Intake of Dietary Nitrate Associated with Lower POAG Risk

Nitric Oxide and Open Angle Glaucoma

Nitric oxide (NO), an important cell signaling molecule and vessel dilator, is formed in the body by the constitutive enzymes endothelial nitric oxide synthase (eNOS) and neuronal NOS (nNOS) from the amino acid L-arginine and oxygen. The inducible form of NOS (iNOS), is involved in the immune response, producing NO as a defense mechanism.

NO derived from the endothelium and nerve cells helps regulate ocular blood flow dynamics. Elevated intraocular pressure (IOP) and impaired auto-regulation of optic nerve blood flow are implicated in primary open-angle glaucoma (POAG). Endothelial dysfunction, a key contributor to vascular regulatory impairment, is involved in both processes. Endothelium dysfunction impairs ocular blood flow by reducing the bioavailability of NO and increasing the production of reactive oxygen species.

Dietary Nitric Oxide Precursors and POAG

An alternative to the L-arginine–NO pathway is the nitrate-nitrite-nitric oxide pathway.  This pathway comes into play under conditions of hypoxia or when NOS may be dysfunctional, which may occur in POAG. In this pathway, dietary nitrate can be reduced to nitrite and converted to NO in tissues.

Evidence supports a role for NO in the development of POAG. Animal studies suggest, for example, that NO may induce IOP lowering. There is also evidence that dietary nitrate or nitrite, precursors for NO, is beneficial for blood circulation.

Although plasma nitrite levels or intake of specific vegetables have been associated with POAG, nitrate intake as a specific nutrient had not been assessed.
This led Harvard researchers to evaluate dietary nitrate and incident POAG in a more than 25-year prospective study of nearly 64,000 women in the Nurses’ Health Study (NHS) and over 41,000 men in the Health Professionals Follow-up Study (HPFS) (1).

Study Design and Methods: Participants in the prospective cohorts of the NHS and HPFS were followed for over 25 years and checked at 2-year risk periods. Eligible participants were 40 years or older, free of POAG, and reported eye examinations. Information on diet and potential confounders was updated with validated questionnaires.

The main outcome was POAG incidence and POAG subtypes; 1483 cases were confirmed with medical records and classified into subtypes defined by IOP (>22 or <22 mmHg), or by visual field loss pattern at diagnosis – peripheral loss only, or early paracentral location loss. Cohort-specific and pooled multivariable rate ratios and 95%CIs were estimated.

Results:  1483 incident cases of POAG were identified. The lowest 20% of dietary nitrate intake (about 80 mg/day) was compared with the highest 20% of intake (about 240 mg/day).  Greater intake of dietary nitrate and green leafy vegetables (a source of nitrates) was associated with a 20-30% lower POAG risk.

The association was particularly strong (40%-50% lower risk) for POAG with early paracentral visual field loss at diagnosis, for which difficulty in regulating ocular blood flow has been implicated.

Comments:  These findings could have important implications for POAG if the association of higher dietary nitrate and green leafy vegetable intake with a lower POAG risk is confirmed in observational or intervention studies.

NO is emerging as a potential target for the treatment of glaucoma (2). Dietary sources of nitrate may be an important alternative source of NO in POAG. One lettuce serving, for example, can yield more NO than that generated daily via the L-arginine–NO pathway.

Overall, the literature on the role of NO in optic neuropathy is suggestive of a dual action, with low levels exhibiting neuro-protective effects and high levels (from induction of iNOS and/or up-regulation of nNOS) bringing about neuro-degenerative effects.

References

1. Kang JH, et al. Association of dietary nitrate intake with primary open-angle glaucoma: A Prospective Analysis from the Nurses’ Health Study and Health Professionals Follow-up Study. JAMA Ophthalmol. Online January 14, 2016.
2. Cavet ME, et al. Nitric oxide (NO): An emerging target for the treatment of glaucoma. Invest Ophthalmol Vis Sci. 55:5005-15, 2014.