Repeated administration of inorganic nitrate on blood pressure and arterial stiffness: a systematic review and meta-analysis of randomized controlled trials

Abstract

Objective: We aim to synthesize effects of repeated administration (≥3 days) of inorganic nitrate on blood pressure and arterial stiffness measures. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials with at least 3 days treatment of inorganic nitrate on blood pressure and arterial stiffness in individuals with or without elevated cardiovascular disease risk. MEDLINE, EMBASE and the Cochrane Library were searched through 2 July 2019. Two independent reviewers extracted relevant study data. Data were pooled using the generic inverse variance method with random-effects model, and expressed as mean differences with 95% confidence intervals. Certainty in the evidence was assessed using GRADE. Results: Forty-seven trials were included (n = 1101). Administration of inorganic nitrate significantly lowered SBP [mean difference: −2.91 mmHg, 95% confidence interval (95% CI): −3.92 to −1.89, I 2 = 76%], DBP (mean difference: −1.45 mmHg, 95% CI: −2.22 to −0.68, I 2 = 78%], central SBP (mean difference: −1.56 mmHg, 95% CI: −2.62 to −0.50, I 2 = 30%) and central DBP (mean difference: −1.99 mmHg, 95% CI: −2.37 to −1.60, I 2 = 0%). There was no effect on 24-h blood pressure, augmentation index or pulse wave velocity. Certainty in the evidence was graded moderate for central blood pressure, pulse wave velocity and low for peripheral blood pressure, 24-h blood pressure and augmentation index. Conclusion: Repeated administration (≥3 days) of inorganic nitrate lower peripheral and central blood pressure. Results appear to be driven by beneficial effects in healthy and hypertensive individuals. More studies are required to increase certainty in the evidence.

Nitric oxide signalling in kidney regulation and cardiometabolic health

“…Notably, the reductions in blood pressure with nitrate supplementation in this meta-analysis, and in meta-analyses of data from healthy individuals 154 , 155 , are comparable with those observed in trials of reduced sodium intake and of a Dietary Approaches to Stop Hypertension (DASH) diet 164 , 165 . Analysis of data from seven trials that measured augmentation index and pulse wave velocity showed no significant effects of nitrate administration on arterial stiffness 163 . However, the researchers note that the number of available trials in individuals with additional cardiovascular disease risk factors (i.e.…”

“…Arterial stiffness is associated with aging and is a major risk factor for cardiovascular events such as myocardial infarction and stroke. A systematic review and meta-analysis of randomized controlled trials was conducted to estimate the effects of repeated nitrate administration (at least 3 days) on peripheral and central blood pressure and arterial stiffness in healthy individuals and in patients at increased risk of cardiovascular disease owing to obesity, hypertension, peripheral artery disease, hypercholesterolaemia and/or heart failure 163 . Pooled data from 45 studies using approximately 500 mg nitrate per day showed significant reductions in systolic (mean −2.91 mmHg) and diastolic blood pressure (mean −1.45 mmHg).…”

Nitric Oxide: The Missing Factor in COVID-19 Severity?

“…In men, medication increased serum NOx concentration in both stages of hypertension, but in women, a significant increase was observed only in stage 1 hypertension. Dietary inorganic nitrate has been utilized with success to lower blood pressure and maintain healthy blood pressure levels with a growing amount of evidence to support it [ 36 ]. Furthermore, it has been well established that hypoxia also raises blood pressure, as the body struggles to pump more blood to provide the necessary oxygen to the tissues [ 37 ].…”

Lost-in-Translation of Metabolic Effects of Inorganic Nitrate in Type 2 Diabetes: Is Ascorbic Acid the Answer?

