casein-hydrolysate and Hypertension

Clinical trials are reviewed, involving proteins and peptides derived from milk (predominantly bovine), with the exception of lactoferrin, which will be the subject of another article. The most explored milk fraction is α-lactalbumin (LA), which is often applied with glycomacropeptide (GMP) - a casein degradation product. These milk constituents are used in health-promoting infant and adult formulae as well as in a modified form (HAMLET) to treat cancer. Lactoperoxidase (LCP) is used as an additive to mouth hygiene products and as a salivary substitute. Casein derivatives are applied, in addition, in the dry mouth syndrome. On the other hand, casein hydrolysates, containing active tripeptides, found application in hypertension and in type 2 diabetes. Lysozyme is routinely used for food conservation and in pharmaceutical products. It was successfully used in premature infants with concomitant diseases to improve health parameters. When used as prophylaxis in patients with scheduled surgery, it significantly reduced the incidence of hepatitis resulting from blood transfusion. Lysozyme was also used in infected children as an antimicrobial agent showing synergistic effects in combination with different antibiotics. Proline-rich polypeptide (PRP) was introduced to therapy of Alzheimer's disease patients. The therapeutic value of PRP was proved in several clinical trials and supported by studies on its mechanism of action. Concentrated immunoglobulin preparations from colostrum and milk of hyperimmunized cows showed efficacy in prevention of infections by bacteria, viruses and protozoa. A nutrition formula with milk-derived TGF-β2 (Modulen IBD®) found application in treatment of pediatric Crohn's disease. In conclusion, the preparations containing milk-derived products are safe and effective measures in prevention and treatment of infections as well as autoimmune and neoplastic diseases.

Topics: Adult; Alzheimer Disease; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antineoplastic Agents; Autoimmune Diseases; Caseins; Cattle; Clinical Trials as Topic; Colostrum; Diabetes Mellitus, Type 2; Drug Synergism; Food Preservation; Humans; Hypertension; Immunoglobulins; Infant; Infant Food; Infant, Premature, Diseases; Infection Control; Lactalbumin; Lactoperoxidase; Milk; Milk Proteins; Neoplasms; Peptide Fragments; Xerostomia

A double-blind, placebo-controlled, randomized clinical trial was conducted to evaluate the effects of ingesting an excess of tablets containing casein hydrolysate, incorporating angiotensin I-converting enzyme (ACE) inhibitory peptides such as Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP), in subjects with blood pressure ranging from normal to mild hypertension. A total of 48 subjects were given either 5 times more than the effective amount of casein hydrolysate or a placebo in tablet form for 4 weeks. In the active group, systolic blood pressure (SBP) decreased significantly as compared with the placebo group. In stratified analysis, however, this antihypertensive effect was not found in normotensive subjects. In addition, neither an acute or nor an excessive reduction in blood pressure nor clinically important adverse events were observed in this study. These findings suggest that intake of a 5-fold excess of tablets containing casein hydrolysate can lead to a mild improvement in hypertension without side effects.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Body Mass Index; Body Weight; Caseins; Double-Blind Method; Female; Humans; Hypertension; Japan; Male; Middle Aged; Oligopeptides; Peptidyl-Dipeptidase A; Placebos; Tablets

This trial evaluated the effects of casein hydrolysate containing milk-derived peptides, Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP), on central blood pressure and arterial stiffness.. A randomized, double-blind, placebo-controlled trial was conducted in 70 Japanese subjects aged 50-69 years with untreated stage-I hypertension. They were randomly assigned to two groups, which received either placebo tablets or active tablets containing 3.4 mg of VPP and IPP. At the beginning and end of the 8-week intervention, hemodynamic parameters, including central blood pressure and brachial-ankle pulse wave velocity (baPWV), a marker of arterial stiffness, were measured.. A significant difference in changes in central systolic blood pressure between the groups was observed (active: -11.0±11.0 vs placebo: -4.5±9.6 mmHg, P<0.01). In the active group, reductions in baPWV (-73.9±130.0 vs -8.4±137.1 cm/s, P<0.05), brachial SBP (-10.5±11.5 vs -3.9±9.6 mmHg, P<0.05), and radial mean blood pressure (-7.3±8.9 vs -2.0±7.4 mmHg, P<0.01) were significantly greater as compared with the placebo group.. Casein hydrolysate containing VPP and IPP improves central SBP and baPWV in hypertensive subjects, which suggests VPP and IPP might have beneficial effects on arterial properties.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Ankle Brachial Index; Antihypertensive Agents; Blood Pressure; Caseins; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Oligopeptides; Vascular Stiffness

