Functional evidence of des-Arg10-kallidin enzymatic inactivating pathway in isolated human umbilical vein

WANDA NOWAK, EZEQUIEL DARIO GOLDSCHMIDT, ALEJANDRA GEORGINA FALCIONI, MARIANA INES PUGLIESE, ANDREA EMILSE ERRASTI, FACUNDO GERMAN PELOROSSO, FEDERICO MANUEL DARAY, JUAN EZEQUIEL GAGO AND RODOLFO PEDRO ROTHLIN

NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY

Berlin Springer / Heidelberg

Lugar: Alemania; Año: 2007 vol. 375 p. 221 - 229

0028-1298

It has been known for many years that plasma and tissues contain a variety of enzymes capable of metabolizing kinins. The aim of the present study was to evaluate, by means of functional studies in a capacitance vessel such as the human umbilical vein (HUV), the possible role played by the metallopeptidases angiotensin-converting enzyme (ACE), neutral endopeptidase (NEP), and aminopeptidase M (APM) as an inactivating pathway of the B1 receptor endogenous agonist des-Arg10-kallidin (DAKD). In HUV rings with and without endothelium, concentration-response curves (CRCs) to DAKD were determined after a 300-min incubation period, and enzymatic inhibitors were added to the organ baths 30 min before construction of the CRC. Presence of endothelial layer was confirmed by histological studies. There was a significant leftward shift observed in control HUV rings devoid of endothelium compared with intact tissues. Exposure to 1 ¦ÌM captopril (ACE inhibitor) potentiated DAKD-elicited vasoconstrictor responses in HUV rings with endothelium while no such effect was observed in tissues devoid of endothelium. Application of 10 ¦ÌM amastatin (APM inhibitor) induced a leftward shift of DAKD-elicited contractile responses in HUV with and without endothelium. On the other hand, 10 ¦ÌM phosphoramidon (NEP inhibitor) showed no potentiating effect in HUV rings either with or without endothelium. However, under concurrent inhibition of ACE, NEP and APM, there was a higher potentiation of DAKD-elicited contractile responses compared with the effect observed with combined inhibition of ACE and APM. Moreover, when we evaluated contractile responses induced by Sar0-D-Phe8-des-Arg9-BK (a metabolically protected B1 receptor agonist), no potentiating effect was observed under triple enzymatic inhibition. In conclusion, in the present study for the first time, we demonstrated in a capacitance vessel, HUV, that metallopeptidases ACE, NEP and APM represent a relevant functional inactivation pathway of DAKD. Keywords  Human umbilical vein - B1 receptor - Des-Arg10-kallidin - Angiotensin-converting enzyme - Neutral endopeptidase - Aminopeptidase M - Biophase - Potentiation