Oral absorption, tissue distribution and excretion of a radiolabelled analog of a milk-derived antihypertensive peptide, Ile-Pro-Pro, in rats

Jauhiainen, T.; Wuolle, K.; Vapaatalo, Heikki; Kerojoki, Outi; Nurmela, Kari; Lowrie, Chris; Korpela, Riitta

doi:10.1016/j.idairyj.2007.02.004

Cited by 34 publications

(24 citation statements)

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“…As was observed in a kinetic study with normotensive Sprague -Dawley rats (75) , tripeptides seem to accumulate in tissues (for example, aorta, kidney). Therefore, it has been Mean value was significantly different from that of the group that received water: *P,0·05, **P,0·01.…”

Section: Discussionsupporting

confidence: 59%

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

et al. 2011

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Milk casein-derived angiotensin-converting enzyme (ACE)-inhibitory tripeptides isoleucine-proline-proline (Ile-Pro-Pro) and valineproline-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 NOdependent 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; P¼ 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.Key words: Milk-derived bioactive peptides: Experimental hypertension: Spontaneously hypertensive rats: Plant sterols: Endothelial function Hypertension is one of the most important risk factors for CHD, heart failure, cerebrovascular disease and chronic kidney disease. The prevalence of hypertension is increasing worldwide, both in developed and developing countries (1) . Up to 30 % of the world's adult population was estimated to have hypertension in 2000 (2) . Any reductions in blood pressure, however small, are meaningful; a systolic blood pressure (SBP) reduction of 9 mmHg and a diastolic blood pressure reduction of 5 mmHg reduce the risk of stroke by [35][36][37][38][39][40] .Besides pharmacological therapy, lifestyle and nutritional factors play a significant role in the prevention and treatment of hypertension and related disorders. Low saturated fat and Na intake and increased consumption of K, Ca and soluble fibre positively affect blood pressure (4) . Plant sterols and stanols (also called as phytosterols and -stanols) have wellestablished cholesterol-lowering effects. The consumption of 2 g plant sterols per d has been shown to lowe...

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Section: Discussionsupporting

confidence: 59%

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

et al. 2011

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“…Some oral bioavailability was indicated when IPP was delivered in a yogurt matrix, showing 2.1-fold increase compared to placebo control in a small randomised human cohort (39), but overall delivery was still very low. Others showed that after oral administration of a [ 14 C]-IPP analogue to rats, peak plasma radioactivity (albeit low level) was seen after 2 h, indicating some absorption across the intestine (40).…”

Section: Discussionmentioning

confidence: 99%

Stability, toxicity and intestinal permeation enhancement of two food-derived antihypertensive tripeptides, Ile-Pro-Pro and Leu-Lys-Pro

et al. 2015

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Publication information Peptides, 71 : 1-7Publisher Elsevier Item record/more information http://hdl.handle.net/10197/8723 Publisher's statementThis is the author's version of a work that was accepted for publication in Peptides. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Peptides (VOL 71, ISSUE 2015, (2015 colonic mucosae were low, but were significantly increased in each tissue type by the medium chain fatty acids (MCFA) permeation enhancers, sodium caprate (C 10 ) and the sodium salt of 10-undecylenic acid (uC 11 ). IPP and LKP were therefore stable against intestinal and liver peptidases and were non-cytotoxic; their P app values across rat intestinal mucosae were low, but could be increased by MCFA. There is potential to make on oral dosage form once in vivo pharmacology is confirmed.

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“…Milk-derived peptides improve vascular response in vitro probably through stimulation of endothelial nitric oxide (NO) release (Sipola et al, 2002b). It has been shown in experimental and clinical trials that the tripeptides Ile-Pro-Pro and Val-Pro-Pro can be absorbed at least partly from the intestine (Foltz et al, 2007;Jauhiainen et al, 2007b). Blood pressure-lowering effects of milk products containing Ile-Pro-Pro and Val-Pro-Pro tripeptides have been shown in several clinical trials (Seppo et al, 2003;Jauhiainen et al, 2005) and a meta-analysis of 12 randomized controlled trials found that the ingestion of tripeptides Ile-Pro-Pro and Val-Pro-Pro for 4-21 weeks decreases systolic blood pressure by 4.8 mm Hg and diastolic blood pressure by 2.2 mm Hg (Xu et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Long-term intervention with Lactobacillus helveticus fermented milk reduces augmentation index in hypertensive subjects

et al. 2010

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Background: The milk casein-derived biologically active tripeptides, isoleucyl-prolyl-proline (Ile-Pro-Pro) and valyl-prolyl-proline (Val-Pro-Pro), have documented antihypertensive effect probably related to reduced angiotensin formation. It has been suggested that these tripeptides may reduce arterial stiffness and improve endothelial function. Our aim was to evaluate whether the milk-based drink containing Ile-Pro-Pro and Val-Pro-Pro influence arterial stiffness, measured as augmentation index (AIx), and endothelial function in man. Methods: In a double-blind parallel group intervention study, 89 hypertensive subjects received daily peptide milk containing a low dose of tripeptides (5 mg/day) for 12 weeks and a high dose (50 mg/day) for the following 12 weeks, or a placebo milk drink to titrate the dose-response effect. Arterial stiffness was assessed by pulse wave analysis at the beginning and end of each intervention period. Endothelial function was tested by examining pulse wave reflection response to sublingual nitroglycerin and salbutamol inhalation. Blood pressure was measured by using office and 24-h ambulatory blood pressure measurement. Results: At the end of the second intervention period, AIx decreased significantly in the peptide group compared with the placebo group (peptide group À1.53% (95% confidence interval (CI) À2.95 to À0.12), placebo group 1.20% (95% CI 0.09-2.32), P ¼ 0 Á 013). No change in endothelial function index was observed (peptide group 0.02 (95% CI À0.06 to 0.08), placebo group 0.04 (95% CI À0.04 to 0.12), P ¼ 0.85). There were no statistically significant differences between the effects of the peptide and placebo treatment on office and 24-h ambulatory blood pressure. Conclusions: Long-term treatment with Lactobacillus helveticus-fermented milk containing bioactive peptides reduces arterial stiffness expressed as AIx in hypertensive subjects.

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Oral absorption, tissue distribution and excretion of a radiolabelled analog of a milk-derived antihypertensive peptide, Ile-Pro-Pro, in rats

Cited by 34 publications

References 15 publications

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

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

Stability, toxicity and intestinal permeation enhancement of two food-derived antihypertensive tripeptides, Ile-Pro-Pro and Leu-Lys-Pro

Long-term intervention with Lactobacillus helveticus fermented milk reduces augmentation index in hypertensive subjects

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