title: Effects of milk casein-derived tripeptides Ile-Pro-Pro, Val-Pro-Pro, and Leu-Pro-Pro on enzymes processing vasoactive precursors in vitro.
abstract: Milk-based drinks containing casein-derived tripeptides isoleucine-proline-proline (Ile-Pro-Pro) and valine-proline-proline (Val-Pro-Pro) have been shown to possess antihypertensive and vascular endothelium-protecting properties in hypertensive animal models. Furthermore in clinical intervention trials they reduce blood pressure and arterial stiffness. The exact mechanisms are not known, but inhibition of angiotensin converting enzyme 1 (ACE1) has been suggested mainly to mediate these beneficial effects. The present study investigated the in vitro effects of three tripeptides: Ile-Pro-Pro, Val-Pro-Pro and leqcine-proline-proline (Leu-Pro-Pro) on four renin-angiotensin system enzymes: ACE1, ACE2, chymase, and cathepsin G. Also their effects on arginase I, a critical enzyme in L-arginine-nitric oxide pathway, were studied. It was shown, apparently for the first time, that the inhibitory effects of Ile-Pro-Pro, Val-Pro-Pro and Leu-Pro-Pro on ACE1 at micromolar concentrations are competitive in nature. Therefore the efficacy of inhibition is largely dependent on the amount of substrate present. Inhibition of ACE2 and arginase I was reached only at concentrations three orders of magnitude greater. No inhibition of chymase and cathepsin G was observed by the tripeptides. The findings support the hypothesis that Ile-Pro-Pro, Val-Pro-Pro and Leu-Pro-Pro act favourably on blood pressure mainly by selective inhibition of ACE1.
authors.affiliation: Institute of Biomedicine, Pharmacology, University of Helsinki, Finland.
authors.forename: Risto
authors.initials: R
authors.lastname: Lehtinen
authors.forename: Tiina
authors.initials: T
authors.lastname: Jauhiainen
authors.forename: Esko
authors.initials: E
authors.lastname: Kankuri
authors.forename: Ken
authors.initials: K
authors.lastname: Lindstedt
authors.forename: Petri T
authors.initials: PT
authors.lastname: Kovanen
authors.forename: Outi
authors.initials: O
authors.lastname: Kerojoki
authors.forename: Riitta
authors.initials: R
authors.lastname: Korpela
authors.forename: Heikki
authors.initials: H
authors.lastname: Vapaatalo
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001119:Arginase / Q000037:antagonists & inhibitors / Q000378:metabolism; D002364:Caseins / Q000494:pharmacology*; D056649:Cathepsin G / Q000037:antagonists & inhibitors / Q000378:metabolism; D053818:Chymases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004798:Enzymes / Q000378:metabolism*; D006801:Humans; D009842:Oligopeptides / Q000494:pharmacology*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D002364:Caseins; D004798:Enzymes; D009842:Oligopeptides; C489032:isoleucyl-prolyl-proline; C535179:leucyl-prolyl-proline; C489031:valyl-prolyl-proline; D007703:Peptidyl-Dipeptidase A; D056649:Cathepsin G; D053818:Chymases; D001119:Arginase