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

Red cell rigidity, microvascular obstruction, haemolysis, inflammation and infarction are well-recognized pathophysiological mechanisms that lead to the debilitating clinical manifestations of sickle cell disease (SCD) (Stuart & Nagel, 2004). However, recently identified additional mechanisms, including cell free haemoglobin-mediated consumption of nitric oxide (NO), oxidant stress, endothelial dysfunction and chronic ischaemia-reperfusion injury, add to our understanding of the pathobiology of SCD (Belcher et al, 2003). Several lines of evidence suggest that patients with SCD with particularly robust haemolysis accumulate haemoglobin into the plasmatic compartment, resulting in impaired NO bioavailability. Cell-free plasma haemoglobin resulting from intravascular haemolysis in patients with SCD rapidly consumes NO, causing a state of functional resistance to NO-dependent vasodilation (Kaul et al, 2000, 2004; Nath et al, 2000; Belhassen et al, 2001; Reiter et al, 2002; Eberhardt et al, 2003; de Montalembert et al, 2007). Consistent with this model, in patients with the highest plasma haemoglobin levels, the blood flow responses to the NO donor sodium nitroprusside (SNP) are reduced. This consumption of NO is compounded by the limited capacity to increase NO synthesis, a result of low plasma levels of L-arginine (the obligate substrate for NO synthases) being depleted by arginase simultaneously released into blood plasma during intravascular haemolysis (Morris et al, 2005). Chronic haemolysis produces a clinical syndrome of vascular dysfunction that ultimately is associated with pulmonary hypertension, cutaneous ulceration and priapism (Gladwin et al, 2004; Nolan et al, 2005a,b; Kato et al, 2006, 2007). As oxidized haemoglobin cannot react with NO, therapeutic modalities based on the oxidation and inactivation of the plasma cell-free haemoglobin might potentially restore regional NO-dependent blood flow. One potential candidate NO therapeutic agent is sodium nitrite, recently shown by our group to induce vasodilation in healthy human subjects (Cosby et al, 2003). The nitrite anion, used for close to a century at high concentrations as an antidote to cyanide poisoning, may act as a vasodilator at low, physiological concentrations by generating NO in tissues with lower oxygen tension and pH. The mechanism involves a novel physiological function of human haemoglobin as an oxygen-and pH-dependent nitrite reductase (Huang et al, 2005; Isbell et al, 2005; Crawford et al, 2006). As a result, nitrite may serve as a highly useful therapeutic agent to generate NO along the physiological oxygen gradient known to exist in arterial blood, accentuating vasodilation specifically in hypoxic tissue. In addition to vasodilation, nitrite treatment significantly reduces liver, heart and brain ischaemia-reperfusion injury and infarction in animal models, prevents cerebral vasospasm after subarachnoid haemorrhage in primates and decreases pulmonary hypertension in hypoxic newborn sheep (Hunter et al, 2004; Webb et al, 2004; Duranski et al, 2005; Pluta et al, 2005; Hataishi et al, 2006; Jung et al, 2006). We therefore hypothesized that the therapeutic application of nitrite in patients with SCD and other diseases associated with haemolysis and ischaemia-reperfusion injury could provide selective vasodilation to those same vascular tissue beds at risk. This study was designed as a phase I/II trial to address whether nitrite infusions will safely vasodilate the circulation and improve regional forearm blood flow in patients with SCD during steady state, with limited formation of methaemoglobin. We additionally hypothesized that nitrite infusion would oxidize cell-free plasma haemoglobin, decrease NO scavenging, and increase SNP vasodilatory response in patients with SCD.