title: Potentiation of des-Arg9-kallidin-induced vasoconstrictor responses by metallopeptidase inhibition in isolated human umbilical artery.
abstract: Several metallopeptidases have been reported to be involved in bradykinin (BK) B(1) 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 BKB(1) receptor agonist Lys-des-Arg(9)-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 microM phosphoramidon (NEP inhibitor) or 10 microM amastatin (APM inhibitor) potentiated DAKD-elicited responses, whereas 1 microM 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 BKB(1) receptor agonist Sar-D-Phe(8)-des-Arg(9)-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-Arg(9)-[Leu(8)]-BK, the potent BKB(1) 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 BKB(1) 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 BKB(1) receptor agonist DAKD in isolated HUA.
authors.affiliation: Departamento de Farmacología, Facultad de Medicine, Universidad de Buenos Aires, Paraguary.
authors.forename: Facundo Germán
authors.initials: FG
authors.lastname: Pelorosso
authors.forename: Paula Tamara
authors.initials: PT
authors.lastname: Brodsky
authors.forename: Camila Lidia
authors.initials: CL
authors.lastname: Zold
authors.forename: Rodolfo Pedro
authors.initials: RP
authors.lastname: Rothlin
mesh_terms: D018826:CD13 Antigens / Q000037:antagonists & inhibitors / Q000502:physiology*; D002216:Captopril / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D066298:In Vitro Techniques; D007609:Kallidin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000502:physiology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D043783:Receptor, Bradykinin B1 / Q000502:physiology; D014469:Umbilical Arteries / Q000187:drug effects* / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D011480:Protease Inhibitors; D043783:Receptor, Bradykinin B1; D007609:Kallidin; C052787:kallidin, des-Arg(10)-; D002216:Captopril; D018826:CD13 Antigens; D015260:Neprilysin