Hypothesis: the effect of oral nitrite on blood pressure in the spontaneously hypertensive rat. Does dietary nitrate mitigate hypertension after conversion to nitrite?
Abstract
Increasing doses of nitrite (3.7-14.8 mg/kg BW) were administered via intragastric intubation to 64 spontaneously hypertensive Sprague-Dawley rats. Systemic blood pressure, measured in conscious animals with the tail cuff method, significantly decreased in a dose-related manner 16 and 32 minutes later, and pulse rate slightly increased. Since orally ingested nitrate may be partially converted to nitrite, it seems worthwhile to study correlations between dietary nitrate and blood pressure in experimental animals and man.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Inorganic nitrite demonstrates robust NO-signaling effects and contributes to basal vascular tone, blood pressure, protection from endothelial dysfunction and vascular inflammation under conditions of metabolic and inflammatory stress.
“As with NOS-derived NO, inorganic nitrite demonstrates robust NO-signaling effects[52,53,57,59] and contributes to basal vascular tone[51,55,60,61], blood pressure[62–66], protection from endothelial dysfunction[67–71] and vascular inflammation[72] under conditions of metabolic and inflammatory stress.”
From Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health (2017) · cites this paper as [62]
Nitrite administered to rats via intragastric route lowered blood pressure.
“Nitrite administered to rats via intragastric route lowered blood pressure [4].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [4]
Classen et al. found that a single oral dose of nitrite acutely decreased blood pressure in spontaneously hypertensive rats.
“They found that a single oral dose of nitrite acutely decreased blood pressure in spontaneously hypertensive rats (SHR) [26].”
From Sodium nitrite downregulates vascular NADPH oxidase and exerts antihypertensive effects in hypertension (2011) · cites this paper as [26]
Cited by
Sorted by citations
The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics
Lundberg, J. O., Weitzberg, E., & Gladwin, M. T. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2466 · Cited by 2,739 · see citing works
Strategies to increase nitric oxide signalling in cardiovascular disease
Lundberg, J. O., Gladwin, M. T., & Weitzberg, E. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4623 · Cited by 576 · see citing works
Roles of dietary inorganic nitrate in cardiovascular health and disease
Lundberg, J. O., Carlström, M., Larsen, F. J., & Weitzberg, E. (2011) · Cardiovascular Research · doi:10.1093/cvr/cvq325 · Cited by 355 · see citing works
NO Generation From Nitrite and Its Role in Vascular Control
Lundberg, J. O., & Weitzberg, E. (2005) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.0000161048.72004.c2 · Cited by 341 · see citing works
Ferguson, S. K., Hirai, D. M., Copp, S. W., Holdsworth, C. T., Allen, J. D., Jones, A. M., Musch, T. I., & Poole, D. C. (2013) · The Journal of Physiology · doi:10.1113/jphysiol.2012.243121 · Cited by 333 · see citing works
Kapil, V., Khambata, R. S., Jones, D. A., Rathod, K., Primus, C., Massimo, G., Fukuto, J. M., & Ahluwalia, A. (2020) · Pharmacological Reviews · doi:10.1124/pr.120.019240 · Cited by 248 · see citing works
“The authors of some of the earlier animal studies assessing responses to NaNO2 hypothesized that elevation of systemic nitrite levels from nitrate via bacterial reduction would reduce BP, although they did not explicitly test this (Classen et al., 1990; Vleeming et al., 1997).”
BackgroundPetersson, J., Carlström, M., Schreiber, O., Phillipson, M., Christoffersson, G., Jägare, A., Roos, S., Jansson, E. Å., Persson, A. E. G., Lundberg, J. O., et al. (2009) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2009.01.011 · Cited by 235 · see citing works
“It has been speculated that parts of these effects can be explained by the high nitrate content in many vegetables [50,51].”
