Many beneficial effects have been ascribed to dietary protein [1,2]. Satiating and lean body mass sparing effects make high protein diets popular in weight loss and weight management programs . Another favorable effect of dietary proteins may be improvement of blood pressure (BP) and cardiovascular health [4,5]. A systematic review of observational and intervention studies until June 2010 concluded that dietary protein may have a small beneficial effect on BP. Strongest evidence for this effect came from randomized controlled trials, which may be due to better controlled food intake and reduced risk of residual confounding in trials compared with observational studies . However, since the publication of this review , new studies have been published on the BP lowering effects of high protein diets. The most recent evidence will be discussed in this review. Beneficial protein sources and BP lowering mechanisms are also addressed. In addition, recent studies on possible adverse effects of high protein diets are discussed. Most of the studies mentioned in this article increased protein intake from 15%, which is considered normal, to 25–30% of energy intake. Thus, a high protein diet of 2000 kcal per day would increase protein intake from the normal value of 74 g per day to a maximum of 148 g per day.
Recently published short-term trials found a BP lowering effect of dietary proteins. The randomized clinical trial on the effects of proteins on blood pressure found that isoenergetically replacing 60 g per day maltodextrin for a protein mixture (30% egg protein, 30% milk protein, 20% soy protein, 20% pea protein) for 4 weeks lowered SBP (−4.9 mmHg, P = 0.005) and DBP (−2.7 mmHg, P = 0.05) [7▪]. Another randomized trial found that supplementation of 40 g per day soy protein or milk protein for 8 weeks compared with a complex carbohydrate lowered SBP (−2.0 mmHg, P = 0.002 and −2.7 mmHg, P = 0.001, respectively), with no differences between the protein sources [8▪▪]. In contrast, longer trials show less clear effects. Supplementation with 30 g per day of whey protein compared with maltodextrin did not lower BP in elderly women after either 1 or 2 years of supplementation [9▪▪]. In type 2 diabetic patients, 12 months (3 months caloric restriction and 9 months weight maintenance) of dietary advice for a high protein diet (30% protein, 40% carbohydrate) versus high carbohydrate diet (15% protein, 55% carbohydrate) reduced SBP more after 3 months (−3.0 mmHg, P = 0.04) as well as after 12 months (−4.3 mmHg, P = 0.05) in the high protein group. However, these differences were no longer statistically significant after stringent corrections for multiple testing . Another study found no differences in BP after 6–18 weeks on a high protein diet (131 g per day), a high carbohydrate diet, a high cereal fiber diet and a mixed diet with increased protein and fiber content . Reasons that long-term studies found no effects may be decreased dietary compliance , higher dropout rates , or weakening of the short-term hypotensive effects of increased protein intake in the long term. More detailed time course trials are needed to study changes in BP during high protein diets over time. Weight loss trials with high protein diets are also inconclusive. One large trial found no effects of high protein diets , whereas the other found significantly lower DBP (−3.7 mmHg, P = 0.01) .
Since the Omniheart trial in 2005 , the question rose whether the beneficial effects of high protein diets on BP are due to increased protein content or due to reduced carbohydrate content . The Omniheart trial, a large well controlled intervention trial, suggested that lowering carbohydrate intake rather than increasing protein intake may lower BP, because only increasing protein intake at the expense of carbohydrates, but not at the expense of fat, reduced SBP . As all abovementioned studies compared dietary protein with carbohydrates, this question remains unanswered. Only one other small study  compared protein with fat intake and found, in contrast to the Omniheart trial, that increased protein intake also lowered BP compared with fat. Larger trials are necessary to confirm this. Therefore, the question whether the beneficial effects of high protein diets on BP are due to increased protein content or due to reduced carbohydrate content  has not been resolved yet.
EFFECTS OF DIFFERENT PROTEIN SOURCES ON BLOOD PRESSURE
Altorf-van der Kuil et al. concluded, based on observational studies, that the small beneficial effect of dietary protein on BP was mainly attributable to plant protein . Additional findings in a Dutch cross-sectional sample confirmed that higher plant protein intake was associated with lower BP, whereas no clear associations were found between total protein or animal protein intake and BP . A cross-sectional study in Iran found that the ratio between animal and plant protein intake was not associated with BP . Also a prospective Dutch cohort study found no association of total protein, plant protein or animal protein with risk for hypertension. Only protein intake from grain was inversely associated with incident hypertension . A 2-year prospective cohort study suggested a beneficial effect of plant versus animal proteins on BP [20▪]. Quartiles of methionine and alanine intake were directly associated with BP, whereas quartiles of threonine and histidine intake showed an inverse association. Plant proteins have a lower ratio of methionine and alanine to threonine and histidine compared with animal proteins [20▪].
