Novel mode of action of angiotensin I converting enzyme inhibitors: direct activation of bradykinin B1 receptor.
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Ignjatovic T, Tan F, Brovkovych V, Skidgel RA, Erdos EG
Novel mode of action of angiotensin I converting enzyme inhibitors: direct activation of bradykinin B1 receptor.
J Biol Chem. 2002 May 10;277(19):16847-52. Epub 2002 Mar 5.
- PubMed ID
- 11880373 [ View in PubMed]
- Abstract
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 Zn(2+)-binding consensus sequence HEXXH (195-199) in B(1), which is present also in ACE but not in the B(2) receptor. Activation elevates [Ca(2+)](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, Zn(2+) 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.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Captopril B1 bradykinin receptor Protein Humans UnknownNot Available Details Enalaprilat B1 bradykinin receptor Protein Humans UnknownNot Available Details Ramipril B1 bradykinin receptor Protein Humans UnknownNot Available Details Zinc B1 bradykinin receptor Protein Humans UnknownNot Available Details Zinc acetate B1 bradykinin receptor Protein Humans UnknownNot Available Details Zinc chloride B1 bradykinin receptor Protein Humans UnknownAgonistDetails Zinc sulfate, unspecified form B1 bradykinin receptor Protein Humans UnknownAgonistDetails