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Downsides to the nitrate–nitrite–nitric oxide pathway in physiology and therapeutics? Reply from Lundberg, Weitzberg and Gladwin

Nature Reviews Drug Discovery volume 7, page 710 (2008)Cite this article

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We appreciate the comments relating to our Review article (The nitrate–nitrite–nitric oxide pathway in physiology and therapeutics. Nature Rev. Drug Discov. 7, 156–167 (2008))1 from Nirmal Singh Panesar (Downsides to the nitrate–nitrite–nitric oxide pathway in physiology and therapeutics? Nature Rev. Drug Discov. 1 Aug 2008 (doi:10.1038/nrd2466-c1))2. As stated in our Review, hypoxia is certainly not a prerequisite for nitrite reduction to nitric oxide (NO); this process occurs along the physiological deoxygenation gradient1. In fact, in our own previous studies we noted vasodilation under normoxic conditions in aortic rings3 and in nitrite infusion studies in humans, during which there is physiological deoxygenation across tissue beds4,5. In addition, in studies using dietary nitrate we have observed a reduction in blood pressure in normoxic individuals6. Although we fully agree with Panesar that nitrite is bioactivated in vivo along the physiological oxygen gradient, it is clear from both in vitro studies of the enzymology of the haemoglobins7 and xanthine oxidoreductase8, and in vivo studies in animals9,10and humans4,11 that nitrite-dependent signalling is potentiated as oxygen tensions decrease. This provides for graded NO production during physiological and pathological hypoxia. Mixed venous oxygen tensions represent a 'step up' in oxygen from specific organ oxygen tensions, secondary to mixing of all systemic blood flow. For example, the coronary sinus PaO2 is only 19 mm Hg at rest (haemoglobin oxygen saturation of less than 50%), and similar oxygen extraction occurs across skeletal muscle, kidney and brain. Thus, the in vivo vasodilatory effects of nitrite occur in a system that efficiently extracts oxygen across resistance vessels at rest12.

With regard to NO and angina pectoris, the endogenous mechanisms for vasodilation are not sufficient when vascular occlusion is severe, and, in such cases, pharmacological treatment with organic nitrates, for example, may be necessary. It would be interesting to study whether therapeutic increases in circulating nitrite levels, by dietary or pharmacological interventions, could help to delay the onset of angina. We disagree about the controversy in circulating nitrite levels. Indeed, in early studies, some very high levels have been reported, but they most probably reflect the sum of nitrate and nitrite rather than only nitrite. Numerous more recent studies using different highly sensitive techniques have clearly showed that normal plasma nitrite levels in humans are in the range 50–500 nM and very seldom above 1 μM1.

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References

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Authors and Affiliations

  1. Jon O. Lundberg is at the Department of Physiology and Pharmacology, Karolinska Institute, SE-171 77 Stockholm, Sweden. jon.lundberg@ki.se,

    Jon O. Lundberg

  2. Department of Physiology and Pharmacology, Eddie Weitzberg is at the Section of Anesthesiology and Intensive Care, Karolinska Institute, SE-171 77 Stockholm. eddie.weitzberg@ki.se,

    Eddie Weitzberg

  3. and at the Critical Care Medicine Department, Mark T. Gladwin is at the Pulmonary and Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Heath, Bethesda, Maryland 20892, USA, Clinical Center, National Institutes of Health, Bethesda. mgladwin@mail.nih.gov,

    Mark T. Gladwin

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Lundberg, J., Weitzberg, E. & Gladwin, M. Downsides to the nitrate–nitrite–nitric oxide pathway in physiology and therapeutics? Reply from Lundberg, Weitzberg and Gladwin. Nat Rev Drug Discov 7, 710 (2008). https://doi.org/10.1038/nrd2466-c2

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