Sodium nitrite promotes regional blood flow in patients with sickle cell disease: a phase I/II study

Abstract

SummaryIn addition to vaso-occlusion by sickled erythrocytes, the pathophysiology of sickle cell disease (SCD) is compounded by the diminished bioavailability of nitric oxide (NO), associated with vasoconstriction, endothelial activation and cell adhesion. We tested the ability of sodium nitrite, which can be converted to NO by deoxyhaemoglobin at acid pH and low oxygen tension, to improve blood flow in patients with SCD. In a phase I/II clinical trial, sodium nitroprusside, NG-monomethyl-L-arginine, and sodium nitrite were infused sequentially into the brachial artery in 14 patients at steady state. In a dose-dependent manner, sodium nitrite infusion rates of 0AE4, 4 and 40 lmol/ min into the brachial artery augmented mean venous plasma nitrite concentrations (P < 0AE0001) and stimulated forearm blood flow up to 77 ± 11% above baseline (P < 0AE0001), measured by venous occlusion strain gauge plethysmography. This nitrite response was blunted significantly compared to controls without SCD, as previously seen with other NO donors. Sodium nitrite infusions were well tolerated without hypotension, clinically significant methaemoglobinaemia or other untoward events. The unique pharmacological properties of nitrite as a hypoxia-potentiated vasodilator and cytoprotective agent in the setting of ischaemia-reperfusion injury make this anion a plausible NO donor for future clinical trials in SCD.

Novel Small Molecule Therapeutics for Sickle Cell Disease: Nitric Oxide, Carbon Monoxide, Nitrite, and Apolipoprotein A-I

“…Our group has recently observed that nitrite infusion in the brachial artery stimulates regional blood flow in 14 patients with SCD. 24 In a phase I/II open label study, we found statistically significant, dose-dependent rises in forearm blood flow by venous occlusion strain gauge plethysmography with sodium nitrite infusions of 0.36, 3.6 and 36 µmol/min, up to 77 ± 11% above baseline (P < .0001) ( Figure 5). Consistent with a NO donor mechanism, the nitrite response in SCD was blunted significantly compared to healthy volunteers, and correlated to the vasodilatory response to another well-known NO donor, sodium nitroprusside (r = 0.75, P = .002).…”

Pharmacology and therapeutic role of inorganic nitrite and nitrate in vasodilatation

“…However, the response/sensitivity to nitrite was reduced in patients with sickle cell disease (Mack et al, 2008) (continued on next page)…”

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“…Sodium nitrite has unique pharmacological and industrial properties; it has been used in human and veterinary medicines as a hypoxic potentiates vasodilators and cytoprotective agent in ischemic conditions 1,2 , also as bronchodilator, intestinal relaxant, and antidote for cyanide poisoning 3 . On the other hand, it's properties make it useful in many industrial fields, such as food industry, which is commonly used as a food additive (E249 and E250) especially in curing meat and fish, due to its action as a preservative to prevent microbial contamination 2 and to prevent rancidity by inhibit lipid oxidation 4,5 and as a color fixative to keep the appearance and taste of the cured meat looks like a fresh meat 3 .…”