Dietary nitrate increases arginine availability and protects mitochondrial complex I and energetics in the hypoxic rat heart

J Physiol. 2014 Nov 1;592(21):4715-31. doi: 10.1113/jphysiol.2014.275263. Epub 2014 Aug 28.


Hypoxic exposure is associated with impaired cardiac energetics in humans and altered mitochondrial function, with suppressed complex I-supported respiration, in rat heart. This response might limit reactive oxygen species generation, but at the cost of impaired electron transport chain (ETC) activity. Dietary nitrate supplementation improves mitochondrial efficiency and can promote tissue oxygenation by enhancing blood flow. We therefore hypothesised that ETC dysfunction, impaired energetics and oxidative damage in the hearts of rats exposed to chronic hypoxia could be alleviated by sustained administration of a moderate dose of dietary nitrate. Male Wistar rats (n = 40) were given water supplemented with 0.7 mmol l(-1) NaCl (as control) or 0.7 mmol l(-1) NaNO3, elevating plasma nitrate levels by 80%, and were exposed to 13% O2 (hypoxia) or normoxia (n = 10 per group) for 14 days. Respiration rates, ETC protein levels, mitochondrial density, ATP content and protein carbonylation were measured in cardiac muscle. Complex I respiration rates and protein levels were 33% lower in hypoxic/NaCl rats compared with normoxic/NaCl controls. Protein carbonylation was 65% higher in hearts of hypoxic rats compared with controls, indicating increased oxidative stress, whilst ATP levels were 62% lower. Respiration rates, complex I protein and activity, protein carbonylation and ATP levels were all fully protected in the hearts of nitrate-supplemented hypoxic rats. Both in normoxia and hypoxia, dietary nitrate suppressed cardiac arginase expression and activity and markedly elevated cardiac l-arginine concentrations, unmasking a novel mechanism of action by which nitrate enhances tissue NO bioavailability. Dietary nitrate therefore alleviates metabolic abnormalities in the hypoxic heart, improving myocardial energetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginase / genetics
  • Arginase / metabolism
  • Arginine / metabolism*
  • Diet
  • Electron Transport Complex I / metabolism*
  • Gene Expression Regulation / drug effects
  • Heart / drug effects*
  • Heart / physiology
  • Hypoxia-Inducible Factor 1 / genetics
  • Hypoxia-Inducible Factor 1 / metabolism
  • Male
  • Myocardium / metabolism*
  • Nitrates / administration & dosage
  • Nitrates / pharmacology*
  • Nitrites / chemistry
  • Nitrites / metabolism
  • Oxidative Stress
  • Oxygen
  • Rats
  • Rats, Wistar


  • Hypoxia-Inducible Factor 1
  • Nitrates
  • Nitrites
  • Arginine
  • Arginase
  • Electron Transport Complex I
  • Oxygen