Ghosh, S. M., Kapil, V., Fuentes-Calvo, I., Bubb, K. J., Pearl, V., Milsom, A. B., Khambata, R., Maleki-Toyserkani, S., Yousuf, M., Benjamin, N., et al. (2013) · Hypertension · doi:10.1161/hypertensionaha.111.00933 · Cited by 218 · see citing works
Koch, C. D., Gladwin, M. T., Freeman, B. A., Lundberg, J. O., Weitzberg, E., & Morris, A. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.12.015 · Cited by 186 · see citing works
Therapeutic effects of inorganic nitrate and nitrite in cardiovascular and metabolic diseases
Omar, S. A., Webb, A. J., Lundberg, J. O., & Weitzberg, E. (2016) · Journal of Internal Medicine · doi:10.1111/joim.12441 · Cited by 175 · see citing works
NO-synthase independent NO generation in mammals
Lundberg, J. O., & Weitzberg, E. (2010) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2010.02.136 · Cited by 172 · see citing works
Mechanisms of nitrite bioactivation
Kim-Shapiro, D. B., & Gladwin, M. T. (2014) · Nitric Oxide · doi:10.1016/j.niox.2013.11.002 · Cited by 157 · see citing works
“This suggestion would explain the observation by Classen and coworkers where intragastric administration of nitrite lowered blood pressure in a rodent model [4].”
ResultMontenegro, M. F., Amaral, J. H., Pinheiro, L. C., Sakamoto, E. K., Ferreira, G. C., Reis, R. I., Marçal, D. M. O., Pereira, R. P., & Tanus-Santos, J. E. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.04.005 · Cited by 152 · see citing works
“They found that a single oral dose of nitrite acutely decreased blood pressure in spontaneously hypertensive rats (SHR) [26].”
BackgroundNitrite is an alternative source of NO in vivo
Tsuchiya, K., Kanematsu, Y., Yoshizumi, M., Ohnishi, H., Kirima, K., Izawa, Y., Shikishima, M., Ishida, T., Kondo, S., Kagami, S., et al. (2005) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00525.2004 · Cited by 127 · see citing works
“Thöni and colleagues (4, 11) suggested that a nitrate-derived NO formation pathway is a possible mechanism for the hypotensive effect of vegetable- and fruit-rich diets.”
BackgroundNitrite Reduction and Cardiovascular Protection
Omar, S. A., & Webb, A. J. (2014) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2014.01.012 · Cited by 121 · see citing works
Regulation of vascular tone homeostasis by NO and H2S: Implications in hypertension
Gheibi, S., Jeddi, S., Kashfi, K., & Ghasemi, A. (2018) · Biochemical Pharmacology · doi:10.1016/j.bcp.2018.01.017 · Cited by 120 · see citing works
Novel Aspects of Endothelium-Dependent Regulation of Vascular Tone
Villar, I. C., Francis, S., Webb, A., Hobbs, A. J., & Ahluwalia, A. (2006) · Kidney International · doi:10.1038/sj.ki.5001680 · Cited by 112 · see citing works
Pinheiro, L. C., Amaral, J. H., Ferreira, G. C., Portella, R. L., Ceron, C. S., Montenegro, M. F., Toledo, J. C., & Tanus-Santos, J. E. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.06.038 · Cited by 108 · see citing works
The solution chemistry of nitric oxide and other reactive nitrogen species
Ford, P. C., & Miranda, K. M. (2020) · Nitric Oxide · doi:10.1016/j.niox.2020.07.004 · Cited by 100 · see citing works
Inorganic nitrate and the cardiovascular system
Kapil, V., Webb, A. J., & Ahluwalia, A. (2010) · Heart · doi:10.1136/hrt.2009.180372 · Cited by 90 · see citing works
“Administration of 20- 100mmol/l NaNO2, in the drinking water for up to 12 months, to spontaneously hypertensive rats caused a sustained BP reduction.74 75 The authors of these reports hypothesised at the time that since NO3 is metabolised to NO2 , it might be worthwhile investigating the effects of dietary NO3 ingesti…”
BackgroundInfluentialGee, L. C., & Ahluwalia, A. (2016) · Current Hypertension Reports · doi:10.1007/s11906-015-0623-4 · Cited by 80 · see citing works
Heinecke, J. L., & Ford, P. C. (2009) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2009.07.021 · Cited by 82 · see citing works
Mechanisms of Human Erythrocytic Bioactivation of Nitrite
Liu, C., Wajih, N., Liu, X., Basu, S., Janes, J., Marvel, M., Keggi, C., Helms, C. C., Lee, A. N., Belanger, A. M., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.609222 · Cited by 76 · see citing works
Consistent antioxidant and antihypertensive effects of oral sodium nitrite in DOCA-salt hypertension
Amaral, J. H., Ferreira, G. C., Pinheiro, L. C., Montenegro, M. F., & Tanus-Santos, J. E. (2015) · Redox Biology · doi:10.1016/j.redox.2015.06.009 · Cited by 75 · see citing works
“[37] were first to show antihypertensive effects of nitrite, studies by other groups have confirmed this finding in different models of hypertension [11,15,20,38].”
