Clinical evidence demonstrating the utility of inorganic nitrate in cardiovascular health

Highlights

• NO₃⁻–NO₂⁻–NO pathway provides an alternative to conventional NO generation in vivo.

• Inorganic NO₃⁻ dose-dependently lowers blood pressure & reduces arterial stiffness.

• Inorganic NO₃⁻ reduces platelet reactivity & protects against endothelial dysfunction.

• Inorganic NO₃⁻ improves metabolic & mechanical efficiency during exercise.

• This pathway has therapeutic potential to target cardiovascular & metabolic systems.

Abstract

The discovery of nitric oxide and its role in almost every facet of human biology opened a new avenue for treatment through manipulation of its canonical signaling and by attempts to augment endogenous nitric oxide generation through provision of substrate and co-factors to the endothelial nitric oxide synthase complex. This has been particularly so in the cardiovascular system and it is well recognized that there is reduced bioavailable nitric oxide in patients with both cardiovascular risk factors and manifest vascular disease. However, these attempts have failed to deliver the expected benefits of such an approach. Recently, an alternative pathway for nitric oxide synthesis has been elucidated that can produce authentic nitric oxide from the 1 electron reduction of inorganic nitrite. Furthermore, it has long been known that symbiotic, facultative, oral microflora can facilitate the reduction of inorganic nitrate, that is ingested in the average diet in millimolar amounts, to inorganic nitrite itself. Thus, there exists an alternative reductive pathway from nitrate, via nitrite as an intermediate, to nitric oxide that provides a novel pathway that may be amenable to therapeutic manipulation. As such, various research groups have explored the utility of manipulation of this nitrate–nitrite–nitric oxide pathway in situations in which nitric oxide is known to have a prominent role. Animal and early-phase human studies of both inorganic nitrite and nitrate supplementation have shown beneficial effects in blood pressure control, platelet function, vascular health and exercise capacity. This review considers in detail the pathways of inorganic nitrate bioactivation and the evidence of clinical utility to date on the cardiovascular system.

Introduction

The elucidation of the identity of EDRF as NO and its protean roles in human physiology and pathophysiology has been one of the seminal discoveries in biology in the late 20th century. Within the cardiovascular system, basal endothelial NO release plays a critical role in sustaining cardiovascular health and it does this in many ways including by exerting vasodilator [1], [2], [3], anti-platelet [4], [5], anti-proliferative [6], [7] and anti-leucocyte phenotype [8].

These beneficial properties of NO in the cardiovascular system, coupled with evidence of reduced, bioavailable NO in patients with classic cardiovascular risk factors, such as hypertension [9], [10] and hypercholesterolaemia [11], and endothelial dysfunction [12], have highlighted the obvious therapeutic potential of NO and NO donors [13]. The organic nitrates, such as GTN and isosorbide mononitrate, represented the first class of NO donors to reach the clinical setting, although tachyphylaxis [14] and induced endothelial dysfunction [15] after prolonged use have limited their clinical utility and likely partly explains the lack of efficacy of organic nitrates in large scale clinical trials [16]. However, the discovery of authentic NO production from the 1 electron reduction of NO₂⁻ [17], [18], [19] and demonstration that symbiotic, facultative, anaerobic, oral bacteria can reduce NO₃⁻ to NO₂⁻ [20], [21], [22], [23], [24] has provided a further avenue within which to explore NO-based therapeutics.

Today, this NO₃⁻–NO₂⁻–NO pathway has been proposed to act as a back-up system for NO generation [25] in situations where the conventional pathways for NO synthesis may be compromised, such as in cardiovascular disease [9], [26], [27]. Perhaps more importantly recent evidence suggests that this pathway also plays a significant role in maintaining levels of bioactive NO that underlie its critical role in cardiovascular homeostasis [28]. These advances have led to a radical revision of the pathways that govern endogenous NO generation and NO metabolism, previously viewed as a one-way, linear termination of activity by the oxidation of NO to both NO₂⁻ and NO₃⁻. However, this novel paradigm reveals the 2 species to be in a ‘NO cycle’ [29] that can be potentiated through the provision of inorganic NO₃⁻, given either by dietary or inorganic supplementary route. This review will discuss the evidence testing the utility of this alternative pathway for NO synthesis in cardiovascular health and disease.