Bizeto L, Antunes E, Portaro F C, Juliano M A, Juliano L, Prado E S, de Nucci G
Department of Pharmacology, Faculty of Medical Sciences, UNICAMP, Campinas-SP, Brazil.
Immunopharmacology. 1996 May;32(1-3):111-4. doi: 10.1016/0162-3109(95)00067-4.
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 (Ki = 0.1 microM; ESP5), PAC-F-S-R-EDDnp (Ki = 0.7 microM; ESP6), Bz-F-F-A-P-R-NH2 (Ki = 7.8 microM; ESP8), PAC-F-F-R-P-R-NH2 (Ki = 0.3 microM; ESP9) and Bz-F-F-S-R-NH2 (Ki = 0.3 microM; 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 (Ki = 0.5 microM; ESP1), Bz-F-F-pNa (Ki = 0.4 microM; ESP3), Bz-F(NH2)-F-R-P-R-NH2 (Ki = 1.1 microM; ESP7) and Bz-F-F-S-P-R-NH2 (Ki = 4.6 microM; 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.
在本研究中，我们调查了新型组织激肽释放酶对猪胰激肽释放酶（PPK）在兔皮肤体内诱导的血浆蛋白渗出的影响。此处所述的组织激肽释放酶抑制剂是基于组织激肽释放酶的肽底物类似物合成的。皮内注射PPK和兔尿激肽释放酶可显著增加微血管通透性，导致兔皮肤局部水肿形成，但兔血浆激肽释放酶则无此作用。在3 - 200 nmol/部位的剂量下，皮内共同给予组织激肽释放酶抑制剂Bz - F - F - S - R - EDDnp（Ki = 0.1 microM；ESP5）、PAC - F - S - R - EDDnp（Ki = 0.7 microM；ESP6）、Bz - F - F - A - P - R - NH2（Ki = 7.8 microM；ESP8）、PAC - F - F - R - P - R - NH2（Ki = 0.3 microM；ESP9）和Bz - F - F - S - R - NH2（Ki = 0.3 microM；ESP11）可剂量依赖性地抑制PPK诱导的血浆蛋白渗出。最有效的化合物是ESP6（IC25 = 7.8 nmol/部位），其次是ESP5（IC25 = 14.2 nmol/部位）、ESP8（IC25 = 25 nmol/部位）、ESP9（IC25 = 30 nmol/部位）和ESP11（IC25 = 50.4 nmol/部位）。化合物Bz - F - F - R - P - R - NH2（Ki = 0.5 microM；ESP1）、Bz - F - F - pNa（Ki = 0.4 microM；ESP3）、Bz - F(NH2)-F - R - P - R - NH2（Ki = 1.1 microM；ESP7）和Bz - F - F - S - P - R - NH2（Ki = 4.6 microM；ESP10）在高达200 nmol/部位的剂量下对PPK诱导的血浆蛋白渗出无显著影响。ESP6全身给药时也可抑制PPK诱导的血浆蛋白渗出。该化合物可能是进一步研究组织激肽释放酶生理和病理作用的有用工具。
