Background
In spite of more than 100 years of investigations the question of whether a reduced sodium intake improves health is still unsolved.

Objectives
To estimate the effects of low sodium intake versus high sodium intake on systolic and diastolic blood pressure (SBP and DBP), plasma or serum levels of renin, aldosterone, catecholamines, cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglycerides.

Search methods
The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to March 2016: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 3), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also searched the reference lists of relevant articles.

Selection criteria
Studies randomising persons to low-sodium and high-sodium diets were included if they evaluated at least one of the above outcome parameters.

Data collection and analysis
Two review authors independently collected data, which were analysed with Review Manager 5.3.

Main results
A total of 185 studies were included. The average sodium intake was reduced from 201 mmol/day (corresponding to high usual level) to 66 mmol/day (corresponding to the recommended level).

The effect of sodium reduction on blood pressure (BP) was as follows: white people with normotension: SBP: mean difference (MD) -1.09 mmHg (95% confidence interval (CI): -1.63 to -0.56; P = 0.0001); 89 studies, 8569 participants; DBP: + 0.03 mmHg (MD 95% CI: -0.37 to 0.43; P = 0.89); 90 studies, 8833 participants. High-quality evidence.

Black people with normotension: SBP: MD -4.02 mmHg (95% CI:-7.37 to -0.68; P = 0.002); seven studies, 506 participants; DBP: MD -2.01 mmHg (95% CI:-4.37 to 0.35; P = 0.09); seven studies, 506 participants. Moderate-quality evidence.

Asian people with normotension: SBP: MD -0.72 mmHg (95% CI: -3.86 to 2.41; P = 0.65); DBP: MD -1.63 mmHg (95% CI:-3.35 to 0.08; P =0.06); three studies, 393 participants. Moderate-quality evidence.

White people with hypertension: SBP: MD -5.51 mmHg (95% CI: -6.45 to -4.57; P < 0.00001); 84 studies, 5925 participants; DBP: MD -2.88 mmHg (95% CI: -3.44 to -2.32; P < 0.00001); 85 studies, 6001 participants. High-quality evidence.

Black people with hypertension: SBP MD -6.64 mmHg (95% CI:-9.00 to -4.27; P = 0.00001); eight studies, 619 participants; DBP -2.91 mmHg (95% CI:-4.52, -1.30; P = 0.0004); eight studies, 619 participants. Moderate-quality evidence.

Asian people with hypertension: SBP: MD -7.75 mmHg (95% CI:-11,44 to -4.07; P < 0.0001) nine studies, 501 participants; DBP: MD -2.68 mmHg (95% CI: -4.21 to -1.15; P = 0.0006). Moderate-quality evidence.

In plasma or serum, there was a significant increase in renin (P < 0.00001), aldosterone (P < 0.00001), noradrenaline (P < 0.00001), adrenaline (P < 0.03), cholesterol (P < 0.0005) and triglyceride (P < 0.0006) with low sodium intake as compared with high sodium intake. All effects were stable in 125 study populations with a sodium intake below 250 mmol/day and a sodium reduction intervention of at least one week.

Authors' conclusions
Sodium reduction from an average high usual sodium intake level (201 mmol/day) to an average level of 66 mmol/day, which is below the recommended upper level of 100 mmol/day (5.8 g salt), resulted in a decrease in SBP/DBP of 1/0 mmHg in white participants with normotension and a decrease in SBP/DBP of 5.5/2.9 mmHg in white participants with hypertension. A few studies showed that these effects in black and Asian populations were greater. The effects on hormones and lipids were similar in people with normotension and hypertension. Renin increased 1.60 ng/mL/hour (55%); aldosterone increased 97.81 pg/mL (127%); adrenalin increased 7.55 pg/mL (14%); noradrenalin increased 63.56 pg/mL: (27%); cholesterol increased 5.59 mg/dL (2.9%); triglyceride increased 7.04 mg/dL (6.3%).