ResultMechanisms impairing blood pressure responses to nitrite and nitrate
Oliveira‐Paula, G. H., Pinheiro, L. C., & Tanus-Santos, J. E. (2019) · Nitric Oxide · doi:10.1016/j.niox.2019.01.015 · Cited by 60 · see citing works
Gill, A., Zajda, J., & Meyerhoff, M. E. (2019) · Analytica Chimica Acta · doi:10.1016/j.aca.2019.05.065 · Cited by 57 · see citing works
Amaral, J. H., Montenegro, M. F., Pinheiro, L. C., Ferreira, G. C., Barroso, R. P., Costa-Filho, A. J., & Tanus-Santos, J. E. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.07.032 · Cited by 53 · see citing works
Montenegro, M. F., Pinheiro, L. C., Amaral, J. H., Marçal, D. M. O., Palei, A. C. T., Costa-Filho, A. J., & Tanus-Santos, J. E. (2012) · Naunyn-Schmiedeberg's Archives of Pharmacology · doi:10.1007/s00210-011-0712-0 · Cited by 52 · see citing works
“This dose of sodium nitrite was chosen with basis on previous work showing significant antihypertensive effects in SHR model of hypertension (Classen et al. 1990) and in our previous study (Montenegro et al. 2011).”
BackgroundMethodInfluentialDietary nitrite ameliorates renal injury in l-NAME-induced hypertensive rats
Tsuchiya, K., Tomita, S., Ishizawa, K., Abe, S., Ikeda, Y., Kihira, Y., & Tamaki, T. (2009) · Nitric Oxide · doi:10.1016/j.niox.2009.12.002 · Cited by 50 · see citing works
The potential of stimulating nitric oxide formation in the treatment of hypertension
Pinheiro, L. C., Tanus-Santos, J. E., & de Castro, M. M. (2017) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2017.1310840 · Cited by 49 · see citing works
“In fact, the inhibition of angiotensin (1–7) formation in SHR abolished the antihypertensive effects of the combined use of losartan and lisinopril [116].”
BackgroundInfluentialKanematsu, Y., Yamaguchi, K., Ohnishi, H., Motobayashi, Y., Ishizawa, K., Izawa, Y., Kawazoe, K., Kondo, S., Kagami, S., Tomita, S., et al. (2008) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00621.2007 · Cited by 44 · see citing works
Ling, W. C., Murugan, D. D., Lau, Y. S., Vanhoutte, P. M., & Mustafa, M. R. (2016) · Scientific Reports · doi:10.1038/srep33048 · Cited by 44 · see citing works
Gonçalves‐Rizzi, V. H., Possomato‐Vieira, J. S., Graça, T. U. D. S., Nascimento, R. A., & Dias-Junior, C. A. (2016) · Nitric Oxide · doi:10.1016/j.niox.2016.05.004 · Cited by 36 · see citing works
Nitrite-stimulated Gastric Formation of S-nitrosothiols As An Antihypertensive Therapeutic Strategy
Oliveira‐Paula, G. H., & Tanus-Santos, J. E. (2018) · Current Drug Targets · doi:10.2174/1389450119666180816120816 · Cited by 33 · see citing works
Khambata, R. S., Ghosh, S. M., & Ahluwalia, A. (2015) · Antioxidants and Redox Signaling · doi:10.1089/ars.2015.6254 · Cited by 30 · see citing works
“Importantly, chronic oral administration of nitrite reduces BP without any evidence of tachyphylaxis in genetic, surgical, and salt-induced animal models of hypertension (8, 12, 13, 41, 88), although in general the doses of nitrite tested in these studies substantially exceed physiological levels.”
