Bradykinin: Difference between revisions

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|SystematicName=(2''S'')-2-{(1²''S'',3²''S'',9''S'',12''S'',14²''S'',17''S'')-1¹-[(2''S'')-2-Amino-5-(carbamimidoylamino)pentanoyl]-9-benzyl-12-(hydroxymethyl)-2,4,7,10,13,15-hexaoxo-5,8,11,16-tetraaza-1(2),3,14(1,2)-tripyrrolidina-19-benzenanonadecaphane-17-carboxamido}-5-(carbamimidoylamino)pentanoic acid

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| C50H73N15O11

{{protein

'''Bradykinin (BK)''' (from Greek ''brady-'' 'slow' + ''-kinin'', ''kīn(eîn)'' 'to move') is a [[peptide]] that promotes [[inflammation]]. It causes [[arteriole]]s to dilate (enlarge) via the release of [[prostacyclin]], [[nitric oxide]], and [[endothelium-derived hyperpolarizing factor]] and makes veins constrict, via [[prostaglandin F2]], thereby leading to leakage into capillary beds, due to the increased pressure in the capillaries. Bradykinin consists of nine [[amino acid]]s, and is a physiologically and pharmacologically active peptide of the [[kinin]] group of [[protein]]s.

A class of drugs called [[angiotensin-converting-enzyme inhibitor]]s (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 [[Translation (genetics)|peptide chain]]. The [[amino acid]] sequence of bradykinin is: [[arginine|Arg]]-[[proline|Pro]]-[[proline|Pro]]-[[glycine|Gly]]-[[phenylalanine|Phe]]-[[serine|Ser]]-[[proline|Pro]]-[[phenylalanine|Phe]]-[[arginine|Arg]] (RPPGFSPFR).<ref name="RPTH">{{cite journal |last1=Pinheiro |first1=AS |last2=Silbak |first2=S |last3=Schmaier |first3=AH |title=Bradykinin — An elusive peptide in measuring and understanding. |journal=Research and Practice in Thrombosis and Haemostasis |date=February 2022 |volume=6 |issue=2 |pages=e12673 |doi=10.1002/rth2.12673 |pmid=35252738 |pmc=8886326 }}</ref> Its empirical formula is therefore {{chem|C|50|H|73|N|15|O|11}}.

The [[kinin–kallikrein system]] makes bradykinin by [[proteolysis|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.<ref>{{cite journal | vauthors = 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 | display-authors = 6 | title = Hyperfibrinolysis increases blood-brain barrier permeability by a plasmin- and bradykinin-dependent mechanism | journal = Blood | volume = 128 | issue = 20 | pages = 2423–2434 | date = November 2016 | pmid = 27531677 | doi = 10.1182/blood-2016-03-705384 | doi-access = free }}</ref>

In humans, bradykinin is broken down by many different [[-ase|kininases]]: [[angiotensin-converting enzyme]] (ACE, kininase II), [[neprilysin]],<ref>{{Cite web|title=MME membrane metalloendopeptidase [Homo sapiens (human)] |url= https://www.ncbi.nlm.nih.gov/gene/4311|access-date=2022-02-06|website=www.ncbi.nlm.nih.gov}}</ref> NEP2, [[aminopeptidase]] P (APP), [[carboxypeptidase]] N (CPN, kininase I), Carboxypeptidase M, Neutral endopeptidase 24.15, Endothelin converting enzyme-1, Endothelin converting enzyme-2.<ref>{{cite journal | vauthors = Campbell DJ | title = Neprilysin Inhibitors and Bradykinin | journal = Frontiers in Medicine | volume = 5 | pages = 257 | date = 2018-09-19 | pmid = 30283782 | pmc = 6157573 | doi = 10.3389/fmed.2018.00257 | doi-access = free }}</ref>

== Function ==

===Effects===

Bradykinin is a potent [[endothelium]]-dependent [[Vasodilation|vasodilator]], causes contraction of non-vascular [[smooth muscle]], increases vascular [[Vascular permeability|permeability]] and is involved in the mechanism of [[pain]]. ,

During inflammation, it is released locally from [[mast cell]]s and [[basophil]]s during tissue damage.<ref>{{cite journal | vauthors = Dray A, Perkins M | title = Bradykinin and inflammatory pain | journal = Trends in Neurosciences | volume = 16 | issue = 3 | pages = 99–104 | date = March 1993 | pmid = 7681240 | doi = 10.1016/0166-2236(93)90133-7 | s2cid = 4061940 }}</ref> 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]].<ref>{{cite journal | vauthors = Mathivanan S, Devesa I, Changeux JP, Ferrer-Montiel A | title = Bradykinin Induces TRPV1 Exocytotic Recruitment in Peptidergic Nociceptors | journal = Frontiers in Pharmacology | volume = 7 | pages = 178 | date = 2016-06-23 | pmid = 27445816 | pmc = 4917537 | doi = 10.3389/fphar.2016.00178 | doi-access = free }}</ref>

