MECHANISMS OF SIGNAL TRANSDUCTION
Novel Mode of Action of Angiotensin I Converting Enzyme Inhibitors: DIRECT ACTIVATION OF BRADYKININ B1 RECEPTOR*

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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 B1 receptors directly in the absence of ACE and the B1 agonist des-Arg10-Lys1-bradykinin. These inhibitors activate at the Zn2+-binding consensus sequence HEXXH (195–199) in B1, which is present also in ACE but not in the B2 receptor. Activation elevates [Ca2+]i and releases NO from endothelial or transfected cells expressing the B1 receptor but is blocked by Ca-EDTA, a B1 receptor antagonist, the synthetic undecapeptide sequence (192–202) of B1, and the mutagenesis of His195 to Ala195. Except for the B1 antagonist, these agents and manipulations did not block activation by a peptide ligand. Thus, Zn2+ is essential for B1 receptor activation by ACE inhibitors at the zinc-binding consensus sequence. Ischemia or cytokines induce abundant B1 receptor expression. B1 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.

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Published, JBC Papers in Press, March 5, 2002, DOI 10.1074/jbc.M200355200

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These studies were partially supported by NHLBI, National Institutes of Health Grants HL36473 and HL58118.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.