Bradykinin

BK, kinin-9, Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg; related kinins: Lys-bradykinin (kallidin), des-Arg9-bradykinin (the B1-receptor agonist metabolite). Drugs acting on the system: icatibant (#135, B2 antagonist), ecallantide, lanadelumab, berotralstat, sebetralstat, garadacimab (kallikrein/factor XIIa inhibitors), C1-esterase inhibitor concentrates; ACE inhibitors raise bradykinin as a side effect

Cardiovascular & circulation

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Summary

Class: Naturally occurring 9-amino-acid peptide (nonapeptide), cut from high-molecular-weight kininogen in plasma by the enzyme kallikrein
Mechanism: A local inflammatory mediator: dilates blood vessels, makes capillaries leak fluid (swelling), triggers pain nerves and causes cough and airway constriction — useful in tissue defence, harmful when overproduced as in hereditary angioedema
Routes studied: Intravenous, intra-arterial, intradermal and inhaled in human physiology research. Not a medicine. All approved drugs block its production or receptor
Half-life: ~15–30 seconds in plasma, destroyed by angiotensin-converting enzyme (kininase II), aminopeptidase P, neprilysin and carboxypeptidase N
Storage: Research reagent only
Regulatory status: Not a medicine. Bradykinin-pathway blockers approved for hereditary angioedema (see table)

Doses are as reported in studies or by the community — never recommendations.

1What it is

Bradykinin was discovered in 1949 by Rocha e Silva and colleagues in Brazil, who noticed that snake venom and trypsin acting on plasma produced a substance that made gut muscle contract slowly — hence brady (slow) kinin (movement). It is a nine-amino-acid peptide released from a large plasma protein, kininogen, by the enzyme kallikrein. Kallikrein is itself activated by factor XII of the clotting cascade, which is why clotting, inflammation and swelling are linked through this "contact system".

In health bradykinin is a short-lived local signal of injury: it opens up blood vessels, lets fluid and immune cells into tissue, and sensitises pain fibres — the redness, swelling and tenderness of inflammation are partly bradykinin at work. It also releases nitric oxide and prostacyclin from endothelium, which is cardioprotective, and in the kidney it promotes sodium excretion. Because it is destroyed within seconds by angiotensin-converting enzyme (ACE), drugs that block ACE for blood pressure also raise bradykinin — which is thought to contribute to their heart and kidney benefits but is also the cause of ACE-inhibitor cough and the rare but dangerous ACE-inhibitor angioedema.

The condition that made bradykinin a drug target is hereditary angioedema (HAE), in which an inherited deficiency of C1-esterase inhibitor leaves kallikrein unchecked and bradykinin surges cause recurrent, sometimes life-threatening swelling of the face, airway and gut. Since 2008 a series of medicines have been developed to block the system at different points. Bradykinin itself is never given therapeutically. Community/self-directed use: essentially none documented.

2How it's thought to work

B2 receptor. constitutively expressed on endothelium, smooth muscle, nerves and many other cells; mediates most acute bradykinin actions — vasodilation (via nitric oxide and prostacyclin), increased vascular permeability, bronchoconstriction, pain. Icatibant blocks it.

B1 receptor. barely present in healthy tissue but induced by inflammation and tissue injury; responds preferentially to the metabolite des-Arg9-bradykinin and sustains chronic inflammatory pain. B1 antagonists have been tested for pain without success.

Generation. two kallikreins — plasma kallikrein (from factor XII activation, making bradykinin) and tissue kallikrein (making kallidin, which is converted to bradykinin). HAE therapies target plasma kallikrein (ecallantide, lanadelumab, berotralstat, sebetralstat) or factor XIIa (garadacimab), or replace the natural brake, C1-inhibitor.

Breakdown. ACE is the main destroyer; neprilysin, aminopeptidase P and dipeptidyl peptidase IV contribute. Combining an ACE inhibitor with a neprilysin inhibitor produced unacceptable angioedema rates (omapatrilat, OCTAVE trial), which shaped the design of sacubitril/valsartan (#167).

Cardiovascular protection. bradykinin contributes to ischaemic preconditioning, improves insulin-mediated glucose uptake and endothelial function — the "good" side exploited indirectly by ACE inhibitors.

