Synthesis and properties of new bradykinin potentiating peptides

Abstract

In a study of the relationship between structure and activity of bradykinin potentiating peptides (BPP), six analogs and homologs of peptides occurring in the venoms of Bothrops jararaca and Agkistrodon halys blomhoffii were synthesized and assayed in the isolated guinea pig ileum and rat uterus. None of the peptides had bradykinin-like activity and their bradykinin potentiating activity was much greater in the guinea pig ileum than in the uterus. The following observations were made with the guinea pig ileum. The introduction of Gln as the eigth residue in potentiator B (pGlu-Gly-Leu-Pro-Pro-Arg-Pro-Lys-Ile-Pro-Pro) and potentiator C (pGlu-Gly-Leu-Pro-Pro-Gly-Pro-Pro-Ile-Pro-Pro) produced a small increase in their bradykinin potentiating activity. Removal of the two N-terminal residues of [Gln8]-potentiator B and [Gln8]-potentiator C led to alterations in activity that paralleled those described earlier for the parent compounds (potentiators B and C). The peptide with the sequence pGlu-Trp-Pro-Ary-Pro-Lys-Trp-Ala-Pro was seven times as active as BPP5a, while the most potent natural BPP, a nonapeptide from B. jararaca venom, is reported to be only four times as active as BPP5a. An analog of the above-mentioned nonapeptide containing Pro8 instead of Ala8 was only as active as BPPa. For all of the peptides, as well as for potentiatrs B and C and BPP5a, the concentration vs. potentiating activity curves had similar shapes, with a plateau at twofold potentiation and a maximum potentiation of 10- to 11-fold. A direct action on the bradykinin receptors may be responsible for the effects observed at lower BPP concentration while the effects at higher concentrations may be due to kininase inhibition. The potentiating activities of potentiator B and its Gln8 analog persisted after the peptides were removed from the medium. This "sensitizing activity" was not observed with any of the other peptides.