PHARMACOLOGICAL CHARACTERIZATION OF NOVEL TISSUE KALLIKREIN INHIBITORS IN-VIVO

In this study we have investigated the effect of novel tissue kallikre ins on the plasma protein exudation induced by porcine pancreatic kall ikrein (PPK) in the rabbit skin in vivo. The tissue kallikrein inhibit ors here described were synthesized based on analogues of peptide subs trates for tissue kallikreins. The intradermal injection of PPK and ra bbit urinary kallikrein, but not of rabbit plasma kallikrein, signific antly increased the microvascular permeability leading to local oedema formation in the rabbit skin. At the dose of 3-200 nmol/site, the int radermal co-administration of the tissue kallikrein inhibitors Bz-F-F- S-R-EDDnp (K-i = 0.1 mu M; ESP5), P-AC-F-S-R-EDDnp (K-i = 0.7 mu M; ES P6), Bz-F-F-A-P-R-NH2 (K-i = 7.8 mu M; ESP8), P-AC-F-F-R-P-R-NH2 (K-i = 0.3 mu M; ESP9) and Bz-F-F-S-R-NH2 (K-i = 0.3 mu M; ESP11) dose-depe ndently inhibited the plasma protein exudation induced by PPK. The mos t potent compound was ESP6 (IC25 = 7.8 nmol/site) followed by ESP5 (IC 25 = 14.2 nmol/site), ESP8 (IC25 = 25 nmol/site), ESP9 (IC25 = 30 nmol /site) and ESP11 (IC25 = 50.4 nmol/site). The compounds Bz-F-F-R-P-R-N H2 (K-i = 0.5 mu M; ESP1), Bz-F-F-pNa (K-i = 0.4 mu M; ESP3), Bz-F(NH2 )-F-R-P-R-NH2 (K-i = 1.1 mu M; ESP7) and Bz-F-F-S-P-R-NH2 (K-i = 4.6 m u M; ESP10) had no significant effect on the PPK-induced plasma protei n exudation in doses up to 200 nmol/site. ESP6 also inhibited the PPK- induced plasma protein exudation when administered systemically. This compound may constitute a useful tool to further investigate both the physiological and pathological role of tissue kallikreins.