BP lowering effects of specific animal and plant protein sources have also been investigated in trials. A meta-analysis of randomized controlled trials found that soy protein lowers BP compared with carbohydrates (SBP −4.5 mmHg, P = 0.002, DBP −3.0 mmHg, P = 0.004), but this BP reduction tended to be smaller and not significant when soy protein was compared with milk proteins (SBP −2.0 mmHg, P = 0.18, DBP −1.3 mmHg, P = 0.13) [21▪]. Soy foods are thought to be hypotensive due to their protein and flavonoid content. Lupin is a legume high in protein and fiber. Consumption of products containing lupin flour (16–20 g protein, 11 g fiber per 100 g), compared with wheat flour (4–11 g protein, 3–5 g fiber per 100 g), during 4 months of weight loss and 8 months of ad libitum weight maintenance reduced 24 h ambulatory BP (SBP −1.3 mmHg, DBP −1.0 mmHg, both P = 0.02) . Many [23–26], but not all  recent observational studies found beneficial effects of dairy or low-fat dairy intake on BP. Recent randomized trials are inconclusive. One trial found that SBP was lowered after 8 weeks of low-fat dairy consumption (−2.9 mmHg, P = 0.03) , whereas another study found no effect on BP after 6 months of increased low-fat dairy consumption (0.9 mmHg, P = 0.51) . Dairy foods may lower BP because of their protein content, their micronutrient content and the formation of angiotensin converting enzyme (ACE) inhibiting bioactive peptides in the gastrointestinal tract [25,30].
Differing amino acid compositions of animal and plant proteins may explain differences in their BP lowering effects. An overview of the effects of different amino acids on BP is provided in the review by Vasdev and Stuckless . Two additional reviews, on the BP lowering effects of taurine and arginine respectively, have been published recently. Taurine is an amino acid-like component of foods of animal origin, which has beneficial effects on BP and the vasculature . Arginine, present in animal and plant proteins, was found to have hypotensive effects according to a meta-analysis of 11 randomized placebo-controlled trials .
Thus, although observational studies suggest that plant protein intake may be more beneficial for BP than animal protein, trials have, thus, far not confirmed such general difference. Further randomized controlled trials are needed to investigate the hypotensive effect of specific proteins, peptides and amino acids.
BLOOD PRESSURE LOWERING MECHANISMS OF DIETARY PROTEINS
Understanding of the mechanisms by which dietary proteins, peptides and amino acids modulate BP, also discussed by Vasdev and Stuckless , can provide further insight into which sources of dietary proteins may lower BP. BP is a product of cardiac output and total peripheral resistance (TPR). Thus, BP lowering mechanisms act via these parameters. One BP lowering mechanism may be ACE inhibition by bioactive peptides. ACE inhibition results in reduced angiotensin II formation, reduced vasoconstriction and lower TPR and BP . Studies with milk-derived ACE inhibiting peptides are inconsistent [34,35]. A recent review  and meta-analysis  both pointed out that even though earlier research has shown promising results, many recent studies could not demonstrate a BP lowering effect or an ACE inhibiting effect of lactotripeptides. An acute study found that active milk (containing bioactive tripeptides and plant sterols) lowered BP postprandially for 8 h compared with control milk. However, the renin–angiotensin system was not affected systemically. Higher urinary NO values and cyclic guanosine monophosphate excretion suggested that improved endothelial function may have reduced BP . Bioactive peptides from other sources apart from milk are being developed and tested for their effects on BP and ACE inhibition [38,39]. However, their effects need to be confirmed in large randomized trials with humans. Although systemic ACE inhibition is usually not found, this does not exclude a role of local ACE inhibition (for example, in the gastrointestinal tract) in the BP lowering effect of bioactive peptides. Taken together, recent trials and reviews do not support the idea that bioactive peptides inhibit ACE systemically. In addition, in the light of recent studies a potential BP lowering effect of bioactive peptides also remains controversial.
Another BP lowering mechanism is arginine-induced vasodilation with arginine serving as a substrate for NO production. L-arginine may only augment NO production when levels of asymmetric dimethylarginine (ADMA), an endogenous NO synthase inhibitor, are elevated. Physiological concentrations of plasma arginine may be sufficient for saturating the NO synthase pathway when ADMA levels are normal . Tryptophan may also reduce BP by augmenting NO production. Tryptophan is a precursor of serotonin, which may stimulate NO-synthase via yet unknown mechanisms . Tryptophan may also modulate BP by reducing epinephrine and norepinephrine release .
