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Inhibitory Efficacy and Biological Variability of Tryptophan Containing Dipeptides on Human Plasma Angiotensin Converting Enzyme Activity

Abstract

Sherif Khedr, Melanie Martin and Andreas Deussen

Background: Hypertension remains a major unsolved health problem with life threatening consequences. A potential innovative prophylactic approach against its development may be supplementation of daily food with natural antihypertensive compounds. In our work we tested the efficacy of novel tryptophan containing dipeptides from whey protein with respect to their inhibitory potency on the angiotensin converting enzyme (ACE) as well as their stability in human plasma. Methods: ACE activity from rabbit lung and human plasma as well as recombinant human ACE activity were measured using benzoyl-glycyl-histidyl-leucine as a substrate. Product formation of hippuric acid and histidyl-leucine was assessed by UV-HPLC. The stability of the peptides was quantified in human plasma and, in case of incubation with recombinant human angiotensin converting enzyme, in buffer. Variability of ACE inhibiting activity of peptides was assessed via analysis of coefficient of variation with particular reference to true inter-individual variability corrected for methodological and analytical errors. Results: Isoleucine-tryptophan (IW) had a stronger ACE inhibiting potency (IC50 of 1.9 and 38.8 μmol/l with rabbit lung and human plasma ACE, respectively) than other tested peptides, i.e. glutamic acid-tryptophan (EW), tryptophanleucine (WL) and tryptophan-glutamic acid (WE). However, stability of IW showed a high degree of variability in plasma of different volunteers. In contrast EW, WL, WE were relatively stable in plasma and no major inter-individual variability was observed. Inhibition of plasma proteases extended plasma half-life of IW significantly. ACE did not contribute to peptide elimination. Conclusion: Milk whey protein represents a valuable source for bioactive peptides with ACE inhibitory potency that can be used as a food supplement to prevent, or in combination with other pharmaceutical agents to treat hypertension. However, in addition to the ACE inhibitory efficacy the stability of these peptides must be considered for in vivo ACE inhibition.