Beilin, Lawrence J.

Blekkenhorst, Lauren C.

Bondonno, Catherine P.

Bondonno, Nicola P.

Croft, Kevin D.

Devine, Amanda

Hodgson, Jonathan M.

Lewis, Joshua R.

Prince, Richard L.

Puddey, Ian B.

Ward, Natalie C.

Wood, Lisa G.

Woodman, Richard J.

English

Crossref

Research Online @ ECU

Edith Cowan University Research Online ECU Publications Post 2013 6-1-2019 Reply to OM Shannon et al Lauren C. Blekkenhorst Edith Cowan University, l.blekkenhorst@ecu.edu.au Joshua R. Lewis Edith Cowan University, joshua.lewis@ecu.edu.au Richard L. Prince Amanda Devine Edith Cowan University, a.devine@ecu.edu.au Nicola P. Bondonno See next page for additional authors Follow this and additional works at: https://ro.ecu.edu.au/ecuworkspost2013  Part of the Dietetics and Clinical Nutrition Commons 10.1093/ajcn/nqy246 Blekkenhorst, L.C., Lewis, J.R., Prince, R.L., Devine, A., Bondonno, N.P., Bondonno, ... Hodgson, J.M. (2018). Reply to OM Shannon et al. The American Journal of Clinical Nutrition, 108(6), 1353–1354. Available here. This Letter to the Editor is posted at Research Online. https://ro.ecu.edu.au/ecuworkspost2013/5434 Authors Lauren C. Blekkenhorst, Joshua R. Lewis, Richard L. Prince, Amanda Devine, Nicola P. Bondonno, Catherine P. Bondonno, Lisa G. Wood, Ian B. Puddey, Natalie C. Ward, Kevin D. Croft, Richard J. Woodman, Lawrence J. Beilin, and Jonathan M. Hodgson This letter to the editor is available at Research Online: https://ro.ecu.edu.au/ecuworkspost2013/5434 1  Response to Letter, “No effect of 4 weeks nitrate-rich vegetable consumption on blood 1 pressure: Reflections for future research” 2 Lauren C Blekkenhorst1, Joshua R Lewis1,2,3,4, Richard L Prince2,5, Amanda Devine1, Nicola 3 P Bondonno2, Catherine P Bondonno1, Lisa G Wood7, Ian B Puddey2, Natalie C Ward2,8, 4 Kevin D Croft2, Richard J Woodman9, Lawrence J Beilin2, Jonathan M Hodgson1 5 1School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia 6 2Medical School, The University of Western Australia, Perth, WA, Australia 7 3Centre for Kidney Research, Children's Hospital at Westmead, Westmead, NSW, Australia 8 4School of Public Health, Sydney Medical School, The University of Sydney, Sydney, NSW, 9 Australia  10 3Centre for Kidney Research, Children's Hospital at Westmead, Westmead, NSW, Australia  11 4School of Public Health, Sydney Medical School, University of Sydney, Sydney, NSW, 12 Australia  13 5Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, 14 Australia 15 7School of Biomedical Science and Pharmacy, University of Newcastle, New Lambton 16 Heights, NSW, Australia 17 8School of Biomedical Sciences & Curtin Health Innovation Research Institute, Curtin 18 University, Bentley, WA, Australia 19 9Flinders Centre for Epidemiology and Biostatistics, Flinders University, Adelaide, SA, 20 Australia 21 Address for correspondence and reprint requests: 22 2  Lauren C Blekkenhorst 23 School of Medical and Health Sciences 24 Edith Cowan University  25 270 Joondalup Drive JOONDALUP WA 6027  26 Tel: 61 8 6304 4604 27 Email: l.blekkenhorst@ecu.edu.au   28 3  Response to letter:  29 We would like to thank Shannon and colleagues for their interest in our recent publication 30 (1). Our approach to increasing nitrate intake was to have participants consume high nitrate 31 vegetables, rather than supplements. The estimated increase in nitrate intake of ~150 mg/d 32 was in addition to an estimated background intake of ~85 mg/d (1). This represents a 33 substantial increase in habitual nitrate intake. With typical median habitual nitrate intakes of 34 ~100 mg/d (2), a