3D model (JSmol)
|Molar mass||060.228 g·mol−1 1|
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
|what is ?)(|
|Alt. symbols||KNG, BDK|
|Locus||Chr. 3 q21-qter|
Bradykinin is an inflammatory mediator. It is a peptide that causes blood vessels to dilate (enlarge), and therefore causes blood pressure to fall. A class of drugs called ACE inhibitors, which are used to lower blood pressure, increase bradykinin (by inhibiting its degradation), further lowering blood pressure. Bradykinin dilates blood vessels via the release of prostacyclin, nitric oxide, and Endothelium-Derived Hyperpolarizing Factor.
The kinin-kallikrein system makes bradykinin by proteolytic cleavage of its kininogen precursor, high-molecular-weight kininogen (HMWK or HK), by the enzyme kallikrein. Moreover, there is compelling evidence that plasmin, a fibrinolytic enzyme, is able to generate bradykinin after HMWK cleavage.
In humans, bradykinin is broken down by three kininases: angiotensin-converting enzyme (ACE), aminopeptidase P (APP), and carboxypeptidase N (CPN), which cleave the 7-8, 1-2, and 8-9 positions, respectively.
Physiological role (function)
Bradykinin is a potent endothelium-dependent vasodilator, leading to a drop in blood pressure. It also causes contraction of non-vascular smooth muscle in the bronchus and gut, increases vascular permeability and is also involved in the mechanism of pain. Bradykinin also causes natriuresis, contributing to the drop in blood pressure.
Bradykinin is also thought to be the cause of the dry cough in some patients on widely prescribed angiotensin-converting enzyme (ACE) inhibitor drugs. It is thought that bradykinin is converted to inactive metabolites by ACE, therefore inhibition of this enzyme leads to increased levels of bradykinin, which causes a dry cough via bronchoconstriction. In severe cases, the elevation of bradykinin may result in angioedema, a medical emergency. People of African descent have up to 5x increased risk of ACE inhibitor induced angioedema due to hereditary predisposing risk factors such as hereditary angioedema. This refractory cough is a common cause for stopping ACE inhibitor therapy, in which case angiotensin II receptor antagonists (ARBs) are the next line of treatment.
Initial secretion of bradykinin post-natally causes constriction and eventual atrophy of the ductus arteriosus, forming the ligamentum arteriosum between the pulmonary trunk and aortic arch. It also plays a role in the constriction and eventual occlusion of a number of other fetal vessels, including the umbilical arteries and vein. The differential vasoconstriction of these fetal vessels compared to the vasodilator response of other vessels suggest that the walls of these fetal vessels are different than other vessels.
- The B1 receptor (also called bradykinin receptor B1) is expressed only as a result of tissue injury, and is presumed to play a role in chronic pain. This receptor has been also described to play a role in inflammation. Most recently, it has been shown that the kinin B1 receptor recruits neutrophil via the chemokine CXCL5 production. Moreover, endothelial cells have been described as a potential source for this B1 receptor-CXCL5 pathway.
- The B2 receptor is constitutively expressed and participates in bradykinin's vasodilatory role.
The kinin B1 and B2 receptors belong to G protein coupled receptor (GPCR) family.
Bradykinin was discovered in 1948 by three Brazilian physiologists and pharmacologists working at the Instituto Biológico, in São Paulo, Brazil, led by Dr. Maurício Rocha e Silva. Together with colleagues Wilson Teixeira Beraldo and Gastão Rosenfeld, they discovered the powerful hypotensive effects of bradykinin in animal preparations. Bradykinin was detected in the blood plasma of animals after the addition of venom extracted from the Bothrops jararaca (Brazilian lancehead snake), brought by Rosenfeld from the Butantan Institute. The discovery was part of a continuing study on circulatory shock and proteolytic enzymes related to the toxicology of snake bites, started by Rocha e Silva as early as 1939. Bradykinin was to prove a new autopharmacological principle, i.e., a substance that is released in the body by a metabolic modification from precursors, which are pharmacologically active. According to B.J. Hagwood, Rocha e Silva's biographer, "The discovery of bradykinin has led to a new understanding of many physiological and pathological phenomena including circulatory shock induced by venoms and toxins." Etymology: brady [Gk] slow, kinin [Gk ] kīn(eîn) to move, set in motion, ? from the effect of snake venom on intestinal smooth muscle, which was noted to slowly contract.
The practical importance of the discovery of bradykinin became apparent when one of his collaborators at the Medical School of Ribeirão Preto at the University of São Paulo, Dr. Sérgio Henrique Ferreira, discovered a bradykinin-potentiating factor (BPF) in the bothropic venom, which increases powerfully both the duration and magnitude of its effects on vasodilation and the consequent fall in blood pressure. On the basis of this finding, Squibb scientists developed the first of a new generation of highly-effective anti-hypertensive drugs, the so-called ACE inhibitors, such as captopril (trademarked Capoten).
Currently, bradykinin inhibitors (antagonists) are being developed as potential therapies for hereditary angioedema. Icatibant is one such inhibitor. Additional bradykinin inhibitors exist. It has long been known in animal studies that bromelain, a substance obtained from the stems and leaves of the pineapple plant, suppresses trauma-induced swelling caused by the release of bradykinin into the bloodstream and tissues. Other substances that act as bradykinin inhibitors include aloe and polyphenols, substances found in red wine and green tea.
