title: Effects of long-term dietary nitrate supplementation in mice.
abstract: BACKGROUND
  Inorganic nitrate (NO3(-)) is a precursor of nitric oxide (NO) in the body and a large number of short-term studies with dietary nitrate supplementation in animals and humans show beneficial effects on cardiovascular health, exercise efficiency, host defense and ischemia reperfusion injury. In contrast, there is a long withstanding concern regarding the putative adverse effects of chronic nitrate exposure related to cancer and adverse hormonal effects. To address these concerns we performed in mice, a physiological and biochemical multi-analysis on the effects of long-term dietary nitrate supplementation.
  
  
  METHODS
  7 week-old C57BL/6 mice were put on a low-nitrate chow and at 20 weeks-old were treated with NaNO3 (1 mmol/L) or NaCl (1 mmol/L, control) in the drinking water. The groups were monitored for weight gain, food and water consumption, blood pressure, glucose metabolism, body composition and oxygen consumption until one group was reduced to eight animals due to death or illness. At that point remaining animals were sacrificed and blood and tissues were analyzed with respect to metabolism, cardiovascular function, inflammation, and oxidative stress.
  
  
  RESULTS
  Animals were supplemented for 17 months before final sacrifice. Body composition, oxygen consumption, blood pressure, glucose tolerance were measured during the experiment, and vascular reactivity and muscle mitochondrial efficiency measured at the end of the experiment with no differences identified between groups. Nitrate supplementation was associated with improved insulin response, decreased plasma IL-10 and a trend towards improved survival.
  
  
  CONCLUSIONS
  Long term dietary nitrate in mice, at levels similar to the upper intake range in the western society, is not detrimental.
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Nanna Svartz väg 2, Stockholm 171 77, Sweden. Electronic address: Michael.Hezel@ki.se.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hezel
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Nanna Svartz väg 2, Stockholm 171 77, Sweden.
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Nanna Svartz väg 2, Stockholm 171 77, Sweden.
authors.forename: Tomas A
authors.initials: TA
authors.lastname: Schiffer
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Nanna Svartz väg 2, Stockholm 171 77, Sweden.
authors.forename: Filip J
authors.initials: FJ
authors.lastname: Larsen
authors.affiliation: Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Antonio
authors.initials: A
authors.lastname: Checa
authors.affiliation: Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Craig E
authors.initials: CE
authors.lastname: Wheelock
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Nanna Svartz väg 2, Stockholm 171 77, Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Carlström
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Nanna Svartz väg 2, Stockholm 171 77, Sweden.
authors.forename: Jon O
authors.initials: JO
authors.lastname: Lundberg
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Nanna Svartz väg 2, Stockholm 171 77, Sweden. Electronic address: Eddie.Weitzberg@ki.se.
authors.forename: Eddie
authors.initials: E
authors.lastname: Weitzberg
mesh_terms: D000596:Amino Acids / Q000097:blood; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D016207:Cytokines / Q000097:blood; D019587:Dietary Supplements; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D009566:Nitrates / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects
chemical_list: D000596:Amino Acids; D016207:Cytokines; D007328:Insulin; D009566:Nitrates; D016753:Interleukin-10; D019255:NADPH Oxidases
keywords: Long-term; Nitrate; Supplementation; Survival; Toxicity; Treatment