Bradykinin at the B2 receptor on the endothelium. Nitric oxide and prostacyclin follow, the vessel widens, and the junctions between endothelial cells loosen so fluid passes into the tissue — the swelling and pain of an inflamed site.Schematic — not to scale

3What the research shows

Bradykinin infusion physiology

Intra-arterial bradykinin produces dose-dependent forearm vasodilation that is enhanced by ACE inhibition and reduced by nitric-oxide synthase blockade (Cockcroft 1994, J Cardiovasc Pharmacol; Hornig 1997, Circulation). B2 blockade with icatibant blunts roughly a third of the acute blood-pressure-lowering effect of ACE inhibitors in humans (Gainer 1998, NEJM), demonstrating bradykinin's contribution. Intradermal injection causes wheal, flare and pain; inhaled bradykinin triggers cough and bronchoconstriction in asthmatics but not healthy subjects. [3]

Graded A (mechanistic and therapeutic)

Bradykinin as the cause of hereditary angioedema

Plasma bradykinin rises sharply during HAE attacks (Nussberger 1998, Lancet). Blocking the pathway at any point treats or prevents attacks: icatibant (#135) resolved attacks faster than placebo in FAST-1/2/3 (Cicardi 2010, NEJM; Lumry 2011); ecallantide likewise (EDEMA3/4); lanadelumab reduced attack rate by ~87% in HELP (Banerji 2018, JAMA); berotralstat, an oral kallikrein inhibitor, reduced attacks by ~44% in APeX-2 (Zuraw 2021, J Allergy Clin Immunol). The oral on-demand kallikrein inhibitor sebetralstat (Ekterly) received FDA approval on 3 July 2025 for patients aged 12 and over, based on KONFIDENT (Riedl 2024, NEJM): median time to beginning of symptom relief 1.61 h (300 mg) and 1.79 h (600 mg) versus 6.72 h with placebo. Garadacimab (anti-factor XIIa) was approved in 2025 for prophylaxis †; donidalorsen (antisense against prekallikrein) also reached approval in 2025 †. [4][5][6][7][8]

ACE-inhibitor angioedema and cough

ACE-inhibitor angioedema (0.1–0.7% of users, more common in Black patients) is bradykinin-mediated; icatibant was tested as a treatment with one positive (Baş 2015, NEJM, n=27) and one larger negative trial (Sinert 2017, J Allergy Clin Immunol Pract), so it is not established. Bradykinin and substance P accumulation explain the dry cough in 5–20% of ACE-inhibitor users, which ARBs lack. [9][10]

Graded D/B (negative)

COVID-19 "bradykinin storm" hypothesis

A 2020 transcriptomic analysis proposed excess bradykinin in severe COVID-19 (Garvin 2020, eLife). Small trials of icatibant and lanadelumab in hospitalised patients did not show convincing benefit †; the hypothesis remains unproven.

Graded C/D

Pain and inflammation

B1 and B2 antagonists reduce inflammatory pain in rodent models; human trials of B1 antagonists for osteoarthritis and other pain were disappointing and discontinued. Bradykinin is a standard algogen (pain-provoking agent) in human experimental pain studies.

Graded C/B

Cardioprotection

Rodent and isolated-heart work shows bradykinin mediates preconditioning; in humans, B2 blockade reduces the benefit of ACE inhibition on endothelial function, and kininogen-deficient individuals have been reported with normal health but altered responses, suggesting redundancy.

4Reported side effects and interactions

Literature-reported

Literature (bradykinin given in research). flushing, headache, hypotension and tachycardia with systemic infusion; local pain, wheal and flare intradermally; cough and bronchospasm when inhaled by asthmatics. Effects last seconds to minutes.

Literature (pathway blockers). icatibant — injection-site reactions in almost all patients; lanadelumab — injection-site reactions, dizziness; berotralstat — GI upset, QT prolongation at high doses; sebetralstat — headache, generally well tolerated in KONFIDENT; C1-inhibitor concentrates — rare thrombosis with high doses. Theoretical concern with long-term kallikrein inhibition is impaired bradykinin-mediated cardiovascular protection; not seen in trials to date.

Community-reported

none documented.

Theoretical. chronic B2 blockade might blunt the vascular benefits of ACE inhibitors; relevant only if both are used long term.

Interactions. ACE inhibitors raise bradykinin and are contraindicated or avoided in HAE; neprilysin inhibitors plus ACE inhibitors give unacceptable angioedema risk (36-hour rule for sacubitril/valsartan); DPP-4 inhibitors (gliptins) modestly impair bradykinin breakdown and increase ACE-inhibitor angioedema risk; oestrogens increase kininogen and worsen HAE; tissue plasminogen activator (alteplase) activates kallikrein and can cause orolingual angioedema, especially in ACE-inhibitor users.

Markers researchers commonly monitor

Bradykinin itself is not given clinically; monitoring relates to the disease and to pathway-blocking drugs:

Marker	Why it's watched
C4, C1-inhibitor level and function	the diagnostic markers of hereditary angioedema (C4 is low in almost all untreated HAE).
Attack frequency and severity diaries	the primary outcome in every HAE prophylaxis trial.
Plasma bradykinin / cleaved high-molecular-weight kininogen	research markers of pathway activation; bradykinin assays are technically difficult because of its 30-second half-life.
ECG (QT interval)	with berotralstat at higher doses.
Liver enzymes	periodically with oral kallikrein inhibitors †.
Blood pressure and heart rate	during any research infusion.
D-dimer, factor XII activity	in contact-system research; note D-dimer rises during HAE attacks without thrombosis.

