Effects of Oral Sodium Nitrite on Blood Pressure, Insulin Sensitivity, and Intima-Media Arterial Thickening in Adults With Hypertension and Metabolic Syndrome

Abstract

The nitrate-nitrite-NO pathway regulates NO synthase–independent vasodilation and NO signaling. Ingestion of inorganic nitrite has vasodilatory and blood pressure–lowering effects. Preclinical studies in rodent models suggest there may be a benefit of nitrite in lowering serum triglyceride levels and improving the metabolic syndrome. In a phase 2 study, we evaluated the safety and efficacy of chronic oral nitrite therapy in patients with hypertension and the metabolic syndrome. Twenty adult subjects with stage 1 or 2 hypertension and the metabolic syndrome were enrolled in an open-label safety and efficacy study. The primary efficacy end point was blood pressure reduction; secondary end points included insulin-dependent glucose disposal and endothelial function measured by flow-mediated dilation of the brachial artery and intima-media diameter of the carotid artery. Chronic oral nitrite therapy (40 mg/3× daily) was well tolerated. Oral nitrite significantly lowered systolic, diastolic, and mean arterial pressures, but tolerance was observed after 10 to 12 weeks of therapy. There was significant improvement in the intima-media thickness of the carotid artery and trends toward improvements in flow-mediated dilation of the brachial artery and insulin sensitivity. Chronic oral nitrite therapy is safe in patients with hypertension and the metabolic syndrome. Despite an apparent lack of enzymatic tolerance to nitrite, we observed tolerance after 10 weeks of chronic therapy, which requires additional mechanistic studies and possible therapeutic dose titration in clinical trials. Nitrite may be a safe therapy to concominantly improve multiple features of the metabolic syndrome including hypertension, insulin resistance, and endothelial dysfunction. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01681810.

Red Blood Cell and Endothelial eNOS Independently Regulate Circulating Nitric Oxide Metabolites and Blood Pressure

“… 44 , 54 Nitrite and iron-nitrosyl-Hb likely relate inversely to BP changes, as suggested by independent groups 7 , 49 , 55 , 56 and confirmed with recent translational human studies. 57 , 58 …”

Nitric oxide signalling in kidney regulation and cardiometabolic health

“…In a mouse model of cardiometabolic disease, no additional beneficial effects on cardiovascular and metabolic parameters were observed when dietary nitrate supplementation was given in combination with metformin 191 , suggesting similar mechanisms of action. A phase II study that investigated the cardiometabolic effects of nitrite therapy (40 mg, three times daily) for 12 weeks in adults with stage 1–2 hypertension, metabolic syndrome and normal kidney function who were not receiving any medications that affect glucose metabolism showed that nitrite gradually lowered blood pressure during the first 8 weeks of treatment (by approximately −10 mmHg), but blood pressure levels started to return to baseline after 10–12 weeks 192 . Hyperinsulinaemic–euglycaemic clamp studies suggested that nitrite supplementation resulted in a trend towards decreased endogenous glucose production and improved insulin sensitivity.…”

Dietary nitrate prevents progression of carotid subclinical atherosclerosis through blood pressure‐independent mechanisms in patients with or at risk of type 2 diabetes mellitus

“…41 In our study, the nitrate intake was $7.5 mmol/d for 3 months, which was increased to oral sodium nitrite (40 mg 3 times a day) reduced CIMT by 0.04 mm from 0.773 ± 0.02 mm at baseline to 0.730 ± 0.02 at 12 weeks (P = .0054) in 20 patients with hypertension and metabolic syndrome. 42 This study provides valuable mechanistic support for an effect of nitrite on CIMT, albeit accompanied by a significant decrease in semi-recumbent SBP and DBP and a significant $11% increase in resting conduit artery diameter (brachial) from 0.36 ± 0.02 mm to 0.40 ± 0.02 mm after 12 weeks of nitrite therapy (P = .0009); this is similar to the acute vasodilatory effect of systemically-infused nitrite we had previously observed. 43 As commented above, our observed effect of dietary nitrate on CIMT was in the absence of changes in BP or carotid diameter.…”