Skip main navigation

Small Amounts of Inorganic Nitrate or Beetroot Provide Substantial Protection From Salt-Induced Increases in Blood Pressure

Originally publishedhttps://doi.org/10.1161/HYPERTENSIONAHA.118.12234Hypertension. 2019;73:1042–1048

Abstract

To reduce the risk of salt-induced hypertension, medical authorities have emphasized dietary guidelines promoting high intakes of potassium and low intakes of salt that provide molar ratios of potassium to salt of ≥1:1. However, during the past several decades, relatively few people have changed their eating habits sufficiently to reach the recommended dietary goals for salt and potassium. Thus, new strategies that reduce the risk of salt-induced hypertension without requiring major changes in dietary habits would be of considerable medical interest. In the current studies in a widely used model of salt-induced hypertension, the Dahl salt-sensitive rat, we found that supplemental dietary sodium nitrate confers substantial protection from initiation of salt-induced hypertension when the molar ratio of added nitrate to added salt is only ≈1:170. Provision of a low molar ratio of added nitrate to added salt of ≈1:110 by supplementing the diet with beetroot also conferred substantial protection against salt-induced increases in blood pressure. The results suggest that on a molar basis and a weight basis, dietary nitrate may be ≈100× more potent than dietary potassium with respect to providing substantial resistance to the pressor effects of increased salt intake. Given that leafy green and root vegetables contain large amounts of inorganic nitrate, these findings raise the possibility that fortification of salty food products with small amounts of a nitrate-rich vegetable concentrate may provide a simple method for reducing risk for salt-induced hypertension.

Introduction

Recently, it has been proposed that the amount of inorganic nitrate naturally present in diets rich in leafy green and root vegetables may be an important factor contributing to the antihypertensive effects of the Dietary Approaches to Stop Hypertension (DASH) diet.1–6 The blood pressure–lowering effects of supplemental inorganic nitrate and of nitrate-rich vegetable products, such as beetroot juice, have been widely discussed and studied.2–4,7–11 For example, in randomized, double-blind, placebo-controlled studies in hypertensive subjects, Kapil et al11 found that acute and chronic administration of beetroot juice significantly reduced systolic and diastolic arterial pressure, whereas nitrate-depleted beetroot juice did not. An extensive body of research has demonstrated that dietary nitrate can be endogenously converted to the potent vasodilator NO, and based on the work of many experts in the field, it is believed that the beneficial effects of supplemental dietary nitrate on blood pressure are largely mediated by increases in NO activity.7,10 It is important to note, however, that the mechanisms mediating the blood pressure–lowering effects of dietary nitrate are subject to ongoing investigations.

In the DASH-Sodium study, the pressor effect of increasing salt intake by 100 mmol/d was substantially lower in subjects consuming the DASH diet than in subjects consuming an American-style control diet.12 This raises the question: is the amount of supplemental nitrate provided by the original DASH study diet sufficient to largely account for the substantial capacity of that diet to protect against salt-induced increases in blood pressure? According to an analysis by Keller et al,6 the original DASH study diet increased nitrate intake ≈1 mmol/d over the level of nitrate provided by a typical American-style diet. It would be remarkable and medically significant if a 1-mmol/d increase in dietary intake of a single electrolyte could substantially protect against the pressor effects of a ≥100-mmol/d increase in salt intake.

Studies by Carlström et al13 indicate that in a surgically induced model of salt sensitivity (unilaterally nephrectomized Sprague Dawley rats), a molar ratio of added dietary nitrate to added salt of ≈1:35 can protect against the hypertensinogenic effects of a high-salt diet. However, it is unknown whether significant resistance to the pressor effects of a high-salt diet can be conferred by the much lower ratio of added nitrate to added salt as used in the DASH-Sodium trial (≈1:100) or even lower. It is also unknown whether supplemental nitrate can protect against initiation of salt-induced hypertension in spontaneous forms of salt sensitivity. If so, this would suggest new approaches for reducing the risk for salt-induced hypertension that do not depend on major alterations in dietary habits, large increases in nitrate intake, or substantial decreases in food salt content. Accordingly, in the most widely studied model of spontaneous salt sensitivity, the Dahl salt-sensitive rat, we investigated whether the pressor effects of a large increase in salt intake can be substantially attenuated by a relatively small increase in nitrate intake.

Methods

The data supporting the findings of this study are available within the article and its online-only Data Supplement and from the corresponding author on appropriate request.

Animal Model

Inbred, male Dahl salt-sensitive rats were obtained as weanlings from a colony maintained at the Institute of Physiology of the Czech Academy of Sciences in Prague, Czech Republic, that was originally established with breeding pairs of inbred Dahl SS/Jr rats provided courtesy of Prof John P. Rapp (hereafter referred to as Dahl SS rats). Experiments were performed in conformance with the Animal Protection Law of the Czech Republic, the Guide to the Care and Use of Laboratory Animals (Eighth Edition) of the US National Research Council, and were approved by the Ethics Committee of the Institute of Physiology, Academy of Sciences of the Czech Republic, Prague.

A detailed discussion of the study design and methods used is available in the online-only Data Supplement.