Free for everyone. Safety information is never behind a paywall.

5Reconstitution and handling

Bradykinin acetate is a research-grade peptide for laboratory and clinical physiology use, stored frozen and dissolved immediately before use because it degrades rapidly in plasma-containing solutions. No pharmaceutical presentation and no self-administered dose exist. Approved HAE drugs are supplied as prefilled syringes, vials or tablets with their own instructions. The site calculator is not applicable.

6Commonly studied alongside

Icatibant (#135), ecallantide, lanadelumab, berotralstat, sebetralstat, garadacimab, C1-esterase inhibitor (the HAE armamentarium); ACE inhibitors and sacubitril/valsartan (drugs that raise bradykinin); the natriuretic peptides (#167) and endothelin-1 (#168) as fellow vascular peptides; substance P and CGRP (co-mediators of neurogenic inflammation and cough); nitric oxide and prostacyclin (its downstream effectors).

Informational cross-links. Not stack recommendations.

7Regulatory status by region

Region	Status (checked —)
United States	Bradykinin not a medicine. Pathway blockers FDA-approved for HAE: C1-inhibitor concentrates (Cinryze 2008, Berinert 2009, Haegarda 2017, Ruconest 2014), ecallantide (Kalbitor, 2009), icatibant (Firazyr, 2011; generics), lanadelumab (Takhzyro, 2018), berotralstat (Orladeyo, 2020), sebetralstat (Ekterly, 3 July 2025, ≥12 years), garadacimab (Andembry, 2025) †, donidalorsen (Dawnzera, 2025) †
European Union	Icatibant, C1-inhibitors, lanadelumab, berotralstat authorised; ecallantide not authorised; garadacimab authorised 2025 †; sebetralstat under review or recently authorised †
United Kingdom	As EU; HAE therapies NHS-commissioned through specialist immunology centres; sebetralstat MHRA status †
Australia	Icatibant, C1-inhibitor, lanadelumab, berotralstat TGA-registered †
South Africa	Icatibant and C1-inhibitor registered †; newer agents not registered †
Sport	Bradykinin and HAE therapies not listed by WADA

8Open questions

Does raising bradykinin account for a meaningful share of ACE-inhibitor cardiovascular benefit, or is it mainly a side-effect pathway?
Will long-term kallikrein or factor XIIa inhibition reveal any cost in vascular protection or thrombosis?
Can B1-receptor antagonism ever deliver on its preclinical promise for chronic inflammatory pain?
Is there a bradykinin-mediated component to other swelling disorders (idiopathic angioedema, capillary leak syndromes) that pathway blockers could treat?

9References

1Rocha 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. Am J Physiol. PubMed
2Leeb-Lundberg LMF et al. (2005). International Union of Pharmacology. XLV. Classification of the kinin receptor family: from molecular mechanisms to pathophysiological consequences. Pharmacol Rev. PubMed · DOI
3Gainer JV et al. (1998). Effect of bradykinin-receptor blockade on the response to angiotensin-converting-enzyme inhibitor in normotensive and hypertensive subjects. NEJM. PubMed · DOI
4Nussberger J et al. (1998). Plasma bradykinin in angio-oedema. Lancet. PubMed · DOI
5Cicardi M et al. (2010). Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema (FAST-1 and FAST-2). NEJM. PubMed · DOI
6Banerji A et al. (2018). Effect of lanadelumab compared with placebo on prevention of hereditary angioedema attacks (HELP). JAMA. PubMed · DOI
7Zuraw B et al. (2021). Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: a randomized, double-blind, placebo-controlled phase 3 trial (APeX-2). J Allergy Clin Immunol. PubMed · DOI
8Riedl MA et al. (2024). Oral sebetralstat for on-demand treatment of hereditary angioedema attacks (KONFIDENT). NEJM. PubMed · DOI
9Baş M et al. (2015). A randomized trial of icatibant in ACE-inhibitor-induced angioedema. NEJM. PubMed · DOI
10Sinert R et al. (2017). Randomized trial of icatibant for angiotensin-converting enzyme inhibitor-induced upper airway angioedema. J Allergy Clin Immunol Pract. PubMed · DOI
11Kaplan AP, Joseph K (2010). The bradykinin-forming cascade and its role in hereditary angioedema. Ann Allergy Asthma Immunol. PubMed · DOI
12US FDA (2025). Ekterly (sebetralstat) prescribing information and approval notice, July 2025. PubMed

References are being resolved to PubMed/DOI identifiers; links search PubMed for the citation until then.

† Being confirmed by our reviewers against current sources.

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30 Oct 2026Profile published — awaiting medical review

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