Dietary nitrate, nitric oxide, and restenosis

Cooke, John P.; Ghebremariam, Yohannes T.

doi:10.1172/jci57193

Cited by 17 publications

(14 citation statements)

References 19 publications

(18 reference statements)

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“…39,40 Furthermore, this pilot study was unblinded due to the cost of obtaining placebo tablets of the same size and shape as the Prevacid pills. Given that vascular reactivity is known to be highly sensitive to emotional and cognitive stressors, it is possible that the knowledge of study drug assignment may have influenced the subject’s performance during the EndoPAT testing.…”

Section: Discussionmentioning

confidence: 99%

Proton pump inhibitors and vascular function: A prospective cross-over pilot study

et al. 2015

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Background Proton pump inhibitors (PPIs) are commonly used drugs for the treatment of gastric reflux. Recent retrospective cohorts and large database studies have raised concern that the use of PPIs is associated with increased cardiovascular (CV) risk. However, there is no prospective clinical study evaluating whether the use of PPIs directly causes CV harm. Methods We conducted a controlled open-label cross-over pilot study among 21 adults aged 18 and older who are healthy (n = 11) or have established clinical cardiovascular disease (n = 10). Study subjects were assigned to receive a PPI (Prevacid; 30 mg) or a placebo pill once daily for 4 weeks. After a 2 week washout period, participants were crossed-over to receive the alternate treatment for the ensuing 4 weeks. Subjects underwent evaluation of vascular function (by the EndoPAT technique) and had plasma levels of asymmetric dimethylarginine (ADMA, an endogenous inhibitor of endothelial function previously implicated in PPI-mediated risk) measured prior to and after each treatment interval. Results We observed a marginal inverse correlation between the EndoPAT score and plasma levels of ADMA (r = −0.364). Subjects experienced a greater worsening in plasma ADMA levels while on PPI than on placebo, and this trend was more pronounced amongst those subjects with a history of vascular disease. However, these trends did not reach statistical significance, and PPI use was also not associated with an impairment in flow mediated vasodilation during the course of this study. Conclusions In this open-label, cross-over pilot study conducted among healthy subjects and coronary disease patients, PPI use did not significantly influence vascular endothelial function. Larger, long-term and blinded trials are needed to mechanistically explain the correlation between PPI use and adverse clinical outcomes, which has recently been reported in retrospective cohort studies.

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Section: Discussionmentioning

confidence: 99%

Proton pump inhibitors and vascular function: A prospective cross-over pilot study

et al. 2015

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“…ADMA, a potent inhibitor of nitric oxide synthase, has been previously shown to adversely affect blood vessel compliance as well as promote atherosclerosis (3,20). ADMA levels are known to increase as kidney function declines because of both decreased renal clearance and impairment of enzymatic breakdown (1).…”

Section: Discussionmentioning

confidence: 99%

“…ADMA decreases blood vessel compliance and promotes atherogenesis (3). High ADMA levels have previously been shown to be an independent risk factor for mortality in both patients with CKD and patients on hemodialysis (4-6).…”

