Angiotensin-Converting Enzyme Inhibitor-Associated Angioedema Is Characterized by a Slower Degradation of des-Arginine9-Bradykinin
Open accessAbstract
Angioedema (AE) is a rare but potentially life-threatening side effect of therapy with inhibitors of angiotensin-converting enzyme (ACE), the main bradykinin (BK)- inactivating metallopeptidase in humans. The pathogenesis of ACE inhibitor (ACEi)- associated AE (AE+) is presently unknown, although there is increasing evidence of a kinin role. We analyzed the metabolism of endogenous BK (B(2) receptor agonist) and its active metabolite, des-Arg(9)-BK (B(1) receptor agonist), in the presence of an ACEi during in vitro contact activation of plasma from hypertensive patients (n = 39) who presented AE+. Kinetic parameters were compared with those measured in a control group (AE-) of hypertensive patients (n = 39) who never manifested any acute or chronic side effects while treated with an ACEi. The different kinetic parameters were analyzed using a mathematical model (y = k t(alpha) e(-beta t)) previously applied to a normal, healthy population. The slope of BK degradation, but not its formation from high-molecular-weight kininogen, was lower in AE+ patients when compared with the AE- controls. des-Arg(9)-BK accumulation during the kinetic measurements was significantly higher in AE+ plasma. This accumulation of the B(1) agonist in AE+ patients paralleled its half-life of degradation. In conclusion, our results show, for the first time, that an abnormality of endogenous des-Arg(9)-BK degradation exists in the plasma of patients with ACEi-associated AE, suggesting that its pathogenetic mechanism lies in the catabolic site of kinin metabolism.
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APP activity and des-Arg9-bradykinin degradation are decreased in the sera of angioedema patients of European origin compared with control subjects.
“Supporting this notion, APP activity and des-Arg 9 -bradykinin degradation are decreased in the sera of angioedema patients of European origin compared with control subjects.13,14”
From Dipeptidyl Peptidase IV in Angiotensin-Converting Enzyme Inhibitor–Associated Angioedema (2008) · cites this paper as [14]
The Discussion reports slower des-Arg9-bradykinin degradation in angioedema patients than controls and cites prior observations of decreased APP activity in the same patients. However, the Blood Samples section says this study tested plasma, not serum, and the Patients section describes participants as white without establishing European origin. (LLM, conf=0.87)
Experimental — accuracy not yet measuredPlasma APP activities are significantly lower in patients with a history of AE-ACEi, and this is strongly correlated with a significant decrease in des-Arg9-bradykinin degradation in vitro.
“We previously reported significantly lower plasma APP activities in patients with a history of AE-ACEi, which is strongly correlated with a significant decrease in desArg 9 -BK degradation in vitro (Blais et al. 1999 a ; Adam et al. 2002; Molinaro et al. 2002).”
From A variant in XPNPEP2 is associated with angioedema induced by angiotensin I-converting enzyme inhibitors. (2005) · cites this paper as Molinaro et al. 2002
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Self-citation
- Authors
- Molinaro, G., Cugno, M., Perez, M., Lepage, Y., Gervais, N., Agostoni, A., & Adam, A.
- Affiliations
- Université de Montréal (CA)
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
- University of Milan (IT)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2002-01
- Volume
- 303
- Issue
- 1
- Pages
- 232-237
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2142111531
- Semantic Scholar
- acc1c950c1f0a91b6c0a72655ed618c47a51490b
- Cited by
- 137
- References
- 35
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2023: 2 · 2022: 1 · 2021: 3 · 2020: 3 · 2019: 6 · 2018: 4 · 2016: 4 · 2015: 9 · 2014: 3 · 2013: 7 · 2012: 7
- FWCI
- 3.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Genetics › Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Keywords
- ACE inhibitors, des-Arg9-bradykinin, bradykinin degradation, bradykinin B1 receptor, bradykinin B2 receptor, high molecular weight kininogen, hypertension, adverse drug reactions
- MeSH terms
- Angioedema, Angiotensin-Converting Enzyme Inhibitors, Biotransformation, Bradykinin, Female, Half-Life, Humans, Hypertension, Kinetics, Male, Mathematics, Models, Theoretical, Reference Values
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