The kallikrein-kinin system (KKS) generates bradykinin and related kinins from high-molecular-weight kininogen (HMWK) via plasma kallikrein, and from low-molecular-weight kininogen (LMWK) via tissue kallikrein. Bradykinin acts on B2 receptors (constitutive, ubiquitous) → vasodilation, increased capillary permeability, NO release from endothelium, prostaglandin generation (cross-link arachidonic acid cascade), sensory neuron C-fiber activation (pain, cough). B1 receptors are induced by inflammation and respond to des-Arg9-bradykinin. Bradykinin is rapidly degraded by ACE (kininase II — primary), neutral endopeptidase, aminopeptidase P, carboxypeptidase N. Clinical relevance — ACE inhibitor adverse effects: ACE-I (captopril, enalapril, lisinopril, ramipril, etc.) block bradykinin degradation → accumulated bradykinin → cough (~10% incidence, more in women + East Asians) via sensory C-fiber activation (Fox 1996); angioedema (~0.3% incidence, life-threatening, more in Black patients) via vasodilation + capillary leak. ARBs (losartan, valsartan, etc.) do NOT block bradykinin degradation → much lower cough/angioedema incidence (preferred when ACE-I intolerant). Sacubitril/valsartan (Entresto): sacubitril inhibits neprilysin → ↑bradykinin (and natriuretic peptides) → modest angioedema risk, contraindicated with concurrent ACE-I (compounded bradykinin). Hereditary angioedema (HAE): C1-INH deficiency → unrestrained plasma kallikrein → bradykinin storm; treated with icatibant (B2 antagonist), ecallantide (kallikrein inhibitor), C1-INH replacement, lanadelumab (anti-kallikrein mAb), berotralstat (oral kallikrein). Cross-links: raas axis (ACE shared with Ang I→II), nitric oxide synthesis (B2R → eNOS), arachidonic acid cascade (PG generation).
Organ Systems
cardiovascular
respiratory
integumentary
immune-hematologic
Pathway Steps
HMWK (plasma) + factor XII / prekallikrein → bradykinin (nonapeptide) — Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg — via plasma kallikrein cleavage; activated by contact-system surfaces (in vitro = glass; in vivo = polyP, NETs). Bradykinin is generated by the plasma kallikrein-kinin (contact) system: activated factor XII converts prekallikrein to kallikrein, which cleaves high-molecular-weight kininogen (HMWK) to release the nonapeptide bradykinin. This contact-activation cascade ties the kinin system to coagulation and to inflammation.
LMWK (tissue) → kallidin (Lys-bradykinin, decapeptide) — via tissue kallikrein cleavage. A parallel tissue system uses tissue kallikrein on low-molecular-weight kininogen to produce kallidin (Lys-bradykinin), a decapeptide. Aminopeptidases can convert kallidin to bradykinin, so the two systems feed a shared pool of active kinins acting on the same receptors.
bradykinin → B2R activation (constitutive) — via endothelium → eNOS → NO + prostacyclin → vasodilation; sensory C-fibers → pain + cough. Bradykinin acts mainly through the B2 receptor, a constitutively expressed GPCR. B2R drives vasodilation (via endothelial NO and prostacyclin), increased vascular permeability, and pain — the classic signs of inflammation, and the receptor behind ACE-inhibitor angioedema and cough.
des-Arg9-bradykinin (inflammation) → B1R activation (induced) — via B1R upregulated by IL-1β / LPS; carboxypeptidase N generates des-Arg9 from BK. Carboxypeptidases remove the C-terminal Arg to form des-Arg9-bradykinin, which activates the B1 receptor. Unlike B2R, B1R is barely expressed normally but is strongly induced by inflammation and cytokines — so the kinin system shifts toward a B1-mediated response in chronic inflammation and injury.
bradykinin → inactive degradation products — via ACE (kininase II) primary, NEP/neprilysin, aminopeptidase P, carboxypeptidase N. Kinins are very short-lived, rapidly inactivated by kininases — chiefly ACE (kininase II) and carboxypeptidases — to inactive fragments. This rapid degradation keeps kinin signaling local and transient, so inhibiting the degrading enzymes markedly potentiates bradykinin’s effects.
ACE inhibition (captopril etc.) → bradykinin accumulation — via → cough (sensory C-fiber sensitization; Fox 1996); → angioedema (capillary leak). Because ACE both makes angiotensin II and degrades bradykinin, ACE inhibitors (captopril and others) cause bradykinin to accumulate. This adds to their vasodilatory benefit but also causes the characteristic dry cough and the risk of angioedema — bradykinin-mediated, not angiotensin-mediated.
C1-INH deficiency (HAE) → unrestrained plasma kallikrein → bradykinin storm — via recurrent angioedema; icatibant + ecallantide + C1-INH replacement. C1-esterase inhibitor (C1-INH) is the key brake on plasma kallikrein and factor XIIa. When deficient (hereditary angioedema), the contact system runs unchecked, producing a bradykinin “storm” and recurrent angioedema. This is why HAE is treated by blocking kallikrein (lanadelumab) or B2R (icatibant), not with antihistamines.