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.<ref>{{Cite book | vauthors = Standring S, Gray H |title=Gray's Anatomy: The Anatomical Basis of Clinical Practice |publisher=Elsevier |year=2016 |isbn=9780702052309 |edition=41st |pages=905–930 |chapter=Ch. 52: Development of the thorax. Section: Changes in the Fetal Circulation and Occlusion of Fetal Vessels after Birth |oclc=920806541 }}</ref>

{{Main|Bradykinin receptor}}

* 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]].<ref name="pmid10934225">{{cite journal | = McLean PG, Ahluwalia A, Perretti M | title = Association between kinin B(1) receptor expression and leukocyte trafficking across mouse mesenteric postcapillary venules | journal = | volume = 192 | issue = 3 | pages = 367–80 | = 2000 | pmid = 10934225 | pmc = 2193221 | doi = 10.1084/jem.192.3.367 }}</ref> 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.<ref name="pmid17878384">{{cite journal | = Duchene J, Lecomte F, Ahmed S, Cayla C, Pesquero J, Bader M, Perretti M, Ahluwalia A | title = A novel inflammatory pathway involved in leukocyte recruitment: role for the kinin B1 receptor and the chemokine CXCL5 | journal = | volume = 179 | issue = 7 | pages = 4849–56 | = 2007 | pmid = 17878384 | = | = }}</ref>

* The B₂ receptor is constitutively expressed and participates in bradykinin's vasodilatory role.

====

Bradykinin is also thought to be the cause of the dry cough in some patients on widely prescribed [[angiotensin-converting enzyme]] [[ACE inhibitor|(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]].<ref>{{cite journal | vauthors = Fox AJ, Lalloo UG, Belvisi MG, Bernareggi M, Chung KF, Barnes PJ | title = Bradykinin-evoked sensitization of airway sensory nerves: a mechanism for ACE-inhibitor cough | journal = Nature Medicine | volume = 2 | issue = 7 | pages = 814–7 | date = July 1996 | pmid = 8673930 | doi = 10.1038/nm0796-814 | s2cid = 6040673 }}</ref><ref>{{cite journal | vauthors = Karlberg BE | title = Cough and inhibition of the renin-angiotensin system | journal = Journal of Hypertension Supplement | volume = 11 | issue = 3 | pages = S49-52 | date = April 1993 | pmid = 8315520 }}</ref>

In severe cases, the elevation of bradykinin may result in [[angioedema]], a medical emergency.<ref>{{cite journal | vauthors = Li HH | date=2018-05-22|title=Angioedema: Practice Essentials, Background, Pathophysiology | journal = Medscape | url = https://emedicine.medscape.com/article/135208-overview#a3 }}</ref> 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]].<ref>{{cite web | vauthors = Guyer AC, Banerji A | url = https://www.uptodate.com/contents/ace-inhibitor-induced-angioedema#! | title = ACE inhibitor-induced angioedema |work = UpToDate |access-date=2018-06-03}}</ref> 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 [[]].<ref name="pmid17620062">{{cite journal | = Bas M, Adams V, Suvorava T, Niehues T, Hoffmann TK, Kojda G | title = Nonallergic angioedema: role of bradykinin | journal = Allergy | volume = 62 | issue = 8 | pages = 842–56 | = 2007 | pmid = 17620062 | doi = 10.1111/j.1398-9995.2007.01427.x | = }}</ref>

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]].<ref>{{Cite journal |last1=Sugawara |first1=Akira |last2=Shimada |first2=Hiroki |last3=Otsubo |first3=Yuri |last4=Kouketsu |first4=Takumi |last5=Suzuki |first5=Susumu |last6=Yokoyama |first6=Atsushi |date=2021-05-27 |title=The usefulness of angiotensin-(1-7) and des-Arg9-bradykinin as novel biomarkers for metabolic syndrome |journal=Hypertension Research |language=en |volume=44 |issue=8 |pages=1034–1036 |doi=10.1038/s41440-021-00671-9 |pmid=34045691 |s2cid=235206108 |issn=1348-4214|doi-access=free }}</ref>

Bradykinins have been implicated in a number of cancer progression processes.<ref name="pmid12025961">{{cite journal | vauthors = Stewart JM, Gera L, Chan DC, Bunn PA, York EJ, Simkeviciene V, Helfrich B | title = Bradykinin-related compounds as new drugs for cancer and inflammation | journal = Canadian Journal of Physiology and Pharmacology | volume = 80 | issue = 4 | pages = 275–80 | date = April 2002 | pmid = 12025961 | doi = 10.1139/y02-030 }}</ref> Increased levels of bradykinins resulting from ACE inhibitor use have been associated with increased lung cancer risks.<ref>{{cite journal | vauthors = Kmietowicz Z | title = ACE inhibitors are linked to increased lung cancer risk, study finds | journal = BMJ | volume = 363 | pages = k4471 | date = October 2018 | pmid = 30355572 | doi = 10.1136/bmj.k4471 | s2cid = 53024740 }}</ref> Bradykinins have been implicated in cell proliferation and migration in gastric cancers,<ref>{{cite journal | vauthors = Wang G, Sun J, Liu G, Fu Y, Zhang X | title = Bradykinin Promotes Cell Proliferation, Migration, Invasion, and Tumor Growth of Gastric Cancer Through ERK Signaling Pathway | journal = Journal of Cellular Biochemistry | volume = 118 | issue = 12 | pages = 4444–4453 | date = December 2017 | pmid = 28464378 | doi = 10.1002/jcb.26100 | s2cid = 3954713 }}</ref> and bradykinin antagonists have been investigated as anti-cancer agents.<ref>{{cite journal | vauthors = Stewart JM | title = Bradykinin antagonists as anti-cancer agents | journal = Current Pharmaceutical Design | volume = 9 | issue = 25 | pages = 2036–42 | date = 2003 | pmid = 14529414 | doi = 10.2174/1381612033454171 }}</ref>

