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 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.
Ignjatovic
Tatjana
T
Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois 60612, USA.
Tan
Fulong
F
Brovkovych
Viktor
V
Skidgel
Randal A
RA
Erdös
Ervin G
EG
D000409:Alanine / Q000737:chemistry; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000737:chemistry; D001665:Binding Sites; D001667:Binding, Competitive; D016466:CHO Cells; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002614:Chelating Agents / Q000494:pharmacology; D006224:Cricetinae; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004492:Edetic Acid / Q000494:pharmacology; D015773:Enalaprilat / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D006639:Histidine / Q000737:chemistry; D006801:Humans; D008024:Ligands; D008239:Lysine / Q000737:chemistry; D016297:Mutagenesis, Site-Directed; D009569:Nitric Oxide / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin / Q000378:metabolism*; D014162:Transfection; D015032:Zinc / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D002614:Chelating Agents; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D008024:Ligands; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin; D009569:Nitric Oxide; D006639:Histidine; D001120:Arginine; D004492:Edetic Acid; D015773:Enalaprilat; D015032:Zinc; D008239:Lysine; D000409:Alanine; D002118:Calcium