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.

Keywords: blood pressure; clinical trial; hypertension; metabolic syndrome; nitrite; vasodilation.

Figures

Figure 1.

Hemodynamic responses and methemoglobin formation over 12 weeks of nitrite treatment. Compared to baseline, systolic (−10 mmHg, A), diastolic (−13 mmHg, B) and mean arterial pressures (−12 mmHg, C) were reduced significantly during the oral nitrite treatment period (all p<0.01). There was no observed rebound tachycardia with changes in blood pressures (D). The % blood methemoglobin increased significantly compared to baseline, but remained within the normal range and ≤3.1% in all subjects (E). Biweekly drug compliance by pill counts did not differ over time (F). Data are presented as mean ± standard error of the mean (SEM).

Figure 2.

Endothelial function and vascular remodeling formation over 12 weeks of nitrite treatment. Carotid IMT decreased from baseline after 12 weeks of nitrite treatment (pA). There were concordant trends towards a reduction in arterial stiffness as measured by PWV (B) and improvements in endothelial function as measured by FMD of the brachial artery (C). Data are presented as mean ± standard error of the mean (SEM).

Figure 3.

Insulin sensitivity over 12 weeks of nitrite treatment. Following 12 weeks of oral nitrite treatment, there was a trend towards improvement in suppression of endogenous glucose production in the final hour of the clamp (p=0.078; A). Overall there was no statistically significant increase in the rate of glucose infusion (GIR) required to maintain euglycemia (p=0.11; B) and no statistically significant increase in insulin-stimulated glucose disposal (Rd) using 6,6,2 stable glucose isotope analyses during the hyperinsulinemic euglycemic clamp (p=0.21; C). Data are presented as mean ± standard error of the mean (SEM).