Category: signaling
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).