phytosterols and valyl-prolyl-proline

Casein-derived tripeptides isoleucine-proline-proline (Ile-Pro-Pro) and valine-proline-proline (Val-Pro-Pro) lower blood pressure (BP) in long-term clinical studies. Their acute effects on BP and vascular function, important for daily dosing scheme, were studied in a placebo-controlled double-blind crossover study using a single oral dose of a fermented milk product containing Ile-Pro-Pro and Val-Pro-Pro as well as plant sterols. Twenty-five subjects with untreated mild hypertension received in random order 250 g of study product (25 mg peptides and 2 g plant sterols) or placebo. Ambulatory BP was monitored for 8 h post-dose and arterial stiffness measured by pulse wave analysis at 2, 4, and 8 h. Blood and urine samples were analyzed for markers of the renin-angiotensin system (RAS) and endothelial function. Baseline adjusted treatment effect for systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial BP was -2.1 mmHg (95% CI: -4.1 to -0.1, p = 0.045), -1.6 mmHg (95% CI: -3.1 to -0.1, p = 0.03), and -1,9 mmHg (95% CI: -3-3 to -0.4, p = 0.0093), respectively, in favor of the active treatment for 8 h post- dose. No significant differences between the treatments were seen in brachial or aortic augmentation index, pulse wave velocity, or markers of RAS. Urinary excretion of cGMP, the second messenger of endothelial nitric oxide, was higher in the active group vs. placebo (p = 0.01). The results indicate that a single dose of a fermented milk product containing Ile-Pro-Pro and Val-Pro-Pro and plant sterols acutely lowers brachial SBP and DBP in mildly hypertensive subjects.

Topics: Administration, Oral; Animals; Antihypertensive Agents; Blood Pressure; Cross-Over Studies; Cultured Milk Products; Cyclic GMP; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Oligopeptides; Phytosterols; Renin-Angiotensin System; Treatment Outcome

Milk casein-derived angiotensin-converting enzyme (ACE)-inhibitory tripeptides isoleucine-proline-proline (Ile-Pro-Pro) and valine-proline-proline (Val-Pro-Pro) have been shown to have antihypertensive effects in human subjects and to attenuate the development of hypertension in experimental models. The aim of the present study was to investigate the effect of a fermented milk product containing Ile-Pro-Pro and Val-Pro-Pro and plant sterols on already established hypertension, endothelial dysfunction and aortic gene expression. Male spontaneously hypertensive rats (SHR) with baseline systolic blood pressure (SBP) of 195 mmHg were given either active milk (tripeptides and plant sterols), milk or water ad libitum for 6 weeks. SBP was measured weekly by the tail-cuff method. The endothelial function of mesenteric arteries was investigated at the end of the study. Aortas were collected for DNA microarray study (Affymetrix Rat Gene 1.0 ST Array). The main finding was that active milk decreased SBP by 16 mmHg compared with water (178 (SEM 3) v. 195 (SEM 3) mmHg; P < 0.001). Milk also had an antihypertensive effect. Active milk improved mesenteric artery endothelial dysfunction by NO-dependent and endothelium-derived hyperpolarising factor-dependent mechanisms. Treatment with active milk caused mild changes in aortic gene expression; twenty-seven genes were up-regulated and eighty-two down-regulated. Using the criteria for fold change (fc) < 0.833 or > 1.2 and P < 0.05, the most affected (down-regulated) signalling pathways were hedgehog, chemokine and leucocyte transendothelial migration pathways. ACE expression was also slightly decreased (fc 0.86; P = 0.047). In conclusion, long-term treatment with fermented milk enriched with tripeptides and plant sterols decreases SBP, improves endothelial dysfunction and affects signalling pathways related to inflammatory responses in SHR.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Caseins; Cultured Milk Products; Endothelium, Vascular; Gene Expression; Hypertension; Male; Nitric Oxide; Oligonucleotide Array Sequence Analysis; Oligopeptides; Peptidyl-Dipeptidase A; Phytosterols; Phytotherapy; Plant Extracts; Rats; Rats, Inbred Strains; Signal Transduction

The effect of chronic treatment with fermented milk products containing bioactive tripeptides and plant sterols on blood pressure and vascular function was investigated in spontaneously hypertensive rats (SHR). Six-weeks old male SHR (n=36) were randomized into 4 groups by body weight and blood pressure to receive either Lactobacillus helveticus fermented standard milk product (containing tripeptides Ile-Pro-Pro, Val-Pro-Pro and Leu-Pro-Pro), test product with enzymatically produced tripeptides without or with plant sterols or control product without the active constituents for 8 weeks. Systolic blood pressure (SBP) was measured weekly using the tail-cuff method. Thoracic aorta and mesenteric artery were excised for vascular response measurements. At the end, SBP values vs. control product group were: standard product group -14 mmHg (P<0.05), test product group -12 mmHg and test product +sterols group -7 mmHg. The average daily tripeptide dose was 2.8-5.2 mg/kg. Total serum cholesterol in the test product +sterols group tended to be lower than in the test product group (P=0.10) whereas serum plant sterol (campesterol, sitosterol) concentrations were higher (P<0.001). In conclusion, bioactive tripeptide-containing milk products attenuated the blood pressure development in SHR. The plant sterols did not improve this effect. Vascular responses did not markedly differ between the groups, except that endothelium-derived hyperpolarizing factor (EDHF) -related aortic relaxation was demonstrated in the test product +sterols group.

Topics: Acetylcholinesterase; Animals; Antihypertensive Agents; Arteries; Blood Pressure; Caseins; Cholesterol; Cultured Milk Products; Hypertension; Lactobacillus helveticus; Male; Oligopeptides; Phytosterols; Random Allocation; Rats; Rats, Inbred SHR; Time Factors