References

● Effect on blood pressure

1. Y. Nakamura et al.: Decrease of Tissue Angiotensin I-Converting Enzyme Activity upon Feeding Sour Milk in Spontaneously Hypertensive Rats, Biosci Biotech Biochem, 60, 448-489 (1996).

Abstract

Blood pressure increases were inhibited by feeding a diet containing sour milk fermented by a starter containing Lactobacillus helveticus and Saccharomyces cerevisiae to spontaneously hypertensive rats. In rats fed with the sour milk, the angiotensin I-converting enzyme activity of the aorta was significantly lower than that of rats fed with the control commercial diet.

2. Y. Nakamura et al.: Antihypertensive Effect of Sour Milk and Peptides Isolated from It That are Inhibitors to Angiotensin I-converting Enzyme, J Dairy Sci, 78, 1253-1257 (1995).

Abstract

This study reports the antihypertensive effect of orally administered doses of either Calpis sour milk or peptides (Val-Pro-Pro and Ile-Pro-Pro), which are inhibitors to angiotensin I-converting enzyme, isolated from the sour milk using strain SHR spontaneously hypertensive rats. Single oral administration of the sour milk (5 ml/kg of BW), corresponding inhibitory units of the peptides Val-Pro-Pro (.6 mg/kg of BW), or Ile-Pro-Pro (.3 mg/kg of BW) significantly decreased the systolic blood pressure from 6 to 8 h after administration. Blood pressure returned to the initial level at 24 h after administration. Antihypertensive activity of these two tripeptides was dose-dependent up to 5 mg/kg of BW. Conversely, the sour milk (25 ml/kg of BW) and mixed tripeptides (10 mg each of Val-Pro-Pro and Ile-Pro-Pro/kg of BW) did not change the systolic blood pressure of the normotensive strain WKY Wistar-Kyoto rats.

3.　Y. Nakamura et al.: Purification and Characterization of Angiotensin I-converting Enzyme Inhibitors from Sour Milk, J Dairy Sci, 78, 777-783 (1995).

Abstract

The inhibitory activity of angiotensin I-converting enzyme in milk increased during fermentation with the Calpis sour milk starter containing Lactobacillus helveticus and Saccharomyces cerevisiae. Two kinds of peptides inhibitory to angiotensin I-converting enzyme were purified from the sour milk by using four-step HPLC. The amino acid sequences of these inhibitors were identified as Val-Pro-Pro and Ile-Pro-Pro. The concentrations of peptides providing 50% inhibition of angiotensin I-converting enzyme were 9 and 5 microM, respectively. Most of the inhibitory activity in sour milk was attributed to these two peptides.

4. O. Masuda et al.: Antihypertensive Peptides Are Present in Aorta after Oral Administration of Sour Milk Containing These Peptides to Spontaneously Hypertensive Rats, J Nutr, 126, 3063-3068 (1996).

Abstract

Absorption of inhibitory peptides to angiotensin I-converting enzyme, L-valyl-L-prolyl-L-proline and L-isoleucyl-L-prolyl-L-proline, was studied in spontaneously hypertensive rats and normotensive Wistar-Kyoto rats after an oral administration of Calpis sour milk, which contains these peptides. Six hours after the administration of Calpis sour milk or saline to spontaneously hypertensive rats or normotensive Wistar-Kyoto rats, the blood pressure was measured and rats were killed. Abdominal aorta, lung, kidney, heart and brain were excised, homogenized and solubilized by detergent treatments. Angiotensin I-converting enzyme activity in the solubilized fractions from the abdominal aorta was significantly lower in spontaneously hypertensive rats given the sour milk than in the rats given saline. L-Valyl-L-prolyl-L-proline and L-isoleucyl-L-prolyl-L-proline were detected by HPLC in the heat-treated solubilized fraction from the abdominal aorta of spontaneously hypertensive rats given the sour milk. In contrast, the tripeptides were not detected in rats given saline, or in normotensive Wistar-Kyoto rats given the sour milk or saline. These data suggest that L-valyl-L-prolyl-L-proline and L-isoleucyl-L-prolyl-L-proline in the Calpis sour milk are absorbed directly without being decomposed by digestive enzymes, reach the abdominal aorta, inhibit the angiotensin I-converting enzyme, and show antihypertensive effects in spontaneously hypertensive rats.