Contrasting data partially support a certain antihypertensive efficacy of lactotripeptides (LTPs) derived from enzymatic treatment of casein hydrolysate. Our aim was to evaluate this effect on a large number of hemodynamic parameters. We conducted a prospective double-blind randomized clinical trial, which included 52 patients affected by high-normal blood pressure (BP) or first-degree hypertension. We investigated the effect of a 6-week treatment with the LTPs isoleucine-proline-proline and valine-proline-proline at 3 mg per day, assumed to be functional food, on office BP, 24-h ambulatory BP monitoring (ABPM) values, stress-induced BP increase and cardiac output-related parameters. In the LTP-treated subjects, we observed a significant reduction in office systolic BP (SBP; -5±8 mm Hg, P=0.013) and a significant improvement in pulse wave velocity (PWV; -0.66±0.81 m s(-1), P=0.001; an instrumental biomarker of vascular rigidity). No effect on 24-h ABPM parameters and BP reaction to stress was observed from treatment with the combined LTPs. LTPs, but not placebo, were associated with a mild but significant change in the stroke volume (SV), SV index (markers of cardiac flow), the acceleration index (ACI) and velocity index (VI) (markers of cardiac contractility). No effect was observed on parameters related to fluid dynamics or vascular resistance. LTPs positively influenced the office SBP, PWV, SV, SV index, ACI and VI in patients with high-normal BP or first-degree hypertension.

Topics: Adult; Aged; Blood Flow Velocity; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Cardiac Output; Caseins; Double-Blind Method; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Oligopeptides; Pulsatile Flow; Stress, Physiological

Contrasting data partially support a certain antihypertensive efficacy of lactotripeptides derived from enzymatic treatment of casein hydrolysate. We carried out a randomized, double-blind, crossover clinical study to investigate the antihypertensive efficacy of a short-term treatment with lactotripeptides in Mediterranean subjects with normal or high-normal blood pressure (BP). We consecutively enrolled 55 untreated subjects (men:women = 30:25), 40.3 ± 9.8 years old, with normal or high-normal BP. After 4 weeks of dietary standardization, they were allocated to treatment with a fruit juice containing 3 mg of added Ile-Pro-Pro/Val-Pro-Pro lactotripeptides or with placebo for 4 weeks. After a 4-week washout period, they were then assigned to the alternative treatment for a further period of 4 weeks. Overall, no significant difference has been observed in office BP comparing baseline data with those posttreatment. Repeating the analysis by basal BP level, a mild but significant reduction in systolic BP (-1.7 ± 2.3 mm Hg; t = 3.5, P = .002) has been observed only in subjects with high-normal BP after treatment with lactotripeptides. With regard to 24-hour BP measurement, after lactotripeptide treatment only, the subjects experienced a significant reduction in diurnal diastolic BP (-1.6 ± 5.4 mm Hg; P = .042), diurnal mean BP (-2.1 ± 5.9 mm Hg; P = .19), and 24-hour (-5.4 ± 14.2 mm Hg; P = .011) and diurnal (-7.1 ± 19.2%; P = .014) diastolic BP value measurements relative to normal values. No modification has been observed in relation to plasma renin activity and aldosteronemia. In conclusion, diurnal diastolic BP is significantly reduced by lactrotripeptide supplementation in untreated Mediterranean subjects with normal or high-normal BP. Office systolic BP is reduced only in subjects with high-normal BP.