Statistical Analysis

The following null hypothesis was tested: a relatively small increase in nitrate intake, achieved by oral administration of either a nitrate-rich vegetable product (beetroot juice) or sodium nitrate, does not attenuate increases in mean arterial pressure otherwise induced by a large increase in dietary sodium chloride. To investigate the primary null hypothesis, we used 1-way ANOVA and the Holm-Sidak procedure to test for differences in the salt-induced changes in mean arterial pressure between the control group and the beetroot-treated and nitrate-treated experimental groups. ANOVA with Holm-Sidak testing was also used in an exploratory analysis of the effects of nitrate supplementation or beetroot supplementation on salt-induced changes in heart rate and locomotor activity. An unpaired t test was used in the analysis of a separate exploratory study of the effects of sodium nitrate supplementation on sodium balance. The results are expressed as means±SEM, and P values are adjusted for the multiple group comparisons (group 1 treated with beetroot plus salt and group 2 treated with sodium nitrate plus salt, each compared with the control group treated with salt alone). Statistical significance was defined as P<0.05, and statistical analyses were performed with GraphPad Prism 6.0 (GraphPad Software, La Jolla, CA).

Results

Figure 1 presents the time course of 24-hour averages of systolic arterial pressure (Figure 1A) and diastolic arterial pressure (Figure 1B) for the 3 experimental groups. Salt loading rapidly induced substantial increases in arterial pressure that were attenuated by treatment with sodium nitrate or beetroot. Administration of sodium nitrate in a molar ratio of added nitrate to added salt of ≈1:170 significantly protected against salt-induced increases in systolic arterial pressure as did administration of beetroot and salt, which provided a nitrate-to-salt ratio of ≈1:110 (Figure 1C). Administration of sodium nitrate or beetroot also attenuated salt-induced increases in diastolic blood pressure, but after adjustment for multiple comparisons, the effect achieved statistical significance only in the beetroot-treated group (Figure 1D). Salt-induced increases in mean arterial pressure were significantly attenuated by treatment with either sodium nitrate or beetroot (Figure 2, top). Based on these results showing that a small molar ratio of added nitrate to added salt provides significant protection against salt-induced increases in mean arterial pressure, the null hypothesis is rejected.

Figure 1.

Figure 1. Effects of supplemental sodium nitrate or beetroot on salt-induced increases in blood pressure (BP). A, Time course of 24-h averages of systolic arterial pressure. B, Time course of 24-h averages of diastolic arterial pressure. C, Mean changes in systolic arterial pressure induced by salt loading. D, Mean changes in diastolic arterial pressure induced by salt loading. The salt-induced changes in arterial pressure were determined by subtracting the average results over the last 3 d on the low-salt diet from the average results over the last 3 d on the high-salt diet. Statistical analysis of the salt-induced changes in BP was performed by ANOVA with Holm-Sidak testing to adjust for multiple comparisons against the control group. *Adjusted P<0.05 compared with the salt-loaded control group.

Figure 2.

Figure 2. Changes in 24-h averages for mean arterial pressure and heart rate induced by salt loading. Top, Changes in mean arterial pressure induced by salt loading. Bottom, Changes in heart rate induced by salt loading. The salt-induced changes in mean arterial pressure and heart rate were determined by subtracting the average results over the last 3 d on the low-salt diet from the average results over the last 3 d on the high-salt diet. Statistical significance was determined by ANOVA with Holm-Sidak testing to adjust for multiple comparisons. The salt-induced changes in mean arterial pressure were 15.7±1.9 mm Hg in the control group, 9.5±2.1 mm Hg in the sodium nitrate group, and 7.6±1.5 mm Hg in the beetroot group. *Adjusted P<0.05 compared with the salt-loaded control group. **Adjusted P<0.025 compared with the salt-loaded control group.

In the control rats (no treatment with either sodium nitrate or beetroot), salt loading induced small reductions in heart rate perhaps mediated by arterial baroreflex responses to the substantial salt-induced increases in blood pressure. Specifically, in the control rats, the salt-induced decrease in heart rate, −21±4 bpm, was significantly greater than in sodium nitrate–treated rats, −1±5 bpm, and beetroot-treated rats, −4±5 bpm (both P<0.025 compared with control; Figure 2, bottom). Salt loading had no significant effect on locomotor activity in any of the groups.

The total intake of nitrate provided by the drinking fluids averaged 0.016±0.0005 mmol/d in the control group, 0.066±0.0019 mmol/d in the sodium nitrate group, and 0.095±0.0029 mmol/d in the beetroot group. Figure 3 (top) shows that the different groups of rats consumed similar amounts of sodium throughout salt loading. The rats treated with sodium nitrate or beetroot did not gain less weight than the control rats (Figure 3, bottom). Thus, in the sodium nitrate group and the beetroot group, the protection against salt-induced increases in blood pressure was not related to lower salt intake or body weight. If anything, the rats in group 1 (salt+beetroot) gained more weight than those in group 2 (salt+sodium nitrate) or those in group 3 (controls treated with salt alone).

Figure 3.

Figure 3. Sodium intakes and body weights before and after salt loading. Top, Daily sodium intakes were nearly identical in all groups throughout salt loading. Bottom, Body weights before and after salt loading were similar among the groups. Greater blood pressure in the salt-loaded control rats was not associated with greater sodium intake or greater body weight in salt-loaded control rats.

To test the effects of sodium nitrate supplementation on sodium balance, we conducted a separate metabolic study in which rats treated with salt plus sodium nitrate were compared with rats treated with salt alone. The amount of sodium retained by rats given salt plus sodium nitrate was significantly greater than that retained by rats given salt alone (Figure S1 in the online-only Data Supplement). This observation suggests that the capacity of nitrate to attenuate salt-induced increases in blood pressure does not require the attenuation of salt-induced increases in sodium balance. As expected, urinary excretion of nitrate was greater in rats treated with sodium nitrate and sodium chloride than control rats treated with sodium chloride alone (Methods in the online-only Data Supplement).

