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High blood pressure-lowering and vasoprotective effects of milk products in experimental hypertension

  • Pauliina I. Ehlers (a1), Anne S. Kivimäki (a1), Anu M. Turpeinen (a2), Riitta Korpela (a1) and Heikki Vapaatalo (a1)...

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.

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*Corresponding author: Dr Pauliina I. Ehlers, fax +358 191 25364, email
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1 Pereira, M, Lunet, N, Azevedo, A, et al. (2009) Differences in prevalence, awareness, treatment and control of hypertension between developing and developed countries. J Hypertens 27, 963975.
2 Kearney, PM, Whelton, M, Reynolds, K, et al. (2005) Global burden of hypertension. Lancet 365, 217223.
3 Mensink, RP, Aro, A, Den Hond, E, et al. (2003) PASSCLAIM – diet-related cardiovascular disease. Eur J Nutr 42, Suppl. 1, 627.
4 Krousel-Wood, MA, Muntner, P, He, J, et al. (2004) Primary prevention of essential hypertension. Med Clin North Am 88, 223238.
5 Katan, MB, Grundy, SM, Jones, P, Stresa Workshop Participants, et al. (2003) Efficacy and safety of plant stanols and sterols in the management of blood cholesterol levels. Mayo Clin Proc 78, 965978.
6 AbuMweis, SS, Barake, R & Jones, PJH (2008) Plant sterols/stanols as cholesterol lowering agents: a meta-analysis of randomized controlled trials. Food Nutr Res 52 (epublication 18 August 2008).
7 Tapola, NS, Lyyra, ML, Karvonen, HM, et al. (2004) The effect of meat products enriched with plant sterols and minerals on serum lipids and blood pressure. Int J Food Sci Nutr 55, 389397.
8 Hallikainen, M, Lyyra-Laitinen, T, Laitinen, T, et al. (2006) Endothelial function in hypercholesterolemic subjects: effects of plant stanol and sterol esters. Atherosclerosis 188, 425432.
9 McCarron, DA, Morris, CD, Henry, HJ, et al. (1984) Blood pressure and nutrient intake in the United States. Science 224, 13921398.
10 Appel, LJ, Moore, TJ, Obarzanek, E, et al. (1997) A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. N Engl J Med 336, 11171124.
11 Toledo, E, Delgado-Rodríguez, M, Estruch, R, et al. (2009) Low-fat dairy products and blood pressure: follow-up of 2290 older persons at high cardiovascular risk participating in the PREDIMED study. Br J Nutr 101, 5967.
12 Korhonen, H (2009) Milk-derived bioactive peptides: from science to applications. J Functional Foods 1, 177187.
13 Pripp, AH (2008) Effect of peptides derived from food proteins on blood pressure: a meta-analysis of randomized controlled trials. Food Nutr Res 52 (epublication 18 January 2008).
14 Xu, JY, Qin, LQ, Wang, PY, et al. (2008) Effect of milk tripeptides on blood pressure: a meta-analysis of randomized controlled trials. Nutrition 24, 933940.
15 Nakamura, Y, Yamamoto, N, Sakai, K, et al. (1995) Antihypertensive effect of sour milk and peptides isolated from it that are inhibitors to angiotensin I-converting enzyme. J Dairy Sci 78, 12531257.
16 Sipola, M, Finckenberg, P, Korpela, R, et al. (2002) Effect of long-term intake of milk products on blood pressure in hypertensive rats. J Dairy Res 69, 103111.
17 Jäkälä, P, Pere, E, Lehtinen, R, et al. (2009) Cardiovascular activity of milk casein-derived tripeptides and plant sterols in spontaneously hypertensive rats. J Physiol Pharmacol 60, 1120.
18 Jäkälä, P, Hakala, A, Turpeinen, AM, et al. (2009) Casein-derived bioactive tripeptides Ile-Pro-Pro and Val-Pro-Pro attenuate the development of hypertension and improve endothelial function in salt-loaded Goto–Kakizaki rats. J Functional Foods 1, 366374.
19 Jauhiainen, T, Pilvi, T, Cheng, ZJ, et al. (2010) Milk products containing bioactive tripeptides have an antihypertensive effect in double transgenic rats (dTGR) harbouring human renin and human angiotensinogen genes. J Nutr Metab 2010, 287030.
