Blood Pressure–Lowering Effect of Orally Ingested Nitrite Is Abolished by a Proton Pump Inhibitor

Abstract

A n association between chronic use of proton pump inhibitors (PPIs) and increased risk of cardiovascular disease has been implicated. [1][2][3][4][5] For example, it seems that PPIs reduce the efficacy of antiplatelet drugs such as clopidogrel by competing with the hepatic isoenzyme CYP2C19, thereby interfering with its capacity to inhibit platelet aggregation. 6 Other studies have associated chronic use of PPI with increased cardiovascular risk, independently of treatment with clopidogrel 4 or CYP2C19 metabolism. 7,8 In addition, a recent study in diabetic patients indicates that PPIs increase blood pressure. 9 The mechanisms behind these effects are still unclear, but a reduced vascular bioavailability of NO has been suggested. 1 Moreover, it has been speculated that bioactivation of some antiplatelet drugs requires gastric nitrosation under acidic conditions. 10,11 We and others have been studying an alternative NO synthase-independent pathway for NO generation in which inorganic nitrate and nitrite from dietary and endogenous sources are metabolized to NO and other bioactive nitrogen oxides in blood and tissues to affect cardiovascular function, including blood pressure.12 Dietary nitrate is absorbed rapidly and is extracted from blood by the salivary glands and greatly concentrated in saliva. In the mouth, commensal bacteria reduce nitrate to the more reactive nitrite anion. Nitrite is then swallowed and enters the acidic stomach where it is nonenzymatically metabolized further to form several potentially bioactive nitrogen oxides, including NO. Orally ingested nitrate clearly has robust NO-like effects systemically, including a decrease in blood pressure, [13][14][15] Abstract-Inorganic nitrate and nitrite from dietary and endogenous sources are metabolized to NO and other bioactive nitrogen oxides that affect blood pressure. The mechanisms for nitrite bioactivation are unclear, but recent studies in rodents suggest that gastric acidity may influence the systemic effects of this anion. In a randomized, double-blind, placebo-controlled crossover study, we tested the effects of a proton pump inhibitor on the acute cardiovascular effects of nitrite. Fifteen healthy nonsmoking, normotensive subjects, aged 19 to 39 years, were pretreated with placebo or esomeprazole (3×40 mg) before ingesting sodium nitrite (0.3 mg kg −1), followed by blood pressure monitoring. Nitrite reduced systolic blood pressure by a maximum of 6±1.3 mm Hg when taken after placebo, whereas pretreatment with esomeprazole blunted this effect. Peak plasma nitrite, nitrate, and nitroso species levels after nitrite ingestion were similar in both interventions. In 8 healthy volunteers, we then infused increasing doses of sodium nitrite (1, 10, and 30 nmol kg −1 min −1 ) intravenously. Interestingly, although plasma nitrite peaked at similar levels as with orally ingested nitrite (≈1.8 µmol/L), no changes in blood pressure were observed. In rodents, esomeprazole did not affect the blood pressure response to the NO donor, DEA NONOate, or vascula...

Effects of organic and inorganic nitrate on aortic and carotid haemodynamics in heart failure with preserved ejection fraction

“…(14, 18) There also appears to be non-enzymatic nitrite reduction to NO in the acid gastric medium. (27) In contrast, organic nitrates require activation in the cytochrome-P450 system, leading to tonic NO release. (28) Alternative activation via mitochondrial aldehyde-dehydrogenase for NTG and other organic nitrates also occurs.…”

Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health

“…Supporting the importance of such mechanisms, a growing body of evidence has linked acid-reducing medications such as proton pump inhibitors and histamine H 2 antagonists, with increased risk of enteric infections such as clostridium difficile[248–250] and profound alterations of the gut microbiome[251–253]. Additionally, acid-reduction is known to reduce gastric production of NO[76,90,254] and has recently been shown to attenuate the blood pressure lowering effects of nitrite in healthy adults[255]. These data then suggest that gastric pH may be equally as important in nitrate bioactivation as a viable oral, nitrate reducing microbiome.…”

Conjugated Linoleic Acid Modulates Clinical Responses to Oral Nitrite and Nitrate

“…This promotes a “redirection” of nitrite chemistry where HNO 2 in turn gives rise to secondary N 2 O 3 species that mediate nitrosation, nitration and oxidation of susceptible targets. These reactions can be blunted by administering proton pump inhibitors such as esomeprazole, thus inhibiting gastric acid secretion and NO 2 − protonation to HNO 2, – a pH response that typifies the pharmacologic action of PPIs 63 . Esomeprazole also inhibited the blood pressure-lowering effects of nitrite.…”