Activation of bradykinin B1 receptor by ACE inhibitors

ACE or kininase II inhibitors are very important, widely used therapeutic agents for the treatment of a variety of diseases. Although they inhibit ACE, thus, angiotensin II release and bradykinin (BK) inactivation, this inhibition alone does not suffice to explain their successful application in medical practice. Enalaprilot and other ACE inhibitors at nanomolar concentrations activate the BK B-1 receptor directly in the absence of ACE and the peptide ligands, des-Arg-kinins. The inhibitors activate at the Zn-binding pentameric consensus sequence HEXXH (195 - 199) of B-1, a motif also present in the active centers of ACE but absent from the BK B-2 receptor. ACE inhibitors, when activating the B-1 receptor, elevate intracellular calcium [Ca2+](i) and release NO from cultured cells. Activation by ACE inhibitor was abolished by Ca-EDTA, a B-1 receptor antagonist, by a synthetic undecapeptide representing the 192 - 202 sequence in the B-1 receptor, and by site-directed mutagenesis of H-195 to A. With the exception of the B, receptor blocker, these agents and the mutation did not affect the actions of the peptide ligand des-Arg(10) -Lys(1)-BK. Ischemia and inflammatory cytokines induce B-1 receptors and elevate its expression. Direct activation of the B-1 receptor by ACE inhibitors can contribute to their therapeutic efficacy, for example, by releasing NO in vascular beds, or to some of their side effects. (C) 2002 Published by Elsevier Science B.V.