Novel peptides with antihypertensive effects in SHR rats have previously been identified in lactoferrin (LP) hydrolysates. To investigate their in vivo antihypertensive mechanism, we have assessed the blood pressure lowering effects of two of these LF-derived peptides (RPYL and DPYKLRP) in Wistar rats subjected to either angiotensin I- or angiotensin II-induced hypertension. Blood pressure was measured by the tail-cuff method, hypertension was induced by subcutaneous infusion of angiotensins, and then captopril, valsartan or LF-derived peptides orally administered. Angiotensin I- and angiotensin II-induced hypertension were reversed by captopril and valsartan, respectively. RPYL and DPYKLRP reversed angiotensin I-induced hypertension, while DPYKLRP but not RPYL produced a modest reversion of angiotensin II-elicited hypertension. Neither RPYL nor DPYKLRP modified normotension. Thus, in vivo ACE inhibition is involved in the antihypertensive effects of LF-derived peptides like RPYL and DPYKLRP, while inhibition of AT(1) receptor-mediated vasoconstriction plays a less relevant role. (C) 2015 Elsevier Ltd. All rights reserved.