Topics: Adult; Aged; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Cardiovascular Diseases; Caseins; Circadian Rhythm; Cross-Over Studies; Dietary Supplements; Double-Blind Method; Female; Hemodynamics; Humans; Hypertension; Male; Mediterranean Region; Middle Aged; Oligopeptides; Severity of Illness Index; Young Adult

Clinical studies have demonstrated a beneficial effect on blood pressure for milk derived material containing isoleucyl-prolyl-proline (IPP) and valine-prolyl-proline (VPP) peptides. The aim of the present study was to evaluate the blood pressure lowering effect of three different IPP and VPP doses in products with a comparable electrolyte and protein composition. The present study was designed as a randomized, double-blind, parallel-group, dose-response trial: 166 subjects (>140/90 mmHg) received placebo during a 2-week run-in, 8-weeks intervention followed by a 2-week washout. Results indicate that materials containing IPP and VPP do lower blood pressure dose-dependently (p < 0.05 for diastolic blood pressure, DBP). The effect on systolic blood pressure (SBP)/DBP over 8 weeks compared with placebo was + 0.1/- 1.3, - 1.5/- 1.4 and - 2.5/- 1.9 mmHg for the low, medium and high dose of peptides, respectively. The percentages of subjects who showed a fall in SBP > 3 mmHg or who attained an SBP below 140 mmHg, were 54% (placebo), 64% (low), 76% (medium) and 71% (high dose) respectively. This effect can only be demonstrated for office pressure and not for home or ambulatory pressure. Furthermore, the results suggest that the magnitude of the fall in blood pressure is a function of baseline blood pressure. We conclude that IPP and VPP may have a modest dose-dependent effect on office blood pressure in mildly hypertensive subjects although this could not be confirmed with ambulatory or home blood pressure measurements.

Topics: Aged; Beverages; Blood Pressure Determination; Blood Pressure Monitoring, Ambulatory; Caseins; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Office Visits; Oligopeptides; Powders; Reproducibility of Results; Yogurt

Pharmaceutical angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce arterial stiffness; the possible effect of food-derived putative ACE inhibitory peptides on this degenerative process, however, has not been reported. In the present study, casein hydrolysate containing the lactotripeptides, Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP), which has been found to have an antihypertensive effect in a number of clinical studies, was investigated for its ability to improve hemodynamic parameters, including central systolic blood pressure (cSBP), in hypertensive subjects. Twelve hypertensive subjects who were not on prescribed medication were monitored for various hemodynamic parameters, including brachial blood pressure (peripheral blood pressure), cSBP, and augmentation index (AI), at the start and then after 3, 6, and 9 weeks of a daily treatment comprising four tablets containing VPP and IPP. Compared with basal levels, treatment with casein hydrolysate for 6 and/or 9 weeks showed a significant reduction in peripheral systolic and diastolic blood pressure, AI, and cSBP, but not in heart rate or pulse pressure. cSBP showed a reduction sooner and greater (-21.8 mm Hg) than did brachial systolic blood pressure (-16.4 mm Hg) during the 9-week treatment. Although small and not placebo-controlled, this study suggests that continuous intake of VPP and IPP might have the potential to improve arterial stiffness as well as cSBP and peripheral brachial blood pressure.

Topics: Adult; Blood Pressure; Caseins; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Oligopeptides

About one in four adults suffer from prehypertension. People with prehypertension are at risk of developing hypertension, being a biomarker for cardiovascular disease risk. The use of milk-derived protein hydrolysates containing peptides with angiotensin-converting enzyme (ACE) inhibiting properties may reduce blood pressure (BP) and thus the risk of developing hypertension.. We investigated the BP-lowering effect of a casein-derived protein hydrolysate (C12 Peptide) during a 4-week intervention period in prehypertensive subjects. After a 2-week run-in period, 48 Taiwanese volunteers were randomly assigned to either placebo or C12 Peptide tablets for 4 weeks, followed by a 2-week off-treatment period. After the run-in period, BP was measured weekly.. Baseline values for systolic BP (mean +/- SEM) in the placebo and C12 Peptide groups were 137.1 +/- 3.1 and 137.9 +/- 2.4 mm Hg, respectively; those for diastolic BP were 85.2 +/- 2.1 and 86.9 +/- 2.0 mm Hg, respectively. Four weeks repeated daily intake of 3.8 g C12 Peptide reduced significantly systolic and diastolic BP by 10.7 +/- 1.6 mm Hg and 6.9 +/- 1.2 mm Hg, respectively, compared to baseline. Furthermore, plasma angiotensin II and aldosterone levels were reduced significantly (P < .05). The placebo group showed a BP reduction of 3.6 +/- 2.4 and 2.7 +/- 1.6 mm Hg in systolic and diastolic BP, respectively (P = not significant). No evidence of side effects was observed.. This study shows that C12 Peptide reduces BP in prehypertensive people.

