Dietary nitrate improves age-related hypertension and metabolic abnormalities in rats via modulation of angiotensin II receptor signaling and inhibition of superoxide generation

M. Hezel, Maria Peleli, M. Liu, C. Zollbrecht, B. L. Jensen, A. Checa, A. Giulietti, C. E. Wheelock, Jon O Lundberg, E. Weitzberg, M Carlström

Research output: Contribution to journalJournal articleResearchpeer-review


Advanced age is associated with increased risk for cardiovascular disease and type 2 diabetes. A proposed central event is diminished amounts of nitric oxide (NO) due to reduced generation by endothelial NO synthase (eNOS) and increased oxidative stress. In addition, it is widely accepted that increased angiotensin II (ANG II) signaling is also implicated in the pathogenesis of endothelial dysfunction and hypertension by accelerating formation of reactive oxygen species. This study was designed to test the hypothesis that dietary nitrate supplementation could reduce blood pressure and improve glucose tolerance in aged rats, via attenuation of NADPH oxidase activity and ANG II receptor signaling. Dietary nitrate supplementation for two weeks reduced blood pressure (10–15 mmHg) and improved glucose clearance in old, but not in young rats. These favorable effects were associated with increased insulin responses, reduced plasma creatinine as well as improved endothelial relaxation to acetylcholine and attenuated contractility to ANG II in resistance arteries. Mechanistically, nitrate reduced NADPH oxidase-mediated oxidative stress in the cardiovascular system and increased cGMP signaling. Finally, nitrate treatment in aged rats normalized the gene expression profile of ANG II receptors (AT1A, AT2, AT1A/AT2 ratio) in the renal and cardiovascular systems without altering plasma levels of renin or ANG II. Our results show that boosting the nitrate-nitrite-NO pathway can partly compensate for age-related disturbances in endogenous NO generation via inhibition of NADPH oxidase and modulation of ANG II receptor expression. These novel findings may have implications for nutrition-based preventive and therapeutic strategies against cardiovascular and metabolic diseases. © 2016 Elsevier Inc.
Original languageEnglish
JournalFree Radical Biology & Medicine
Pages (from-to)87-98
Publication statusPublished - Oct 2016


  • Aging
  • Angiotensin II receptors
  • Endothelial dysfunction
  • Hypertension
  • Metabolic syndrome
  • NADPH oxidase
  • Nitric oxide
  • Nitrite
  • Renin
  • Superoxide
  • Receptors, Angiotensin/blood
  • Nitrites/blood
  • Nitric Oxide Synthase Type III/blood
  • Male
  • Nitrates/administration & dosage
  • Angiotensin II/blood
  • Cyclic GMP/blood
  • Aging/genetics
  • Glucose Tolerance Test
  • Signal Transduction
  • Tissue Culture Techniques
  • Gene Expression Regulation
  • Acetylcholine/pharmacology
  • Rats
  • Hypertension/blood
  • Rats, Sprague-Dawley
  • NADPH Oxidases/antagonists & inhibitors
  • Animals
  • Endothelium, Vascular/drug effects
  • Mesenteric Arteries/drug effects
  • Blood Pressure/drug effects
  • Dietary Supplements

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