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INFLAMMATION AND IMMUNOPHARMACOLOGY

Potentiation of des-Arg⁹-Kallidin-Induced Vasoconstrictor Responses by Metallopeptidase Inhibition in Isolated Human Umbilical Artery

Departamento de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay, Buenos Aires, Argentina

Several metallopeptidases have been reported to be involved in bradykinin (BK) B₁ receptor agonist metabolism. Our goal was to evaluate in vitro roles of metallopeptidases [e.g., neutral endopeptidase (NEP), aminopeptidase M (APM), and angiotensin-converting enzyme (ACE)] as functional inactivators of the selective BKB₁ receptor agonist Lys-des-Arg⁹-BK (DAKD) in isolated human umbilical artery (HUA) rings. Concentration-response curves (CRCs) to DAKD were performed after a 5-h incubation period. Treatment with 10 µM phosphoramidon (NEP inhibitor) or 10 µM amastatin (APM inhibitor) potentiated DAKD-elicited responses, whereas 1 µM captopril (ACE inhibitor) had no significant effects. However, when the three enzymes were simultaneously inhibited, a significant potentiation over responses obtained under concurrent NEP and aminopeptidase M inhibition was observed. In contrast, responses induced by the peptidase resistant BKB₁ receptor agonist Sar-D-Phe⁸-des-Arg⁹-BK were not modified by triple peptidase inhibition. In addition, endothelial denudation failed to alter DAKD-induced responses in HUA. Finally, in the presence of NEP, ACE, and APM inhibition, Lys-des-Arg⁹-[Leu⁸]-BK, the potent BKB₁ receptor antagonist, produced a parallel, concentration-dependent, rightward shift of DAKD CRCs. The obtained pK_B (8.57) and the Schild slope not different from unity are in agreement with an interaction at a single homogeneous BKB₁ receptor population. In summary, this work constitutes the first pharmacological evidence that metallopeptidases NEP, APM, and ACE represent a relevant inactivation mechanism of the endogenous BKB₁ receptor agonist DAKD in isolated HUA.

Address correspondence to: Rodolfo Pedro Rothlin, Paraguay 2155, 9th floor, Ciudad Autónoma de Buenos Aires (1121), Argentina. E-mail: farmaco3{at}fmed.uba.ar

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