Sodium nitrite therapy rescues ischemia-induced neovascularization and blood flow recovery in hypertension

Abstract

Background Arterial hypertension is a major risk factor that can lead to complication of peripheral vascular disease due, in part, to endothelial dysfunction. Because sodium nitrite (SN) can be converted to nitric oxide (NO), which counteracts endothelial dysfunction, we explored the effect of nitrite on neovascularization following hind-limb ischemia in different models of hypertension (HT). Methods and results Chronic delivery of angiotensin-II (Ang-II, 400ng/Kg/min) or N(omega)-nitro-L-arginine-methyl-ester (L-NAME, 0.1g/L) were used for a two week period to induce hypertension. Mice were subjected to femoral artery ligation induced-ischemia in the hind-limb followed by treatment with SN (50mg/L) for 2-weeks. SN significantly reduced systolic arterial blood pressure in mice receiving Ang-II and L-NAME, but had no effect in sham animals. After 2 weeks, blood flow and microangiography showed 60%±1.0 recovery in sham compared to 40%±1.3 in HT mice. Importantly, sham and HT mice treated with SN showed a 100% blood flow recovery associated with normalization in capillary density. The inhibition of xanthine-oxido-reductase (allopurinol) or VEGFR (SU-5416) prevented the neovascularization in HT mice treated with SN. Cyclic GMP (cGMP) content in the hind-limb was significantly increased in mice treated with SN compared to non-treated mice. Nitrite/nitrate content was only increased in the sham group treated with SN. Immunoprecipitation and Western blot analysis revealed an increase in eNOS/Akt/VEGFR phosphorylation in skeletal muscle from mice treated with SN compared to non-treated mice. Conclusion Our findings indicate that SN therapy rescues the neovascularization and blood flow recovery in ischemic hind-limb of sham and HT mice likely through the Akt/NO/cGMP and VEGFR pathways.

Pharmacology and therapeutic role of inorganic nitrite and nitrate in vasodilatation

“…Inhibition of XOR prevented this recovery, suggesting a role for XOR-mediated reduction of nitrite to NO in blood flow under these conditions, as suggested in in vitro studies (Li et al, 2003;Amin et al, 2012). Hypertensive mice also demonstrated a decrease in cGMP levels compared to control mice in the hind limb (Amin et al, 2012). However, treatment with sodium nitrite was found to significantly enhance cGMP levels; thus in this study, it was suggested that sodium nitrite could be used as a therapy for full recovery of blood flow.…”

“…In a mouse model of ischemic (hypoxic) hind-limb, hypertensive mice showed a significantly decreased blood flow compared to sham operated mice, and blood flow could be recovered in both hypertensive and normotensive mice when treated with sodium nitrite compared to non-treated mice. Inhibition of XOR prevented this recovery, suggesting a role for XOR-mediated reduction of nitrite to NO in blood flow under these conditions, as suggested in in vitro studies (Li et al, 2003;Amin et al, 2012). Hypertensive mice also demonstrated a decrease in cGMP levels compared to control mice in the hind limb (Amin et al, 2012).…”

Sodium Nitrite Prevents both Reductions in Circulating Nitric Oxide and Hypertension in 7‐Day Lead‐Treated Rats

“…Accordingly, the present study shows that lead‐induced hypertension was found in rats, which presented whole‐blood lead levels of 11.5 ± 1.2 µg/dL. Therefore, to expand the understanding of lead‐induced hypertension, we assessed plasma metabolites of NO (NOx levels), which reflect the bioavailability of NO . In support of previous studies, our present findings show that rats intoxicated with a similar dosage of lead acetate presented reductions in the NO bioavailability associated with increases in systolic blood pressure .…”

Simultaneous Determination of Nitrite and Nitrate in Milk Samples by Ion Chromatography Method and Estimation of Dietary Intake

“…[1][2][3] However, the therapeutic potential effect of nitrite in the treatment of a number of cardiovascular including ischemia/reperfusion (I/R) injured; hypercholesterolemia induced microvascular inflammation as well as ischemia-induced angiogenesis are established. [4] Previous reports indicate that these compounds may damage the nervous system, liver, kidneys, and spleen of small fish. [5] In addition, some study suggests that infant formula has too much nitrite would have the possibility of methaemoglobinaemia.…”