Effects of low sodium diet versus high sodium diet on blood pressure, renin, aldosterone, catecholamines, cholesterol, and triglyceride

Background Angiotensin-converting–enzyme (ACE) inhibitors not only decrease the production of angiotensin II but also decrease the degradation of bradykinin. In this study, a specific bradykinin-receptor antagonist, icatibant acetate (HOE 140), was used to determine the contribution of bradykinin to the short-term effects of ACE inhibition on blood pressure and plasma renin activity in both normotensive and hypertensive subjects. Methods We compared the hemodynamic, renal, and endocrine effects of captopril alone (25 mg), captopril plus icatibant (100 μg per kilogram of body weight), the angiotensin II subtype 1–receptor antagonist losartan (75 mg), and placebo in 20 subjects with normal blood pressure and 7 subjects with hypertension. The subjects were studied while they were salt depleted (i.e., in balance on a diet in which they were allowed 10 mmol of sodium per day). The drugs were administered on four separate study days in a single-blind, randomized fashion. Results The coadministration of icatiban...

Effect of bradykinin-receptor blockade on the response to angiotensin-converting-enzyme inhibitor in normotensive and hypertensive subjects.

Objective To examine the dose-response relation between reduction in dietary sodium and blood pressure change and to explore the impact of intervention duration. Design Systematic review and meta-analysis following PRISMA guidelines. Data sources Ovid MEDLINE(R), EMBASE, and Cochrane Central Register of Controlled Trials (Wiley) and reference lists of relevant articles up to 21 January 2019. Inclusion criteria Randomised trials comparing different levels of sodium intake undertaken among adult populations with estimates of intake made using 24 hour urinary sodium excretion. Data extraction and analysis Two of three reviewers screened the records independently for eligibility. One reviewer extracted all data and the other two reviewed the data for accuracy. Reviewers performed random effects meta-analyses, subgroup analyses, and meta-regression. Results 133 studies with 12 197 participants were included. The mean reductions (reduced sodium v usual sodium) of 24 hour urinary sodium, systolic blood pressure (SBP), and diastolic blood pressure (DBP) were 130 mmol (95% confidence interval 115 to 145, P Conclusions The magnitude of blood pressure lowering achieved with sodium reduction showed a dose-response relation and was greater for older populations, non-white populations, and those with higher blood pressure. Short term studies underestimate the effect of sodium reduction on blood pressure. Systematic review registration PROSPERO CRD42019140812.

https://www.bmj.com/content/bmj/368/bmj.m315.full.pdf

Effect of dose and duration of reduction in dietary sodium on blood pressure levels: systematic review and meta-analysis of randomised trials.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(06)69442-7.pdf

Oral renin inhibitors

Angiotensin receptor antagonists: focus on losartan

In a dose-ranging study, the angiotensin type I receptor antagonist losartan (DuP753/MK954) was administered orally to normal volunteers in whom the renin-angiotensin system (RAS) had been activated by a low sodium diet (40 mmol) and frusemide (40 mg twice daily) for 3 days before study. On the fourth day, subjects (n = 12) received placebo and three active doses (5, 10, 25, 50, or 100 mg) in a randomized, double-blind, three-panel, dose-ranging design. On the study day, 24-h urinary sodium excretion was approximately 10-20 mmol Na, with an increase in renin and aldosterone levels at baseline. Dose-dependent decreases in supine and erect blood pressures (BP) were statistically significant for 50 and 100 mg and were associated with a modest increase in supine heart rate (HR) at the higher dose. The peak BP decreases observed suggested that the highest dose studied (100 mg) was not necessarily the maximal response. Active treatments caused no increase in the sodium loss on the study day. Renin was significantly increased by doses > 10 mg in a dose-dependent fashion but there was little change in plasma aldosterone profile. Increase in renin was evident at doses (10 mg) below those significantly affecting overall BP (50 mg). Adverse symptoms were uncommon and limited to postural lightheadedness which was largely dose related. Our results indicate a BP and plasma renin dose-response relation for the orally active angiotensin II (AII) receptor blocker losartan in normotensive subjects with an activated RAS.

Dose-ranging study of the angiotensin type I receptor antagonist losartan (DuP753/MK954), in salt-deplete normal man.

