Pharmacological characterization of novel tissue kallikrein inhibitors in vivo

Pharmacological characterization of novel tissue kallikrein inhibitors in vivo

Author Bizeto, L. Google Scholar
Antunes, E. Google Scholar
Portaro, FCV Google Scholar
Juliano, M. A. Google Scholar
Juliano, L. Google Scholar
Prado, E. S. Google Scholar
deNucci, G. Google Scholar
Institution Universidade Estadual de Campinas (UNICAMP)
Universidade Federal de São Paulo (UNIFESP)
Abstract In this study we have investigated the effect of novel tissue kallikreins on the plasma protein exudation induced by porcine pancreatic kallikrein (PPK) in the rabbit skin in vivo. the tissue kallikrein inhibitors here described were synthesized based on analogues of peptide substrates for tissue kallikreins. the intradermal injection of PPK and rabbit urinary kallikrein, but not of rabbit plasma kallikrein, significantly increased the microvascular permeability leading to local oedema formation in the rabbit skin. At the dose of 3-200 nmol/site, the intradermal 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; ESP6), 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-dependently inhibited the plasma protein exudation induced by PPK. the most potent compound was ESP6 (IC25 = 7.8 nmol/site) followed by ESP5 (IC25 = 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-NH2 (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 mu M; ESP10) had no significant effect on the PPK-induced plasma protein 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.
Keywords tissue kallikrein
vascular permeability
rabbit skin
Language English
Date 1996-05-01
Published in Immunopharmacology. Amsterdam: Elsevier B.V., v. 32, n. 1-3, p. 111-114, 1996.
ISSN 0162-3109 (Sherpa/Romeo, impact factor)
Publisher Elsevier B.V.
Extent 111-114
Access rights Closed access
Type Article
Web of Science ID WOS:A1996UR64300029

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