Discussion

In the most widely studied animal model of spontaneous salt sensitivity, we found that supplemental dietary sodium nitrate confers significant and substantial protection from the pressor effects of increased salt intake when the molar ratio of added nitrate to added salt is only ≈1:170. Furthermore, provision of a low molar ratio of added nitrate to added salt of ≈1:110 by supplementing the diet with beetroot and a large amount of salt also conferred significant and substantial protection against salt-induced increases in blood pressure. Beetroot treatment reduced the effect of salt loading on mean arterial pressure by 60%. To our knowledge, no other dietary ingredient has been identified that can provide this degree of protection against salt-induced increases in blood pressure when added to the diet in such low molar amounts relative to that of added salt. The present findings suggest that the greater amount of nitrate provided in the original DASH diet (≈160 mg/d)6 compared with that provided in a typical American-style diet (≈100 mg/d),14 a difference of just 1 mmol/d, may be sufficient to substantially account for the capacity of the DASH diet to protect against the pressor effects of a 100-mmol increase in salt intake (from 50 to 150 mmol/d).12

To put the current findings in perspective, it is instructive to consider the capacity of supplemental dietary potassium to protect against the pressor effects of salt loading. In classic studies conducted in salt-sensitive rats >40 years ago, Dahl et al15 found that a molar ratio of added dietary potassium to added dietary salt of ≈1:1 was required for supplemental potassium to strongly protect against the pressor effects of a large increase in salt intake. In the present study, we found that a much lower molar ratio of added dietary nitrate to added dietary salt in the range of ≈1:170 to 1:110 affords substantial protection against the pressor effects of a large increase in salt intake. These findings suggest that on a molar basis or a weight basis, dietary nitrate may be ≈100× more potent than dietary potassium with respect to providing substantial protection from the pressor effects of increased salt intake.

Various medical and governmental authorities, including the World Health Organization, have issued guidelines recommending high intakes of potassium and low intakes of salt that provide molar ratios of dietary potassium to salt of ≥1:1.16–19 However, only small fractions of populations in the United States and around the world are meeting joint guidelines on potassium intake and salt intake.20,21 Because substantial changes in dietary habits are required to meet the joint guidelines, the feasibility of achieving the recommended molar ratios of potassium intake to salt intake has come into question.20,21 In addition, although the DASH diet provides substantial protection against salt-induced increases in blood pressure, sustained adherence to the DASH diet can be challenging.22–25 Thus, additional strategies for preventing salt-induced hypertension, beyond the use of potassium supplementation/salt restriction, and the DASH diet, would be of considerable medical interest. For individuals who are unable or unwilling to adequately reduce salt intake or follow the original DASH diet, increasing daily intake of inorganic nitrate by ≈1 mmol, a relatively small amount that can be safely provided by just 2 additional ounces of a raw, nitrate-rich vegetable8 may afford significant protection against salt-induced increases in blood pressure. This amount of nitrate is well within the World Health Organization limit for the acceptable daily intake of nitrate (≈262 mg/d for a 70-kg human) and the reference dose for nitrate set by the US Environmental Protection Agency (≈490 mg/d for a 70-kg human).26–28

We found that small amounts of added dietary nitrate can substantially protect against the pressor effects of relatively large amounts of added dietary salt without reducing salt consumption or weight gain. In addition, we found that administration of sodium nitrate did not attenuate salt-induced increases in sodium balance (Figure S1). Thus, the current findings suggest that the capacity of dietary nitrate to protect against salt-induced increases in blood pressure is not mediated by reductions in salt intake, sodium balance, or body weight. An extensive body of evidence has indicated that the blood pressure–lowering effects of supplemental dietary nitrate may be largely mediated by increases in NO activity.7 As discussed by Carlström et al,7 NO can be endogenously generated by reduction of nitrite derived from dietary or nondietary sources of nitrate. Based on the studies of Gao et al,29 it appears that the renal microvasculature may be a primary target for blood pressure regulation by nitrite and nitrate because preglomerular resistance vessels are particularly sensitive to the capacity of nitrite to promote vasodilation and to inhibit vasoconstriction induced by angiotensin II. Thus, NO-mediated renal vasodilation and associated reductions in renal vascular resistance may help protect against salt-induced increases in blood pressure.30,31 However, it has also been proposed that NO enhances renal pressure natriuresis and sodium excretion,32 which may limit salt-induced increases in blood volume, cardiac output, and blood pressure. The usual mechanistic pathways through which changes in NO activity and other factors protect against salt-induced hypertension are controversial and are discussed in detail elsewhere.30–35

The present findings are consistent with the results of seminal studies by Chen and Sanders36 >25 years ago in which they found that in Dahl SS rats, oral administration of large amounts of L-arginine—the substrate for enzymatic generation of NO by NO synthase—prevents salt-induced hypertension. However, the use of L-arginine, or its precursor L-citrulline, for regulating blood pressure in humans has gained limited traction possibly due, in part, to the relatively large doses required to achieve an antihypertensive effect (≈4000–10 000 mg/d).37,38 The utility of these agents could also be limited because in patients with endothelial dysfunction, the capacity to convert L-arginine to NO may be impaired.39 Moreover, as noted by Higashi et al,40 the ability of L-arginine to increase endothelial NO synthesis seems to be attenuated by a high-salt diet. In contrast to supplemental L-arginine or L-citrulline, the antihypertensive effects of supplemental inorganic nitrate do not depend on NO synthase activity, and much lower amounts of nitrate may be sufficient to substantially reduce the risk for salt-induced hypertension. Recent studies by Chien et al41 suggest that in SHR (spontaneously hypertensive rats) consuming normal rat chow, oral administration of sodium nitrate in amounts sufficient to provide a molar ratio of nitrate to salt of ≈1:10 may attenuate the development of increased blood pressure. However, it remains to be determined whether the much lower ratios of nitrate to salt used in the current study will also attenuate development of spontaneous hypertension in SHR consuming a normal-salt diet.

