Low-dose sodium nitrite attenuates myocardial ischemia and vascular ischemia-reperfusion injury in human models

Objectives: The aim of this study was to assess the potential benefits of inorganic nitrite in 2 clinical models: stress-induced myocardial ischemia and whole-arm ischemia-reperfusion. Background: Inorganic nitrite, traditionally considered a relatively inert metabolite of nitric oxide, may exert vasomodulatory and vasoprotective effects. Despite promising results from animal models, few have shown effectiveness in human model systems, and none have fully translated to the clinical setting. Methods: In 10 patients with inducible myocardial ischemia, saline and low-dose sodium nitrite (NaNO2) (1.5 μmol/min for 20 min) were administered in a double-blind fashion during dobutamine stress echocardiography, at separate visits and in a random order; long-axis myocardial function was quantified by peak systolic velocity (Vs) and strain rate (SR) responses. In 19 healthy subjects, flow-mediated dilation was assessed before and after whole-arm ischemia-reperfusion; nitrite was given before ischemia or during reperfusion. Results: Comparing saline and nitrite infusions, Vs and SR at peak dobutamine increased in regions exhibiting ischemia (Vs from 9.5 ± 0.5 cm/s to 12.4 ± 0.6 cm/s, SR from −2.0 ± 0.2 s−1 to −2.8 ± 0.3 s−1), whereas they did not change in normally functioning regions (Vs from 12.6 ± 0.4 cm/s to 12.6 ± 0.6 cm/s, SR from −2.6 ± 0.3 s−1 to −2.3 ± 0.1 s−1) (p < 0.001, analysis of variance). With NaNO2, the increment of Vs (normalized for increase in heart rate) increased only in poorly functioning myocardial regions (+122%, p < 0.001). Peak flow-mediated dilation decreased by 43% after ischemia-reperfusion when subjects received only saline (6.8 ± 0.7% vs. 3.9 ± 0.7%, p < 0.01); administration of NaNO2 before ischemia prevented this decrease in flow-mediated dilation (5.9 ± 0.7% vs. 5.2 ± 0.5%, p = NS), whereas administration during reperfusion did not. Conclusions: Low-dose NaNO2 improves functional responses in ischemic myocardium but has no effect on normal regions. Low-dose NaNO2 protects against vascular ischemia-reperfusion injury only when it is given before the onset of ischemia