5.　Y. Hata et al.: A placebo-controlled study of the effect of sour milk on blood pressure in hypertensive subjects, Am J Clin Nutr, 64, 767-771 (1996).

Abstract

A placebo-controlled study was conducted to test the effect of Calpis (Calpis Food Industry Co, Ltd, Tokyo, Japan) sour milk, i.e., a milk fermented with a starter containing Lactobacillus helveticus and Saccharomyces cerevisiae, on the blood pressure of 30 elderly hypertensive patients, most of whom were taking antihypertensive medication. Subjects were randomly assigned to two groups. One group ingested daily 95 mL of the sour milk for 8 wk, and the other group ingested the same amount of artificially acidified milk as a placebo for 8 wk. In the sour-milk group, systolic blood pressure decreased significantly 4 and 8 wk after ingestion, by 9.4 +/- 3.6 mm Hg (mean+/- SE, P < 0.05) and 14.1 +/- 3.1 mm Hg (P < 0.01), respectively. The diastolic blood pressure also decreased significantly, by 6.9 +/- 2.2 mm Hg (P < 0.01), by 8 wk after ingestion of the sour milk began. No significant changes in blood pressure were observed in the placebo group. The decrease in systolic and diastolic blood pressure in the sour-milk group tended to be greater than in the placebo group. No marked changes were observed in other indexes, including pulse rate, body weight, and blood serum variables in both groups.

6.　Y. Hirata et al.: Effect of new fermented milk drinks on subjects with mild hypertension or high-normal blood pressure: New drugs and clinical practice. 51, 60-69 (2002)

7.　Y. Nakamura et al.: Effects of liquid yogurts containing “Lactotripeptides (VPP, IPP)” on high-normal blood pressure. Japan Health and Nutrition Food Association, 7, 123-137 (2004)

8.　J. Sano et al.: Effect of Casein Hydrolysate, Prepared with Protease Derived from Aspergillus oryzae, on Subjects with High-Normal Blood Pressure or Mild Hypertension, J Med Food,8,423-430(2005)

Abstract

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.

9.　H. Itakura et al.: The effect of sour milk on blood pressure in untreated hypertensive and normotensive subjects. Journal of the Japan Society of Clinical Nutrition, 23, 26-31 (2001)

10.　O. Kajimoto et al.: Safety evaluation of tablets containing “Lactotripeptides (VPP, IPP)” on healthy volunteers. Japan Health and Nutrition Food Association, 4, 37-46 (2001)

● Effect on blood vessels

11.　S. Akagiri et al.: Effect of Lactobacillus helveticus CM4 fermented milk against arteriosclerosis in mice with ApoE deficiency. 39th Annual Scientific Meeting of the Japan Atherosclerosis Society (2007)

Abstract

[Details published]
[Objectives]
Milk fermented with Lactobacillus helveticus strain CM4 contains large quantities of tripeptides (VPP, IPP). VPP and IPP are casein-derived peptides that have an inhibitory effect on CE. Foods containing VPP and IPP have been proven in human trials to be effective in lowering blood pressure and improving vascular endothelial functions. The objective of this study was to confirm the anti-arteriosclerotic effects of long-term ingestion of CM4 fermented milk in mice.
[Method]
Tests were carried out on B6.129P2-Apoetm1Unc mice (ApoE K.O.), as model subjects with arteriosclerosis, and C57BL/6J mice, by way of a control group. Both groups of mice were given an unlimited amount of either control feed (CE-2), feed with unfermented milk, or feed with fermented milk, from the age of 6 to 31 weeks. After the test, biochemical examinations were carried out on blood samples and measurement of the intimal thickness and DNA microarray on aorta.
[Results]
Whereas there was no change in lipids in the plasma as a result of feed eaten by the ApoE K.O. mice, ingestion of feed with CM4 fermented milk had a significant effect on inhibiting intimal thickness in the aortic arch. Given that CM4 fermented milk exhibited anti-arteriosclerotic effects, differences between strains used in fermentation were then examined. The results confirmed that strains such as Lactobacillus helveticus strain CM4, which produces large quantities of VPP and IPP, are effective in inhibiting intimal thickness in the aortic arch. The results of an aortic DNA microarray also indicated suppression of gene expression in multiple cardiovascular-related genes.
[Conclusion]
Based on the above results, CM4 fermented milk was confirmed to have anti-arteriosclerotic effects, indicating that fermented milk containing large quantities of VPP and IPP has potential as a preventive foodstuff for arteriosclerosis.

