Dietary nitrate attenuates oxidative stress, prevents cardiac and renal injuries, and reduces blood pressure in salt-induced hypertension
Abstract
AIMS: Reduced bioavailability of endogenous nitric oxide (NO) is a central pathophysiological event in hypertension and other cardiovascular diseases. Recently, it was demonstrated that inorganic nitrate from dietary sources is converted in vivo to form nitrite, NO, and other bioactive nitrogen oxides. We tested the hypothesis that dietary inorganic nitrate supplementation may have therapeutic effects in a model of renal and cardiovascular disease. METHODS AND RESULTS: Sprague-Dawley rats subjected to unilateral nephrectomy and chronic high-salt diet from 3 weeks of age developed hypertension, cardiac hypertrophy and fibrosis, proteinuria, and histological as well as biochemical signs of renal damage and oxidative stress. Simultaneous nitrate treatment (0.1 or 1 mmol nitrate kg⁻¹ day⁻¹), with the lower dose resembling the nitrate content of a diet rich in vegetables, attenuated hypertension dose-dependently with no signs of tolerance. Nitrate treatment almost completely prevented proteinuria and histological signs of renal injury, and the cardiac hypertrophy and fibrosis were attenuated. Mechanistically, dietary nitrate restored the tissue levels of bioactive nitrogen oxides and reduced the levels of oxidative stress markers in plasma (malondialdehyde) and urine (Class VI F2-isoprostanes and 8-hydroxy-2-deoxyguanosine). In addition, the increased circulating and urinary levels of dimethylarginines (ADMA and SDMA) in the hypertensive rats were normalized by nitrate supplementation. CONCLUSION: Dietary inorganic nitrate is strongly protective in this model of renal and cardiovascular disease. Future studies will reveal if nitrate contributes to the well-known cardioprotective effects of a diet rich in vegetables.
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Carlström et al. showed that dietary nitrate increased tissue levels of nitrite and S-nitrosothiols in the heart, attenuated oxidative stress, and prevented cardiac injury in Sprague-Dawley rats subjected to unilateral nephrectomy and a high-salt diet.
“Carlström et al., showed that dietary nitrate increased the tissue levels of nitrite and S-nitrosothiols in the heart, and attenuated oxidative stress and prevented cardiac injury in Sprague-Dawley rats subjected to unilateral nephrectomy and a high-salt diet [37].”
From NO-Rich Diet for Lifestyle-Related Diseases (2015) · cites this paper as [37]
Nitrate supplementation offers cardioprotection against doxorubicin-induced cardiomyopathy and prevents oxidative stress and cardiovascular and renal injury in salt-induced hypertension.
“In addition, nitrate supplementation offered cardioprotection against doxorubicin-induced cardiomyopathy 37 and prevented oxidative stress and cardiovascular and renal injury in salt-induced hypertension.39”
From Dietary nitrate supplementation improves revascularization in chronic ischemia (2012) · cites this paper as [39]
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InfluentialSelf-citationDietary nitrate supplementation improves revascularization in chronic ischemia
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“Other studies have shown that higher doses of nitrate 373 can reduce blood pressure in animal models that have been shown to have reduced NO 374 bioavailability (100, 101, 103).”
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“Published by John Wiley & Sons Ltd | 1 of 25 (ROS) or by attenuating the generation of ROS.10 In addition, NO has been shown to be involved in renal salt handling by affecting tubular sodium handling and modulating pressure natriuresis.11 It is now evident that reduced NO bioactivity is a central event in cardiovascul…”
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Enhanced XOR activity in eNOS-deficient mice
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“Treatment with inorganic nitrate could attenuate reduced levels of total antioxidant capacity and catalase activity as well as increase the level of pro-inflammatory cytokines in diabetic condition [45, 67, 68].”
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“(26,27).”
Inorganic nitrite supplementation for healthy arterial aging
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“Nitrate supplementation reduced oxidative stress in spontaneously hypertensive rats (30), in rats with unilateral nephrectomy that consumed a high-salt diet (25), and in a mouse model of cardiomyopathy (196, 199).”
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“From this viewpoint, a study by Carlstrom et al. found that nitrate administration was able to increase bioavailability and reverse cardiovascular dysfunction in mice with impaired function of the L-arginine–NOS pathway (48) .”
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“However, in rats subjected to unilateral nephrectomy and chronic high-salt diet, dietary nitrate prevented proteinuria and histological signs of renal injury (Carlstrom et al., 2011).”
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“It is possible that NO3− supplementation enhanced the antioxidant defence system [76,77], reducing the rate of reactive oxygen species production.”
BackgroundMechanisms impairing blood pressure responses to nitrite and nitrate
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“These effects include vasodilation (14, 15), reduction in blood pressure (16), protection against experimental ischemia reperfusion injury (17), reduction in cellular oxygen consumption (18, 19), reversal of metabolic syndrome (20), reduction in oxidative stress (21), stimulation of mucosal blood flow and mucus format…”
BackgroundSelf-citationHow May Proton Pump Inhibitors Impair Cardiovascular Health?
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“Of note, dietary supplementation with nitrate prevented ADMA accumulation in a rodent model of chronic cardiovascular disease, likely, by protecting DDAH from oxidative stress [72].”
