Vasopeptidase-activated latent ligands of the histamine receptor-1

Élément Dublin CoreValeurLangue
dc.contributor.authorGera, Lajos-
dc.contributor.authorRoy, Caroline-
dc.contributor.authorCharest-Morin??, Xavier-
dc.contributor.authorMarceau, François-
dc.description.abstractWhether peptidases present in vascular cells can activate prodrugs active on vascular cells has been tested with 2 potential latent ligands of the histamine H1 receptor (H1R). First, a peptide consisting of the antihistamine cetirizine (CTZ) condensed at the N-terminus of ε-aminocaproyl-bradykinin (εACA-BK) was evaluated for an antihistamine activity that could be revealed by degradation of the peptide part of the molecule. CTZ-εACA-BK had a submicromolar affinity for the BK B2 receptor (B2R; IC50 of 590 nM, [(3)H]BK binding competition), but a non-negligible affinity for the human H1 receptor (H1R; IC50 of 11 μM for [(3)H]pyrilamine binding). In the human isolated umbilical vein, a system where both endogenous B2R and H1R mediate strong contractions, CTZ-εACA-BK exerted mild antagonist effects on histamine-induced contraction that were not modified by omapatrilat or by a B2R antagonist that prevents endocytosis of the BK conjugate. Cells expressing recombinant ACE or B2R incubated with CTZ-εACA-BK did not release a competitor of [(3)H]pyrilamine binding to H1Rs. Thus, there is no evidence that CTZ-εACA-BK can release free cetirizine in biological environments. The second prodrug was a blocked agonist, L-alanyl-histamine, potentially activated by aminopeptidase N (APN). This compound did not compete for [(3)H]pyrilamine binding to H1Rs. The human umbilical vein contractility assay responded to L-alanyl-histamine (EC50 54.7 μM), but the APN inhibitor amastatin massively (17-fold) reduced its apparent potency. Amastatin did not influence the potency of histamine as a contractile agent. One of the 2 tested latent H1R ligands, L-alanyl-histamine, supported the feasibility of pro-drug activation by vascular ectopeptidasesfr
dc.subjectAminopeptidase Nfr
dc.subjectAngiotensin converting enzymefr
dc.subjectBradykinin B(2) receptorfr
dc.subjectHistamine H(1) receptorfr
dc.subjectHuman umbilical veinfr
dc.titleVasopeptidase-activated latent ligands of the histamine receptor-1fr
dc.typeCOAR1_1::Texte::Périodique::Revue::Contribution à un journal::Article::Article de recherchefr
dcterms.bibliographicCitationInternational Immunopharmacology, Vol. 17 (3), 677–683 (2013)fr
dc.subject.rvmAntigène CD13fr
dc.subject.rvmEnzyme de conversion de l'angiotensinefr
dc.subject.rvmBradykinine -- Récepteursfr
dc.subject.rvmHistamine -- Récepteursfr
dc.subject.rvmVeine ombilicalefr
rioxxterms.versionAccepted Manuscriptfr
rioxxterms.project.funder_nameCanadian Institutes for Health Researchfr
bul.rights.periodeEmbargo12 moisfr
Collection :Articles publiés dans des revues avec comité de lecture

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