12.　T. Hirota et al.: Milk casein-derived tripeptides, VPP and IPP induced NO production in cultured endothelial cells and endothelium-dependent relaxation of isolated aortic rings, Heart Vessels, 26(5), 549-556 (2011).

Abstract

Milk casein-derived tripeptides, valyl prolyl proline (VPP), and isoleucyl prolyl proline (IPP) inhibit angiotensin-converting enzyme (ACE) and both fermented milk and proteolytic hydrolysates of milk casein containing these peptides exert blood pressure-lowering effects in animals and humans. On the top of these results, we have recently reported that the hydrolysate of milk casein containing both VPP and IPP improved the vascular endothelial function of subjects with stage I hypertension, enforcing us to elucidate the mechanism of the improvement of endothelial dysfunction by these peptides. For this purpose, we examined the effect of VPP and IPP on induction of nitric oxide (NO) production using cultured vascular endothelial cells and isolated arterial vessels. When both VPP and IPP were added to the medium of cultured endothelial cells at final concentrations of more than 100 nmol/l, the NO(x) (NO(2) and NO(3)) concentration in the medium was significantly higher than that of the control. Moreover, both VPP and IPP induced endothelium-dependent relaxation of isolated aortic rings, and these effects were inhibited by NO synthase inhibitors, K channel inhibitors, and bradykinin B2 receptor antagonists. These lines of results suggested that both VPP and IPP induced production of vasodilative substances including NO.

13.　T. Nakamura et al.: Milk-derived peptides, Val-Pro-Pro and Ile-Pro-Pro, attenuate
atherosclerosis development in apolipoprotein E-deficient mice: a preliminary study.,J Med Food, 16 (5):396–403 (2013)

Abstract

Milk-derived peptides, Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP), have angiotensin I-converting enzyme inhibitory activities and blood pressure-lowering effects. We examined the effects of these peptides on the development of atherosclerosis in apolipoprotein E-deficient [apoE(-/-)] mice. For 31 weeks, six-week-old male apoE(-/-) mice received a diet that included one of the following: fermented milk containing both VPP and IPP; casein hydrolysate containing both of these peptides; synthesized VPP; synthesized IPP; enalapril; captopril; or control diet. At the end of feeding, blood biochemistry, aortic atherogenesis, and gene expression by DNA microarray analysis were evaluated. There were no significant changes in the plasma lipid levels and 8-isoprostane, a marker of oxidative stress. The area ratio of intima to media in the aortic arch was significantly lower in the fermented milk, casein hydrolysate, synthesized VPP, enalapril, and captopril groups than in the control group. As is common with diets containing VPP and/or IPP, we observed reductions in mRNA expression of inflammatory cytokines, such as interleukin (IL)-6 and IL-1β, oxidized low-density lipoprotein receptor, and transcription regulators. These results suggest that a continuous intake of VPP and IPP might be beneficial for preventing atherosclerosis caused by hypercholesterolemia.

14.　T. Hirota et al.: Casein Hydrolysate containing the Antihypertensive Tripeptides
Val-Pro-Pro and Ile-Pro-Pro Improves Vascular Endothelial Function Independent of blood Pressure- Lowering Effects:Contribution of the Inhibitory Action of
Angiotensin-Converting Enzyme, Hypertens Res, 30, 489-496 (2007).

Abstract

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.

