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.

This study aimed to determine the effects of a Lactobacillus helveticus-fermented milk drink containing lactononadecapeptide (NIPPLTQTPVVVPPFLQPE) on the cognitive function of healthy middle-aged adults. A randomised, double-blind controlled study was conducted in healthy participants who were randomly assigned to receive a L. helveticus-fermented milk drink (190 g/day) or the equivalent amount of a placebo drink once a day for eight weeks. Cognitive function was evaluated using the Japanese version of the repeatable battery for the assessment of neuropsychological status (RBANS) test. There was a statistically significant improvement in the total score, attention score, and delayed memory score of participants who received the L. helveticus-fermented milk drink. There was also a significant difference in the attention score between the placebo and test groups after eight weeks (p = .028). Therefore, supplementation of healthy middle-aged adults with a L. helveticus-fermented milk drink for eight weeks improved both attention and delayed memory.

These results suggest that Calpis sour milk whey may be useful for the prevention of neurodegenerative disorders, such as Alzheimer's disease, and enhancing learning and memory in healthy human subjects; however, human clinical studies are necessary.

Both studies were associated with methodological issues, including populations with different disease entities, small sample sizes, use of concomitant analgesics, and possible placebo effect that may have led to the failure to differentiate between tapentadol ER and placebo.

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