Prevention Versus Reversal of Hypertension

In the present study, we focused on using small molar ratios of added nitrate to added salt to attenuate the initiation of salt-induced hypertension. The current observations are not intended to imply that small amounts of supplemental nitrate or nitrate-rich vegetables are likely to be sufficient for reducing blood pressure in individuals with established hypertension. As noted by Sanders et al36 in their studies in Dahl SS rats, supplemental arginine was effective in attenuating salt-induced increases in blood pressure but not in reversing established hypertension. Similarly, we observed that while supplemental intake of a relatively small amount of nitrate relative to salt can provide substantial protection from initiation of salt-induced hypertension, it did not attenuate or reverse the course of salt-induced hypertension that was already well underway (Figure S2). It is possible that larger doses of nitrate are required for reversal of hypertension than for prevention of salt-induced hypertension. In rats with established renal artery hypertension, Montenegro et al42 reported that administration of large amounts of nitrite in the drinking water (5–50 mmol/L sodium nitrite) can decrease blood pressure. In the randomized, placebo-controlled trial conducted in the United Kingdom by Kapil et al11 in humans with established hypertension, supplemental intake of a relatively large amount of nitrate (≈4× more than the usual dietary intake of 100 mg/d) was used to reduce blood pressure.11 Assuming the normal subjects in the study of Kapil et al43 ingested the average amount of salt consumed in the United Kingdom (≈9 g/d), the total amount of nitrate ingested provided a molar ratio of nitrate to salt of ≈1:20. Interestingly, in some subjects consuming a DASH-style diet, intake of nitrate may be high and exceed 1000 mg/d, depending on the extent to which nitrate-rich vegetables are incorporated into the diet.5

Limitations

The present studies investigated whether a low molar ratio of added dietary nitrate to added dietary salt protects against the pressor effects of short-term salt loading and did not involve testing with long-term salt loading. However, the studies by Carlström et al13 and Chen et al44 indicate that protection by supplemental nitrate or arginine against the pressor effects of short-term salt loading is predictive of protection by these agents against the pressor effects of long-term salt loading. In addition, the current studies focused on testing the antihypertensive effects of a low ratio of added nitrate to added salt and did not investigate the effects of other ratios of added nitrate to salt. In future studies, it would be of interest to test the effects of additional ratios of nitrate to salt on salt-induced changes in blood pressure in a variety of animal models of salt sensitivity and in salt-sensitive humans. Although extrapolation of findings in animal models to humans should always be done with caution, it should be noted that the Dahl SS rat is considered to be an excellent model of human salt sensitivity and shows blood pressure responses to dietary interventions consistent with observations made in clinical studies.15,45–47

The results of the present studies are consistent with the view that the antihypertensive effects of beetroot may largely be mediated by nitrate. However, it should be recognized that beetroot also contains a variety of other compounds that could be influencing blood pressure, including flavonoids, phenolic acids and amides, carotenoids, betacyanin, betaxanthin, ascorbic acid, and potassium.48 With respect to potassium, the amount of potassium added by the beetroot in the current studies was small relative to the amount of added salt and is unlikely to account for the protection against salt-induced increases in blood pressure.15 In addition, in humans with hypertension, it has been reported that nitrate-depleted beetroot juice has relatively little or no effect on blood pressure compared with beetroot juice that has not been depleted of nitrate.11 Although these observations suggest that nitrate may be necessary for the beneficial effects of beetroot on blood pressure, we cannot exclude the possibility that other ingredients may also be influencing the capacity of beetroot to protect against salt-induced hypertension. Finally, it should be pointed out that natural products, such as beetroot, can vary considerably in their biochemical makeup (including nitrate levels) depending on the cultivar type, soil conditions, time of harvesting, use of fertilizers, etc.49 Thus, when studying beetroot or other nitrate-rich vegetable ingredients, it is important that investigators check the nitrate levels to insure consistency of the products and to consider the use of relevant control groups in their experiments (eg, groups treated specifically with a nitrate salt itself and groups treated with a nitrate-depleted product).

Perspectives and Conclusions

During the past few decades, medical and governmental authorities worldwide have called for extensive efforts to reduce salt intake at the population level with the hope that such efforts would reduce the risk for salt-induced hypertension and related cardiovascular diseases.50–54 In most countries, however, average salt intakes have remained well above recommended targets, and in some population subgroups (eg, hypertensive subjects in the United States), salt intake appears to have increased.43,53,55,56 In addition, prominent scientists continue to raise questions about the wisdom of attempts to reduce salt intake in the population as a whole.57–62 Thus, new approaches to reducing the risk for salt-induced hypertension are of considerable medical and scientific interest.

The results of the present study indicate that fortifying salty food products with surprisingly small amounts of vegetable products naturally rich in inorganic nitrate may provide a safe and simple strategy for reducing the risk for salt-induced hypertension. Because relatively low concentrations of an added vegetable concentrate could provide the desired amount of nitrate, this approach might be implemented in many cases without affecting the taste or physical properties of the salty food product of interest and without requiring a change in eating habits. For example, soy sauces, including reduced sodium soy sauces, typically have high concentrations of salt ranging from ≈10% to 15%, and in Japan, soy sauce is the major source of salt in the diet.63,64 Given that vegetables, such as beetroot or arugula, can have high concentrations of inorganic nitrate, the desired molar ratio of nitrate to salt in soy sauce could be achieved by adding a few grams of an appropriate vegetable concentrate to 100 mL of soy sauce. In other sauces and condiments that contain less salt than soy sauce, even smaller amounts of a nitrate-rich vegetable product could be added to achieve the desired ratio of nitrate to sodium chloride. This approach need not interfere with conventional strategies for reducing the risk for salt-induced hypertension and would not require a change in dietary habits or the need to purchase and consume a salt substitute or a separate dietary supplement.