Section: Introductionmentioning

confidence: 99%

Asymmetric Dimethylarginine, Race, and Mortality in Hemodialysis Patients

Drew¹,

Tighiouart

Scott

et al. 2014

Clinical Journal of the American Society of Nephrology

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Background and objectives Levels of asymmetric dimethylarginine, an inhibitor of nitric oxide synthase, are elevated in kidney disease and associated with mortality in white European hemodialysis populations. Nitric oxide production and degradation are partially genetically determined and differ by racial background. No studies have measured asymmetric dimethylarginine in African Americans on dialysis and assessed whether differences exist in its association with mortality by race.Design, setting, participants, & measurements Asymmetric dimethylarginine was measured in 259 patients on maintenance hemodialysis assembled from 2004 to 2012 in Boston area outpatient centers. Cox proportional hazards models were used to determine the association between asymmetric dimethylarginine and all-cause mortality, and an interaction with race was tested.Results Mean (SD) age was 63 (17) years, 46% were women, and 22% were African American. Mean asymmetric dimethylarginine in non-African Americans was 0.79 mmol/L (0.16) versus 0.70 mmol/L (0.11) in African Americans (P,0.001); 130 patients died over a median follow-up of 2.3 years. African Americans had lower mortality risk than non-African Americans (hazard ratio, 0.27; 95% confidence interval, 0.15 to 0.50) that was robust to adjustment for age, comorbidity, and asymmetric dimethylarginine (hazard ratio, 0.35; 95% confidence interval, 0.17 to 0.69). An interaction was noted between race and asymmetric dimethylarginine (P=0.03), such that asymmetric dimethylarginine was associated with higher mortality in non-African Americans (adjusted hazard ratio, 1.29; 95% confidence interval, 1.06 to 1.57 per 1 SD higher asymmetric dimethylarginine) but not in African Americans (adjusted hazard ratio, 0.57; 95% confidence interval, 0.28 to 1.18). Additional adjustment for fibroblast growth factor 23 partially attenuated the association for non-African Americans (adjusted hazard ratio, 1.22; 95% confidence interval, 0.98 to 1.50).Conclusions African Americans have lower asymmetric dimethylarginine levels and lower hazard for mortality compared with non-African Americans. Levels of asymmetric dimethylarginine did not explain lower hazard for mortality in non-African American patients. High asymmetric dimethylarginine was a risk factor for mortality exclusively in non-African Americans. Mechanisms explaining these relationships need to be evaluated.

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“…The critical evidence of such an association, however, rests in the global dependency of enterosalivary nitrate reduction on living oral microbiota to enact its biologic activity[73,99,109]. As reviewed, oral administration of nitrate and nitrite provides dose-dependent improvement in endothelial dysfunction, inflammation and vascular function[71], protection from ischemia-reperfusion injury[97,98,272], and reversal of vascular and ventricular remodeling in several models of PAH[147,150]. Clinically, nitrate supplementation will reliably produce anti-hypertensive effects[107], improved exercise efficiency[127], and improved exercise performance in patients with heart failure and HFpEF[135,137,151].…”

Section: Dysbiosis Of the Microbiome In Pulmonary Hypertension And Vascmentioning

confidence: 99%

Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health

Koch

Gladwin

Freeman

et al. 2017

Free Radical Biology and Medicine

141

127

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Recent insights into the bioactivation and signaling actions of inorganic, dietary nitrate and nitrite now suggest a critical role for the microbiome in the development of cardiac and pulmonary vascular diseases. Once thought to be the inert, end-products of endothelial-derived nitric oxide (NO) heme-oxidation, nitrate and nitrite are now considered major sources of exogenous NO that exhibit enhanced vasoactive signaling activity under conditions of hypoxia and stress. The bioavailability of nitrate and nitrite depend on the enzymatic reduction of nitrate to nitrite by a unique set of bacterial nitrate reductase enzymes possessed by specific bacterial populations in the mammalian mouth and gut. The pathogenesis of pulmonary hypertension (PH), obesity, hypertension and CVD are linked to defects in NO signaling, suggesting a role for commensal oral bacteria to shape the development of PH through the formation of nitrite, NO and other bioactive nitrogen oxides. Oral supplementation with inorganic nitrate or nitrate-containing foods exert pleiotropic, beneficial vascular effects in the setting of inflammation, endothelial dysfunction, ischemia-reperfusion injury and in pre-clinical models of PH, while traditional high-nitrate dietary patterns are associated with beneficial outcomes in hypertension, obesity and CVD. These observations highlight the potential of the microbiome in the development of novel nitrate- and nitrite-based therapeutics for PH, CVD and their risk factors.

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Dietary nitrate, nitric oxide, and restenosis

Cited by 17 publications

References 19 publications

Proton pump inhibitors and vascular function: A prospective cross-over pilot study

Proton pump inhibitors and vascular function: A prospective cross-over pilot study

Asymmetric Dimethylarginine, Race, and Mortality in Hemodialysis Patients

Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health

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