Arginine therapy: a novel strategy to induce nitric oxide production in sickle cell disease

Abstract

To determine the effects of l‐arginine (l‐Arg) supplementation on nitric oxide metabolite (NOx) production, oral l‐Arg was given to normal controls, sickle cell disease (SCD) patients at steady state and SCD patients hospitalized with a vaso‐occlusive crisis (VOC). l‐Arg (0·1 g/kg) increased NOx formation by 18·8 ± 68% in normal controls, whereas steady‐state SCD patients demonstrated a paradoxical decrease in NOx of −16·7 ± 4% (P = 0·004). In contrast, patients with VOC demonstrated a dramatic increase in NOx production by +77·7 ± 103%, a response that was dose dependent. l‐Arg appears to be the rate‐limiting step in NOx production during VOC. Oral arginine may therefore benefit SCD patients by inducing an increase in NO production during VOC.

A randomized, placebo-controlled trial of arginine therapy for the treatment of children with sickle cell disease hospitalized with vaso-occlusive pain episodes

“…32 Short-term arginine therapy improved pulmonary hypertension in SCD, 22 and acutely increased both plasma NO x and exhaled NO when administered to ethnically matched normal controls and SCD patients with VOE. 20,33 However when given to SCD patients at steady-state, a paradoxical decrease in plasma NO x ; this decrease is not overcome by higher doses, 20 indicating that arginine is metabolized differently in SCD than in healthy volunteers, and differently in SCD at steady-state than during periods of acute illness including painful VOE and ACS. 16,20,33 These early observations may explain the negative outcome of the Comprehensive Sickle Cell Centers' (CSCC) arginine trial, 34 particularly since the primary outcome measure of that study was an increase in plasma NO x concentration, a biomarker which actually decreases with arginine supplementation in SCD patients at steadystate.…”

“…Of interest, low plasma arginine alone was a sensitive predictor for admission, 16 while NO x levels were not, suggesting a function for arginine bioavailability in VOE severity that goes beyond NO. Although supplemental arginine increases plasma NO x in normal controls, when given to SCD patients at steady-state, a paradoxical decrease in NO x occurs that is not overcome by higher doses, 20 indicating that arginine is metabolized differently in patients with SCD than in healthy volunteers. However, when a single dose of arginine is given to patients with SCD during VOE, there is a robust dosedependent increase in plasma NO x .…”

“…16,20,33 These early observations may explain the negative outcome of the Comprehensive Sickle Cell Centers' (CSCC) arginine trial, 34 particularly since the primary outcome measure of that study was an increase in plasma NO x concentration, a biomarker which actually decreases with arginine supplementation in SCD patients at steadystate. 20 Furthermore, low-dose arginine therapy is likely to be sub-therapeutic in SCD, and may represent an additional flaw in the design of the CSCC prophylactic arginine trial, as doses used were close to placebo based on the cardiovascular literature. 35 Previous studies have shown that low-dose arginine is unlikely to affect NO synthesis, 35 an observation confirmed in SCD by the CSCC study.…”

“…Experience with arginine therapy in SCD is growing, 20,22,25,28,33,34 and no safety issues have emerged. We learned through this study that intravenous administration is preferred by patients and improves feasibility of study drug delivery compared to oral administration in the acute setting.…”

“…However, when a single dose of arginine is given to patients with SCD during VOE, there is a robust dosedependent increase in plasma NO x . 20 Based on these promising data, we designed a randomized, placebo-controlled trial to determine the safety and efficacy of arginine therapy in children with SCD requiring hospitalization for severe pain necessitating parenteral narcotics. …”