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

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Abstract

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 μM 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 μM amastatin (APM inhibitor) induced a leftward shift of DAKD-elicited contractile responses in HUV with and without endothelium. On the other hand, 10 μM 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.

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Authors and Affiliations

  1. 3° Cátedra de Farmacología, Departamento de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, Piso 9, CP 1121, Buenos Aires, Argentina

    Wanda Nowak, Ezequiel Dario Goldschmidt, Alejandra Georgina Falcioni, Mariana Ines Pugliese, Facundo German Pelorosso, Federico Manuel Daray, Juan Ezequiel Gago & Rodolfo Pedro Rothlin

  2. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 3° Cátedra de Farmacología, Departamento de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, Piso 9, CP 1121, Buenos Aires, Argentina

    Andrea Emilse Errasti

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  1. Wanda Nowak
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  2. Ezequiel Dario Goldschmidt
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Correspondence to Rodolfo Pedro Rothlin.

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Nowak, W., Goldschmidt, E.D., Falcioni, A.G. et al. Functional evidence of des-Arg10-kallidin enzymatic inactivating pathway in isolated human umbilical vein. Naunyn-Schmied Arch Pharmacol 375, 221–229 (2007). https://doi.org/10.1007/s00210-007-0145-y

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