The Kallikrein-Kinin System: Current and Future Pharmacological Targets
Open accessAbstract
The kallikrein-kinin system is an endogenous metabolic cascade, triggering of which results in the release of vasoactive kinins (bradykinin-related peptides). This complex system includes the precursors of kinins known as kininogens and mainly tissue and plasma kallikreins. The pharmacologically active kinins, which are often considered as either proinflammatory or cardioprotective, are implicated in many physiological and pathological processes. The interest of the various components of this multi-protein system is explained in part by the multiplicity of its pharmacological activities, mediated not only by kinins and their receptors, but also by their precursors and their activators and the metallopeptidases and the antiproteases that limit their activities. The regulation of this system by serpins and the wide distribution of the different constituents add to the complexity of this system, as well as its multiple relationships with other important metabolic pathways such as the renin-angiotensin, coagulation, or complement pathways. The purpose of this review is to summarize the main properties of this kallikrein-kinin system and to address the multiple pharmacological interventions that modulate the functions of this system, restraining its proinflammatory effects or potentiating its cardiovascular properties.
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When ACE is inhibited, aminopeptidase P (APP) is the main enzyme that inactivates bradykinin.
“During ACE inhibition, bradykinin is primarily inactivated by aminopeptidase P (APP).”
From Sex-dependent and race-dependent association of XPNPEP2 C-2399A polymorphism with angiotensin-converting enzyme inhibitor-associated angioedema (2010) · cites this paper as [8]
Section 3.3 (page not available) says APP inactivates bradykinin in human plasma, but identifies it as the major inactivation pathway for des-Arg9-bradykinin, not bradykinin itself. The paper does not establish that APP becomes the primary enzyme inactivating bradykinin during ACE inhibition. (LLM, conf=0.88)
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New topics in bradykinin research
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Medeiros, R., Passos, G. F., Vitor, C. E., Koepp, J., Mazzuco, T. L., Pianowski, L. F., Campos, M. M., & Calixto, J. B. (2007) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0707270 · Cited by 167 · see citing works
Angiotensin-converting enzyme inhibitor-associated angioedema
Byrd, J. B., Adam, A., & Brown, N. J. (2006) · Immunology and Allergy Clinics of North America · doi:10.1016/j.iac.2006.08.001 · Cited by 160 · see citing works
Self-citationDipeptidyl Peptidase IV in Angiotensin-Converting Enzyme Inhibitor–Associated Angioedema
Byrd, J. B., Touzin, K., Sile, S., Gainer, J. V., Yu, C., Nadeau, J., Adam, A., & Brown, N. J. (2008) · Hypertension · doi:10.1161/hypertensionaha.107.096552 · Cited by 147 · see citing works
Self-citationFryer, R. M., Segreti, J., Banfor, P. N., Widomski, D. L., Backes, B. J., Lin, C. W., Ballaron, S. J., Cox, B. F., Trevillyan, J. M., Reinhart, G. A., et al. (2008) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0707641 · Cited by 130 · see citing works
The role of kinin receptors in cancer and therapeutic opportunities
da Costa, P. L. N., Sirois, P., Tannock, I. F., & Chammas, R. (2014) · Cancer Letters · doi:10.1016/j.canlet.2013.12.009 · Cited by 133 · see citing works
Drouet, C., Désormeaux, A., Robillard, J., Ponard, D., Bouillet, L., Martin, L., Kanny, G., Moneret-Vautrin, D.-A., Bosson, J.-L., Quesada, J.-L., et al. (2008) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2007.10.048 · Cited by 112 · see citing works
Self-citationWoodard-Grice, A. V., Lucisano, A. C., Byrd, J. B., Stone, E. R., Simmons, W. H., & Brown, N. J. (2010) · Pharmacogenetics and Genomics · doi:10.1097/fpc.0b013e32833d3acb · Cited by 92 · see citing works
Self-citationThe Renin-Angiotensin-Aldosterone System in Postmenopausal Women: The Promise of Hormone Therapy
Gersh, F. L., O’Keefe, J. H., Lavie, C. J., & Henry, B. M. (2021) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2021.08.009 · Cited by 57 · see citing works
Hillmeister, P., & Persson, P. B. (2012) · Acta Physiologica · doi:10.1111/apha.12007 · Cited by 54 · see citing works
Moholisa, R. R., Rayner, B. R., Patricia Owen, E., Schwager, S. L. U., Stark, J. S., Badri, M., Cupido, C. L., & Sturrock, E. D. (2013) · The Journal of Clinical Hypertension · doi:10.1111/jch.12104 · Cited by 42 · see citing works
Kinin-dependent hypersensitivity reactions in hemodialysis: metabolic and genetic factors
Molinaro, G., Duan, Q. L., Chagnon, M., Moreau, M. E., Simon, P., Clavel, P., Lavaud, S., Boileau, G., Rouleau, G. A., Lepage, Y., et al. (2006) · Kidney International · doi:10.1038/sj.ki.5001873 · Cited by 29 · see citing works
Self-citation
- Authors
- Moreau, M. E., Garbacki, N., Molinaro, G., Brown, N. J., Marceau, F., & Adam, A.
- Affiliations
- Université de Montréal (CA)
- University of Liège (BE)
- Vanderbilt University (US)
- Centre hospitalier universitaire de Québec (CA)
- Venue
- Journal of Pharmacological Sciences
- Publisher
- Japanese Pharmacological Society
- Published
- 2005
- Volume
- 99
- Issue
- 1
- Pages
- 6-38
- ISSN
- 1347-8613 (ISSN-L)
- 1347-8648
- OpenAlex
- W1967632907
- Semantic Scholar
- 11ef9af17a7b09227baf4d743022d17406b6c59a
- Cited by
- 457
- References
- 327
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 19 · 2023: 14 · 2022: 7 · 2021: 20 · 2020: 24 · 2019: 9 · 2018: 20 · 2017: 13 · 2016: 29 · 2015: 23 · 2014: 24 · 2013: 37 · 2012: 33
- FWCI
- 4.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Pharmacological Sciences (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- ORBi (University of Liège) (submittedVersion, other-oa)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL079184)
- Topics
- Health Sciences › Medicine › Genetics › Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pineapple and bromelain studies
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Keywords
- kallikrein-kinin system, bradykinin, kininogen, tissue kallikrein, plasma kallikrein, kinin receptors, metalloproteinases, antiproteases, serpins, pro-inflammatory effects, cardioprotection, renin-angiotensin system, coagulation, complement system, therapeutic target
- MeSH terms
- Angioedema, Angiotensin-Converting Enzyme Inhibitors, Animals, Bradykinin, Cardiovascular Diseases, Complement C1 Inactivator Proteins, Humans, Inflammation, Kallikreins, Aprotinin, Kidney Diseases, Peptidyl-Dipeptidase A, Kinins, Polymorphism, Genetic, Pyridines, Thiazepines, Neprilysin, Serpins, Randomized Controlled Trials as Topic, Kallikrein-Kinin System, Receptor, Bradykinin B2, Receptor, Bradykinin B1, Complement C1 Inhibitor Protein, Bradykinin B2 Receptor Antagonists
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