nitrate intake of >200 mg/d would represent high nitrate intake within most 35 populations. We believe that an increase in nitrate intake of >100 mg/d is readily achievable 36 for the wider population. Although a very high nitrate intake (>500 mg/d) can be achieved 37 through dietary means, this is unrealistic on a long-term basis for the majority of the general 38 population. Such intakes usually require supplementation with nitrate salts (NaNO3; KNO3) 39 or concentrated beetroot juice. The feasibility of translation of findings to shift behaviours of 40 the wider population should be taken into account in designing future studies. 41 Many trials have now investigated the effects of increased nitrate intake on blood pressure (3-42 6). Results of acute studies are largely consistent and indicate dose-related blood pressure 43 lowering with increased nitrate intake. The chronic effects following a sustained increase in 44 nitrate intake are less consistent (3-5). Several previous trials indicate that a short-term 45 increase in nitrate intake does not result in lower blood pressure (7-10): results that align with 46 our recent trial (1). However, other short-term trials have demonstrated blood pressure 47 lowering effects following sustained short-term increases in nitrate intake (3-5, 11).  48 The reasons for the inconsistent results from short-term trials are unclear. We agree that 49 nitrate dose may be a factor, but counterintuitively, a meta-analysis of short-term studies 50 indicated smaller effect sizes for blood pressure among trials with the highest nitrate intakes 51 (3). This contrasts with data from acute studies (4), and suggests that factors other than dose 52 4  may account for the inconsistent findings. One explanation may be that sustained higher 53 nitrate intakes can result in down-regulation of nitric oxide synthase leading to reduced 54 endogenous nitric oxide production and/or reduced sensitivity of cellular targets to nitric 55 oxide (12). Another possibility is an interaction between sulphur-containing compounds and 56 nitrate (13, 14). In a study by Dewhurst-Trigg and others (14), the ingestion of vegetables 57 with high thiocyanate (a sulphur-containing compound) attenuated the blood pressure 58 lowering-effects of nitrate-rich vegetables. Several of the high nitrate vegetables consumed 59 by the participants in our study were also likely to include sulphur-containing compounds. 60 Furthermore, the age and health status of participants may be important. Older individuals 61 and those at an increased risk of cardiovascular disease may respond differently to healthy 62 populations (3-5, 7-9). This is supported by Ashor and colleagues who reported that when 63 short-term trials that recruited active, healthy individuals were excluded from their meta-64 analysis, effects on blood pressure became non-significant (3). 65 In summary, we agree with Shannon and colleagues that dose of nitrate may be a contributing 66 factor to the inconsistencies in nitrate intervention trials. However, we believe that factors 67 other than nitrate dose are more likely to explain the inconsistent findings in this field.  68 5  Disclosures: None. 69 References:  70 1. Blekkenhorst LC, Lewis JR, Prince RL, Devine A, Bondonno NP, Bondonno CP, 71 Wood LG, Puddey IB, Ward NC, Croft KD, et al. Nitrate-rich vegetables do not lower 72 blood pressure in individuals with mildly elevated blood pressure: a 4-wk randomized 73 controlled crossover trial. Am J Clin Nutr 2018;107(6):894-908. doi: 74 10.1093/ajcn/nqy061. 