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

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Abstract
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 pKB (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.

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