Safety and Feasibility of Long-term Intravenous Sodium Nitrite Infusion in Healthy Volunteers

Abstract

BackgroundInfusion of sodium nitrite could provide sustained therapeutic concentrations of nitric oxide (NO) for the treatment of a variety of vascular disorders. The study was developed to determine the safety and feasibility of prolonged sodium nitrite infusion.MethodologyHealthy volunteers, aged 21 to 60 years old, were candidates for the study performed at the National Institutes of Health (NIH; protocol 05-N-0075) between July 2007 and August 2008. All subjects provided written consent to participate.Twelve subjects (5 males, 7 females; mean age, 38.8±9.2 years (range, 21–56 years)) were intravenously infused with increasing doses of sodium nitrite for 48 hours (starting dose at 4.2 µg/kg/hr; maximal dose of 533.8 µg/kg/hr). Clinical, physiologic and laboratory data before, during and after infusion were analyzed.FindingsThe maximal tolerated dose for intravenous infusion of sodium nitrite was 267 µg/kg/hr. Dose limiting toxicity occurred at 446 µg/kg/hr. Toxicity included a transient asymptomatic decrease of mean arterial blood pressure (more than 15 mmHg) and/or an asymptomatic increase of methemoglobin level above 5%. Nitrite, nitrate, S-nitrosothiols concentrations in plasma and whole blood increased in all subjects and returned to preinfusion baseline values within 12 hours after cessation of the infusion. The mean half-life of nitrite estimated at maximal tolerated dose was 45.3 minutes for plasma and 51.4 minutes for whole blood.ConclusionSodium nitrite can be safely infused intravenously at defined concentrations for prolonged intervals. These results should be valuable for developing studies to investigate new NO treatment paradigms for a variety of clinical disorders, including cerebral vasospasm after subarachnoid hemorrhage, and ischemia of the heart, liver, kidney and brain, as well as organ transplants, blood-brain barrier modulation and pulmonary hypertension.Clinical Trial Registration Information http://www.clinicaltrials.gov; NCT00103025

Blood Pressure–Lowering Effect of Orally Ingested Nitrite Is Abolished by a Proton Pump Inhibitor

“…Although surprising, these results are in fact in line with a previous study by Pluta et al, 36 who reported no changes in blood pressure during sodium nitrite infusions at even higher doses and reaching plasma levels similar or higher than the ones reported here. 36 Similar results showing absence of changes in peripheral blood pressure mediated by nitrite infusions were recently reported also by Omar et al 27 In this regard, although previous studies have clearly showed that nitrite infusions increase peripheral blood flow at plasma concentrations close to the physiological range, 26,35 it seems that nitrite-induced changes in blood pressure requires higher intravenous nitrite doses 35 or, as suggested by the current study, a different administration route. For example, Webb et al 14 reported changes in blood pressure 2 to 3 hours after oral ingestion of inorganic nitrate, when nitrate was cumulatively converted to nitrite by the enterosalivary pathway.…”

“…This is in line with previous studies demonstrating pH-dependent nonenzymatic NO formation from nitrite immediately on contact with the acidic gastric juice. 28,[35][36][37] We cannot fully exclude that NO itself can escape directly into the systemic circulation to affect blood pressure. However, considering the high reactivity of the NO radical, in particular with oxyhemoglobin, another more stable NO reaction product is a more likely candidate for exerting such systemic effect.…”

“…A puzzling observation is the fact that orally ingested nitrate has robust cardiovascular effects despite modest increases in plasma nitrite, 13,15 whereas in some clinical trials systemic nitrite administration, resulting in much higher plasma nitrite, has little or no effect on hemodynamic parameters. [35][36][37] One possibility is that the metabolism and subsequent bioactivation of nitrate or nitrite are influenced by the route of administration. Indeed, recent studies in rodents suggest that gastric acidity may influence the degree of systemic nitrite bioactivity.…”

Pharmacology and therapeutic role of inorganic nitrite and nitrate in vasodilatation

“…Furthermore the apparent lack of tolerance (Haas et al, 1999;Dejam et al, 2007) would be an additional advantage over organic nitrates (Sage et al, 2000). However sustained high dose nitrite infusion can cause methemoglobinemia and hemolysis (Pluta et al, 2011). To date there have been no large scale studies of nitrite infusion in heart failure.…”

“…Of interest, nitrate was used in very high doses (often for weeks) at the beginning of the last century as a diuretic (Butler & Feelisch, 2008). Recent studies by Pluta et al (2011) have investigated the safety and feasibility of long-term intravenous infusion of sodium nitrite in healthy subjects. The authors demonstrated that acute intravenous infusion of sodium nitrite was tolerated up to a maximum dose at 267 μg/kg/h, and that the dose-limiting toxicity was reached at 446 μg/kg/h.…”