Topics: Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Caseins; Cattle; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged

Accumulating evidence shows that deterioration of vascular endothelial function underlies the pathophysiology of cardiovascular diseases following lifestyle-related diseases. Both Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP), which are tripeptides derived from proteolytic hydrolysate of milk casein, inhibit angiotensin-converting enzyme (ACE), suggesting that both VPP and IPP may improve vascular endothelial function, because many ACE inhibitors are known to improve endothelial function. We investigated the effects of ACE-inhibitory food component in humans with mild hypertension, since there has been no report on such effects. The study was conducted by the placebo-controlled, double-blind crossover method in 25 male subjects with mild hypertension. After casein hydrolysate containing both VPP and IPP were administered for 1 week, reactive hyperemia of the left upper forearm was measured using plethysmography as an index of vascular endothelial function. Since one subject dropped out, we analyzed the data of 24 subjects. The reactive hyperemia of the left upper forearm was produced by a 5 min occlusion using inflation of a cuff. The maximum blood flow during reactive hyperemia was 20.8+/-6.7 mL/min/100 mL tissue in the placebo group, whereas it increased remarkably to 30.0+/-10.4 mL/min/100 mL tissue in the group administered casein hydrolysate containing both VPP and IPP (p<0.001). There was no change in systemic blood pressure, indicating that the improvement of the vascular endothelial function attributable to VPP and IPP is independent of hemodynamic changes. We conclude that casein hydrolysate containing VPP and IPP improves the vascular endothelial dysfunction in subjects with mild hypertension. The continuous intake of VPP and IPP could help to prevent cardiovascular diseases in hypertensive subjects.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Blood Pressure; Caseins; Cross-Over Studies; Endothelium, Vascular; Forearm; Humans; Hypertension; Male; Middle Aged; Oligopeptides

We describe a clinical trial to study the efficacy of a casein hydrolysate, prepared using an Aspergillus oryzae protease, containing the major angiotensin-I-converting enzyme inhibitory peptides Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP) in a single-blind, placebo-controlled study. A total of 131 volunteers with high-normal blood pressure and mild hypertension were randomly divided into four groups (n 32 or 33 in each group). Each volunteer was given two tablets containing four different dosages of VPP and IPP (VPP+IPP: 0, 1.8, 2.5 and 3.6 mg), daily for 6 weeks. A significant decrease in systolic blood pressure was observed at 6 weeks in the active group receiving 1.8 mg (P<0.01) VPP and IPP; in the active groups receiving either 2.5 mg or 3.6 mg, systolic blood pressure was decreased at both 3 weeks (P<0.05 and P<0.05) and 6 weeks (P<0.001 and P<0.0001) compared with systolic blood pressure measured before treatment. Changes in the systolic blood pressure after 6 weeks of treatment in the four groups were --1.7, --6.3, --6.7 and --10.1 mmHg, and these effects were dose dependent. In addition, a significant difference in systolic blood pressure between the placebo group and the VPP and IPP group receiving 3.6 mg was observed (P<0.001) by two-way ANOVA. The antihypertensive effect was greater in mildly hypertensive subjects (n 20 or 21 in each group) than in any of the other subjects. No significant change of diastolic blood pressure was observed for all the test groups, and no differences in diastolic blood pressure in the test sample groups compared with the placebo group were observed during the test period.

Topics: Administration, Oral; Adult; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Aspergillus oryzae; Blood Pressure; Body Mass Index; Body Weight; Caseins; Dietary Supplements; Female; Humans; Hypertension; Male; Oligopeptides; Single-Blind Method

Casein hydrolysate, prepared with Aspergillus oryzae protease, contains angiotensin I-converting enzyme inhibitory peptides, such as Val-Pro-Pro and Ile-Pro-Pro. We conducted a randomized, double-blind, placebo-controlled study to evaluate the effect of casein hydrolysate on the blood pressure of 144 subjects with high-normal blood pressure (n = 104) and mild hypertension (n = 40). Subjects were randomly assigned to two groups for a 12-week intake period. In the test group, both systolic (SBP) and diastolic (DBP) blood pressure decreased significantly compared with the placebo group: SBP/DBP significantly decreased from 138.2 +/- 6.5/84.4 +/- 5.3 mm Hg at week 0 to 132.3 +/- 7.3 (P < .001)/81.2 +/- 4.8 mm Hg (P < .001) at week 12. In the stratified analysis, the test product showed an antihypertensive effect in both the subject group with high-normal blood pressure and that with mild hypertension. No side effect was observed in any subjects in this study. These results demonstrate that the casein hydrolysate, prepared with A. oryzae protease, produced a significant reduction in blood pressure in a population of subjects with high-normal blood pressure or mild hypertension without an adverse event.

