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Received for publication January 3, 2005.
Revised March 3, 2005.
Accepted for publication March 9, 2005.
Several metallopeptidases have been reported to be involved in bradykinin (BK) B1 receptor agonists 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 while 1 µM captopril (ACE inhibitor) had no significant effects. However, when the three enzimes 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 receptors 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.
Key words:
ACE, APM, BK, HUA, NEP, des-Arg9-KD
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