Do angiotensin-converting enzyme inhibitors directly stimulate the kinin B1 receptor?
It has been recently claimed that the human B1 receptors for kinins bind angiotensin-converting enzyme (ACE) inhibitors via a potential zinc-binding domain and are pharmacologically stimulated by these drugs. We verified whether ACE inhibitors stimulate B1 receptors in vitro. The isolated rabbit aorta or mouse stomach responded by negligible contractions to the application of captopril, enalaprilat, or zofenoprilat. The human isolated umbilical vein also failed to respond to enalaprilat. All of these preparations were responsive to the B1 receptor agonists des-Arg9-bradykinin (BK) or Lys-des-Arg9-BK. Furthermore, enalaprilat applied continuously had no significant interaction with the effects of Lys-des-Arg9-BK on the rabbit aorta. Enalaprilat failed to stimulate [3H]arachidonate release, translocate the receptors (confocal microscopy), or stimulate ERK1/2 phosphorylation (immunoblot) in HEK-293 cells stably expressing the rabbit B1 receptor conjugated to yellow fluorescent protein. The phospho-ERK1/2 content of arterial smooth muscle cells of human or rabbit origin was increased by treatment with Lys-des-Arg9-BK but not with enalaprilat. ACE inhibitors do not act as bona fide agonists of the kinin B1 receptors.
Fortin
Jean-Philippe
JP
Centre de recherche en cancérologie de l'Université Laval, Centre Hospitalier Universitaire de Québec, Centre de recherche du Pavillon l'Hôtel-Dieu de Québec, Canada G1R 2J6. Francois.marceau@crhdq.ulaval.ca
Gobeil
Fernand
F
Adam
Albert
A
Regoli
Domenico
D
Marceau
Francois
F
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D016718:Arachidonic Acid / Q000378:metabolism; D001426:Bacterial Proteins; D002460:Cell Line; D015773:Enalaprilat / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007609:Kallidin / Q000031:analogs & derivatives / Q000494:pharmacology; D008164:Luminescent Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D010741:Phospholipases A / Q000378:metabolism; D010766:Phosphorylation; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin / Q000187:drug effects*; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D014178:Translocation, Genetic / Q000187:drug effects; D014471:Umbilical Veins / Q000187:drug effects / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D001426:Bacterial Proteins; D008164:Luminescent Proteins; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin; C054562:yellow fluorescent protein, Bacteria; D016718:Arachidonic Acid; D007609:Kallidin; C052787:kallidin, des-Arg(10)-; D020928:Mitogen-Activated Protein Kinases; D010741:Phospholipases A; D015773:Enalaprilat