Footnotes

The online-only Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/HYPERTENSIONAHA.118.12234.

Correspondence to Theodore W. Kurtz, Department of Laboratory Medicine, University of California, 185 Berry St, Suite 290, San Francisco, CA 94107. Email

References

  • 1. Lundberg JO, Feelisch M, Björne H, Jansson EA, Weitzberg E. Cardioprotective effects of vegetables: is nitrate the answer?Nitric Oxide. 2006; 15:359–362. doi: 10.1016/j.niox.2006.01.013CrossrefMedlineGoogle Scholar
  • 2. Gee LC, Ahluwalia A. Dietary nitrate lowers blood pressure: epidemiological, pre-clinical experimental and clinical trial evidence.Curr Hypertens Rep. 2016; 18:17. doi: 10.1007/s11906-015-0623-4CrossrefMedlineGoogle Scholar
  • 3. Khatri J, Mills CE, Maskell P, Odongerel C, Webb AJ. It is rocket science - why dietary nitrate is hard to ‘beet’! Part I: twists and turns in the realization of the nitrate-nitrite-NO pathway.Br J Clin Pharmacol. 2017; 83:129–139. doi: 10.1111/bcp.12913CrossrefMedlineGoogle Scholar
  • 4. Mills CE, Khatri J, Maskell P, Odongerel C, Webb AJ. It is rocket science - why dietary nitrate is hard to ‘beet’! Part II: further mechanisms and therapeutic potential of the nitrate-nitrite-NO pathway.Br J Clin Pharmacol. 2017; 83:140–151. doi: 10.1111/bcp.12918CrossrefMedlineGoogle Scholar
  • 5. Hord NG, Tang Y, Bryan NS. Food sources of nitrates and nitrites: the physiologic context for potential health benefits.Am J Clin Nutr. 2009; 90:1–10. doi: 10.3945/ajcn.2008.27131CrossrefMedlineGoogle Scholar
  • 6. Keller RM, Beaver L, Prater MC, Hord NG. Dietary nitrate and nitrite concentrations in food patterns and dietary supplements [published online December 27, 2017].Nutrition Today. 2017. doi: 10.1097/NT.0000000000000253. https://journals.lww.com/nutritiontodayonline/Abstract/publishahead/Dietary_Nitrate_and_Nitrite_Concentrations_in_Food.99968.aspx.CrossrefGoogle Scholar
  • 7. Carlström M, Lundberg JO, Weitzberg E. Mechanisms underlying blood pressure reduction by dietary inorganic nitrate.Acta Physiol (Oxf). 2018; 224:e13080. doi: 10.1111/apha.13080CrossrefMedlineGoogle Scholar
  • 8. Lidder S, Webb AJ. Vascular effects of dietary nitrate (as found in green leafy vegetables and beetroot) via the nitrate-nitrite-nitric oxide pathway.Br J Clin Pharmacol. 2013; 75:677–696. doi: 10.1111/j.1365-2125.2012.04420.xCrossrefMedlineGoogle Scholar
  • 9. Webb AJ, Patel N, Loukogeorgakis S, Okorie M, Aboud Z, Misra S, Rashid R, Miall P, Deanfield J, Benjamin N, MacAllister R, Hobbs AJ, Ahluwalia A. Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite.Hypertension. 2008; 51:784–790. doi: 10.1161/HYPERTENSIONAHA.107.103523LinkGoogle Scholar
  • 10. Ahluwalia A, Gladwin M, Coleman GD, et al. Dietary nitrate and the epidemiology of cardiovascular disease: report from a National Heart, Lung, and Blood Institute Workshop.J Am Heart Assoc. 2016; 5: e003402.LinkGoogle Scholar
  • 11. Kapil V, Khambata RS, Robertson A, Caulfield MJ, Ahluwalia A. Dietary nitrate provides sustained blood pressure lowering in hypertensive patients: a randomized, phase 2, double-blind, placebo-controlled study.Hypertension. 2015; 65:320–327. doi: 10.1161/HYPERTENSIONAHA.114.04675LinkGoogle Scholar
  • 12. Sacks FM, Svetkey LP, Vollmer WM, Appel LJ, Bray GA, Harsha D, Obarzanek E, Conlin PR, Miller ER, Simons-Morton DG, Karanja N, Lin PH; DASH-Sodium Collaborative Research Group. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group.N Engl J Med. 2001; 344:3–10. doi: 10.1056/NEJM200101043440101CrossrefMedlineGoogle Scholar
  • 13. Carlström M, Persson AE, Larsson E, Hezel M, Scheffer PG, Teerlink T, Weitzberg E, Lundberg JO. Dietary nitrate attenuates oxidative stress, prevents cardiac and renal injuries, and reduces blood pressure in salt-induced hypertension.Cardiovasc Res. 2011; 89:574–585. doi: 10.1093/cvr/cvq366CrossrefMedlineGoogle Scholar
  • 14. Gangolli SD, van den Brandt PA, Feron VJ, Janzowsky C, Koeman JH, Speijers GJ, Spiegelhalder B, Walker R, Wisnok JS. Nitrate, nitrite and N-nitroso compounds.Eur J Pharmacol. 1994; 292:1–38.MedlineGoogle Scholar
  • 15. Dahl LK, Leitl G, Heine M. Influence of dietary potassium and sodium/potassium molar ratios on the development of salt hypertension.J Exp Med. 1972; 136:318–330.CrossrefMedlineGoogle Scholar
  • 16. Institute of Medicine (U.S.). Panel on dietary reference intakes for electrolytes and water.DRI, Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate. Washington, D.C.: National Academies Press; 2005.Google Scholar
