The Discovery of Bradykinin

Overview

Bradykinin is a 9-amino-acid peptide (H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH) that mediates vasodilation, increased vascular permeability, pain, and smooth muscle contraction. It was discovered in 1949 by Mauricio Rocha e Silva, Wilson Beraldo, and Gastão Rosenfeld at the Biological Institute of São Paulo, Brazil, while studying the effects of snake venom and trypsin on plasma. They observed a peptide-mediated "slow contraction" of guinea pig ileum — much slower than the rapid contractions produced by histamine or substance P — and named the substance "bradykinin," from the Greek bradys (slow) and kinein (to move).

Bradykinin belongs to the kallikrein-kinin system, which generates kinins from high-molecular-weight kininogen and low-molecular-weight kininogen precursors through the enzymatic action of plasma and tissue kallikreins. The system is closely intertwined with the renin-angiotensin and coagulation pathways. Bradykinin acts through two G protein-coupled receptors, B1 and B2, with B2 being constitutively expressed and B1 being induced by inflammation.

Bradykinin research has had wide clinical consequences, ranging from the classical side effects of ACE inhibitors (cough and angioedema) to the pathophysiology and treatment of hereditary angioedema.

Key People

• Maurício Rocha e Silva (1910–1983): Brazilian pharmacologist who led the bradykinin discovery.
• Wilson T. Beraldo and Gastão Rosenfeld: Rocha e Silva's co-authors on the 1949 paper.
• Sergio Ferreira: Brazilian scientist whose later work on "bradykinin-potentiating factor" from Bothrops jararaca snake venom led to the discovery of ACE inhibitors.
• Dennis Regoli and João Bosco Pesquero: Contributors to bradykinin receptor pharmacology.

Timeline

• 1949: Rocha e Silva and colleagues describe bradykinin.
• 1960s: Bradykinin's amino acid sequence is determined; related kinins identified.
• 1965: Ferreira isolates bradykinin-potentiating factor from Bothrops jararaca venom.
• 1977: Captopril, the first oral ACE inhibitor, is developed from kinin research.
• 1990s: B1 and B2 receptors are cloned.
• 2008: Icatibant, a B2 receptor antagonist, is approved for hereditary angioedema attacks.
• 2009: Ecallantide, a plasma kallikrein inhibitor, is approved for hereditary angioedema.

Background

The kallikrein-kinin system plays important roles in vascular biology, inflammation, pain, and fluid balance. Kinins cause vasodilation, increased capillary permeability, and stimulation of sensory nerve fibers. They also trigger prostaglandin and nitric oxide release, contributing to their inflammatory effects. In certain disease states, uncontrolled bradykinin generation produces life-threatening angioedema.

Hereditary angioedema is a dramatic example of bradykinin biology gone wrong. Most cases arise from deficiency or dysfunction of C1 esterase inhibitor, which normally restrains the kallikrein-kinin and complement systems. Without adequate C1-INH activity, repeated episodes of bradykinin-driven angioedema occur, sometimes involving the larynx and leading to asphyxiation if untreated.

Modern Relevance

Bradykinin-focused therapies are central to hereditary angioedema management. Prophylactic and acute treatments include C1 inhibitor replacement, plasma kallikrein inhibitors (ecallantide, lanadelumab, berotralstat), and the B2 receptor antagonist icatibant. These agents have transformed what was once a frequently fatal condition into a manageable chronic disease.

Bradykinin also remains clinically relevant through ACE inhibitors, which block the degradation of bradykinin by angiotensin-converting enzyme. This mechanism contributes to both their therapeutic effects (vasodilation, cardioprotection) and their side effects (dry cough, angioedema). Research on bradykinin's role in neuroinflammation, COVID-19, and chronic pain continues to expand the kinin system's reach. For related vasoactive peptides, see angiotensin-history.

Related Compounds

• Bradykinin
• Kallidin
• Icatibant
• Ecallantide
• Lanadelumab