Therapeutic potential of sustained-release sodium nitrite for critical limb ischemia in the setting of metabolic syndrome

Nitrite is a storage reservoir of nitric oxide that is readily reduced to nitric oxide under pathological conditions. Previous studies have demonstrated that nitrite levels are significantly reduced in cardiovascular disease states, including peripheral vascular disease. We investigated the cytoprot...

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Published in:American journal of physiology. Heart and circulatory physiology 2015-07, Vol.309 (1), p.H82-H92
Main Authors: Polhemus, David J, Bradley, Jessica M, Islam, Kazi N, Brewster, Luke P, Calvert, John W, Tao, Ya-Xiong, Chang, Carlos C, Pipinos, Iraklis I, Goodchild, Traci T, Lefer, David J
Format: Article
Language:English
Subjects:
Angiogenesis Inducing Agents - pharmacology
Animals
Cardiovascular disease
Delayed-Action Preparations
Disease Models, Animal
Hindlimb - blood supply
Hindlimb - drug effects
Iliac Artery - surgery
Ischemia
Metabolic Syndrome
Muscle, Skeletal - blood supply
Muscle, Skeletal - drug effects
Muscle, Skeletal - metabolism
Neovascularization, Physiologic - drug effects
Nitrates - metabolism
Nitric oxide
Nitrites - metabolism
Oxidative stress
Pathology
Peripheral Arterial Disease
Physiology
S-Nitrosothiols - metabolism
Sodium Nitrite - pharmacology
Swine
Vascular Biology and Microcirculation
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Summary:Nitrite is a storage reservoir of nitric oxide that is readily reduced to nitric oxide under pathological conditions. Previous studies have demonstrated that nitrite levels are significantly reduced in cardiovascular disease states, including peripheral vascular disease. We investigated the cytoprotective and proangiogenic actions of a novel, sustained-release formulation of nitrite (SR-nitrite) in a clinically relevant in vivo swine model of critical limb ischemia (CLI) involving central obesity and metabolic syndrome. CLI was induced in obese Ossabaw swine (n = 18) by unilateral external iliac artery deployment of a full cross-sectional vessel occlusion device positioned within an endovascular expanded polytetrafluoroethylene-lined nitinol stent-graft. At post-CLI day 14, pigs were randomized to placebo (n = 9) or SR-nitrite (80 mg, n = 9) twice daily by mouth for 21 days. SR-nitrite therapy increased nitrite, nitrate, and S-nitrosothiol in plasma and ischemic skeletal muscle. Oxidative stress was reduced in ischemic limb tissue of SR-nitrite- compared with placebo-treated pigs. Ischemic limb tissue levels of proangiogenic growth factors were increased following SR-nitrite therapy compared with placebo. Despite the increases in cytoprotective and angiogenic signals with SR-nitrite therapy, new arterial vessel formation and enhancement of blood flow to the ischemic limb were not different from placebo. Our data clearly demonstrate cytoprotective and proangiogenic signaling in ischemic tissues following SR-nitrite therapy in a very severe model of CLI. Further studies evaluating longer-duration nitrite therapy and/or additional nitrite dosing strategies are warranted to more fully evaluate the therapeutic potential of nitrite therapy in peripheral vascular disease.
ISSN:0363-6135
1522-1539
DOI:10.1152/ajpheart.00115.2015