15), renal hyperfiltration (16), a tendency for priapism (17), and elevated plasma nitrite and nitrate (NO 2 Ϫ ϩ NO 3 Ϫ ) levels occur in SCD (18). During vaso-occlusive crisis, an increased metabolic demand for arginine and an inverse relationship between subjective pain scores and plasma NO 2 Ϫ ϩ NO 3 Ϫ levels has been reported (18,19). Finally, therapeutic benefit has been observed in SCD patients receiving inhaled ⅐ NO and hydroxyurea, a drug frequently used to treat SCD that not only induces fetal Hb levels in SCD patients but also is metabolized to ⅐ NO (20,21).…”

Nitric oxide in gingival crevicular fluid and nitric oxide synthase expression in the gingiva of patients with sickle cell disease

“…A deficient plasma concentration in microcirculation promotes prolonged vascular transit time. In a clinical study plasma NO x concentrations in steady-state SCD patients were significantly higher than in controls and there was no difference compared to the onset of painful crises [16]. Lopez et al [56] studied adult SCD patients with vaso-occlusive crises and reported that both plasma arginine and NO x levels were significantly lower in the SCD patients than in the controls.…”

“…Additionally, it was shown that iNOS inhibition significantly limits tissue ischemia-reperfusion injury in the liver and kidneys [10,11]; however, inhibition of iNOS attenuated ischemia-reperfusion injury in the rat heart [12] and did not affect ischemia-reperfusion injury in the rat lung [13]. Increased levels of iNOS expression were shown in the kidneys of transgenic mice [9], but Nath et al [14] reported the lack of upregulation of iNOS in the intrarenal vasculature and increased expression of iNOS in the [15][16][17] and in vitro [18]. It was reported that NOS activity plays a role in stimulating production of NO x .…”