We examined the haemodynamic and renal response to oral losartan potassium (100 mg) during activation of the renin system in humans. Eight healthy volunteers followed a low-salt (40 mmol sodium) diet for 4 days on four occasions 2 weeks apart. Double-blind salt depletion was achieved by 3-day administration of frusemide (40 mg twice daily, b.i,d.) with placebo salt replacement, salt repletion by placebo frusemide (b.i.d.), and active salt replacement (100 mmol/day). On day 4, subjects received randomised double-blind placebo or losartan. Prestudy salt depletion was associated with nonsignificant decreases in serum sodium (138±2 mM), potassium (3.5±0.2 mM) and increased urea (6.5±1.1 mM), and creatinine (91±6 μM) as compared with screening. Prestudy (day 3) 24-h urinary volume was similar during deplete preparation (placebo 1.707±0.81 L, losartan 1.509±0.626 L) or deplete preparation (placebo 1.726± 0.5 L, losartan 1.764±0.52 L), but sodium excretion was greater during replete preparation. Salt replete supine blood pressure (BP) profiles showed little effect of losartan (mean maximal supine BP-9±6 mm Hg) as compared with placebo (-1±4 mm Hg), with a similar relative result for erect BP. After salt depletion, losartan caused a greater response in both supine (-24±9) and erect (-33±15) BP than did placebo (supine -12±5, erect -14±9). In this protocol after salt depletion, losartan caused a transient increase in urea and creatinine (143±40 μML) 8 h after dosing as compared with placebo (105±13 μM). Creatinine clearance (6-8 h) was similar after placebo (161±37 ml/min) and losartan (147 ±32 ml/min) in salt repletion but was significantly less after losartan (47±54) than placebo after salt depletion (140±24). Pretreatment renin (salt replete) was similar (placebo 2.0±1.4, losartan 1.2±0.6 ngAI/ml/h) to screening (1.64±1.47 ngAI/ml/h). Salt deplete preparation increased baseline plasma renin activity (PRA) (placebo 7.7±4.5, losartan 11.5±8.7), with losartan producing a greater increase in PRA after salt depletion. In a controlled setting, losartan had little or no haemodynamic effect in salt-replete normal volunteers. Activation of the renin-angiotensin system (RAS) low salt by diet and loop-acting diuretics produces powerful BP-lowering activity associated with significant decreases in creatinine clearance. Care should be taken in susceptible patients in whom such combination therapy is deemed appropriate

Haemodynamic and renal responses to oral losartan potassium during salt depletion or salt repletion in normal human volunteers.

