Inorganic Nitrite and Conduit Artery Function

Abstract

Background Inorganic nitrite, a metabolite of endogenously produced nitric oxide (NO) from NO synthases, provides the largest endocrine source of directly bioavailable NO. The conversion of nitrite to NO occurs mainly through enzymatic reduction, which is particularly favoured under hypoxia. Thus, current evidence shows that nitrite dilates small resistance arterioles where conditions of hypoxia predominate. Although organic nitrates/nitrites also mediate their principal effects via NO, they are not hypoxia dependent; hence, they selectively dilate muscular conduit arteries, lowering central blood pressures. Inorganic nitrite would be expected to lack such effects. Methods and Results The effects of local and systemic administration of sodium nitrite on the radial artery (RA) a muscular conduit artery, forearm resistance vessels (forearm blood flow) and systemic haemodynamics in healthy male volunteers (n=43) were examined. Intra-brachial sodium nitrite (8.7 μmol/min) increased RA diameter by 28.3% (95% CI 20.3 to 36.2). Nitrite (0.087-87 μmol/min) displayed similar selectivity as glyceryl trinitrate (0.003-1 μg/min) for conduit arteries, compared to 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). Vasodilatation of the RA by nitrite was enhanced by administration of acetazolamide (oral or i.a.) 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 RA by 10.7% (95% CI 6.8 to 14.7) and reduced central systolic BP by 11.6 mmHg (95% CI of difference 2.4 to 20.7), augmentation index and pulse wave velocity, without changing peripheral BP. Conclusions Nitrite is a normoxia-dependent selective conduit artery dilator. The mechanism is via cGMP, and the effect is enhanced by acetazolamide and raloxifene. The selective central blood pressure-lowering effects of nitrite have therapeutic potential to reduce cardiovascular events.

Date of Award	2015
Original language	English
Awarding Institution	King's College London
Supervisor	Andrew Webb (Supervisor) & Philip Chowienczyk (Supervisor)