Paradoxical Normoxia-Dependent Selective Actions of Inorganic Nitrite in Human Muscular Conduit Arteries and Related Selective Actions on Central Blood Pressures

Abstract

Responses to nitrite are further enhanced under hypoxic conditions in resistance arterioles (FBF). 3,4 Indeed, all the nitrite reductases identified to date display selective activity under conditions of hypoxia or ischemia 5 , including the other globins (myoglobin, cytoglobin, and neuroglobin), xanthine oxidase, endothelial NO synthase, and aldehyde oxidase (AO). [6][7][8] Conversely, oxygenated hemoglobin and myoglobin are avid scavengers of nitrite-derived NO, suggesting that an intricate balance exists between production and consumption. [7][8][9] Most antihypertensive vasodilators selectively dilate small resistance arterioles, 10 (mainly reducing peripheral blood pressure [BP]). Notable exceptions are the organic nitrates, eg, glyceryl trinitrate (GTN), a selective dilator of muscular conduit arteries, 10-12 the accepted mechanism by which GTN Background-Inorganic nitrite dilates small resistance arterioles via hypoxia-facilitated reduction to vasodilating nitric oxide. The effects of nitrite in human conduit arteries have not been investigated. In contrast to nitrite, organic nitrates are established selective dilators of conduit arteries. Methods and Results-We examined the effects of local and systemic administration of sodium nitrite on the radial artery (a muscular conduit artery), forearm resistance vessels (forearm blood flow), and systemic hemodynamics in healthy male volunteers (n=43). Intrabrachial sodium nitrite (8.7 μmol/min) increased radial artery diameter by a median of 28.0% (25th and 75th percentiles, 25.7% and 40.1%; P<0.001). Nitrite (0.087-87 μmol/min) displayed conduit artery selectivity similar to that of glyceryl trinitrate (0.013-4.4 nmol/min) over resistance arterioles. Nitrite dose-dependently increased local cGMP production at the dose of 2.6 μmol/min by 1.1 pmol·min −1 ·100 mL −1 tissue (95% confidence interval, 0.5-1.8). Nitriteinduced radial artery dilation was enhanced by administration of acetazolamide (oral or intra-arterial) and oral raloxifene (P=0.0248, P<0.0001, and P=0.0006, respectively) but was inhibited under hypoxia (P<0.0001) and hyperoxia (P=0.0006) compared with normoxia. Systemic intravenous administration of sodium nitrite (8.7 μmol/min) dilated the radial artery by 10.7% (95% confidence interval, 6.8-14.7) and reduced central systolic blood pressure by 11.6 mm Hg (95% confidence interval, 2.4-20.7), augmentation index, and pulse wave velocity without changing peripheral blood pressure. Conclusions-Nitrite selectively dilates conduit arteries at supraphysiological and near-physiological concentrations via a normoxia-dependent mechanism that is associated with cGMP production and is enhanced by acetazolamide and raloxifene. The selective central blood pressure-lowering effects of nitrite have therapeutic potential to reduce cardiovascular events.

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

“…Although surprising, these results are in fact in line with a previous study by Pluta et al, 36 who reported no changes in blood pressure during sodium nitrite infusions at even higher doses and reaching plasma levels similar or higher than the ones reported here. 36 Similar results showing absence of changes in peripheral blood pressure mediated by nitrite infusions were recently reported also by Omar et al 27 In this regard, although previous studies have clearly showed that nitrite infusions increase peripheral blood flow at plasma concentrations close to the physiological range, 26,35 it seems that nitrite-induced changes in blood pressure requires higher intravenous nitrite doses 35 or, as suggested by the current study, a different administration route. For example, Webb et al 14 reported changes in blood pressure 2 to 3 hours after oral ingestion of inorganic nitrate, when nitrate was cumulatively converted to nitrite by the enterosalivary pathway.…”

“…[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.…”

Dietary nitrate from beetroot juice selectively reduces central blood pressure in type 2 diabetes: the randomized, controlled VaSera trial

“…However, plasma nitrate and nitrite concentrations did increase 4-and 2-fold respectively (p < 0·001 and = 0·02), suggesting the nitrate-nitrite-nitric oxide pathway was not interrupted. This was simultaneous to a decrease in central systolic BP on nitrate-containing juice versus placebo (mean [95 %CI]; −2·6[−4·5, −0·8] mmHg, p = 0·007), consistent with our previous findings of normoxia-dependent conduit artery dilatation after inorganic nitrite, selectively reducing central systolic BP (6) . Dietary nitrate also decreased left ventricular end diastolic and systolic volume (−6·3[−11·1, −1·6] mL and −3·2[−5·9, −0·5] mL, p < 0·05) and increased end diastolic mass/volume ratio (0·04 [0, 0·7] g/mL, p < 0·05) versus placebo, which are beneficial cardiac changes.…”

Harnessing the Nitrate–Nitrite–Nitric Oxide Pathway for Therapy of Heart Failure With Preserved Ejection Fraction

“…A second study by Omar and colleagues 9 published in this issue of Circulation explored in more detail the pharmacological properties of nitrite in the human circulation, reporting for the first time that nitrite vasodilates not only the arteriolar and venous circulation, as previously described, but also the conduit blood vessels, an effect similar to that observed with nitroglycerin. This effect was associated with a reduction in central systolic blood pressure, augmentation index, and pulsed-wave velocity, which represent hemodynamic effects that might show therapeutic promise in the setting of HFpEF [ Figure (C)].…”

“…Omar and colleagues 9 infused 2 drugs to test the mechanisms for nitrite bioactivation in conduit arteries. The first was reloxifene, an inhibitor of aldehyde oxidize, classically considered an oxidase that generates superoxide but recently shown also to possess nitrite reductase activity under hypoxic conditions.…”