“…Despite being effective in animal models of T2DM, as it is summarized in Table 2 , all acute [ 67 ], mid-term [ 68 , 69 ], and long-term [ 70 , 71 , 72 ] oral dosing of inorganic NO 3 − and NO 2 − , either as pharmacological forms (i.e., KNO 3 , NaNO 3 , and NaNO 2 ) or food-based supplementation (i.e., NO 3 − -rich beetroot juice or powder) have failed to show beneficial effects on glucose and insulin parameters, including fasting and post-prandial serum glucose and insulin concentrations, insulin resistance indices, and HbA1c levels in patients with T2DM. However, ergogenic [ 73 , 74 ] and beneficial cardiovascular effects of inorganic NO 3 − and NO 2 − , e.g., reducing peripheral and central systolic and diastolic blood pressures [ 75 ], have been highlighted in non-diabetic subjects by several clinical studies.…”

“…↓ Serum glucose by 13% ↓ Serum insulin by 23% ↑ cGMP level in epididymal adipose tissue by 85% ↑ Adipocyte density by 193% (epididymal adipose tissue) ↓ Adipocyte area by 53% (epididymal adipose tissue) ↑ Expression of browning genes in epididymal adipose tissue (↑ mRNA and protein levels of PPAR-γ, PGC1-α, and UCP-1 to their normal values) ↓ Fasting glucose ↓ Gluconeogenesis (measured by IP-PTT) Improved glucose tolerance Restored CAT activity to near normal value Restored elevated TOS to near normal value Restored decreased TAC levels to near normal value ↑ Serum SOD, GSH, and GSH-to-GSSG ratio ↓ Serum glucose and insulin, ↔ HbA1c ↑ Glucose tolerance (measured by IP-GTT) ↑ Insulin sensitivity (measured by QUICKI) ↓ Gluconeogenesis (measured by IP-PTT) ↑ GLUT4 mRNA expression and protein levels in the soleus muscle by 215% and 17% ↑ GLUT4 mRNA expression and protein levels in the epididymal adipose tissue by 344% and 22% ↔ GSIS, islet insulin content ↑ Serum CAT activity, ↓ Serum IL-1β ↔ Serum TBARS ↓ Elevated iNOS mRNA expression in the soleus ↑ GSIS (by 34%), ↔ BIS ↑ ↓ HbA1c, Fasting glucose ↓ Pro-insulin to insulin ratio ↑ Glucose tolerance (measured by IP-GTT)↔, no change; ↑, increase; ↓, decrease. ACh, acetylcholine; BIS, basal insulin secretion; CAT, catalase; cGMP, cyclic guanosine monophosphate; eNOS, endothelial nitric oxide synthase; G6P, glucose-6-phosphatase; GSH, reduced glutathione; GSIS, glucose-stimulated insulin secretion; GSSG, oxidized glutathione; HbA1C, glycated hemoglobin; HDL-C, high-density lipoprotein-cholesterol; HO-1; heme oxygenase-1; HOMA-IR, homeostasis model assessment of insulin resistance; IL-1β, interleukin -1β; iNOS, inducible NOS; IP-GTT, intraperitoneal glucose tolerance test; IP-ITT, intraperitoneal insulin tolerance test; IP-PTT, intraperitoneal pyruvate tolerance test; IV-GTT, intravenous glucose tolerance test; LDL-C, low-density lipoprotein-cholesterol; NADPH, nicotinamide adenine dinucleotide phosphate oxidase; PC, pyruvate carboxylase; PEPCK, phosphoenolpyruvate carboxykinase; PGC1-α, PPAR-γ coactivator 1 alpha; PPAR-γ, peroxisome proliferator activated receptor gamma; phox, phagocyte oxidase; QUICKI, quantitative insulin-sensitivity check index; ROS, reactive oxygen species; SOD, superoxide dismutase; STZ, streptozotocin; TAC, total antioxidant capacity; TBARS, thiobarbituric reactive substances; TG, triglycerides; TOS, total oxidant status; TC, total cholesterol; UCP-1, uncoupling protein 1.− and NO 2− , e.g., reducing peripheral and central systolic and diastolic blood pressures[75], have been highlighted in non-diabetic subjects by several clinical studies.…”