75 2. Shannon OM, Babateen A, Grisotto G, Mathers JC, Siervo M. No effect of 4 weeks 76 nitrate-rich vegetable consumption on blood pressure: reflections for future research. 77 Am J Clin Nutr 2018. 78 3. Ashor AW, Lara J, Siervo M. Medium-term effects of dietary nitrate supplementation 79 on systolic and diastolic blood pressure in adults: a systematic review and meta-80 analysis. J Hypertens 2017;35(7):1353-9. 81 4. Jackson JK, Patterson AJ, MacDonald-Wicks LK, Oldmeadow C, McEvoy MA. The 82 role of inorganic nitrate and nitrite in cardiovascular disease risk factors: a systematic 83 review and meta-analysis of human evidence. Nutr Rev 2018;76(5):348-71. doi: 84 10.1093/nutrit/nuy005. 85 5. Blekkenhorst LC, Bondonno NP, Liu AH, Ward NC, Prince RL, Lewis JR, Devine A, 86 Croft KD, Hodgson JM, Bondonno CP. Nitrate, the oral microbiome, and 87 cardiovascular health: a systematic literature review of human and animal studies. Am 88 J Clin Nutr 2018;107(4):504-22. doi: 10.1093/ajcn/nqx046. 89 6. Siervo M, Lara J, Ogbonmwan I, Mathers JC. Inorganic nitrate and beetroot juice 90 supplementation reduces blood pressure in adults: a systematic review and meta-91 analysis. J Nutr 2013;143(6):818-26. 92 6  7. Bondonno CP, Liu AH, Croft KD, Ward NC, Yang X, Considine MJ, Puddey IB, 93 Woodman RJ, Hodgson JM. Short-term effects of nitrate-rich green leafy vegetables 94 on blood pressure and arterial stiffness in individuals with high-normal blood 95 pressure. Free Radic Biol Med 2014;77:353-62. 96 8. Bondonno CP, Liu AH, Croft KD, Ward NC, Shinde S, Moodley Y, Lundberg JO, 97 Puddey IB, Woodman RJ, Hodgson JM. Absence of an effect of high nitrate intake 98 from beetroot juice on blood pressure in treated hypertensive individuals: a 99 randomized controlled trial. Am J Clin Nutr 2015;102(2):368-75. 100 9. Gilchrist M, Winyard PG, Aizawa K, Anning C, Shore A, Benjamin N. Effect of 101 dietary nitrate on blood pressure, endothelial function, and insulin sensitivity in type 2 102 diabetes. Free Radic Biol Med 2013;60:89-97. 103 10. Velmurugan S, Gan JM, Rathod KS, Khambata RS, Ghosh SM, Hartley A, Van Eijl 104 S, Sagi-Kiss V, Chowdhury TA, Curtis M, et al. Dietary nitrate improves vascular 105 function in patients with hypercholesterolemia: a randomized, double-blind, placebo-106 controlled study. Am J Clin Nutr 2016;103(1):25-38. 107 11. Kapil V, Khambata RS, Robertson A, Caulfield MJ, Ahluwalia A. Dietary nitrate 108 provides sustained blood pressure lowering in hypertensive patients: a randomized, 109 phase 2, double-blind, placebo-controlled study. Hypertension 2015;65(2):320-7. 110 12. Carlström M, Liu M, Yang T, Zollbrecht C, Huang L, Peleli M, Borniquel S, 111 Kishikawa H, Hezel M, Persson AEG. Cross-talk between nitrate-nitrite-NO and NO 112 synthase pathways in control of vascular NO homeostasis. Antioxid Redox Sign 113 2015;23(4):295-306. 114 13. Kuhnle GG, Luben R, Khaw K-T, Feelisch M. Sulfate, nitrate and blood pressure – an 115 EPIC interaction between sulfur and nitrogen. Pharmacol Res 2017;122:127-9. 116 7  14. Dewhurst-Trigg R, Yeates T, Blackwell JR, Thompson C, Linoby A, Morgan PT, 117 Clarke I, Connolly LJ, Wylie LJ, Winyard PG, et al. Lowering of blood pressure after 118 nitrate-rich vegetable consumption is abolished with the co-ingestion of thiocyanate-119 rich vegetables in healthy normotensive males. Nitric Oxide 2018;74:39-46. doi: 120 10.1016/j.niox.2018.01.009. 121  122 

Reply to OM Shannon et al

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Reply to OM Shannon et al

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