Inorganic nitrite bioactivation and role in physiological signaling and therapeutics
Amdahl, M. B., DeMartino, A. W., & Gladwin, M. T. (2019) · Biological Chemistry · doi:10.1515/hsz-2019-0349 · Cited by 31 · see citing works
“Several studies have shown that infusion of sodium nitrite causes a measurable decrease in blood pressure and an increase in blood flow in both animal and human models (Classen et al., 1990; Gladwin et al., 2000; Cosby et al., 2003; Dejam et al., 2007).”
BackgroundOliveira‐Paula, G. H., Pinheiro, L. C., Guimarães, D. A., Conde-Tella, S. O., Blanco, A. L. F., de Angelis, C. D., Schechter, A. N., & Tanus-Santos, J. E. (2016) · Redox Biology · doi:10.1016/j.redox.2016.04.001 · Cited by 27 · see citing works
Utilization and Metabolism of Nitrogen by Humans
Follett, J. R., & Follett, R. F. (2001) · Elsevier eBooks · doi:10.1016/b978-044450486-9/50006-6 · Cited by 27 · see citing works
Pinheiro, L. C., Amaral, J. H., Ferreira, G. C., Montenegro, M. F., Oliveira‐Paula, G. H., & Tanus-Santos, J. E. (2014) · Nitric Oxide · doi:10.1016/j.niox.2014.05.009 · Cited by 26 · see citing works
The Nitrate–Nitrite–Nitric Oxide Pathway in Mammals
Lundberg, J. O., Weitzberg, E., Shiva, S., & Gladwin, M. T. (2011) · Humana Press eBooks · doi:10.1007/978-1-60761-616-0_3 · Cited by 26 · see citing works
Nitric oxide and nitrite-based therapeutic opportunities in intimal hyperplasia
Alef, M. J., Tzeng, E., & Zuckerbraun, B. S. (2012) · Nitric Oxide · doi:10.1016/j.niox.2012.03.014 · Cited by 20 · see citing works
Dosunmu-Ogunbi, A. M., Galley, J. C., Yuan, S. S., Schmidt, H. M., Wood, K. C., & Straub, A. C. (2021) · Hypertension · doi:10.1161/hypertensionaha.121.16493 · Cited by 17 · see citing works
Mechanisms of Nitrite Reduction in Ischemia in the Cardiovascular System
Webb, A., & Ahluwalia, A. (2010) · Elsevier eBooks · doi:10.1016/b978-0-12-373866-0.00017-4 · Cited by 15 · see citing works
Pellegrino, D., & Parisella, M. L. (2010) · Recent Advances in Cardiovascular Drug Discovery (Formerly Recent Patents on Cardiovascular Drug Discovery) · doi:10.2174/157489010791515340 · Cited by 11 · see citing works
“Other studies have shown that ingestion of fairly large amounts of inorganic nitrite can reduce blood pressure in spontaneously hypertensive rats [71-73].”
