3D model (JSmol)
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|Molar mass||1,060.23 g·mol−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.
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