Bradykinin
BK, kinin-9, RPPGFSPFR, KNG1-derived kinin
Bradykinin is a nine-residue kinin released from kininogen by plasma kallikrein during contact system activation. It is a potent vasodilator and permeability factor, and a direct algogen at sensory nerve endings. The kallikrein-kinin axis is one of the best-validated targets in medicine, underpinning all modern hereditary angioedema treatment.
Mechanism
High-molecular-weight kininogen, encoded by KNG1, is cleaved by plasma kallikrein to liberate bradykinin; tissue kallikrein instead releases kallidin (Lys-bradykinin) from low-molecular-weight kininogen. The trigger is contact system activation, in which factor XII autoactivates on negatively charged surfaces and converts prekallikrein to kallikrein, a loop normally restrained by C1 esterase inhibitor. Loss of that restraint in hereditary angioedema types I and II produces unopposed bradykinin generation, which is the direct cause of attacks.
Bradykinin acts at two receptors. B2 is constitutively expressed and mediates the acute response: endothelial Gq signalling raises intracellular calcium, activating endothelial nitric oxide synthase and phospholipase A2, producing vasodilatation, prostaglandin release and, critically, opening of interendothelial junctions with plasma extravasation and tissue oedema. B1 is barely expressed at baseline but is strongly induced by inflammation and by interleukin-1, and responds to the des-Arg metabolites, sustaining chronic inflammatory pain. On sensory neurons B2 activation directly excites and sensitises nociceptors, partly by phosphorylating TRPV1, making bradykinin one of the few substances that produces pain on application to human skin blister bases.
What the research shows
The decisive evidence is in hereditary angioedema. Icatibant, a selective B2 receptor antagonist, produced significantly faster symptom relief than placebo in randomised trials, establishing that blocking the bradykinin receptor alone aborts attacks and confirming bradykinin as the direct mediator. Upstream kallikrein blockade works equally well: ecallantide, lanadelumab, berotralstat and, most recently, oral sebetralstat have all shown benefit. In the KONFIDENT crossover trial, sebetralstat gave faster onset of symptom relief than placebo, with median times of 1.61 hours at 300 mg and 1.79 hours at 600 mg, and faster attack resolution.
Outside hereditary angioedema the record is poor, and this is important. Icatibant failed in a randomised trial of ACE inhibitor-induced upper airway angioedema despite an apparently identical mechanism: in 121 patients, median time to meeting discharge criteria was 4.0 hours in both groups. Bradykinin-directed approaches have also not translated into useful analgesics despite the peptide being a proven human algogen, and B1 antagonists developed for chronic pain have not succeeded. The lesson is that a mediator can be causal in one syndrome and unhelpful as a drug target in another.
Evidence assessment
High-quality evidence
Regulator-approved labelling exists in both the US and UK for icatibant, a selective B2 antagonist, and for multiple kallikrein-directed agents, supported by replicated randomised placebo-controlled trials with verified publications, including a recent phase 3 crossover trial in the New England Journal of Medicine. The pathway is definitively validated in humans. Note that the strong rating covers pathway blockade, and that a verified negative trial in a different indication is included deliberately.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema Preclinical only
Selective B2 receptor blockade shortened time to clinically significant symptom relief, proving bradykinin is the direct mediator of hereditary angioedema attacks.
Oral Sebetralstat for On-Demand Treatment of Hereditary Angioedema Attacks Preclinical only
Median time to beginning of symptom relief was 1.61 hours (300 mg) and 1.79 hours (600 mg) versus placebo, with faster attack resolution.
Randomized Trial of Icatibant for Angiotensin-Converting Enzyme Inhibitor-Induced Upper Airway Angioedema Preclinical only
Icatibant did not improve time to meeting discharge criteria versus placebo (median 4.0 hours in each group, P=.63), nor time to onset of symptom relief. An important negative result despite a shared mechanism.
Safety
Bradykinin is not administered therapeutically; experimental application causes pain, flushing, hypotension and bronchoconstriction. For the licensed antagonists, icatibant commonly causes injection site reactions and is otherwise well tolerated. The clinically important safety point runs the other way: ACE inhibitors raise bradykinin, causing cough in a substantial minority of patients and rare but potentially fatal angioedema, and this risk is increased when combined with neprilysin inhibition or with DPP-4 inhibitors.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | No UK marketing authorisation for bradykinin. Icatibant, lanadelumab, berotralstat and C1 esterase inhibitor concentrates hold MHRA authorisation for hereditary angioedema, with NICE guidance on their use. |
| United States | Bradykinin has no FDA approval. FDA has approved icatibant (B2 antagonist), ecallantide, lanadelumab, berotralstat and sebetralstat for hereditary angioedema, all acting on the kallikrein-kinin pathway. |
| WADA (sport) | Bradykinin is not named on the Prohibited List and would fall under section S0 as a non-approved substance. The licensed antagonists used for hereditary angioedema are not prohibited. |
Questions
Angiotensin-converting enzyme is the main enzyme that destroys bradykinin. Inhibiting it raises bradykinin levels, sensitising airway sensory nerves (cough) and increasing vascular permeability, which occasionally produces angioedema.
It has not worked. Bradykinin reliably produces pain when applied to human tissue, but B1 and B2 antagonists developed as analgesics have failed to show useful clinical benefit. Causal mediator does not automatically mean good drug target.