Sodium nitrite promotes regional blood flow in patients with sickle cell disease: a phase I/II study.
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.
Mack
A Kyle
AK
Pulmonary and Vascular Medicine Branch, National Heart, Lung and Blood Institute; National Institutes of Health, Bethesda, MD, USA.
McGowan Ii
Vicki R
VR
Tremonti
Carole K
CK
Ackah
Diana
D
Barnett
Christopher
C
Machado
Roberto F
RF
Gladwin
Mark T
MT
Kato
Gregory J
GJ
D000328:Adult; D000755:Anemia, Sickle Cell / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D005542:Forearm / Q000098:blood supply; D006801:Humans; D008875:Middle Aged; D020030:Nitric Oxide Donors; D009599:Nitroprusside; D012039:Regional Blood Flow / Q000187:drug effects; D012977:Sodium Nitrite / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D055815:Young Adult
D020030:Nitric Oxide Donors; D014665:Vasodilator Agents; D009599:Nitroprusside; D012977:Sodium Nitrite