  • 17. US Department of Agriculture, US Department of Health and Human Services. Dietary Guidelines for Americans, 2015–2020.https://health.gov/dietaryguidelines/2015/guidelines/. Accessed September 24, 2018.Google Scholar
  • 18. World Health Organization. WHO Issues New Guidance on Dietary Salt and Potassium.http://www.who.int/mediacentre/news/notes/2013/salt_potassium_20130131/en/. Accessed September 24, 2018.Google Scholar
  • 19. Whelton PK. Sodium and potassium intake in US adults.Circulation. 2018; 137:247–249. doi: 10.1161/CIRCULATIONAHA.117.031371LinkGoogle Scholar
  • 20. Drewnowski A, Maillot M, Rehm C. Reducing the sodium-potassium ratio in the US diet: a challenge for public health.Am J Clin Nutr. 2012; 96:439–444. doi: 10.3945/ajcn.111.025353CrossrefMedlineGoogle Scholar
  • 21. Drewnowski A, Rehm CD, Maillot M, Mendoza A, Monsivais P. The feasibility of meeting the WHO guidelines for sodium and potassium: a cross-national comparison study.BMJ Open. 2015; 5:e006625. doi: 10.1136/bmjopen-2014-006625CrossrefMedlineGoogle Scholar
  • 22. Mellen PB, Gao SK, Vitolins MZ, Goff DC. Deteriorating dietary habits among adults with hypertension: DASH dietary accordance, NHANES 1988-1994 and 1999-2004.Arch Intern Med. 2008; 168:308–314. doi: 10.1001/archinternmed.2007.119CrossrefMedlineGoogle Scholar
  • 23. Kim H, Andrade FC. Diagnostic status of hypertension on the adherence to the Dietary Approaches to Stop Hypertension (DASH) diet.Prev Med Rep. 2016; 4:525–531. doi: 10.1016/j.pmedr.2016.09.009CrossrefMedlineGoogle Scholar
  • 24. Kwan MW, Wong MC, Wang HH, Liu KQ, Lee CL, Yan BP, Yu CM, Griffiths SM. Compliance with the Dietary Approaches to Stop Hypertension (DASH) diet: a systematic review.PLoS One. 2013; 8:e78412. doi: 10.1371/journal.pone.0078412CrossrefMedlineGoogle Scholar
  • 25. Epstein DE, Sherwood A, Smith PJ, Craighead L, Caccia C, Lin PH, Babyak MA, Johnson JJ, Hinderliter A, Blumenthal JA. Determinants and consequences of adherence to the dietary approaches to stop hypertension diet in African-American and white adults with high blood pressure: results from the ENCORE trial.J Acad Nutr Diet. 2012; 112:1763–1773. doi: 10.1016/j.jand.2012.07.007CrossrefMedlineGoogle Scholar
  • 26. Hord NG, Conley MN. Regulation of dietary nitrate and nitrite: balancing essential physiological roles with potential health risks.Bryan NS, Loscalzo J, eds. In: Nitrite and Nitrate in Human Health and Disease. 2nd ed. Cham, Switzerland: Springer International Publishing; 2017:153–162.Google Scholar
  • 27. Agency for Toxic Substances and Disease Registry, U.S. Department of Health and Human Services. Nitrate and Nitrite Toxicity. What are U.S. Standards and Regulations for Nitrates and Nitrites Exposure?https://www.atsdr.cdc.gov/csem/csem.asp?csem=28&po=8. Accessed September 25, 2018.Google Scholar
  • 28. European Food Safety Authority. Nitrate in vegetables: scientific opinion of the panel on contaminants in the food chain.The EFSA Journal. 2008; 689:1–79. doi: 10.2903/j.efsa.2008.689Google Scholar
  • 29. Gao X, Yang T, Liu M, Peleli M, Zollbrecht C, Weitzberg E, Lundberg JO, Persson AE, Carlström M. NADPH oxidase in the renal microvasculature is a primary target for blood pressure-lowering effects by inorganic nitrate and nitrite.Hypertension. 2015; 65:161–170. doi: 10.1161/HYPERTENSIONAHA.114.04222LinkGoogle Scholar
  • 30. Kurtz TW, DiCarlo SE, Pravenec M, Schmidlin O, Tanaka M, Morris RC. An alternative hypothesis to the widely held view that renal excretion of sodium accounts for resistance to salt-induced hypertension.Kidney Int. 2016; 90:965–973. doi: 10.1016/j.kint.2016.05.032CrossrefMedlineGoogle Scholar
  • 31. Kurtz TW, DiCarlo SE, Pravenec M, Morris RC. The pivotal role of renal vasodysfunction in salt sensitivity and the initiation of salt-induced hypertension.Curr Opin Nephrol Hypertens. 2018; 27:83–92. doi: 10.1097/MNH.0000000000000394CrossrefMedlineGoogle Scholar
  • 32. Granger JP, Alexander BT. Abnormal pressure-natriuresis in hypertension: role of nitric oxide.Acta Physiol Scand. 2000; 168:161–168. doi: 10.1046/j.1365-201x.2000.00655.xCrossrefGoogle Scholar
  • 33. Hall JE. Renal dysfunction, rather than nonrenal vascular dysfunction, mediates salt-induced hypertension.Circulation. 2016; 133:894–906. doi: 10.1161/CIRCULATIONAHA.115.018526LinkGoogle Scholar
  • 34. Morris RC, Schmidlin O, Sebastian A, Tanaka M, Kurtz TW. Vasodysfunction that involves renal vasodysfunction, not abnormally increased renal retention of sodium, accounts for the initiation of salt-induced hypertension.Circulation. 2016; 133:881–893. doi: 10.1161/CIRCULATIONAHA.115.017923LinkGoogle Scholar
