Vasopeptidase-activated latent ligands of the histamine receptor-1

Abstract

Whether peptidases present in vascular cells can activate prodrugs active on vascular cells has been tested with 2 potential latent ligands of the histamine H 1 receptor (H 1 R). 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 B 2 receptor (B 2 R; IC 50 of 590 nM, [ The human umbilical vein contractility assay responded to L-alanyl-histamine (EC 50 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 H 1 R ligands, Lalanyl-histamine, supported the feasibility of pro-drug activation by vascular ectopeptidases.

Pharmacological evidence of bradykinin regeneration from extended sequences that behave as peptidase–activated B2 receptor agonists

“…The umbilical vein contractility assay did not show a loss of apparent potency in the presence of the DPP-IV inhibitor NVP-DPP728 ( Figure 5B ; Table 2 ). Alternatively, BK could be regenerated by two enzymatic cycles catalyzed by aminopeptidases widely expressed in blood vessels, such as aminopeptidase N (Gera et al, 2013b). The aminopeptidase inhibitor amastatin also failed to modify the contractile effect of Arg-Pro-BK ( Figure 5B ; Table 2 ).…”

“…The latter finding does not automatically apply to all isolated blood vessels, as the BK contractile effect on the rabbit isolated jugular vein was clearly potentiated by enalaprilat treatment (Gera et al, 2011). Previous immunohistochemistry and immunofluorescence studies showed that the umbilical vein possesses a relatively thick media composed of ~30 layers of compactly organized smooth muscle cells (positive for α-actin), while immunoreactive ACE is represented in the single endothelial cell layer (Koumbadinga et al, 2010; Gera et al, 2013b). By comparison, the rabbit jugular vein is very thin, with a higher endothelium/smooth muscle ratio.…”

“…The conserved affinity of Arg-Pro-BK for the B 2 R precludes the observation of an activation reaction in the venous contractility system. However, the latter may contain such aminopeptidases: we have recently observed that L-Ala-histamine-induced contraction of the isolated umbilical vein largely results from the regeneration of free histamine by aminopeptidase(s) sensitive to amastatin (Gera et al, 2013b), thus extending the concept of vasopeptidase-activated prodrug to another receptor system (the histamine H 1 receptor).…”

Pharmacological effects of recombinant human tissue kallikrein on bradykinin B2 receptors

“…; Gera et al. ). The assay demonstrates that the vascular pharmacology of DM199 is dependent on kinin release from an exhaustible supply of LMW‐KNG, as shown by the loss of contractility following kininogen depletion and restoration of contractility following exogenous LMW‐KNG addition (Figs.…”

Interactions between histamine H1 receptor and its antagonists by using cell membrane chromatography method

“…Histamine mediates its effects through binding to G protein‐associated histamine H 1–4 receptors, resulting in activation of different signal transduction pathways [1,2]. Many of the allergic actions of histamine are mediated via H 1 R, such as redness, itching, and swelling [3,4]. H 1 R has a broad distribution in the central nervous system [5–7].…”