The degradation of bradykinin (BK) and of des-Arg9-BK in plasma

Abstract

The metabolism of bradykinin (BK), des-Arg9-BK and 2 analogs of the latter was studied in human, rat and rabbit plasma, using bioassays and high pressure liquid chromatography (HPLC) for measuring the concentrations and characterizing the types of metabolites. A solution of BK containing 100 .mu.g/ml was added to 20% (vol/vol) l plasma and incubated for up to 75 min at 37.degree. C. The concentration of BK, measured by the rabbit isolated jugular vein assay, decreased progressively; that of the fragment des-Arg9-BK, measured on the rabbit mesenteric vein, increased. A carboxypeptidase apparently is present in the plasma of the 3 spp. and transforms BK into des-Arg9-BK. Solutions of BK (3 mg/ml) containing 20% human plasma were incubated for 1 - 18 h and then analyzed by HPLC to identify the metaboli fragments resulting from the action of peptidases in human plasma. des-Arg9-BK is the principal metabolite and the 1st fragment to appear; this compound is further transformed into des-(Phe8, Arg9)-BK. No other fragments were present in significant amounts. The addition of Captopril (100 ng/ml), an inhibitor of the converting enzyme, did not change the pattern of appearance or the quantities of metabolites. The degradation of synthetic des-Arg9-BK was measured by bioassay after incubation with the plasma of the 3 spp. The fragment is inactivated, although more slowly than BK, and is presumably transformed into des-(Phe8, Arg9)-BK by the action of a carboxypeptidase. The 2 analogs, [phe-OMe8]-des-Arg9-BK and [D-Phe8]-des-Arg9-BK, are more resistant to degradation than des-Arg9-BK. As des-Arg9-BK is a strong stimulant of the B1 receptor for kinins, the generation and degradation of des-Arg9-BK is discussed in view of a possible involvement of this receptor in pathological states.