Angiotensin I–Converting Enzyme Inhibitors Are Allosteric Enhancers of Kinin B1 and B2 Receptor Function

Abstract

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. Key Words: angiotensin I-converting enzyme inhibitors Ⅲ kininase II Ⅲ kinins Ⅲ bradykinin B2 receptor Ⅲ bradykinin B1 receptor Ⅲ allosteric regulation Ⅲ 7-transmembrane G protein-coupled receptor M illions of patients are treated with angiotensin I-converting enzyme (ACE) inhibitors to combat hypertension, congestive heart failure or diabetic renal diseases. 1-4 ACE inhibitors significantly reduce mortality after myocardial infarction 3 and are beneficial in other high risk patients.ACE inhibitors block the metabolism of several peptides by ACE, notably the conversion of angiotensin (Ang) I to II, 5 and the inactivation of bradykinin (BK) 6 -8 or the hemoregulatory tetrapeptide Ac-Ser-Asp-Lys-Pro. 9 The conversion of Ang I to Ang II was first found to occur in horse plasma 5 ; with kidney and human plasma, one of us reported the identity of ACE and kininase II, which we had discovered previously. 6 -8,10,11 Consequently, a single peptidyldipeptidase not only releases the hypertensive Ang II, but also inactivates the hypotensive BK. How much of the therapeutic effectiveness of ACE inhibitors is attributable to blocking Ang II release 12 or to prolonging the short half-life of BK 7 and its congener Lys1-BK (kallidin) has been debated. This is further complicated by the existence of 2 kinin receptors. The first characterized, but incongruously named, B2 receptor (B2R) is activated by native BK or kallidin. 13 The second, so-called B1 receptor (B1R), does not bind native kinins; its ligands are metabolites of BK and kallidin lacking the C-terminal arginine 14 removed by plasma carboxypeptidase (CP)N 15-17 or membrane CPM. 18 -20 Whereas the B2R is widely expressed constitutively, B1R expression is usually induced after noxious stimuli or by inflammatory cytokines, 13,14,[21][22][23] although some cells (bovine lung endothelial or human fibroblasts) express B1Rs constitutively.ACE inhibitors can enhance both B2 and B1R signaling. Blocking kinin inactivation by ACE raises the concentration of intact B2R agonists, which are also the substrates of CPN and -M. This can generate more des-Arg-kinin B1R agonists (Figure). The successful use of antagonists of the Ang II type 1 receptor (AT 1 R) for many of the same indications as ACE inhibitors does not prove ACE inhibitors work only through reducing Ang II as there are complex interrelationships among Ang II, BK and their receptors. Ang II has 2 receptors, AT 1 R and AT 2 R. AT 1 R is blocked by drugs such as losartan, which can shift Ang II actions to the AT 2 R. This switching of receptors further counteracts AT 1 R effects because it leads to the release of mediators such as nitric oxide (NO) and is attributed partially to release of BK to activate B2Rs, a form of "...

Cross-talk between Carboxypeptidase M and the Kinin B1 Receptor Mediates a New Mode of G Protein-coupled Receptor Signaling

“…The extracellular loops of GPCRs contain potential ligand-binding sites for allosteric control of receptor functions (5); thus, a membrane peptidase whose active site domain is extracellular could regulate receptor function by interacting with such a site. For example, there is growing evidence for a functional complex between ACE and the B2R (55). ACE enzymatically inactivates BK, thus ACE inhibitors prolong BK half-life, indirectly enhancing B2R responses.…”

A review of sleep disorders and melatonin

“…Melatonin and melatonin-mimicking agents inhibit B2 bradykinin receptors (B2Rs), as well as the dimerization of angiotensin converting enzyme I (ACE) to inhibit ACE activity, thereby lowering blood pressure [30]. Melatonin and its agonist stabilize ACE-B2R dimers [31] and angiotensin type II receptors (AT2R). B2R complex (AT2R-B2R) [32] activation increases nitric oxide production by endothelial cells to dilate arterials to increase blood flow in poorly perfused tissues.…”

Carboxypeptidase M Is a Positive Allosteric Modulator of the Kinin B1 Receptor

“…A further level of reduction of B1R activity could be achieved by adding a specific CPM inhibitor to further reduce agonist generation without completely eliminating it from other sources. Because ACE inhibitors can also act as direct allosteric agonists of B1Rs (24,74), disruption of the CPM/B1R interaction could potentially affect the therapeutic and/or side effects of these drugs as well.…”