20 Jauhiainen, T, Collin, M, Narva, M, et al. (2005) Effect of long-term intake of milk peptides and minerals on blood pressure and arterial function in spontaneously hypertensive rats. Milk Sci Int 60, 358362.
21 Jäkälä, P, Turpeinen, AM, Rajakari, K, et al. (2010) Biological effects of casein-derived tripeptide powders are not affected by fermentation process. Int Dairy J 20, 366370.
22 Masuda, O, Nakamura, Y & Takano, T (1996) Antihypertensive peptides are present in aorta after oral administration of sour milk containing these peptides to spontaneously hypertensive rats. J Nutr 126, 30633068.
23 Ghiadoni, L, Bruno, RM, Stea, F, et al. (2009) Central blood pressure, arterial stiffness, and wave reflection: new targets of treatment in essential hypertension. Curr Hypertens Rep 11, 190196.
24 Taddei, S, Virdis, A, Ghiadoni, L, et al. (2000) Endothelial dysfunction in hypertension. J Nephrol 23, 205210.
25 Mäkynen, H, Kähönen, M, Arvola, P, et al. (1995) Dietary calcium and magnesium supplements in spontaneously hypertensive rats and isolated arterial reactivity. Br J Pharmacol 115, 14551462.
26 Sipola, M, Finckenberg, P, Vapaatalo, H, et al. (2002) α-Lactorphin and β-lactorphin improve arterial function in spontaneously hypertensive rats. Life Sci 71, 12451253.
27 Bagnost, T, Berthelot, A, Bouhaddi, M, et al. (2008) Treatment with the arginase inhibitor Nω-hydroxy-nor-l-arginine improves vascular function and lowers blood pressure in adult spontaneously hypertensive rat. J Hypertens 26, 11101118.
28 Dal-Ros, S, Bronner, C, Schott, C, et al. (2009) Angiotensin II-induced hypertension is associated with a selective inhibition of endothelium-derived hyperpolarizing factor-mediated responses in the rat mesenteric artery. J Pharmacol Exp Ther 328, 478486.
29 Kane, MO, Etienne-Selloum, N, Madeira, SV, et al. (2010) Endothelium-derived contracting factors mediate the Ang II-induced endothelial dysfunction in the rat aorta: preventive effect of red wine polyphenols. Pflügers Arch 459, 671679.
30 Mervaala, EM, Cheng, ZJ, Tikkanen, I, et al. (2001) Endothelial dysfunction and xanthine oxidoreductase activity in rats with human renin and angiotensinogen genes. Hypertension 37, 414418.
31 Cheng, ZJ, Vaskonen, T, Tikkanen, I, et al. (2001) Endothelial dysfunction and salt-sensitive hypertension in spontaneously diabetic Goto–Kakizaki rats. Hypertension 37, 433439.
32 Jäkälä, P, Jauhiainen, T, Korpela, R, et al. (2009) Milk protein-derived bioactive tripeptides Ile-Pro-Pro and Val-Pro-Pro protect endothelial function in vitro in hypertensive rats. J Functional Foods 1, 266273.
33 Nakamura, Y, Yamamoto, N, Sakai, K, et al. (1995) Purification and characterization of angiotensin I-converting enzyme inhibitors from sour milk. J Dairy Sci 78, 777783.
34 Lehtinen, R, Jauhiainen, T, Kankuri, E, et al. (2010) Effects of milk casein-derived tripeptides Ile-Pro-Pro, Val-Pro-Pro and Leu-Pro-Pro on enzymes processing vasoactive precursors in vitro. Arzneim Forsch/DrugRes 60, 182185.
35 Jauhiainen, T, Vapaatalo, H, Poussa, T, et al. (2005) Lactobacillus helveticus fermented milk lowers blood pressure in hypertensive subjects in 24-h ambulatory blood pressure measurement. Am J Hypertens 18, 16001605.
36 Engberink, MF, Schouten, EG, Kok, FJ, et al. (2008) Lactotripeptides show no effect on human blood pressure. Results from a double-blind randomized controlled trial. Hypertension 51, 399405.
37 Usinger, L, Ibsen, H, Linneberg, A, et al. (2010) Human in vivo study of the renin–angiotensin–aldosterone system and the sympathetic activity after 8 weeks daily intake of fermented milk. Clin Physiol Funct Imaging 30, 162168.
