title: Therapeutic potential of sustained-release sodium nitrite for critical limb ischemia in the setting of metabolic syndrome.
abstract: 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.
authors.affiliation: Cardiovascular Center of Excellence and Department of Pharmacology, LSU Health Sciences Center, New Orleans, Louisiana;
authors.forename: David J
authors.initials: DJ
authors.lastname: Polhemus
authors.affiliation: Cardiovascular Center of Excellence and Department of Pharmacology, LSU Health Sciences Center, New Orleans, Louisiana;
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Bradley
authors.affiliation: Cardiovascular Center of Excellence and Department of Pharmacology, LSU Health Sciences Center, New Orleans, Louisiana;
authors.forename: Kazi N
authors.initials: KN
authors.lastname: Islam
authors.affiliation: Department of Surgery, Emory University School of Medicine, Atlanta, Georgia; Surgery and Research Services, Atlanta Veterans Affairs Medical Center, Decatur, Georgia; Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia;
authors.forename: Luke P
authors.initials: LP
authors.lastname: Brewster
authors.affiliation: Department of Surgery, Emory University School of Medicine, Atlanta, Georgia;
authors.forename: John W
authors.initials: JW
authors.lastname: Calvert
authors.affiliation: Department of Anatomy, Physiology, and Pharmacology, Auburn University College of Veterinary Medicine, Auburn, Alabama;
authors.forename: Ya-Xiong
authors.initials: YX
authors.lastname: Tao
authors.affiliation: T3 Labs, Emory University, Atlanta, Georgia; and.
authors.forename: Carlos C
authors.initials: CC
authors.lastname: Chang
authors.affiliation: Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Iraklis I
authors.initials: II
authors.lastname: Pipinos
authors.affiliation: Cardiovascular Center of Excellence and Department of Pharmacology, LSU Health Sciences Center, New Orleans, Louisiana;
authors.forename: Traci T
authors.initials: TT
authors.lastname: Goodchild
authors.affiliation: Cardiovascular Center of Excellence and Department of Pharmacology, LSU Health Sciences Center, New Orleans, Louisiana; dlefe1@lsuhsc.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Lefer
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000818:Animals; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D006614:Hindlimb / Q000098:blood supply / Q000187:drug effects; D007083:Iliac Artery / Q000601:surgery*; D007511:Ischemia; D024821:Metabolic Syndrome; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D058729:Peripheral Arterial Disease; D026403:S-Nitrosothiols / Q000378:metabolism; D012977:Sodium Nitrite / Q000494:pharmacology*; D013552:Swine
chemical_list: D043925:Angiogenesis Inducing Agents; D003692:Delayed-Action Preparations; D009566:Nitrates; D009573:Nitrites; D026403:S-Nitrosothiols; D012977:Sodium Nitrite
keywords: Ossabaw swine; angiogenesis; endothelial nitric oxide synthase; metabolic syndrome; nitric oxide; nitrite; peripheral arterial disease