Dietary Nitrate Reduces Blood Pressure in Rats With Angiotensin II–Induced Hypertension via Mechanisms That Involve Reduction of Sympathetic Hyperactivity

Abstract

Several experimental and clinical studies have shown that dietary nitrate supplementation can increase nitric oxide bioavailability. In the oral cavity, commensal bacteria reduce nitrate to nitrite, which is subsequently absorbed into the circulation where reduction to nitric oxide by enzymatic systems occur. Although it is well-known that boosting the nitrate-nitrite-nitric oxide pathway can improve cardiovascular, renal, and metabolic functions and that sympathoexcitation contributes to the development of the same disorders, the potential effects of dietary nitrate on sympathetic activity remain to be elucidated. In this study, we hypothesized that treatment with inorganic nitrate could prevent the increase in sympathetic nerve activity in an experimental model of Ang II (angiotensin II)–induced hypertension. Multiple in vivo approaches were combined, that is, Wistar rats orally treated with the nitric oxide synthase inhibitor L-NAME (N(G)-nitro-L-arginine methyl ester, 0.5 g/L) and implanted with subcutaneous osmotic minipump for continuous delivery of Ang II (120 ng/kg per minute; 14 days). Simultaneously, rats were supplemented with sodium nitrate (10 mmol/L) or placebo (sodium chloride; 10 mmol/L) in the drinking water. Blood pressure, heart rate, and renal sympathetic nerve activity were recorded. In placebo-treated rats, Ang II+L-NAME treatment–induced arterial hypertension, which was linked with reduced spontaneous baroreflex sensitivity and increased renal sympathetic nerve activity, as well as upregulation of AT 1 Rs (Ang II type-1 receptors) in the rostral ventrolateral medulla. Supplementation with nitrate normalized the expression of AT 1 Rs in rostral ventrolateral medulla and reduced sympathetic nerve activity, which was associated with attenuated development of hypertension. In conclusion, chronic dietary nitrate supplementation blunted the development of hypertension via mechanisms that involve reduction of sympathetic outflow.

Central Inhibition of Tumor Necrosis Factor Alpha Reduces Hypertension by Attenuating Oxidative Stress in the Rostral Ventrolateral Medulla in Renovascular Hypertensive Rats

“…Combining both analyses allows for the evaluation of the baroreflex function in a wide range of the reflex. This is in agreement with what we have recently shown (Guimaraes et al, 2019). We believe that this improvement in baroreflex sensitivity may be related to reduction in superoxide accumulation in RVLM promoted by central inhibition of TNF-α.…”

Nitric oxide signalling in kidney regulation and cardiometabolic health

“…In numerous experimental studies, chronic treatment with inorganic nitrate and nitrite has been associated with therapeutic effects such as attenuation of kidney injury and preservation of kidney blood flow and GFR in models of kidney disease with or without coexistent hypertension and metabolic disease 8 , 181 , including models with chronic pharmacological inhibition of NOS 177 , unilateral nephrectomy combined with a high-salt diet 198 , two-kidney one clip, deoxycorticosterone acetate salt, Ang II infusion 199 , 200 , ageing 201 and kidney IRI 202 , 203 . Based on these studies, several mechanisms have been proposed to contribute to the favourable effects of nitrate and nitrite supplementation.…”

The Noncanonical Pathway for In Vivo Nitric Oxide Generation: The Nitrate-Nitrite-Nitric Oxide Pathway

“…Elevation of systemic nitrite levels reduces renal sympathetic nerve signaling in rats under L-NAME or angiotensin II-driven hypertension. This treatment also reduces muscle sympathetic nerve activity in humans, a gold-standard measure of efferent sympathetic signaling (Notay et al, 2017;Guimarães et al, 2019). The precise mechanism of nitrite-derived •NO sympatholysis is not known but may relate to alterations in expression of angiotensin II receptors in the rostral ventral lateral medulla, the brainstem sympathetic control center (Guimarães et al, 2019), or to changes in peripheral chemoreflex activity.…”

“…This treatment also reduces muscle sympathetic nerve activity in humans, a gold-standard measure of efferent sympathetic signaling (Notay et al, 2017;Guimarães et al, 2019). The precise mechanism of nitrite-derived •NO sympatholysis is not known but may relate to alterations in expression of angiotensin II receptors in the rostral ventral lateral medulla, the brainstem sympathetic control center (Guimarães et al, 2019), or to changes in peripheral chemoreflex activity. The peripheral chemoreflex is primarily responsible for augmenting ventilation in response to hypoxia but is known to be augmented in human hypertension in the absence of hypoxia and responsible for elevated BP through efferent central sympathetic signaling (Marshall, 1994), and this mechanism is attenuated after inorganic nitrate supplementation in older adult humans (Bock et al, 2018b).…”