Sodium nitrite downregulates vascular NADPH oxidase and exerts antihypertensive effects in hypertension

Abstract

Dietary nitrite and nitrate are important sources of nitric oxide (NO). However, the use of nitrite as an antihypertensive drug may be limited by increased oxidative stress associated with hypertension. We evaluated the antihypertensive effects of sodium nitrite given in drinking water for 4 weeks in two-kidney one-clip (2K1C) hypertensive rats and the effects induced by nitrite on NO bioavailability and oxidative stress. We found that, even under the increased oxidative stress conditions present in 2K1C hypertension, nitrite reduced systolic blood pressure in a dose-dependent manner. Whereas treatment with nitrite did not significantly change plasma nitrite concentrations in 2K1C rats, it increased plasma nitrate levels significantly. Surprisingly, nitrite treatment exerted antioxidant effects in both hypertensive and sham-normotensive control rats. A series of in vitro experiments was carried out to show that the antioxidant effects induced by nitrite do not involve direct antioxidant effects or xanthine oxidase activity inhibition. Conversely, nitrite decreased vascular NADPH oxidase activity. Taken together, our results show for the first time that nitrite has antihypertensive effects in 2K1C hypertensive rats, which may be due to its antioxidant properties resulting from vascular NADPH oxidase activity inhibition.

NADPH Oxidase in the Renal Microvasculature Is a Primary Target for Blood Pressure–Lowering Effects by Inorganic Nitrate and Nitrite

“…[24][25][26] Here, inhibition of NADPH oxidases with apocynin markedly attenuated the contractile response to ANG II during NOS inhibition ( Figure 3A). This supports the notion that ANG II-induced contraction is linked to increased NADPH oxidase activity.…”

“…22 In addition, these anions can partly compensate for metabolic disturbances in aged endothelial NOS knockout mice, 23 reduce hypertension and markers of oxidative stress, and ameliorate organ injuries in models of renal and cardiovascular disease. [24][25][26] The mechanisms for nitrate-and nitritemediated antihypertensive effects along with renal and cardiac protection are not yet clear. In the present study, we tested the hypothesis that stimulation of a nitrate-nitrite-NO pathway, with inorganic nitrate or nitrite, limits afferent arteriolar responsiveness and hypertension in response to ANG II by modulating the balance between superoxide and NO.…”

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

“…[18][19][20] Studies have shown that the NO-like effects of nitrate are blocked if bacterial nitrate reduction in the mouth is abrogated with an antiseptic mouthwash, indicating that nitrite is an obligate intermediate in nitrate bioactivation. 21,22 Direct administration of nitrite to humans or animals has demonstrated many similar effects as nitrate, including protection against ischemia-reperfusion injury and [23][24][25] vasodilatory, 26,27 antihypertensive, [28][29][30][31][32] and metabolic effects. 33,34 Several pathways have been described for the reduction of nitrite to more bioactive nitrogen Abstract-Inorganic nitrate and nitrite from dietary and endogenous sources are metabolized to NO and other bioactive nitrogen oxides that affect blood pressure.…”

Letter by Pinheiro et al Regarding Article, “Unexpected Effect of Proton Pump Inhibitors: Elevation of the Cardiovascular Risk Factor Asymmetric Dimethylarginine”

“…2 Although the precise mechanisms explaining nitrite-induced vasodilation under normoxia have not been clearly defined yet, there is now evidence that orally administered nitrite reduces blood pressure, 3 and this effect involves gastric formation of NO, because the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethyli-midazoline-1-oxyl-3-oxide almost completely blunted the hypotensive effects of oral nitrite. 4,5 Importantly, the PPI omeprazole consistently attenuated nitriteinduced reduction in blood pressure by ≈40%.…”