38 Grundy, SM, Cleeman, JI, Merz, CN, et al. (2004) Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol 44, 720732.
39 Laakso, P (2005) Analysis of sterols from various food matrices. Eur J Lipid Sci Technol 107, 402410.
40 Ovaska, K, Laakso, M, Haapa-Paananen, S, et al. (2010) Large-scale data integration framework provides a comprehensive view on glioblastoma multiforme. Genome Med 2, 65.
41 Irizarry, RA, Bolstad, BM, Collin, F, et al. (2003) Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res 31, e15.
42 Benjamini, Y & Hochberg, Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc B 57, 289300.
43 Tarca, AL, Draghici, S, Khatri, P, et al. (2009) A novel signaling pathway analysis impact analysis. Bioinformatics 25, 7582.
44 Kanehisa, M, Goto, S, Furumichi, M, et al. (2010) KEGG for representation and analysis of molecular networks involving diseases and drugs. Nucleic Acids Res 38, D355D360.
45 Nakamura, Y, Masuda, O & Takano, T (1996) Decrease of tissue angiotensin I-converting enzyme activity upon feeding sour milk in spontaneously hypertensive rats. Biosci Biotech Biochem 60, 488489.
46 Chen, Q, Gruber, H, Swist, E, et al. (2009) Influence of dietary phytosterols and phytostanols on diastolic blood pressure and the expression of blood pressure regulatory genes in SHRSP and WKY inbred rats. Br J Nutr 102, 93101.
47 Hilary Green, J, Richards, JK & Bunning, RL (2000) Blood pressure responses to high-calcium skim milk and potassium-enriched high-calcium skim milk. J Hypertens 18, 13311339.
48 Buonopane, GJ, Kilara, A, Smith, JS, et al. (1992) Effect of skim milk supplementation on blood cholesterol concentration, blood pressure, and triglycerides in a free-living human population. J Am Coll Nutr 11, 5667.
49 Van Beresteijn, EC, Van Schaik, M & Schaafsma, G (1990) Milk: does it affect blood pressure? A controlled intervention study. J Intern Med 228, 477482.
50 Nurminen, ML, Sipola, M, Kaarto, H, et al. (2000) α-Lactorphin lowers blood pressure measured by radiotelemetry in normotensive and spontaneously hypertensive rats. Life Sci 66, 15351543.
51 Miguel, M, Recio, I, Ramos, M, et al. (2006) Antihypertensive effect of peptides obtained from Enterococcus faecalis-fermented milk in rats. J Dairy Sci 89, 33523359.
52 Miguel, M, Gómez-Ruiz, , Recio, I, et al. (2010) Changes in arterial blood pressure after single oral administration of milk-casein-derived peptides in spontaneously hypertensive rats. Mol Nutr Food Res 54, 14221427.
53 Costa, EL, Almeida, AR, Netto, FM, et al. (2005) Effect of intraperitoneally administered hydrolyzed whey protein on blood pressure and renal sodium handling in awake spontaneously hypertensive rats. Braz J Med Biol Res 38, 18171824.
54 Geerlings, A, Villar, IC, Hidalgo Zarco, F, et al. (2006) Identification and characterization of novel angiotensin-converting enzyme inhibitors obtained from goat milk. J Dairy Sci 89, 33263335.
55 Miguel, M, Muguerza, B, Sánchez, E, et al. (2005) Changes in arterial blood pressure in hypertensive rats caused by long-term intake of milk fermented by Enterococcus faecalis CECT 5728. Br J Nutr 94, 3643.
56 Pörsti, I, Arvola, P, Wuorela, H, et al. (1992) High calcium diet augments vascular potassium relaxation in hypertensive rats. Hypertension 19, 8592.
57 Tolvanen, JP, Mäkynen, H, Wu, X, et al. (1998) Effects of calcium and potassium supplements on arterial tone in vitro in spontaneously hypertensive rats. Br J Pharmacol 124, 119128.
58 Bernatova, I, Conde, MV, Kopincova, J, et al. (2009) Endothelial dysfunction in spontaneously hypertensive rats: focus on methodological aspects. J Hypertens 27, Suppl. 6, S27S31.
