A class of drugs called
angiotensin-converting-enzyme inhibitors (ACE inhibitors) increase bradykinin levels by inhibiting its degradation, thereby increasing its blood pressure lowering effect. ACE inhibitors are FDA approved for the treatment of
hypertension and
heart failure.
Structure
Bradykinin, sometimes referred to as BK, is a 9–amino acid
peptide chain. The
amino acid sequence of bradykinin is:
Arg-
Pro-
Pro-
Gly-
Phe-
Ser-
Pro-
Phe-
Arg (RPPGFSPFR).[1] Its empirical formula is therefore C 50H 73N 15O 11.
Bradykinin is a potent
endothelium-dependent
vasodilator and mild
diuretic, which may cause a lowering of the 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.[5]
During inflammation, it is released locally from
mast cells and
basophils during tissue damage.[6] Specifically in relation to pain, bradykinin has been shown to sensitize
TRPV1 receptors, thus lowering the temperature threshold at which they activate, thus presumably contributing to
allodynia.[7]
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 suggests that the walls of these fetal vessels are different from other vessels.[8]
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.[9] It was 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.[10]
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.
Disorders
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; increased bradykinin sensitizes somatosensory fibers and thus causes hyperalgesia. Bradykinin may mediate this via pro-inflammatory peptides (e.g.
substance P,
neuropeptide Y) and a local release of
histamine.[11][12]
In severe cases, the elevation of bradykinin may result in
angioedema, a medical emergency.[13] People of African descent have up to five times increased risk of ACE inhibitor induced angioedema due to hereditary predisposing risk factors such as
hereditary angioedema.[14] This refractory cough is a common cause for stopping
ACE inhibitor therapy.
Overactivation of bradykinin is thought to play a role in a rare disease called
hereditary angioedema.[15]
Low levels of bradykinin in the body correlate to with obesity in adolescents; it has been proposed that bradykinin can be used as a
biomarker for
metabolic syndrome.[16]
Bradykinins have been implicated in a number of cancer progression processes.[17] Increased levels of bradykinins resulting from ACE inhibitor use have been associated with increased lung cancer risks.[18] Bradykinins have been implicated in cell proliferation and migration in gastric cancers,[19] and bradykinin antagonists have been investigated as anti-cancer agents.[20]
Bradykinin has been proposed as an explanation for many symptoms associated with
COVID-19, including dry coughs,
myalgia, fatigue, nausea, vomiting, diarrhea, anorexia, headaches, decreased cognitive function,
arrhythmia, and sudden cardiac death.[21]
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.[23] Other substances that act as bradykinin inhibitors include
aloe[24][25] and
polyphenols, substances found in red wine and green tea.[26]
The discovery of bradykinin has led to a new understanding of many physiological and pathological phenomena including circulatory shock induced by venoms and toxins.
See also
Look up bradykinin in Wiktionary, the free dictionary.
^Mutschler E, Schäfer-Korting M (1997). Arzneimittelwirkungen (in German) (7 ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft.
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^Standring S, Gray H (2016). "Ch. 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 (41st ed.). Elsevier. pp. 905–930.
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^Stewart JM, Gera L, Chan DC, Bunn PA, York EJ, Simkeviciene V, Helfrich B (April 2002). "Bradykinin-related compounds as new drugs for cancer and inflammation". Canadian Journal of Physiology and Pharmacology. 80 (4): 275–80.
doi:
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^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:
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PMID28464378.
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^Stewart JM (2003). "Bradykinin antagonists as anti-cancer agents". Current Pharmaceutical Design. 9 (25): 2036–42.
doi:
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^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.
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^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:
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^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.
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10.1080/07391102.2003.10506933.
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^Rocha e Silva M, Beraldo WT, Rosenfeld G (1949). "Bradykinin, a hypotensive and smooth muscle stimulating factor released from plasma globulin by snake venoms and by trypsin". American Journal of Physiology. 156 (2): 261–73.
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