We read with interest the editorial by Sparacino-Watkins et al 1 that accompanied our recent article 2 demonstrating the beneficial effects of dietary inorganic nitrate supplementation in experimental models of pulmonary hypertension (PH). The editorial provides a timely overview of the scientific rationale for exploiting the recently characterized nitrate-nitrite-nitric oxide pathway in PH and other cardiovascular disorders. We agree with the authors that a therapeutic approach based on this

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... thway represents an exciting new avenue for a debilitating disease with very poor outcome. However, we wish to clarify an apparent misunderstanding regarding the dose required for efficacy in humans. Sparacino-Watkins et al suggest that the concentrations of nitrate (and nitrite) shown to prevent and reverse PH in our study are very high and unrealistic in terms of translation to the human condition. They extrapolate from the mouse to humans and intimate that a 70-kg individual would need to consume 36 g of inorganic nitrate per day, equating to ≈30 L of beetroot juice, to achieve similar results. This is not the case. A common oversight in this field is the disconnect between the amount of inorganic nitrate consumed, the resultant increase in circulating nitrite levels, and the nitric oxide-dependent bioactivity. The doses of nitrate we used in our report were chosen, based on extensive pilot investigation, to mimic the increase in circulating nitrite concentrations observed in healthy volunteers following ingestion of ≈310 mg (≈5 mmol) inorganic nitrate per day (ie, 250 mL or ≈1 glass of beetroot juice), which we have shown to cause a significant drop in systemic blood pressure. 3 The reason underlying this murine-human difference in nitrate-nitrite-nitric oxide signaling is not clear, but it may be the result of less efficient nitrate reductase pathways, or increased elimination of nitrate and nitrite, in mice. Regardless, achieving a similar rise in circulating nitrite levels via dietary nitrate supplementation in patients with PH is achievable and should be associated with a comparable (therapeutic) benefit. However, clinical studies testing this possibility are clearly needed. Sparacino-Watkins et al also urge caution in the use of high doses of nitrate and nitrite and the possibility of generating significant levels of nitric oxide, nitrosothiols, and nitrosamines in the stomach. We agree with this note of restraint in terms of nitrite; however, the same issues do not apply to inorganic nitrate supplementation. This fact is exemplified by statements from independent bodies such as the World Health Organization and European Food Standards Agency indicating a lack of carcinogenesis associated with ingestion of nitrate. 4 Finally, an important consideration in this issue is that consumption of a diet rich in fruit and vegetables (in which the recommended acceptable daily intake of nitrate is exceeded severalfold) provides an estimated daily nitrate dose of ≈20 mmol but is not associated with increased carcinogenesis or mortality. 5 Disclosures Dr Ahluwalia is a Director of Heartbeet References 1. Sparacino-Watkins CE, Lai YC, Gladwin MT. Nitrate-nitrite-nitric oxide pathway in pulmonary arterial hypertension therapeutics. Circulation. 2012;125:2824-2826. 2. Baliga RS, Milsom AB, Ghosh SM, Trinder SL, Macallister RJ, Ahluwalia A, Hobbs AJ. Dietary nitrate ameliorates pulmonary hypertension: cytoprotective role for endothelial nitric oxide synthase and xanthine oxidoreductase. . Fruit and vegetable intake and risk of major chronic disease.