Bradykinin

Bradykinin is a nine-amino acid peptide (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) generated from the high-molecular-weight kininogen (HMWK) precursor by the serine protease kallikrein. First identified in 1949 by Maurício Rocha e Silva and colleagues in Brazil (named from the Greek "bradys" meaning slow and "kinein" meaning to move, referring to its slow contraction of smooth muscle), bradykinin is a central mediator in the kallikrein-kinin system (KKS), one of the body's major inflammatory and vasoactive cascades.

Bradykinin acts through two G-protein coupled receptors: B2 receptors (constitutively expressed) and B1 receptors (upregulated during inflammation). Through B2 receptors, bradykinin causes endothelium-dependent vasodilation by stimulating nitric oxide and prostacyclin release, increases vascular permeability leading to edema, stimulates sensory nerve endings to produce pain, and promotes bronchoconstriction. These effects make bradykinin a key mediator of inflammation and a significant factor in blood pressure regulation.

The bradykinin system intersects critically with common pharmaceutical interventions. ACE inhibitors (enalapril, lisinopril, etc.) reduce the degradation of bradykinin by inhibiting angiotensin-converting enzyme, which is also the primary bradykinin-degrading enzyme (kininase II). The resulting elevation of bradykinin contributes to both the therapeutic benefits (vasodilation, blood pressure lowering) and the side effects (dry cough in approximately 10-15% of patients, and rare but serious angioedema) of ACE inhibitors.

Bradykinin is also central to the pathophysiology of hereditary angioedema (HAE), a rare genetic disorder caused by deficiency or dysfunction of C1-inhibitor, which normally regulates kallikrein and thus bradykinin production. Excessive bradykinin generation in HAE causes recurrent episodes of severe subcutaneous and submucosal edema. This understanding has led to the development of bradykinin-targeted therapies including icatibant (a B2 receptor antagonist), ecallantide (a kallikrein inhibitor), and lanadelumab (an anti-kallikrein antibody).