Inhibition of human and rat tissue kallikreins by peptide analog antagonists of bradykinin.

Three representative bradykinin receptor antagonists have been examined for their capacity to inhibit purified human and rat urinary kallikreins. In an amidolytic assay, the Ki values for the inhibition of human urinary kallikrein were 0.5, 0.3, and 2.5 microM for B4307 (DArg-Arg-Pro-Hyp-Gly-Thi-Ser-DPhe-Thi-Arg), B4308 (Lys-Lys-Arg-Hyp-Hyp-Gly-Thi-Ser-DPhe-Thi-Arg) and B3852 (Arg-Pro-Hyp-Gly-Phe-Ser-DPhe-Phe-Arg), respectively. B4308 and B3852 inhibited rat urinary kallikrein with Ki's of 1.0 and 5.5 microM, respectively. B4308 (0.4 to 1.6 microM) also inhibited the kininogenase activity of human urinary kallikrein on human low molecular weight kininogen in a dose-dependent fashion. These bradykinin receptor antagonists may inhibit the kallikrein-kinin system both by blocking the binding of kinins to B2 receptors and by inhibiting the cleavage of kinins from kininogens.