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.<ref>{{cite journal | vauthors = Garvin MR, Alvarez C, Miller JI, Prates ET, Walker AM, Amos BK, et. al. | title = A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm | journal = eLife | date = July 7, 2020 | volume = 9 | doi = 10.7554/eLife.59177 | pmid = 32633718 | pmc = 7410499 | doi-access = free }}</ref>

==Therapeutic ==

A [[bradykinin potentiating factor|bradykinin-potentiating factor]] (BPF) which increases both the duration and magnitude of the effects of bradykinin on vasodilation and the consequent fall in [[blood pressure]], was discovered in ''[[Bothrops jararaca]]'' venom.<ref name="pmid14302350">{{cite journal | vauthors = Ferreira S | title = A bradykinin-potentiation factor (BPF) present in the venom of Bothrops jararaca | journal = British Journal of Pharmacology and Chemotherapy | volume = 24 | issue = 1 | pages = 163–69 | date = 1965 | pmid = 14302350 | pmc=1704050 |doi = 10.1111/j.1476-5381.1965.tb02091.x | doi-access = free }}</ref> On the basis of this finding, a non-protein analog of BPF which was effective orally was developed: the first [[angiotensin converting enzyme inhibitor]] [[captopril]]. {{citation needed|date=April 2019}} It was approved by the FDA for the treatment of hypertension in 1981.{{citation needed|date=April 2019}}

Currently, bradykinin inhibitors ([[Receptor antagonist|antagonists]]) are being developed as potential therapies for [[Angioedema#Hereditary|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.<ref>Lotz-Winter H On the pharmacology of bromelain: an update with special regard to animal studies on dose-dependent effects Planta 563.</ref> Other substances that act as bradykinin inhibitors include [[aloe]]<ref name="pmid15182910">{{cite journal | = Bautista-Pérez R, Segura-Cobos D, Vázquez-Cruz B | title = In vitro antibradykinin activity of Aloe barbadensis gel | journal = | volume = 93 | issue = 1 | pages = 89–92 | = 2004 | pmid = 15182910 | doi = 10.1016/j.jep.2004.03.030 }}</ref><ref name="pmid7143219">{{cite journal | = Yagi A, Harada N, Yamada H, Iwadare S, Nishioka I | title = Antibradykinin active material in Aloe saponaria | journal = | volume = 71 | issue = 10 | pages = 1172–4 | = 1982 | pmid = 7143219 | doi = 10.1002/jps.2600711024 }}</ref> and [[polyphenol]]s, substances found in red wine and green tea.<ref name="pmid14616033">{{cite journal | = Richard T, Delaunay JC, Mérillon JM, Monti JP | title = Is the C-terminal region of bradykinin the binding site of polyphenols? | journal = | volume = 21 | issue = 3 | pages = 379–85 | = 2003 | pmid = 14616033 | doi = | = }}</ref>

==History==

Bradykinin was discovered in 1948 by three [[Brazil]]ian physiologists and pharmacologists working at the [[ ]], in [[São Paulo ()|São Paulo]], [[Brazil]], led by Dr. [[Maurício Rocha e Silva]]. Together with colleagues [[Wilson Teixeira Beraldo]] and [[Gastão Rosenfeld]], they discovered the powerful [[hypotension|hypotensive]] effects of bradykinin in [[animal model|animal preparations]]. Bradykinin was detected in the [[blood plasma]] of animals after the addition of [[venom (poison)|venom]] extracted from the ''[[Bothrops jararaca]]'' (Brazilian [[lancehead]] [[snake]]), brought by Rosenfeld from the [[Instituto Butantan|Butantan Institute]]. The discovery was part of a continuing study on circulatory [[Shock ()|shock]] and [[proteolysis|proteolytic]] [[enzyme]]s related to the [[toxicology]] of snake bites, started by Rocha e Silva as early as 1939. Bradykinin was to prove a new [[autopharmacology|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 biographerThe 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==

{{wiktionary|bradykinin}}

==References==

{{Reflist}}

{{Transient receptor potential channel modulators}}

[[Category: system]]

[[Category:Nonapeptides]]