  • 35. Manning RD, Hu L, Tan DY, Meng S. Role of abnormal nitric oxide systems in salt-sensitive hypertension.Am J Hypertens. 2001; 14(6pt 2):68S–73S.CrossrefGoogle Scholar
  • 36. Chen PY, Sanders PW. L-arginine abrogates salt-sensitive hypertension in Dahl/Rapp rats.J Clin Invest. 1991; 88:1559–1567. doi: 10.1172/JCI115467CrossrefMedlineGoogle Scholar
  • 37. Siani A, Pagano E, Iacone R, Iacoviello L, Scopacasa F, Strazzullo P. Blood pressure and metabolic changes during dietary L-arginine supplementation in humans.Am J Hypertens. 2000; 13(5pt 1):547–551.CrossrefGoogle Scholar
  • 38. Mahboobi S, Tsang C, Rezaei S, Jafarnejad S. Effect of L-citrulline supplementation on blood pressure: a systematic review and meta-analysis of randomized controlled trials.J Hum Hypertens. 2019; 33:10–21. doi: 10.1038/s41371-018-0108-4CrossrefGoogle Scholar
  • 39. Zand J, Lanza F, Garg HK, Bryan NS. All-natural nitrite and nitrate containing dietary supplement promotes nitric oxide production and reduces triglycerides in humans.Nutr Res. 2011; 31:262–269. doi: 10.1016/j.nutres.2011.03.008CrossrefGoogle Scholar
  • 40. Higashi Y, Oshima T, Watanabe M, Matsuura H, Kajiyama G. Renal response to L-arginine in salt-sensitive patients with essential hypertension.Hypertension. 1996; 27(3pt 2):643–648.LinkGoogle Scholar
  • 41. Chien SJ, Lin KM, Kuo HC, Huang CF, Lin YJ, Huang LT, Tain YL. Two different approaches to restore renal nitric oxide and prevent hypertension in young spontaneously hypertensive rats: l-citrulline and nitrate.Transl Res. 2014; 163:43–52. doi: 10.1016/j.trsl.2013.09.008CrossrefMedlineGoogle Scholar
  • 42. Montenegro MF, Amaral JH, Pinheiro LC, Sakamoto EK, Ferreira GC, Reis RI, Marçal DM, Pereira RP, Tanus-Santos JE. Sodium nitrite downregulates vascular NADPH oxidase and exerts antihypertensive effects in hypertension.Free Radic Biol Med. 2011; 51:144–152. doi: 10.1016/j.freeradbiomed.2011.04.005CrossrefMedlineGoogle Scholar
  • 43. Powles J, Fahimi S, Micha R, Khatibzadeh S, Shi P, Ezzati M, Engell RE, Lim SS, Danaei G, Mozaffarian D; Global Burden of Diseases Nutrition and Chronic Diseases Expert Group (NutriCoDE). Global, regional and national sodium intakes in 1990 and 2010: a systematic analysis of 24 h urinary sodium excretion and dietary surveys worldwide.BMJ Open. 2013; 3:e003733. doi: 10.1136/bmjopen-2013-003733CrossrefMedlineGoogle Scholar
  • 44. Chen PY, St John PL, Kirk KA, Abrahamson DR, Sanders PW. Hypertensive nephrosclerosis in the Dahl/Rapp rat. Initial sites of injury and effect of dietary L-arginine supplementation.Lab Invest. 1993; 68:174–184.MedlineGoogle Scholar
  • 45. Adrogué HJ, Madias NE. The impact of sodium and potassium on hypertension risk.Semin Nephrol. 2014; 34:257–272. doi: 10.1016/j.semnephrol.2014.04.003CrossrefMedlineGoogle Scholar
  • 46. Mattson DL, Kunert MP, Kaldunski ML, Greene AS, Roman RJ, Jacob HJ, Cowley AW. Influence of diet and genetics on hypertension and renal disease in Dahl salt-sensitive rats.Physiol Genomics. 2004; 16:194–203. doi: 10.1152/physiolgenomics.00151.2003CrossrefMedlineGoogle Scholar
  • 47. Abais-Battad JM, Mattson DL. Influence of dietary protein on Dahl salt-sensitive hypertension: a potential role for gut microbiota.Am J Physiol Regul Integr Comp Physiol. 2018; 315:R907–R914. doi: 10.1152/ajpregu.00399.2017CrossrefMedlineGoogle Scholar
  • 48. Chhikara N, Kushwaha K, Sharma P, Gat Y, Panghal A. Bioactive compounds of beetroot and utilization in food processing industry: a critical review.Food Chem. 2019; 272:192–200. doi: 10.1016/j.foodchem.2018.08.022CrossrefGoogle Scholar
  • 49. Keeton JT. History of nitrite and nitrate in food.Bryan NS, Loscalzo J, eds. In: Nitrite and Nitrate in Human Health and Disease. 2nd ed. Cham, Switzerland: Springer International; 2017:85–97.Google Scholar
  • 50. Lichtenstein AH, Appel LJ, Brands M, et al. Diet and lifestyle recommendations revision 2006: a scientific statement from the American Heart Association Nutrition Committee.Circulation. 2006; 114:82–96.LinkGoogle Scholar
  • 51. Krauss RM, Eckel RH, Howard B, et al. AHA dietary guidelines: revision 2000: a statement for healthcare professionals from the Nutrition Committee of the American Heart Association.Circulation. 2000; 102:2284–2299.LinkGoogle Scholar
  • 52. World Health Organization. Diet, Nutrition and the Prevention of Chronic Disease. Report of a Joint WHO/FAO Expert Consultation. Geneva, Switzerland: WHO; 2003.Google Scholar
