Commentary on “The blood pressure-lowering effect of orally ingested nitrite is abolished by a proton pump inhibitor” by M. F. Montenegro et al

In this issue of Hypertension is a paper from several investigators in Stockholm, primarily of the Lundberg / Weitzberg groups at the Karolinska Institutet, which addresses one aspect of the potential use of orally ingested nitrite ions as therapies in humans for various diseases or, perhaps in food or food supplements, for some general improvement in cardiovascular or metabolic parameters. The most significant finding of this work is that pre-treatment with a proton pump inhibitor (PPI), esomeprazole, to minimize gastric acidification blunts the measured effects of 0.3 mg/kg of sodium nitrite on lowering systolic blood pressure by about 6 +/− mmHg maximally. These findings are consistent with previous work from this group on the importance of the entero-salivary pathway of nitrate reduction to nitrite and then the non-enzymatic metabolism of nitrite in the acidic stomach to form various nitrite derivatives, including nitric oxide (NO) itself [1]. Further, recent work from the group of Tanus-Santos in Sao Paolo, Brazil has shown similar effects in administration of sodium nitrite to rats [2].

Thus these results are relevant to the potential confounding effect of PPI use in studies of nitrate/nitrite administration in food or as drugs to patients or populations. Moreover, there is a recent literature suggesting that PPIs can increase the likelihood of adverse cardiovascular events or even mortality in “at risk” populations by 25 to 100% [3]. Thus, the hypothesis implicit in the current paper is that PPI administration blunts beneficial effects of usual nitrate and nitrite consumption in food, including the effects of certain drugs used in these patient groups. Although these studies are not all consistent, the effects are large enough to cause some clinical concerns and the impetus to search for the possible mechanisms involved. The new studies demonstrate that the effect of esomeprazole is not due to changes in the NO signaling pathway but, unlike the results from rat studies, does not suggest involvement of S-nitrosothiol formation in the anti-hypertensive effect.

Less clear cut results from this new work relate to two other important questions related to potential nitrite/nitrate pharmacological uses: 1) whether there are marked differences in the effects of oral vs infused ions and 2) whether lowering of blood pressure is to be expected and its role, if any, in the potential beneficial effects of these agents. The new report very surprisingly finds that the effect on systolic blood pressure is limited to the oral doses and that intravenous doses that achieve comparable blood levels of nitrite ions do not have such an effect, suggesting some important biochemical “activation” in the stomach or portal circulation. However, one should be aware that the total oral dose, which is expected to be almost entirely absorbed [4], appears to be more than ten times that of the maximal total infused nitrite dose. Perhaps technical problems related to the blood measurements, such as the kinetics of dose responses, have contributed to this apparent paradox. Indeed many other studies have shown robust cardiovascular effects of infused nitrite in normal volunteers and those with various illnesses [5–7].

Of related importance is the question of whether nitrite ions should be expected to affect blood pressure at physiological or pharmacological doses. At higher doses adverse effects such as methemoglobin formation and precipitous circulatory changes can occur [4, 8]. The literature on pharmacological studies of nitrate and nitrite administration, in human beings and in animal models, is inconsistent, with a wide range of results with respect to blood pressure changes. The consensus seems to be that small decreases in systolic blood pressure may be expected in human populations. (In the presence of cell free hemoglobin, such as in acute or chronic hemolytic anemias, these effects are likely to be blunted.) However, in view of the fact that NO appears to primarily increase blood flow in most tissues and organs studied and that measured blood pressure (systolic, diastolic, or mean arterial) is a composite of changes in peripheral vascular resistance and cardiac output and is subject to many other agonists and antagonists-some of which may change rapidly in compensation for pharmacological administrations, the complexity of clinical results reported up to now is perhaps not surprising. Further some effects of NO may be immediate while others, such as increases in numbers or sizes of tissue micro-vessels and mitochondria, may only occur with chronic administration [9].

Equally important, is the fact that potential benefits of circulating NO or nitrite ions may include other processes, such as inhibition of platelet reactivity and blood clotting [10], or even complex metabolic pathways, rather than primarily blood pressure lowering. For these reasons, continued clinical studies of nitrate and nitrite administration in humans, at a range of doses and routes of administration, are necessary to establish whether these agents can enter medical use beyond the still well-tested injunction that we should all eat maximal amounts of green leafy vegetables and related foods.

Figure. Overview of Nitric Oxide (NO) Metabolism in Humans.

This schematic diagram illustrates current understanding of major pathways of NO formation and consumption in mammals, including human beings. In the last decade pathways for reduction of nitrate to nitrite and nitrite to form NO have been extensively studied, in addition to the more classical NO formation from arginine by the three groups of nitric oxide synthase (NOS I, II, and III) enzymes. Some of the major mechanisms of these reductive pathways, as well as the oxidative pathways, are shown.

Nitrate reductase enzymes in salivary and possibly gut bacteria can reduce oral nitrate (both from immediate ingestion and that secreted into the mouth from blood by the salivary glands) to nitrite and stomach acid reduces some of this to NO, which is absorbed into the bloodstream along with the remaining nitrite and nitrate. The current paper reports that gastric acidification is important for the therapeutic goal of lowering systolic blood pressure with oral nitrite but that this ion has no affect on blood pressure if given intravenously, although the mechanism for this difference is not clear.

XOR: xanthine oxidoreductase enzyme; oxyHb: oxyhemoglobin; oxyMb: oxymyoglobin.