The bradykinin B 2 receptor antagonist icatibant (Hoe 140) blocks aminopeptidase N at micromolar concentrations: Off-target alterations of signaling mediated by the bradykinin B 1 and angiotensin receptors

Abstract

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 μM). In the rabbit aorta, icatibant (10–30 μM) 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.