The bradykinin B2 receptor antagonist icatibant (Hoe 140) blocks aminopeptidase N at micromolar concentrations: off-target alterations of signaling mediated by the bradykinin B1 and angiotensin receptors.
The N-terminal sequence of icatibant, a widely used peptide antagonist of the bradykinin B(2) receptors, is analogous to that of other known aminopeptidase N inhibitors. Icatibant competitively inhibited the hydrolysis of L-Ala-p-nitroanilide by recombinant aminopeptidase N (K(i) 9.1 microM). In the rabbit aorta, icatibant (10-30 microM) potentiated angiotensin III, but not angiotensin II (contraction mediated by angiotensin AT(1) receptors), and Lys-des-Arg(9)-bradykinin, but not des-Arg(9)-bradykinin (effects mediated by the bradykinin B(1) receptors), consistent with the known susceptibility of these agonists to aminopeptidase N. At concentrations possibly reached in vivo (e.g., in kidneys), icatibant alters physiological systems different from bradykinin B(2) receptors.
Bawolak
Marie-Thérèse
MT
Centre de Recherche en Rhumatologie et Immunologie, Centre Hospitalier Universitaire de Québec, Québec Qc, Canada G1V 4G2.
Fortin
Jean-Philippe
JP
Vogel
Lotte K
LK
Adam
Albert
A
Marceau
François
F
D000804:Angiotensin II / Q000494:pharmacology; D000805:Angiotensin III / Q000494:pharmacology; D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D065094:Bradykinin B2 Receptor Antagonists; D018826:CD13 Antigens / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007609:Kallidin / Q000031:analogs & derivatives / Q000494:pharmacology; D007700:Kinetics; D011480:Protease Inhibitors / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology; D011817:Rabbits; D043783:Receptor, Bradykinin B1 / Q000187:drug effects / Q000378:metabolism*; D043782:Receptor, Bradykinin B2 / Q000378:metabolism; D011945:Receptors, Angiotensin / Q000187:drug effects / Q000378:metabolism*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000814:Aniline Compounds; D065094:Bradykinin B2 Receptor Antagonists; C403051:LF 16-0687; D011480:Protease Inhibitors; D011804:Quinolines; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D011945:Receptors, Angiotensin; D011994:Recombinant Proteins; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D000805:Angiotensin III; C024626:bradykinin, des-Arg(9)-; C004813:alanine-4-nitroanilide; D007609:Kallidin; C052787:kallidin, des-Arg(10)-; C065679:icatibant; D018826:CD13 Antigens; D001920:Bradykinin