Effect of bradykinin metabolism inhibitors on evoked hypotension in rats: rank efficacy of enzymes associated with bradykinin‐mediated angioedema
- 1 March 2008
- journal article
- Published by Wiley in British Journal of Pharmacology
- Vol. 153 (5), 947-955
- https://doi.org/10.1038/sj.bjp.0707641
Abstract
Inhibition of bradykinin metabolizing enzymes (BMEs) can cause acute angioedema, as demonstrated in a recent clinical trial in patients administered the antihypertensive, omapatrilat. However, the relative contribution of specific BMEs to this effect is unclear and confounded by the lack of a predictive pre-clinical model of angioedema. Rats were instrumented to record blood pressure and heart rate; inhibitors were infused for 35 min and bradykinin was infused during the last 5 min to elicit hypotension, as a functional marker of circulating bradykinin and relative angioedema risk. In the presence of omapatrilat bradykinin produced dose-dependent hypotension, an effect abolished by B(2) blockade. In the presence of lisinopril (ACE inhibitor), but not candoxatril (NEP inhibitor) or apstatin (APP inhibitor), bradykinin also elicited hypotension. Lisinopril-mediated hypotension was unchanged with concomitant blockade of NEP or NEP/DPPIV (candoxatril+A-899301). However, hypotension was enhanced upon concomitant blockade of APP and further intensified in the presence of NEP inhibition to values not different from omapatrilat alone. We demonstrated that bradykinin is degraded in vivo with an enzyme rank-efficacy of ACE>APP>>NEP or DPPIV. These results suggest the effects of omapatrilat are mediated by inhibition of three BMEs, ACE/APP/NEP. However, dual inhibition of ACE/NEP or ACE/NEP/DPPIV elicits no increased risk of angioedema compared to ACE inhibition alone. Thus, novel BME inhibitors must display no activity against APP to avoid angioedema risk due to high prevalence of ACE inhibitor therapy in patients with diabetes and cardiovascular disease.This publication has 57 references indexed in Scilit:
- Dipeptidyl peptidase IV deficiency increases susceptibility to angiotensin-converting enzyme inhibitor–induced peritracheal edemaJournal of Allergy and Clinical Immunology, 2007
- ACE Inhibitors and Angiotensin Receptor Antagonists and the Incidence of New-Onset Diabetes MellitusDrugs, 2006
- Angiotensin-(1–7) Acts as a Vasodepressor Agent Via Angiotensin II Type 2 Receptors in Conscious RatsHypertension, 2005
- Human recombinant membrane-bound aminopeptidase P: production of a soluble form and characterization using novel, internally quenched fluorescent substratesBiochemical Journal, 2005
- Differential tissue and enzyme inhibitory effects of the vasopeptidase inhibitor omapatrilat in the ratClinical Science, 2003
- Angiotensin-Converting Enzyme Inhibitor-Associated Angioedema Is Characterized by a Slower Degradation of des-Arginine9-BradykininThe Journal of pharmacology and experimental therapeutics, 2002
- Role of angiotensin converting enzyme and other peptidases in in vivo metabolism of kinins.Hypertension, 1989
- Cleavage of des-Arg9-bradykinin by angiotensin I-converting enzyme from pig kidney cortexCellular and Molecular Life Sciences, 1985
- Effect of angiotensin-converting enzyme inhibition on circulating and local kinin levelsThe American Journal of Cardiology, 1982
- Relationship between the inhibition constant (KI) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reactionBiochemical Pharmacology, 1973