Olive‐derived bioactive combinations: synergistic angiotensin‐I‐converting enzyme ( ACE ) inhibition and distinct mechanisms of triterpenic acids and phenolics

BACKGROUND Cardiovascular diseases, largely driven by hypertension, remain the leading cause of mortality worldwide. Angiotensin‐I‐converting enzyme (ACE) inhibition is a well‐established therapeutic approach; however, synthetic inhibitors are frequently associated with adverse effects. Natural bioactive compounds, particularly those derived from olives, have been proposed as potential alternatives or complementary agents. RESULTS This study evaluated the ACE‐inhibitory potential of olive‐derived triterpenic acids (oleanolic acid (OA) and maslinic acid (MA)) and phenolic compounds (hydroxytyrosol (HT), 3,4‐dihydroxyphenylglycol (DHPG), verbascoside (VER), luteolin (LUT), and comselogoside (COM)). Among the individual compounds, OA (half‐maximal inhibitory concentration (IC 50 ) = 18.43 μmol L −1 ) and MA (IC 50 = 25.66 μmol L −1 ) exhibited the strongest ACE inhibition, acting through different mechanisms: OA as a competitive, MA as an uncompetitive, and COM as a non‐competitive inhibitor. Notably, certain binary combinations revealed notable interactions, particularly HT:COM, which displayed strong synergistic inhibition at concentrations where individual components were inactive. In contrast, combinations such as COM:MA and COM:LUT demonstrated additive or antagonistic effects depending on molar ratios and concentration. CONCLUSIONS These findings highlight the potential of individual olive‐derived compounds, especially OA and MA, as natural ACE inhibitors with distinct mechanisms of action. Moreover, specific synergistic interactions, such as HT:COM, represent promising candidates for the development of safer and more effective dietary interventions in hypertension management.