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Do angiotensin-converting enzyme inhibitors directly stimulate the kinin B₁ receptor?

¹Centre 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; ²Institut de Pharmacologie, Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Canada J1H 5N4; ³Faculté de Pharmacie, Université de Montréal, Montréal, Québec, Canada H3C 3J7; and ⁴Institute of Pharmacology, University of Ferrara, Ferrara, 44100, Italy

Submitted 23 December 2002 ; accepted in final form 17 March 2003

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.

enalaprilat; angiotensin II; des-Arg⁹-bradykinin

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