title: Sustained release nitrite therapy results in myocardial protection in a porcine model of metabolic syndrome with peripheral vascular disease.
abstract: Metabolic syndrome (MetS) reduces endothelial nitric oxide (NO) bioavailability and exacerbates vascular dysfunction in patients with preexisting vascular diseases. Nitrite, a storage form of NO, can mediate vascular function during pathological conditions when endogenous NO is reduced. The aims of the present study were to characterize the effects of severe MetS and obesity on dyslipidemia, myocardial oxidative stress, and endothelial NO synthase (eNOS) regulation in the obese Ossabaw swine (OS) model and to examine the effects of a novel, sustained-release formulation of sodium nitrite (SR-nitrite) on coronary vascular reactivity and myocardial redox status in obese OS subjected to critical limb ischemia (CLI). After 6 mo of an atherogenic diet, obese OS displayed a MetS phenotype. Obese OS had decreased eNOS functionality and NO bioavailability. In addition, obese OS exhibited increased oxidative stress and a significant reduction in antioxidant enzymes. The efficacy of SR-nitrite therapy was examined in obese OS subjected to CLI. After 3 wk of treatment, SR-nitrite (80 mg · kg(-1) · day(-1) bid po) increased myocardial nitrite levels and eNOS function. Treatment with SR-nitrite reduced myocardial oxidative stress while increasing myocardial antioxidant capacity. Ex vivo assessment of vascular reactivity of left anterior descending coronary artery segments demonstrated marked improvement in vasoreactivity to sodium nitroprusside but not to substance P and bradykinin in SR-nitrite-treated animals compared with placebo-treated animals. In conclusion, in a clinically relevant, large-animal model of MetS and CLI, treatment with SR-nitrite enhanced myocardial NO bioavailability, attenuated oxidative stress, and improved ex vivo coronary artery vasorelaxation.
authors.affiliation: Cardiovascular Center of Excellence and Department of Pharmacology, Louisiana State University 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, Louisiana State University Health Sciences Center, New Orleans, Louisiana;
authors.forename: Kazi N
authors.initials: KN
authors.lastname: Islam
authors.affiliation: Cardiovascular Center of Excellence and Department of Pharmacology, Louisiana State University 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, Louisiana State University Health Sciences Center, New Orleans, Louisiana;
authors.forename: Erminia
authors.initials: E
authors.lastname: Donnarumma
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; and.
authors.forename: Luke P
authors.initials: LP
authors.lastname: Brewster
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: Cardiovascular Center of Excellence and Department of Pharmacology, Louisiana State University 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, Louisiana State University Health Sciences Center, New Orleans, Louisiana; dlefe1@lsuhsc.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Lefer
mesh_terms: D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D050171:Dyslipidemias / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D006331:Heart Diseases / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D016491:Peripheral Vascular Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D012720:Severity of Illness Index; D012977:Sodium Nitrite / Q000494:pharmacology*; D013552:Swine; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D003692:Delayed-Action Preparations; D052250:Nitric Oxide Synthase Type III; D012977:Sodium Nitrite
keywords: Ossabaw swine; atherosclerosis; endothelial dysfunction; nitric oxide; sustained-release sodium nitrite