Despite these and other  BP lowering effects associated with dietary protein intake, acute BP responses to protein consumption compared with other macronutrients are not always in line with the chronic hypotensive effect of dietary protein. For instance, isoenergetic breakfasts supplemented with 45 g casein, whey or glucose did not differ in 6 h postprandial response of BP, augmentation index and inflammatory markers [42▪▪]. Although 60 g per day of whey protein isolate during 20 weeks (8 weeks weight loss, 12 weeks ad libitum diet) reduced SBP compared with the control (carbohydrate) diet . Another acute study found that postprandial TPR and mean arterial pressure (MAP) were decreased in elderly patients after consumption of meals composed of high carbohydrate or high fat foods, but not after an isoenergetic meal composed of high protein foods. The absence of a response after the protein meal was ascribed to differences in postprandial gut hormones. However, these were not measured [44▪▪]. Interactions of dietary proteins with the gastrointestinal tract and release of vasoactive hormones, such as glucagon-like-peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and insulin, from the gastrointestinal tract have been reviewed recently [45▪].
In summary, dietary proteins may lower BP via several mechanisms. However, postprandial changes in BP after protein consumption are not necessarily in line with long-term effects. Divergent postprandial BP responses may be explained by differences in the degree of vasodilation, mediated by NO, ACE inhibition or gastrointestinal hormones, and differences in the compensatory response of cardiac output, although this mechanism has hardly been studied so far. Further research is necessary to explore mechanisms involved in postprandial responses to dietary protein and to find out whether and how differences in acute responses are linked to differences in long-term effects of increased protein intake.
ADVERSE EFFECTS OF INCREASED PROTEIN INTAKE
A concern of high protein intake is that it may be harmful for renal function, especially in vulnerable groups. Therefore, patients with chronic renal failure are advised to consume 0.6–0.75 g protein/kg body weight per day. This amount of protein intake should be enough to maintain a healthy nutritional status, although limiting possible adverse effects of high protein intake . It has been suggested that mainly animal protein may be harmful for kidney function . One of the reasons why increased protein intake may negatively affect renal function and BP is the increased acid load associated with high protein intake. This could introduce a vicious cycle because acid load may lead to kidney damage and hypertension, which are interrelated . Indeed, increased protein intake was directly associated with net acid excretion in a cross-sectional sample of renal transplant recipients, but no associations were observed between net acid excretion and acidosis related complications like hypertension and insulin resistance in this susceptible group . Furthermore, no association between dietary acid load and risk of hypertension was found in a Dutch prospective cohort .
Three months on a high protein weight loss diet was shown to induce hyperfiltration [51▪▪]. Hyperfiltration is hypothesized to be a precursor of intraglomerular hypertension leading to albuminuria. Glomerular filtration rate (GFR) then falls progressively, which may lead, in the long run, to end-stage renal failure . However, no adverse effects were found on GFR, albuminuria or fluid and electrolyte balance after 2 years on the high protein weight loss diet in healthy obese patients [51▪▪]. This could be because increased GFR with high protein intake is associated with increased renal size .
It has been suggested that colonic health may be adversely affected by high protein diets characterized by high meat intake. Four weeks on high protein (138 g per day) weight loss diets increased the amount of fecal carcinogenic N-nitroso compounds (NOCs) [54▪]. Further analyses revealed that the amount of fecal NOC was directly associated with meat intake and nitrate intake (from vegetables) and inversely associated with energy intake, vitamin C intake and nonstarch polysaccharides . This suggests that both increased meat protein intake and low carbohydrate intake may be harmful for colonic health. Other studies also suggested that a very low carbohydrate content in high protein diets may increase the risk for all-cause mortality , cardiovascular disease  and type 2 diabetes .
In summary, concerns still exist for the safety of high protein diets, especially in vulnerable subgroups, due to increased acid loading and hyperfiltration. However, recent studies found that increased acid load and hyperfiltration induced by high protein diets may not be as harmful as initially thought. In addition other possible adverse effects from high protein diets, like decreased colonic health, may arise from the low carbohydrate intake characterizing these diets rather than the high protein intake per se.
Randomized trials, especially long-term trials, remain inconclusive on the BP lowering effects of dietary proteins. This may result from different protein sources affecting differing hypotensive mechanisms. Available evidence shows no clear differences in the hypotensive effects of plant protein intake versus animal protein intake. Acute studies may give insight into their hypotensive mechanisms but are not easily translated to long-term effects. Evidence suggests that it may be safe for kidney function to increase protein intake. The question whether it is increased protein intake or decreased carbohydrate intake that affects BP has not yet been answered.
TI Food and Nutrition is a public private partnership of science, industry and government conducting strategic research in food and nutrition (http://www.tifn.nl).
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 92–93).
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