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

Abstract

In 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 0.4, 4 and 40 micromol/min into the brachial artery augmented mean venous plasma nitrite concentrations (P < 0.0001) and stimulated forearm blood flow up to 77 +/- 11% above baseline (P < 0.0001), 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.

Figures

Fig 1

Schematic diagram of forearm blood flow study. Upper boxes indicate timing of arterial infusions of sodium nitroprusside (SNP), the NO synthase inhibitor L-NMMA, and sodium nitrite. Lower boxes indicate timing of blood sampling and echocardiography. Venous occlusion plethysmography measurements of forearm blood flow were made prior to each set of infusions and immediately following each infusion.

Fig 2

Sodium nitrite infusions increase regional blood flow and venous plasma nitrite levels as a function of nitrite dosing. (A) Sodium nitrite infusions into the brachial artery of patients with SCD increases forearm blood flow in a dose-dependent manner (P < 0·0001). Values represent means ± SEM. (B) Mean venous plasma concentrations increase from baseline in a dose-dependent manner. The systemic mean venous plasma nitrite concentration is from the contralateral arm 5 min after maximal nitrite infusion. The last bar represents the mean venous plasma nitrite concentration 30 min after the maximal nitrite infusion dose. Bars represent mean ± SEM. *P < 0·05; **P < 0·001, paired t-test compared to baseline. (C) Sodium nitrite dosing controlled for weight and expressed as µmol/kg, correlates positively with the corresponding venous plasma nitrite concentration sampled from the ipsilateral vein after arterial infusions (Spearman r = 0·93, P < 0·0001). The solid line represents the regression line, and the dashed lines the 95% confidence limits.

Fig 3

Sodium nitrite dosing and venous plasma nitrite concentrations correlate positively with regional forearm blood flow in patients with sickle cell disease. (A) Sodium nitrite infusions, expressed as µmol/kg, correlate positively with percentage increase over baseline forearm blood flow in patients with SCD in steady state (Spearman r = 0·70, P < 0·0001). (B) The corresponding venous plasma nitrite concentrations positively correlated with the regional forearm blood flow circulation, expressed in standard units of ml/min/100 ml of forearm tissue (Spearman r = 0·51, P = 0·003). The solid lines represent the regression line, and the dashed lines the 95% confidence limits.

Fig 4

Interaction of nitrite and nitroprusside on regional blood flow. (A) Baseline and nitroprusside-induced absolute blood flow (dashed line) is enhanced globally following sodium nitrite infusion (solid line, P < 0·001, two-way anova with repeated measures), although (B) the degree of vasodilation above baseline is not changed. (C) The vasodilatory response to the maximal dose nitroprusside correlates highly with the response to the maximal nitrite dose (Pearson correlation, r = 0·75, P = 0·002). Solid line indicates the regression line, and dotted lines indicate 95% confidence limits.