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

TY - JOUR

T1 - Paradoxical Normoxia-Dependent Selective Actions of Inorganic Nitrite in Human Muscular Conduit Arteries, and Related Selective Actions on Central Blood Pressures

AU - Omar, Sami A

AU - Fok, Henry

AU - Tilgner, Katharina D

AU - Nair, Ashok

AU - Hunt, Joanne

AU - Jiang, Benyu

AU - Taylor, Paul

AU - Chowienczyk, Philip

AU - Webb, Andrew

PY - 2015/1/27

Y1 - 2015/1/27

N2 - BACKGROUND: -Inorganic nitrite dilates small resistance arterioles, via hypoxia-facilitated reduction to vasodilating nitric oxide (NO). Nitrite's effects 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 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). Intra-brachial sodium nitrite (8.7 µmol/min) increased radial artery diameter by 28.0% (25.7, 40.1), median (25(th), 75(th) percentiles), P<0.001. Nitrite (0.087-87 µmol/min) displayed similar conduit artery selectivity as glyceryl trinitrate (0.013-4.4 nmol/min), over resistance arterioles. Nitrite dose-dependently increased local cGMP production from the dose of 2.6 µmol/min, by 1.1 pmol/min/100ml tissue (95% CI 0.5 to 1.8). Nitrite-induced 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 to normoxia. Systemic intravenous administration of sodium nitrite (8.7 µmol/min) dilated the radial artery by 10.7% (95% CI 6.8 to 14.7) and reduced central systolic BP by 11.6 mmHg (95% CI 2.4 to 20.7), augmentation index and pulse wave velocity, without changing peripheral BP.CONCLUSIONS: -Nitrite selectively dilates conduit arteries at supra-physiological and near-physiological concentrations via a normoxia-dependent mechanism, which is associated with cGMP production, and is enhanced by acetazolamide and raloxifene. Nitrite's selective central BP-lowering effects have therapeutic potential to reduce cardiovascular events.

AB - BACKGROUND: -Inorganic nitrite dilates small resistance arterioles, via hypoxia-facilitated reduction to vasodilating nitric oxide (NO). Nitrite's effects 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 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). Intra-brachial sodium nitrite (8.7 µmol/min) increased radial artery diameter by 28.0% (25.7, 40.1), median (25(th), 75(th) percentiles), P<0.001. Nitrite (0.087-87 µmol/min) displayed similar conduit artery selectivity as glyceryl trinitrate (0.013-4.4 nmol/min), over resistance arterioles. Nitrite dose-dependently increased local cGMP production from the dose of 2.6 µmol/min, by 1.1 pmol/min/100ml tissue (95% CI 0.5 to 1.8). Nitrite-induced 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 to normoxia. Systemic intravenous administration of sodium nitrite (8.7 µmol/min) dilated the radial artery by 10.7% (95% CI 6.8 to 14.7) and reduced central systolic BP by 11.6 mmHg (95% CI 2.4 to 20.7), augmentation index and pulse wave velocity, without changing peripheral BP.CONCLUSIONS: -Nitrite selectively dilates conduit arteries at supra-physiological and near-physiological concentrations via a normoxia-dependent mechanism, which is associated with cGMP production, and is enhanced by acetazolamide and raloxifene. Nitrite's selective central BP-lowering effects have therapeutic potential to reduce cardiovascular events.

U2 - 10.1161/CIRCULATIONAHA.114.009554

DO - 10.1161/CIRCULATIONAHA.114.009554

M3 - Article

C2 - 25533964

SN - 0009-7322

VL - 131

SP - 381

EP - 389

JO - Circulation (Baltimore)

JF - Circulation (Baltimore)

IS - 4

ER -