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.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.)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.