Angiotensin I-converting enzyme inhibitors are allosteric enhancers of kinin B1 and B2 receptor function

Abstract

The beneficial effects of angiotensin I-converting enzyme (ACE) inhibitors go beyond the inhibition of ACE to decrease angiotensin (Ang) II or increase kinin levels. ACE inhibitors also affect kinin B1 and B2 receptor (B1R and B2R) signaling, which may underlie some of their therapeutic usefulness. They can indirectly potentiate the actions of bradykinin (BK) and ACE-resistant BK analogs on B2Rs to elevate arachidonic acid and NO release in laboratory experiments. Studies indicate that ACE inhibitors and some Ang metabolites increase B2R functions as allosteric enhancers by inducing a conformational change in ACE. This is transmitted to B2Rs via heterodimerization with ACE on the plasma membrane of cells. ACE inhibitors are also agonists of the B1R, at a Zn-binding sequence on the second extracellular loop that differs from the orthosteric binding site of the des-Arg-kinin peptide ligands. Thus, ACE inhibitors act as direct allosteric B1R agonists. When ACE inhibitors enhance B2R and B1R signaling, they augment NO production. Enhancement of B2R signaling activates endothelial NO synthase, yielding a short burst of NO; activation of B1Rs results in a prolonged high output of NO by inducible NO synthase. These actions, outside inhibiting peptide hydrolysis, may contribute to the pleiotropic therapeutic effects of ACE inhibitors in various cardiovascular disorders.

Fig. 1. How ACE inhibitors can enhance kinin signaling

1. ACE inhibitors block the degradation of B2R agonist kinins, thus enhancing B2R signaling. Prolonging kinin half-life increases substrate concentration for carboxypeptidase (CP) M or N to generate des-Arg-kinins, agonists of the B1R.

2. Human ACE associates with B2Rs in a heterodimer on cell membranes. In the crystal structure, the N- and C-domains of ACE have a deep active site cleft and a “lid” region that restricts access of substrates or inhibitors prior to a conformational change. The two domains exhibit negative cooperativity; binding ACE inhibitor to one domain can alter the conformation of the other domain. Transmission of ACE's conformational change to the associated B2R is likely mediated by the C-domain. Enhanced mediator release or resensitization of the B2R is the consequence. (Modified from Fig. 11.3 in Erdös, EG, Tan, F and Skidgel, RA, Kinin receptors and ACE inhibitors: An interrelationship, DeMello WC, Frohlich ED, eds. Renin Angiotensin System and Cardiovascular Disease. New York: Humana Press; 2009:135-150. Used with permission of Springer Science + Business Media.)

3. In the third mode of action, ACE inhibitors are direct allosteric agonists of B1Rs. The canonical zinc binding motif in the second extracellular loop (HEAWH) is important for ACE inhibitors to activate B1Rs but not for des-Arg-kinin ligands. In human endothelial cells under inflammatory conditions, ACE inhibitors activate B1Rs that in turn post-translationally activate iNOS producing a prolonged high output of nitric oxide.