Lack of direct interaction between enalaprilat and the kinin B1 receptors

Peptides
G MorissetteF Marceau

Abstract

It has been recently proposed that the second extracellular loop of the human bradykinin (BK) B1 receptor (B1R) contains a conserved HExxH motif also present in peptidases possessing a Zn2+ prosthetic group, such as angiotensin converting enzyme (ACE), and that ACE inhibitors directly activate B1R signaling in endothelial cells. However, the binding of ACE inhibitors to the B1Rs has never been directly evaluated. Information about binding of a radiolabeled inhibitor to natural or recombinant ACE in intact cells (physiologic ionic composition) was also collected. We used the tritiated form of an ACE inhibitor previously proposed to activate the B1R, enalaprilat, to address these questions using recombinant human B1Rs and naturally expressed or recombinant ACE. [3H]Lys-des-Arg9-BK bound to the human recombinant B1Rs with high affinity (KD 0.35 nM) in HEK 293a cells. [3H]Enalaprilat (0.25-10 nM) did not bind to cells expressing recombinant human B1R, but bound with a subnanomolar affinity to recombinant ACE or to naturally expressed ACE in human umbilical vein endothelial cells. The radioligand was further validated using a binding competition assay that involved unlabeled ACE inhibitors or their prodrug forms in endothelial cells...Continue Reading

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Citations

Apr 28, 2012·Pharmacology & Therapeutics·Domenico RegoliFernand Gobeil
Aug 26, 2011·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Lajos GeraFrançois Marceau
Nov 24, 2011·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Marie-Thérèse BawolakFrançois Marceau
Mar 5, 2014·Neonatal Network : NN·Michele J Beaulieu, Christina Carsello
Aug 23, 2020·Pharmaceuticals·François MarceauGeorges E Rivard

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