15. K. Adachi et al.: Effects of dietary instructions and Lactotripeptides (LTP) on blood vessels. 29th Annual Meeting of the Japanese Society of Clinical Nutrition (2007)

Abstract

[Details published]
[Objectives]
To reduce the risk of arteriosclerosis, it is important to take care of your blood vessels. It has recently become possible to measure baPWV (pulse wave velocity) and assess a person’s “vascular age”. It has been widely reported that improving your diet or ingesting LTP helps to reduce blood pressure, but there have been few reports on vascular age. The objective of this study was therefore to confirm the effects of dietary instructions or LTP on vascular age, and to examine whether or not LTP has the potential to be used as a support or substitute to help improve people’s diet.
[Method]
Out of a group of 86 healthy women (with an average age of 45.4±4.7), 14 subjects whose vascular age was +1SD higher than the norm were selected to take part in this study. The subjects were divided into two groups, with eight given dietary instructions (Group A) and six given LTP (Group B). Their baPWV was then measured after zero, four and eight weeks, and their vascular age calculated. As subjects had a tendency to consume large quantities of meat and lower quantities of vegetables, soy and fish, Group A was given dietary advice with a particular emphasis on those four categories. Group B was asked to continue eating as normal and to consume one cultured milk drink containing 3.4mg of LTP every day.
[Results and observations]
At the start of the study, subjects in both groups had a vascular age approximately 20 years higher than their actual age. Whereas that had fallen by 6.4 years in Group A after four weeks of dietary instructions (P<0.01), there was no significant difference after eight weeks. In contrast, the vascular age in Group B had fallen by 3.0 years (P<0.05) after four weeks, and by 4.8 years (P<0.05) after eight weeks.
[Conclusion]
Although it is possible for dietary instructions to improve a person’s vascular age, instructions need to be more rigorous. Ingestion of LTP on the other hand was confirmed to improve a person’s vascular age even after eight weeks, indicating that LTP has potential as a support or substitute to improve people’s diet.

16.　T. Nakamura et al.: Beneficial Potential of Casein Hydrolysate Containing Val-Pro-Pro and Ile-Pro-Pro on Central Blood Pressure and Hemodynamic Index: A Preliminary Study, J Med Food, 12(6), 1221–6 (2009)

Abstract

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.

17.　M. Yoshizawa et al.: Additive beneficial effects of Lactotripeptides and aerobic exercise on arterial compliance in postmenopausal women. Am J Physiol Heart Circ Physiol, 297(5), H1899-903(2009).

Abstract

Central arterial compliance plays an important role in the functional abilities of the vasculature. Two active tripeptides, valine-proline-proline and isoleucine-proline-proline, were isolated from sour milk and were referred to as Lactotripeptides (LTP). Because LTP appears to act as an angiotensin-converting enzyme inhibitor, it is plausible to hypothesize that LTP improves arterial compliance. We determined the effects of LTP ingestion alone or in combination with regular aerobic exercise on arterial compliance. A total of 55 postmenopausal women (50-65 yr old) were randomly divided into four groups: placebo, LTP, exercise and placebo (Ex + placebo), or exercise and LTP (Ex + LTP). LTP or placebo was administered orally for 8 wk. The exercise groups completed an 8-wk moderate aerobic exercise intervention. There were no differences in baseline arterial compliance and most other key dependent variables among the groups. Carotid arterial compliance increased significantly in the LTP (0.93 + or - 0.07 vs. 0.99 + or - 0.08 mm(2)/mmHg x 10(-1)), Ex + placebo (0.92 + or - 0.04 vs. 1.00 + or - 0.05 mm(2)/mmHg x 10(-1)), and Ex + LTP groups (0.86 + or - 0.06 vs. 1.00 + or - 0.06 mm(2)/mmHg x 10(-1)), whereas no such changes were observed in the placebo control group (0.86 + or - 0.06 vs. 0.85 + or - 0.07 mm(2)/mmHg x 10(-1)). The magnitude of increases in carotid arterial compliance was significantly greater in the Ex + LTP group (19 + or - 4%) than in other groups. The improvements in arterial compliance with LTP were associated with the corresponding reductions in arterial blood pressure and plasma angiotensin II concentrations. We concluded that LTP ingestion improves carotid arterial compliance and that the combination of LTP ingestion and regular exercise is additive and synergistic in improving arterial compliance in postmenopausal women.