  • 53. Barberio AM, Sumar N, Trieu K, Lorenzetti DL, Tarasuk V, Webster J, Campbell NRC, McLaren L. Population-level interventions in government jurisdictions for dietary sodium reduction: a Cochrane Review.Int J Epidemiol. 2017; 46:1551–1405. doi: 10.1093/ije/dyw361CrossrefMedlineGoogle Scholar
  • 54. Campbell NR, Lackland DT, Chockalingam A, Lisheng L, Harrap SB, Touyz RM, Burrell LM, Ramírez AJ, Schmieder RE, Schutte AE, Prabhakaran D, Schiffrin EL; Executive Board of the World Hypertension League; Executive Committee of the International Society of Hypertension. The International Society of Hypertension and World Hypertension League call on governments, nongovernmental organizations and the food industry to work to reduce dietary sodium.J Hypertens. 2014; 32:446–447. doi: 10.1097/HJH.0000000000000079CrossrefGoogle Scholar
  • 55. Dolmatova EV, Moazzami K, Bansilal S. Dietary sodium intake among US adults with hypertension, 1999-2012.J Hypertens. 2018; 36:237–242. doi: 10.1097/HJH.0000000000001558CrossrefMedlineGoogle Scholar
  • 56. Meyer KA, Harnack LJ, Luepker RV, Zhou X, Jacobs DR, Steffen LM. Twenty-two-year population trends in sodium and potassium consumption: the Minnesota Heart Survey.J Am Heart Assoc. 2013; 2:e000478. doi: 10.1161/JAHA.113.000478LinkGoogle Scholar
  • 57. Mente A, O’Donnell M, Rangarajan S, et al. Urinary sodium excretion, blood pressure, cardiovascular disease, and mortality: a community-level prospective epidemiological cohort study.Lancet. 2018; 392:496–506.CrossrefMedlineGoogle Scholar
  • 58. Mente A, O’Donnell M, Rangarajan S, et al; PURE, EPIDREAM and ONTARGET/TRANSCEND Investigators. Associations of urinary sodium excretion with cardiovascular events in individuals with and without hypertension: a pooled analysis of data from four studies.Lancet. 2016; 388:465–475. doi: 10.1016/S0140-6736(16)30467-6CrossrefMedlineGoogle Scholar
  • 59. Graudal N, Hubeck-Graudal T, Jürgens G, McCarron DA. The significance of duration and amount of sodium reduction intervention in normotensive and hypertensive individuals: a meta-analysis.Adv Nutr. 2015; 6:169–177. doi: 10.3945/an.114.007708CrossrefMedlineGoogle Scholar
  • 60. Stolarz-Skrzypek K, Staessen JA. Reducing salt intake for prevention of cardiovascular disease–times are changing.Adv Chronic Kidney Dis. 2015; 22:108–115. doi: 10.1053/j.ackd.2014.12.002CrossrefGoogle Scholar
  • 61. Alderman MH. Dietary sodium: where science and policy diverge.Am J Hypertens. 2016; 29:424–427. doi: 10.1093/ajh/hpu256CrossrefMedlineGoogle Scholar
  • 62. Graudal N, Jürgens G. Conflicting evidence on health effects associated with salt reduction calls for a redesign of the salt dietary guidelines.Prog Cardiovasc Dis. 2018; 61:20–26. doi: 10.1016/j.pcad.2018.04.008CrossrefGoogle Scholar
  • 63. Okuda N, Okayama A, Miura K, Yoshita K, Saito S, Nakagawa H, Sakata K, Miyagawa N, Chan Q, Elliott P, Ueshima H, Stamler J. Food sources of dietary sodium in the Japanese adult population: the international study of macro-/micronutrients and blood pressure (INTERMAP).Eur J Nutr. 2017; 56:1269–1280. doi: 10.1007/s00394-016-1177-1CrossrefGoogle Scholar
  • 64. Asakura K, Uechi K, Masayasu S, Sasaki S. Sodium sources in the Japanese diet: difference between generations and sexes.Public Health Nutr. 2016; 19:2011–2023. doi: 10.1017/S1368980015003249CrossrefGoogle Scholar

Novelty and Significance

What Is New?

  • In the Dahl salt-sensitive rat—a widely used model of salt-induced hypertension, a low molar ratio of added dietary nitrate to added dietary salt of ≈1:170 affords substantial protection against the pressor effects of a large increase in salt intake.

  • This finding suggests that on a molar basis and on a weight basis, dietary nitrate may be ≈100× more potent than dietary potassium with respect to providing substantial resistance to the pressor effects of increased salt intake.

What Is Relevant?

  • The present results are relevant for identifying new strategies for the prevention of salt-induced hypertension that may not require restricting salt intake or making major changes in dietary habits.

Summary

A small increase in dietary inorganic nitrate can substantially protect against salt-induced increases in blood pressure. This finding suggests that fortification of salty food products with small amounts of a nitrate-rich vegetable ingredient may provide a safe and simple method for reducing risk for salt-induced hypertension.

eLetters(0)

eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.

Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.