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Activation of bradykinin B1 receptor by ACE inhibitors

2002; Elsevier BV; Volume: 2; Issue: 13-14 Linguagem: Inglês

10.1016/s1567-5769(02)00146-7

1878-1705

Tatjana Ignjatovic, Fulong Tan, Viktor Brovkovych, Randal A. Skidgel, Ervin G. Erdös,

Peptidase Inhibition and Analysis

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. Enalaprilat and other ACE inhibitors at nanomolar concentrations activate the BK B1 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 B1, a motif also present in the active centers of ACE but absent from the BK B2 receptor. ACE inhibitors, when activating the B1 receptor, elevate intracellular calcium [Ca2+]i and release NO from cultured cells. Activation by ACE inhibitor was abolished by Ca–EDTA, a B1 receptor antagonist, by a synthetic undecapeptide representing the 192–202 sequence in the B1 receptor, and by site-directed mutagenesis of H195 to A. With the exception of the B1 receptor blocker, these agents and the mutation did not affect the actions of the peptide ligand des-Arg10-Lys1-BK. Ischemia and inflammatory cytokines induce B1 receptors and elevate its expression. Direct activation of the B1 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.