Dietary nitrate provides sustained blood pressure lowering in hypertensive patients: a randomized, phase 2, double-blind, placebo-controlled study

Abstract

Single dose administration of dietary inorganic nitrate acutely reduces blood pressure (BP) in normotensive healthy volunteers, via bioconversion to the vasodilator nitric oxide. We assessed whether dietary nitrate might provide sustained BP lowering in patients with hypertension. We randomly assigned 68 patients with hypertension in a double-blind, placebo-controlled clinical trial to receive daily dietary supplementation for 4 weeks with either dietary nitrate (250 mL daily, as beetroot juice) or a placebo (250 mL daily, as nitrate-free beetroot juice) after a 2-week run-in period and followed by a 2-week washout. We performed stratified randomization of drug-naive (n=34) and treated (n=34) patients with hypertension aged 18 to 85 years. The primary end point was change in clinic, ambulatory, and home BP compared with placebo. Daily supplementation with dietary nitrate was associated with reduction in BP measured by 3 different methods. Mean (95% confidence interval) reduction in clinic BP was 7.7/2.4 mm Hg (3.6-11.8/0.0-4.9, P<0.001 and P=0.050). Twenty-four-hour ambulatory BP was reduced by 7.7/5.2 mm Hg (4.1-11.2/2.7-7.7, P<0.001 for both). Home BP was reduced by 8.1/3.8 mm Hg (3.8-12.4/0.7-6.9, P<0.001 and P<0.01) with no evidence of tachyphylaxis over the 4-week intervention period. Endothelial function improved by ≈20% (P<0.001), and arterial stiffness was reduced by 0.59 m/s (0.24-0.93; P<0.01) after dietary nitrate consumption with no change after placebo. The intervention was well tolerated. This is the first evidence of durable BP reduction with dietary nitrate supplementation in a relevant patient group. These findings suggest a role for dietary nitrate as an affordable, readily-available, adjunctive treatment in the management of patients with hypertension (funded by The British Heart Foundation).

Clinical trial registration url: http://www.clinicaltrials.gov. Unique identifier: NCT01405898.

Keywords: blood pressure; nitrate; nitric oxide; nitrites.

© 2014 American Heart Association, Inc.

Figures

Figure 1

Dietary nitrate consumption elevates nitrite concentration in biological compartments in hypertensive patients. The effects of 4 weeks dietary nitrate consumption (nitrate-rich juice 250 mL daily) or placebo (nitrate-depleted juice 250 mL daily) on nitrite concentrations in (A) plasma, (B) urine (C) saliva and (D) plasma cGMP concentrations. Data are expressed as mean±SD. Significance shown for comparisons between treatment allocations of the change between Pre and Post for unpaired Student t test; and as +++ppost hoc test comparison to baseline (Pre) following 2 way ANOVA for changes within each treatment allocation cohort. (cGMP=cyclic guanosine monophosphate; Pre=1st visit pre-intervention; Post=2nd visit post-intervention; W/o=3rd visit washout).

Figure 2

Dietary nitrate consumption reduces clinic and 24h ABP in hypertensive patients. The effects of 4 weeks dietary nitrate consumption (beetroot juice 250 mL daily) or placebo (nitrate-depleted beetroot juice 250 mL daily) on clinic measures of (A) SBP and (C) DBP and (E) HR; and on 24h ABP measures of (B) SBP and (D) DBP and (F) HR. Data are expressed as mean±SD. Significance shown for comparisons between treatment allocations of the change between Pre and Post for unpaired Student t test; and as ++ppost hoc test comparison to baseline (Pre) following 2 way ANOVA for changes within each treatment allocation cohort. (ABP=ambulatory blood pressure; BP=blood pressure; DBP=diastolic blood pressure; HR=heart rate; SBP=systolic blood pressure; Pre=1st visit pre-intervention; Post=2nd visit post-intervention; W/o=3rd visit washout).

Figure 3

Dietary nitrate consumption reduces home BP over entire 4 week intervention period in hypertensive patients. The effects of 4 weeks dietary nitrate consumption (beetroot juice 250 mL daily) or placebo (nitrate-depleted beetroot juice 250 mL daily) on change in weekly (A) SBP and (B) DBP and (C) HR from baseline (Week 1) measured at home. Data are expressed as mean±SD. Significance shown for comparisons between treatment allocations for 2-way ANOVA; followed by ##ppost hoc test. (BP=blood pressure; DBP=diastolic blood pressure; HR=heart rate; SBP=systolic blood pressure). The vertical dotted lines at 2 and 7 weeks signify the end of the 2-week run-in and the beginning of the washout periods.

Figure 4

Dietary nitrate consumption improves arterial function in hypertensive patients. The effects of 4 weeks dietary nitrate consumption (beetroot juice 250 mL daily) or placebo (nitrate-depleted beetroot juice 250 mL daily) on clinic measures of (A) PWV, (B) AIx and (C) % and (D) absolute increase in vessel diameter with FMD. Data are expressed as mean±SD. Significance shown for comparisons between treatment allocations of the change between Pre and Post for unpaired Student t test; and as ++ppost hoc test comparison to baseline (Pre) following 2 way ANOVA for changes within each treatment allocation cohort. (AIx=augmentation index; FMD=flow mediated dilatation; PWV=pulse wave velocity; Pre=1st visit pre-intervention; Post=2nd visit post-intervention; W/o=3rd visit washout).