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Self-citationDietary inorganic nitrate alleviates doxorubicin cardiotoxicity: Mechanisms and implications
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“[53] Rat (SHBP) High salt-induced hypertension; NaNO3 (1 mmol/kg/day); myocardial infarct size MAP ↓ cardiac hypertrophy ↓ cardiac fibrosis ↓ Blood lipid peroxidation ↓”
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“Our data are in agreement with a previous study showing that inorganic nitrate can lower BP in a hypertensive model [34].”
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“Furthermore, decreased endothelial NOS-derived NO has been shown previously to be central in the development of cardiovascular disorders [128] and LVH [129].”
BackgroundDietary nitrite supplementation attenuates cardiac remodeling in l -NAME-induced hypertensive rats
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“reported similar findings using nitrate instead of nitrite in a saltinduced hypertension model (Carlström et al. 2011).”
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“Most recent findings imply beneficial cardio-renal protective and antihypertensive outcomes following short-term administration of inorganic NO3 [16,19,24,47].”
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“…since NO is known to play a role in maintaining gastric integrity by increasing mucosal blood flow and mucus secretion (Bjorne et al. 2004), cytoprotection (Duranski et al. 2005; Shiva et al. 2007) as well as anti-inflammatory and antioxidant effects (Stokes et al. 2009; Carlstrom et al. 2011).”
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“Recently, it was demonstrated that nitrate treatment almost completely prevented proteinuria and histological signs of renal injury, and the cardiac hypertrophy and fibrosis were attenuated [Carlström et al., 2011].”
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“1 mmol/kg/day) in rats, which led to significant cardiorenal protective effects against the pathological changes caused by salt-induced hypertension.(45) There is a high probability that such a low dose of sodium nitrate may protect against I/R injury as well.”
BackgroundThe role of inorganic nitrate and nitrite in CVD
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“found that dietary nitrate supplementation can partly prevent the development of cardiac hypertrophy and high nitrate doses significantly reduced the fibrotic changes which were observed in the high-salt group, two factors which are major predictors of heart failure((152)).”
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“combination with HS (UNX-HS) were accompanied with increased preglomerular reactivity and abnormal renal autoregulation and are associated with increased oxidative stress, nitric oxide deficiency, and infiltration of inflammatory cells in the kidney.(5,6) Similar findings regarding nitric oxide deficiency and vascular…”
InfluentialSelf-citationVascular function in rats with adenine-induced chronic renal failure
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“The analytes were then extracted using Oasis Mixed-Mode Anion Exchange cartridges (3 cc/60 mg; Waters, Milford, MA), as described before (2).”
MethodSelf-citationPinheiro, L. C., Oliveira‐Paula, G. H., Ferreira, G. C., de Paula, T. D., Duarte, D. Â., Costa-Neto, C. M., & Tanus-Santos, J. E. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101769 · Cited by 34 · see citing works
- Authors
- Carlström, M., Persson, A. E. G., Larsson, E., Hezel, M., Scheffer, P. G., Teerlink, T., Weitzberg, E., & Lundberg, J. O.
- Affiliations
- Uppsala University (SE)
- Karolinska Institutet (SE)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Corresponding author
- Carlström, Mattias
- Weitzberg, Eddie
- Lundberg, Jon O.
- ORCID
- Venue
- Cardiovascular Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-11-19
- Volume
- 89
- Issue
- 3
- Pages
- 574-585
- ISSN
- 0008-6363 (ISSN-L)
- 1755-3245
- OpenAlex
- W1974569195
- Semantic Scholar
- b3bf26b82cdbdf00b0fade39de86bb83ed79872b
- Cited by
- 261
- References
- 55
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 12 · 2023: 11 · 2022: 10 · 2021: 11 · 2020: 16 · 2019: 13 · 2018: 25 · 2017: 31 · 2016: 22 · 2015: 23 · 2014: 22 · 2013: 20 · 2012: 20
- FWCI
- 11.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cardiovascular Research (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Wenner-Gren Foundation
- Massachusetts General Hospital
- Vrije Universiteit Amsterdam
- Svenska Sällskapet för Medicinsk Forskning
- Karolinska Institutet
- Vetenskapsrådet
- Magnus Bergvalls Stiftelse
- Svenska Läkaresällskapet
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Health Sciences › Nursing › Nutrition and Dietetics › Sodium Intake and Health
- Keywords
- dietary nitrate, nitric oxide bioavailability, salt-induced hypertension, oxidative stress, kidney injury, cardiac hypertrophy, myocardial fibrosis, proteinuria, dimethylarginines, asymmetric dimethylarginine, SDMA, malondialdehyde, F2-isoprostanes, 8-hydroxy-2'-deoxyguanosine, high-salt diet, cardioprotection
- MeSH terms
- Animals, Arginine, Blood Pressure, Disease Models, Animal, Cardiomegaly, Hypertension, Renal, Kidney, Male, Nephrectomy, Nitrates, Nitric Oxide, Nitrogen, Proteinuria, Rats, Sprague-Dawley, Sodium Chloride, Dietary, Oxidative Stress, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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