BackgroundHossain, E., Sarkar, O., Li, Y., & Anand‐Srivastava, M. B. (2018) · Physiological Reports · doi:10.14814/phy2.13658 · Cited by 9 · see citing works
“…of exogenous nitrite, an inert metabolic by-product of the oxidation of NO (Bryan 2009), attenuates blood pressure (Beier et al. 1995; Classen et al. 1990) and endotheliumdependent relaxation in isolated aortae of SHR by activating the eNOS-NO-soluble guanylyl cyclase (sGC)cGMP…”
BackgroundMartins, L. Z., da Silva, M. L. S., Rodrigues, S. D., Gomes, S. E. B., Molezini, L., Rizzi, É., Montenegro, M. F., & Dias-Junior, C. A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241612818 · Cited by 6 · see citing works
“217 mmol/kg) daily, via gavage, from the 14th gestational day until the end of pregnancy, as previously demonstrated that this dose exerted antihypertensive effects in several experimental models of hypertension [6,36,53,54].”
MethodLiao, G., He, C., Zhang, Y., & Zhang, J. (2025) · Obesity Reviews · doi:10.1111/obr.70021 · Cited by 5 · see citing works
Relationship of Environmental Nitrogen Metabolism to Human Health
Follett, J. R., & Follett, R. F. (2008) · Elsevier eBooks · doi:10.1016/b978-0-12-374347-3.00004-4 · Cited by 4 · see citing works
Nitric Oxide and Cardiovascular Health
Li, Y., Srivastava, A. K., & Anand‐Srivastava, M. B. (2023) · Advances in biochemistry in health and disease · doi:10.1007/978-3-031-24778-1_2 · Cited by 2 · see citing works
Influence of oxygen on vascular tone during acute hypoxia
Dada, J. (2013) · ORCA Online Research @Cardiff (Cardiff University)
INORGANIC AND ORGANIC NITRATES AS SOURCES OF NITRIC OXIDE
Govoni, M. (2012) · Figshare · doi:10.13140/rg.2.2.17705.85607
Nitrite Ion : Its role in vasoregulation and host defenses
Björne, H. (2005) · Figshare
Inorganic nitrite and conduit artery function
Omar, S. A. (2015)
Biophysical Studies Aimed at Potential Therapies of Hemoglobin Associated Diseases
Belanger, A. (2015) · WakeSpace Scholarship (Wake Forest University)
Nitrite and Nitrate as a Treatment for Hypertension
Kapil, V. (2017) · Springer eBooks · doi:10.1007/978-3-319-46189-2_17
Estudo de mecanismos anti-hipertensivos do nitrito de sódio na hipertensão renovascular experimental
Pinheiro, L. C. (2017) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/t.17.2017.tde-18032015-230532
da Costa, L. C., Silva, M. L. S., Toghi, C. D. J., et al. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1939792
“The dose of sodium nitrite was chosen based on previous studies showing that this dose exerts relevant antihypertensive effects without observing adverse toxicological effects in rats (Amaral et al., 2015; Classen et al., 1990; Pinheiro et al., 2014; Pinheiro et al., 2015).”
- Authors
- Classen, H. G., Stein-Hammer, C., & Thöni, H.
- Affiliations
- University of Hohenheim (DE)
- Venue
- Journal of the American College of Nutrition
- Publisher
- Informa UK Limited
- Published
- 1990-10
- Volume
- 9
- Issue
- 5
- Pages
- 500-502
- ISSN
- 0731-5724 (ISSN-L)
- 1541-1087
- OpenAlex
- W2085281764
- Cited by
- 59
- References
- 0
- Citations by year
- 2026: 1 · 2025: 1 · 2023: 2 · 2021: 1 · 2020: 2 · 2019: 3 · 2018: 5 · 2017: 3 · 2016: 5 · 2015: 7 · 2014: 3 · 2013: 4 · 2012: 4
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of the American College of Nutrition (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Keywords
- blood pressure, spontaneously hypertensive rats, hypertension, dietary nitrate, intragastric administration, pulse rate, dose-response relationship
- MeSH terms
- Administration, Oral, Analysis of Variance, Animals, Blood Pressure, Diet, Male, Nitrates, Nitrites, Rats, Inbred SHR, Rats, Inbred Strains, 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 ›
Are you an author, or do you see a problem with this page? Request a review