The biological effects of dose-dependent inhibition of renin have rarely been extensively studied after oral (p.o.) dosing in humans. We studied remikiren (Ro42–4892), a selective renin inhibitor, in normal volunteers after activation of the renin-angiotensin system (RAS) based on salt depletion. Twelve normal men (28 ± 9 years, 77 ± 10 kg), comprising three consecutive dose panels of 4 subjects, received four treatments, double-blind and randomised 2 weeks apart: panel I, placebo (P). or 30. 100. and 300 mg. remikiren: panel II. placebo or 300. 600 mg, 1,000; panel III, placebo or 30, 600, and 1,000 mg. The RAS was activated by 40 mmol/day sodium diet plus frusemide (40 mg BDS), for 3 days before each study day. Data (mean ± SD) were examined by repeated-measures analysis of variance (ANOVA). RAS activation was confirmed by 24-h urinary sodium excretion (screen, 142 ± 74 mmol/24 h: prestudy, 66 ± 33. 59 ± 41, 78 ± 4. 73 ± 30 mmol/24 h) and increase in plasma renin activity (PRA) (screen, 0.8 ± 0.3 ng AI/ml/h; before dosing. P, 6.5 ± 3.1: 30 mg. 8.2 ± 3; 100 mg. 9.4 ± 5.7: 300 mg. 6.5 ± 2.4; 600 mg. 5.2 ± 2: 1,000 mg. 6.2 ± 4.4 ng AI/ml/h). PRA was reduced in dose dependently (mean minimal activity: 30 mg 1.4 ± 1.2: 100 mg. 1.6 ± 1: 300 mg, 0.1 ± 0.1,600 mg, 0.1 ± 0.1:1,000 mg, 0.01 ± 0.02), and active renin was increased (mean maximal active renin; 30 mg. 182 ± 186; 100 mg. 185 ± 83: 300 mg. 252 ± 240; 600 mg. 262 ± 100, 1.000 mg. 1.417 ± 2.008 pg/ml). Maximal effects were noted soon after dosing for PRA (30 mg. 1.1 ± 0.3: 100 mg. 1 ± 0; 300 mg. 1 ± 0; 600 mg. 1.3 ± 0.4; 1.000 mg. 1.3 ± 0.4 h) but slower for increase in active renin (30 mg. 4.6 ± 1.3. 100 mg. 3 ± 1.4; 300 mg. 1.8 ± 1.6: 600 mg. 2.8 ± 1.5; 1,000 mg. 3.4 ± 1.4 h). Despite evidence of biochemical effect, supine blood pressure (BP) was not significantly affected by active treatment. Erect BP did show a significant decrease from pretreatment values, but only after 1,000 mg remikiren 1 h after dosing (P. baseline, 116 ± 12/68 ± 7: 1 h, 112 ± 8/65 ± 7; 1.000 mg. baseline, 114 ± 12/65 ± 7; 1 h, 96 ± 9/50 ± 18). Drug concentrations showed a wide dose-related spectrum of mean maximal concentrations (30 mg. 1.07 ± 1.64; 100 mg, 2.17 ± 1.38; 300 mg. 28.88 ± 16.95; 600 mg. 67.76 ± 36.06: 1.000 mg. 136.9 ± 156 ng/ml). Values for Tmax were generally observed soon after dosing and were not clearly dose related (30 mg. 0.5 ± 0.5; 100 mg. 0.56 ± 0.77; 300 mg, 0.66 ± 0.51: 600 mg. 0.44 ± 0.11; 1,000 mg. 0.94 ± 0.63 h). Remikiren is enzymatically active after p.o. administration in humans in a dose-dependent manner. Only the dose of 1.000 mg reduced BP in salt-deplete subjects. Haemodynamic effects are therefore demonstrable but are slight, dissociated from RAS inhibition in blood, despite confirmed activation of the RAS. BP changes parallel the pharmacokinetic profile. The latter is unlikely to permit once daily dosing with 24-h effect. Higher doses and or controlled-release p.o. formulations or alternative routes of administration would be required to achieve antihypertensive efficacy. Owing to the selective nature of renin inhibition, a separate profile of efficacy and response in hypertensive patients is unlikely.

Responses to an orally active renin inhibitor, remikiren (Ro 42-5892), after controlled salt depletion in humans.

Renin inhibitors are an alternative means of blockade of circulating and tissue-based renin-angiotensin systems (RAS). We studied a new renin inhibitor, Ro 42-5892, by low-dose (0.1 mg/kg) intravenous (i.v.) infusion in 10 min (fast) or 6 h (slow) or placebo in a double-blind cross-over study to assess the relationship between drug concentration and response. Fasting salt-replete normotensive male volunteers (n = 9) aged 18-32 years were studied supine. There were no significant changes in blood pressure (BP) or heart rate (HR) between drug and placebo infusion. Drug concentration peaked (482 +/- 140 ng/ml) at the end of the fast infusion or showed a sustained plateau (25.9 +/- 6.1 ng/ml) with the slow infusion (mean time to peak 121 +/- 99 min). Both fast (135.2 +/- 26 ng/ml/h2) and slow (121.0 +/- 31.1 ng/ml/h2) infusions had similar area under the curve (AUC)0-24-values. Plasma renin activity (PRA) was dramatically reduced by both strategies, but AUC0-10 for PRA was significantly less for slow (1.7 +/- 0.6 ngAI/ml/h2) than fast (4.9 +/- 2.5 ngAI/ml/h2) infusions. Mean peak plasma active renin (AR) concentration was increased by both fast (102.2 +/- 65.9 pg/ml) and slow (195.2 +/- 110.5 pg/ml) infusions as compared with placebo (49.9 +/- 18.6 pg/ml). Similarly, AUC0-10 for AR was greater for slow (990.2 +/- 582.1 pg/ml/h) than fast (512.4 +/- 189.4 pg/ml/h) infusions. Plasma angiotensin-converting enzyme (ACE) activity was unaltered. Our results indicate that protracted low concentrations of Ro 42-5892 may provide more effective and long-lasting inhibition of renin.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurohormonal and blood pressure responses to low-dose infusion of an orally active renin inhibitor, Ro 42-5892, in salt-replete men.

54 Haemodynamic and renal response to losartan during salt depletion or salt repletion

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