Novel mode of action of angiotensin I converting enzyme inhibitors -: Direct activation of bradykinin B1 receptor

Angiotensin I converting enzyme (kininase II; ACE) inhibitors are important therapeutic agents widely used for treatment in cardiovascular and renal diseases. They inhibit angiotensin II release and bradykinin inactivation; these actions do not explain completely the clinical benefits. We found that enalaprilat and other ACE inhibitors in nanomolar concentrations activate human bradykinin B-1 receptors directly in the absence of ACE and the B-1 agonist des-Arg(10)-Lys(1)-bradykinin. These inhibitors activate at the Zn2+-binding consensus sequence HEXXH (195-199) in B-1 which is present also in ACE but not in the B-2 receptor. Activation elevates [Ca2+](i) and releases NO from endothelial or transfected cells expressing the B-1 receptor but is blocked by Ca-EDTA, a B-1 receptor antagonist, the synthetic undecapeptide sequence (192-202) of B-1, and the mutagenesis of His(195) to Ala(195). Except for the B-1 antagonist, these agents and manipulations did not block activation by a peptide ligand. Thus, Zn2+ is essential for B-1 receptor activation by ACE inhibitors at the zinc-binding consensus sequence. Ischemia or cytokines induce abundant B-1 receptor expression. B-1 receptor activation by ACE inhibitors, a novel mode of action reported here first, can contribute to their therapeutic effects by releasing NO in the heart and to some side effects.