59 Onaka, U, Fujii, K, Abe, I, et al. (1998) Antihypertensive treatment improves endothelium-dependent hyperpolarization in the mesenteric artery of spontaneously hypertensive rats. Circulation 98, 175182.
60 Büssemaker, E, Popp, R, Fissthaler, B, et al. (2003) Aged spontaneously hypertensive rats exhibit a selective loss of EDHF-mediated relaxation in the renal artery. Hypertension 42, 562568.
61 Michel, FS, Man, GS, Man, RY, et al. (2008) Hypertension and the absence of EDHF-mediated responses favour endothelium-dependent contractions in renal arteries of the rat. Br J Pharmacol 155, 217226.
62 Goto, K, Fujii, K, Kansui, Y, et al. (2004) Changes in endothelium-derived hyperpolarizing factor in hypertension and ageing: response to chronic treatment with renin–angiotensin system inhibitors. Clin Exp Pharmacol Physiol 31, 650655.
63 Chandan, RC (2006) Milk composition, physical and processing characteristics. In Manufacturing Yogurt and Fermented Milks, pp. 1740 [Chandan, RC, editor]. Oxford: Blackwell Publishing.
64 Arvola, P, Pörsti, I, Vuorinen, P, et al. (1992) l-Cysteine augments the vasorelaxation induced by sodium nitrite and SIN-1 but not that due to acetylcholine. Eur J Pharmacol 214, 289292.
65 Wang, EQ, Lee, WI, Brazeau, D, et al. (2002) cDNA microarray analysis of vascular gene expression after nitric oxide donor infusions in rats: implications for nitrate tolerance mechanisms. AAPS Pharm Sci 4, E10.
66 Abd Alla, J, Langer, A, Elzahwy, SS, et al. (2010) Angiotensin-converting enzyme inhibition down-regulates the pro-atherogenic chemokine receptor 9 (CCR9)–chemokine ligand 25 (CCL25) axis. J Biol Chem 285, 2349623505.
67 Linz, W, Jessen, T, Becker, RH, et al. (1997) Long-term ACE inhibition doubles lifespan of hypertensive rats. Circulation 96, 31643172.
68 Miguel-Carrasco, JL, Zambrano, S, Blanca, AJ, et al. (2010) Captopril reduces cardiac inflammatory markers in spontaneously hypertensive rats by inactivation of NF-κB. J Inflamm (Lond) 7, 21.
69 Yamaguchi, N, Kawaguchi, K & Yamamoto, N (2009) Study of the mechanism of antihypertensive peptides VPP and IPP in spontaneously hypertensive rats by DNA microarray analysis. Eur J Pharmacol 620, 7177.
70 Rodriguez-Rodriguez, R, Herrera, MD, de Sotomayor, MA, et al. (2007) Pomace olive oil improves endothelial function in spontaneously hypertensive rats by increasing endothelial nitric oxide synthase expression. Am J Hypertens 20, 728734.
71 Li, H, Witte, K, August, M, et al. (2006) Reversal of endothelial nitric oxide synthase uncoupling and up-regulation of endothelial nitric oxide synthase expression lowers blood pressure in hypertensive rats. J Am Coll Cardiol 47, 25362544.
72 Rush, JW, Quadrilatero, J, Levy, AS, et al. (2007) Chronic resveratrol enhances endothelium-dependent relaxation but does not alter eNOS levels in aorta of spontaneously hypertensive rats. Exp Biol Med (Maywood) 232, 814822.
73 Okuda, T, Sumiya, T, Iwai, N, et al. (2002) Difference of gene expression profiles in spontaneous hypertensive rats and Wistar–Kyoto rats from two sources. Biochem Biophys Res Commun 296, 537543.
74 Marchesi, C, Paradis, P & Schiffrin, EL (2008) Role of the renin–angiotensin system in vascular inflammation. Trends Pharmacol Sci 29, 367374.
75 Jauhiainen, T, Wuolle, K, Vapaatalo, H, et al. (2007) Oral absorption, tissue distribution and excretion of a radiolabelled analog of a milk-derived antihypertensive peptide, Ile-Pro-Pro, in rats. Int Dairy J 17, 12161223.
76 Foltz, M, Meynen, EE, Bianco, V, et al. (2007) Angiotensin-converting enzyme inhibitory peptides from a lactotripeptide-enriched milk beverage are absorbed intact into the circulation. J Nutr 137, 953958.
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