Topics: Adult; Aspergillus oryzae; Blood Pressure; Body Mass Index; Caseins; Diet; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Peptide Hydrolases; Placebos; Potassium; Sodium

Many patients seek complementary medicine treatments like neutraceuticals for common conditions such as hypertension.. We conducted a placebo-controlled prospective randomized crossover study in 10 hypertensive subjects to determine whether a single dose of a hydrolysate of bovine milk protein (designated C12 peptide; low and high dose), either alone or combined with alginic acid (low and high dose), reduced daytime blood pressure (BP), as determined by ambulatory BP monitoring.. Within the five treatment regimens a significant reduction of 9.2 +/- 3.2 mm Hg in systolic BP at h 6 compared with h 2 occurred on the higher dose of alginic acid (1754 mg) combined with C12 (P = .02). The C12 peptide with the higher dose of alginic acid also showed a significant reduction of 6.0 +/- 2.0 mm Hg in diastolic BP at h 6 compared with h 2 (P = .015).. These preliminary data are encouraging and deserve testing in a larger and longer treatment trial.

Topics: Alginates; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Caseins; Complementary Therapies; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Glucuronic Acid; Hexuronic Acids; Humans; Hypertension; Male; Middle Aged; Prospective Studies

Essential hypertension is considered a serious health problem and diet can play an important role in its prevention and treatment. The aim of this study was to evaluate the effect of the long-term intake of a product based on milk casein hydrolysate on the development of hypertension in spontaneously hypertensive rats (SHR). A daily dose of 800 mg/kg body weight of the casein hydrolysate product was administered dissolved in drinking water during 6 weeks. Systolic and diastolic blood pressures were measured weekly by the tail-cuff method. Endothelial function in aorta and mesenteric segments, left ventricular hypertrophy, endothelial nitric oxide synthase (eNOS) expression in aorta and plasmatic angiotensin conversion enzyme (ACE) activity were also evaluated at the end of treatment. The development of hypertension was attenuated in the group treated with the casein hydrolysate product; in this sense the systolic blood pressure increased 33±3 mmHg in control group and only 18±5 mmHg in the treated group during the experimental period. In addition, the treatment improved aorta and mesenteric acetylcholine relaxations and increased the eNOS expression in aorta. Left ventricular hypertrophy decreased in treated SHR accompanied by a significant decrease in interstitial fibrosis. These results warrant evaluation in humans to determine if the product based on a casein hydrolysate could be used as a functional food ingredient to prevent blood pressure increased with additional cardiovascular benefits.

Topics: Animals; Antihypertensive Agents; Aorta; Blood Pressure; Caseins; Hypertension; Hypertrophy, Left Ventricular; Male; Milk; Nitric Oxide Synthase Type III; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR

In this study we evaluated the short-term oral antihypertensive effect of several peptide sequences isolated from casein fractions, previously characterized as in vitro angiotensin-converting enzyme-inhibitors, in spontaneously hypertensive rats (SHR). Systolic blood pressure (SBP) and the diastolic blood pressure (DBP) of the rats were measured by the tail cuff method before administration and also 2, 4, 6, 8 and 24 h post-administration. The sequences LVYPFTGPIPN, HLPLP, IAK, YAKPVA and WQVLPNAVPAK showed a clear decrease in SBP and DBP in SHR. HPHPHLSF caused a significant decrease of the DBP in the SHR, but this sequence did not modify the SBP of these animals in a significant manner. KKYNVPQL did not modify SBP in the SHR, and caused a slight, but significant and maintained, decrease in DBP in these animals. SBP and DBP returned to baseline values 24 h post-administration of all peptides. In conclusion, these peptides are bioactive ingredients with potential benefit in the prevention and treatment of hypertension or other associated disorders.

Topics: Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Caseins; Hypertension; Male; Oligopeptides; Peptide Fragments; Protein Isoforms; Rats; Rats, Inbred SHR; Time Factors