title: Clinical evidence demonstrating the utility of inorganic nitrate in cardiovascular health.
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.
authors.affiliation: William Harvey Research Institute, Centre for Clinical Pharmacology, NIHR Cardiovascular Biomedical Research Unit, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; Barts Hypertension Clinic, Barts Health NHS Trust, London, United Kingdom. Electronic address: v.kapil@qmul.ac.uk.
authors.forename: V
authors.initials: V
authors.lastname: Kapil
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Weitzberg
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: J O
authors.initials: JO
authors.lastname: Lundberg
authors.affiliation: William Harvey Research Institute, Centre for Clinical Pharmacology, NIHR Cardiovascular Biomedical Research Unit, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: A
authors.initials: A
authors.lastname: Ahluwalia
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000178:diet therapy / Q000378:metabolism; D002319:Cardiovascular System / Q000378:metabolism*; D006262:Health; D006801:Humans; D009566:Nitrates / Q000008:administration & dosage / Q000378:metabolism*
chemical_list: D009566:Nitrates
keywords: Hypertension; Ischemia–reperfusion injury; Nitrate; Nitrite; Platelet function