Role in carcinogenesis and progression
Bradykinins have been implicated in a number of cancer progression processes. Increased levels of bradykinins resulting from ACE inhibitor use have been associated with increased lung cancer risks Bradykinins have been implicated in cell proliferation and migration in gastric cancers, and bradykinin antagonists have been investigated as anti-cancer agents.
- Marcos-Contreras OA, Martinez de Lizarrondo S, Bardou I, Orset C, Pruvost M, Anfray A, Frigout Y, Hommet Y, Lebouvier L, Montaner J, Vivien D, Gauberti M (November 2016). "Hyperfibrinolysis increases blood-brain barrier permeability by a plasmin- and bradykinin-dependent mechanism". Blood. 128 (20): 2423–2434. doi:10.1182/blood-2016-03-705384. PMID 27531677.
- Dendorfer A, Wolfrum S, Wagemann M, Qadri F, Dominiak P (May 2001). "Pathways of bradykinin degradation in blood and plasma of normotensive and hypertensive rats". American Journal of Physiology. Heart and Circulatory Physiology. 280 (5): H2182–8. doi:10.1152/ajpheart.2001.280.5.H2182. PMID 11299220.
- Kuoppala A, Lindstedt KA, Saarinen J, Kovanen PT, Kokkonen JO (April 2000). "Inactivation of bradykinin by angiotensin-converting enzyme and by carboxypeptidase N in human plasma". American Journal of Physiology. Heart and Circulatory Physiology. 278 (4): H1069–74. doi:10.1152/ajpheart.2000.278.4.H1069. PMID 10749699.
- Mutschler, Ernst; Schäfer-Korting, Monika (1997). Arzneimittelwirkungen (in German) (7 ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. ISBN 978-3-8047-1377-2.
- Parpura V, Basarsky TA, Liu F, Jeftinija K, Jeftinija S, Haydon PG (June 1994). "Glutamate-mediated astrocyte-neuron signalling". Nature. 369 (6483): 744–7. Bibcode:1994Natur.369..744P. doi:10.1038/369744a0. PMID 7911978.
- Li HH (2018-05-22). "Angioedema: Practice Essentials, Background, Pathophysiology". Medscape.
- Guyer AC, Banerji A. "ACE inhibitor-induced angioedema". UpToDate. Retrieved 2018-06-03.
- Bas M, Adams V, Suvorava T, Niehues T, Hoffmann TK, Kojda G (August 2007). "Nonallergic angioedema: role of bradykinin". Allergy. 62 (8): 842–56. doi:10.1111/j.1398-9995.2007.01427.x. PMID 17620062.
- Standring, Susan (2016). "Chapter 52: Development of the thorax. Section: Changes in the Fetal Circulation and Occlusion of Fetal Vessels after Birth". Gray's anatomy : the anatomical basis of clinical practice. Standring, Susan (Forty-first ed.). [Philadelphia]. pp. 905–930. ISBN 9780702052309. OCLC 920806541.
- McLean PG, Ahluwalia A, Perretti M (August 2000). "Association between kinin B(1) receptor expression and leukocyte trafficking across mouse mesenteric postcapillary venules". The Journal of Experimental Medicine. 192 (3): 367–80. doi:10.1084/jem.192.3.367. PMC 2193221. PMID 10934225.
- Duchene J, Lecomte F, Ahmed S, Cayla C, Pesquero J, Bader M, Perretti M, Ahluwalia A (October 2007). "A novel inflammatory pathway involved in leukocyte recruitment: role for the kinin B1 receptor and the chemokine CXCL5". Journal of Immunology. 179 (7): 4849–56. doi:10.4049/jimmunol.179.7.4849. PMC 3696729. PMID 17878384.
- Lotz-Winter H (June 1990). "On the pharmacology of bromelain: an update with special regard to animal studies on dose-dependent effects". Planta Medica. 56 (3): 249–53. doi:10.1055/s-2006-960949. PMID 2203073.
- Bautista-Pérez R, Segura-Cobos D, Vázquez-Cruz B (July 2004). "In vitro antibradykinin activity of Aloe barbadensis gel". Journal of Ethnopharmacology. 93 (1): 89–92. doi:10.1016/j.jep.2004.03.030. PMID 15182910.
- Yagi A, Harada N, Yamada H, Iwadare S, Nishioka I (October 1982). "Antibradykinin active material in Aloe saponaria". Journal of Pharmaceutical Sciences. 71 (10): 1172–4. doi:10.1002/jps.2600711024. PMID 7143219.
- Richard T, Delaunay JC, Mérillon JM, Monti JP (December 2003). "Is the C-terminal region of bradykinin the binding site of polyphenols?". Journal of Biomolecular Structure & Dynamics. 21 (3): 379–85. doi:10.1080/07391102.2003.10506933. PMID 14616033.
- "Canadian Science Publishing". doi:10.1139/y02-030#.w9xy2ntkiuk (inactive 2019-02-15).
- Kmietowicz Z (October 2018). "ACE inhibitors are linked to increased lung cancer risk, study finds". BMJ. 363: k4471. doi:10.1136/bmj.k4471. PMID 30355572.
- Wang G, Sun J, Liu G, Fu Y, Zhang X (December 2017). "Bradykinin Promotes Cell Proliferation, Migration, Invasion, and Tumor Growth of Gastric Cancer Through ERK Signaling Pathway". Journal of Cellular Biochemistry. 118 (12): 4444–4453. doi:10.1002/jcb.26100. PMID 28464378.
- Stewart JM (2003). "Bradykinin antagonists as anti-cancer agents". Current Pharmaceutical Design. 9 (25): 2036–42. doi:10.2174/1381612033454171. PMID 14529414.