Importance Nitric oxide (Zero) signaling alterations in outflow facility and retinal blood circulation autoregulation are implicated in major open-angle glaucoma (POAG). highest quintile (Q5;240 mg/day) was 0.79 (95%CI, 0.66,0.93; p for trend [p-trend]=0.02). The dose-response TRICKB was more powerful (p for heterogeneity [p-het]=0.01) for POAG with early paracentral VF reduction (433 instances; Q5 versus. Q1 MVRR=0.56; 95%CI, 0.40,0.79; p-trend=0.0003) than for POAG with peripheral VF reduction only (835 instances; Q5 versus. Q1 MVRR=0.85; 95%CI, 0.68,1.06; p-trend=0.50). The association didn’t differ (p-het=0.75) by POAG subtypes defined by IOP (997 instances with IOP22 AZD4547 enzyme inhibitor mm Hg: Q5 vs. Q1 MVRR=0.82; 95%CI, 0.67,1.01; p-tendency=0.11 vs. 486 instances with IOP 22 mm Hg: Q5 versus. Q1 MVRR=0.71; 95%CI, 0.53,0.96; p-trend=0.12). AZD4547 enzyme inhibitor Green leafy vegetables accounted for 56.7% of nitrate intake variation. Weighed against eating 0.31 servings/day time, the MVRR for consuming 1.45+ servings/day was 0.82 for all POAG (95%CI, 0.69,0.97; p-tendency=0.02) and 0.52 for POAG with paracentral VF reduction (95%CI, 0.29,0.96; p-trend=0.0002). Summary and relevance Higher dietary nitrate and green leafy veggie intake was connected with a lesser POAG risk, especially POAG with early paracentral VF reduction at diagnosis. Intro Elevated intraocular pressure (IOP) and impaired autoregulation of optic nerve blood circulation are implicated in major open-position glaucoma (POAG).1-10 Endothelial dysfunction, an integral contributor to vascular regulatory impairment, is definitely involved with both processes.11 The vascular endothelium regulates the microcirculation via vasoactive factors; one potent element can be nitric oxide (NO). In the L-arginine-NO pathway, Simply no is shaped from L-arginine and oxygen by Simply no synthases (NOS) such as for example endothelial NOS (NOS3).12 Abundant evidence supports NO’s role in POAG pathogenesis.13 With administration of a systemic NOS inhibitor, differences in ocular blood flow response was observed between POAG cases and controls.14 Also, polymorphisms in study, glaucomatous Schlemm’s canal cells produced negligible NO after shear stress compared to non-glaucomatous cells.70 Thus, exogenous NO AZD4547 enzyme inhibitor donators are emerging as new glaucoma therapeutics.13 The nitrate-nitrite-NO pathway may be an important alternative source of NO in POAG. One lettuce serving can yield more NO than that generated daily via the L-arginine-NO pathway.71 Tissue NO bioavailability and cerebral blood flow can increase with nitrate salts72,73 and nitrate-rich beet juice supplementation.74-79 Therefore, dietary nitrate supplementation represents a practical method to increase NO levels. Indeed, across the two cross-sectional studies in all (95 cases among 1,155 total)45 or only African-American (77 cases among 587 total)46 women in the Study of Osteoporotic Fractures, the only vegetable that was consistently inversely associated with POAG was kale/collard greens: 1 serving/month of kale/collard greens was significantly associated with 55-70% reduced odds of POAG. The stronger inverse association with POAG with early paracentral VF loss is consistent with evidence that this subtype is more strongly associated with vascular dysregulation.69,80,81 The blood vessels for the inferior paracentral fibers are in the macula vulnerability zone82 and make more acute arcuate turns than others, creating greater shear forces that could compromise local blood flow.61 Also, among glaucoma patients with autonomic dysfunction or abnormal peripheral microcirculation, paracentral VF defects were more common;80 one hypothesis is that central fibers may have relatively high oxygen demand and thus be more vulnerable to vascular dysregulation.83,84 Furthermore, genetic loci related to the NO pathway (e.g., regions69) are most strongly associated with POAG with paracentral loss. Thus, further studies are warranted of exogenous nitrate and POAG with paracentral VF loss. This was a large prospective study with 1483 incident cases identified from 63,893 women and 41,094 men followed for 25+ years, with high follow-up rates. With repeated questionnaires, we evaluated nitrate intake and POAG in various ways (i.e., baseline, recent, cumulative intake) and controlled for numerous updated POAG risk factors. Our study had a few limitations. We could not conduct repeated eye exams, and thus, we relied on questionnaires and medical records for disease confirmation. Our case ascertainment method had low sensitivity; however, methodologically, incidence rate can still be valid if the case definition is highly specific and the ascertainment method is unrelated to exposure.86 Our case definition was highly specific with requirement of reproducible VF loss, the case ascertainment was unlikely to be related to diet, and we required eye exams at each follow-up cycle to minimize biases. Another limitation was residual confounding by other dietary factors, as nitrate-rich vegetables may have other nutrients. However, we adjusted for intake of other nutrients, and the inverse associations were robust. We may have had some misclassification.