18.　M. Yoshizawa et al.: Additive beneficial effects of Lactotripeptides intake with regular exercise on endothelium-dependent dilatation in postmenopausal women., Am J Hypertens, 23(4).368-72. (2010).

Abstract

BACKGROUND:
Peripheral conduit artery endothelium-dependent dilatation decreases with aging in humans. Lactotripeptides (LTPs) and regular exercise can improve endothelium-dependent dilatation, but combining these lifestyle modifications may be more effective than either treatment alone. We conducted a randomized, place-controlled trial with four different intervention arms.
METHODS:
A total of 43 postmenopausal women (50-65 years old) were randomly divided into placebo, LTP, exercise and placebo (Ex+placebo), or exercise and LTP (Ex+LTP) groups. LTP or placebo was administered orally for 8 weeks. The exercise groups completed an 8-week moderate aerobic exercise (walking or cycling) intervention.
RESULTS:
There were no statistically significant differences in baseline flow-mediated dilatation (FMD) and most other key dependent variables among the groups. FMD significantly increased in the LTP, Ex+placebo, and Ex+LTP groups whereas no such changes were observed in the placebo control group. The magnitude of increases in FMD was significantly greater in the Ex+LTP group than other intervention groups.
CONCLUSION:
We concluded that LTP ingestion combined with regular aerobic exercise improves endothelium-dependent dilatation to a greater extent than monotherapy with either intervention alone in postmenopausal women.

19.　T. Nakamura et al.: Casein hydrolysate containing Val-Pro-Pro and Ile-Pro-Pro improves central blood pressure and arterial stiffness in hypertensive subjects: A randomized, double-blind, placebo-controlled trial. Atherosclerosis, 219, 298-303 (2011).

Abstract

OBJECTIVE:
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.
METHODS:
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.
RESULTS:
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.
CONCLUSION:
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.

20. C. Suzuki et al.: Effects of lactic casein-derived peptides Val-Pro-Pro and Ile-Pro-Pro on vascular endothelial functions and arterial stiffness in menopausal animal subjects. 46th Annual Scientific Meeting of the Japan Atherosclerosis Society (2014)

Abstract

[Details published]
[Background and objectives]
Lactic casein-derived peptides Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP) contain large quantities of Lactobacillus helveticus. In recent years, studies on hypertensive animal subjects have indicated that VPP and IPP have the potential to inhibit vascular dysfunction. It has also been established that, female hormones which reduce with age have the effect of reducing vascular functions. The objective of this study is therefore to evaluate the effect of VPP and IPP on vascular functions in menopausal animal subjects.
[Method]
Menopausal animal subjects, consisting of SD rats with their ovaries removed, were divided into three groups and given an unlimited amount of either tap water (OVX Group), VPP (VPP Group) or IPP (IPP Group). A control group was given an unlimited amount of tap water. After 24 weeks of being given samples, aortic pressure pulse waves were measured, using catheters fitted with pressure sensors, and pulse wave velocity (PWV) calculated. The thoracic aorta was also removed and acetylcholine-derived endothelial dependent vasodilation observed using the Magnus Method. After measuring pressure pulse waves, blood samples were taken from the abdominal aorta and measured for NOx concentration in the blood.
[Conclusion]
Compared to the control group, the OVX Group had significantly higher PWV and saw a significant drop in vasodilatory response. In the VPP Group and the IPP Group meanwhile, both PWV and vasodilatory response were markedly inhibited compared to the OVX Group. The concentration of NOx in the blood was significantly lower in the OVX Group compared to the control group. In the VPP Group and the IPP Group, concentrations were significantly inhibited compared to the OVX Group.
[Observations]
Results indicated that VPP and IPP have the potential to stimulate NO production, and to improve vascular endothelial functions and arterial stiffness in menopausal animal subjects.

21. H. Miyazaki et al.: Effects of lactic casein-derived peptides Val-Pro-Pro and Ile-Pro-Pro on vascular endothelial functions in animal subjects with type 1 diabetes. 47th Annual Scientific Meeting of the Japan Atherosclerosis Society (2015)