Bradykinin

Bradykinin is a physiologically and pharmacologically active peptide of the kinin group of proteins, consisting of nine amino acids.

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Structure

Bradykinin is a 9-amino acid peptide chain. The amino acid sequence of bradykinin is: Arg - Pro - Pro - Gly - Phe - Ser - Pro - Phe - Arg. Its empirical formula is therefore C₅₀H₇₃N₁₅O₁₁.

Synthesis

The kinin-kallikrein system makes bradykinin by proteolytic cleavage of its kininogen precursor, high-molecular-weight kininogen (HMWK), by the enzyme kallikrein. ACE inhibitors prevent ACE (angiotensin-converting enzyme) from degrading bradykinin, which accumulates in the lungs and acts as an irritant and provokes coughing.

Metabolism

In humans, bradykinin is broken down by three kininases: angiotensin-converting enzyme (ACE), aminopeptidase P (APP), and carboxypeptidase N (CPN), which cleave the 7-8, 1-2, and 8-9 positions, respectively ^[1][2].

Physiological role

Effects

Bradykinin is a potent endothelium-dependent vasodilator, causes contraction of non-vascular smooth muscle, increases vascular permeability and also is involved in the mechanism of pain. In some aspects, it has similar actions to that of histamine, and like histamine is released from venules rather than arterioles.

Bradykinin raises internal calcium levels in neocortical astrocytes causing them to release glutamate.^[3]

Bradykinin is also thought to be the cause of the dry cough in some patients on angiotensin converting enzyme (ACE) inhibitor drugs. This refractory cough is a common cause for stopping ACE-inhibitor therapy.

Receptors

• The B₁ receptor is only expressed as a result of tissue injury, and is presumed to play a role in chronic pain. This receptor has been also described to play a role in inflammation. ^[4]. Most recently, it has been shown that the kinin B₁ receptor recruits neutrophil via the chemokine CXCL5 production. Moreover, endothelial cells have been described as a potential source for this B₁ receptor-CXCL5 pathway. ^[5]

• The B₂ receptor is constitutively active and participates in bradykinin's vasodilatory role.

The kinin B₁ and B₂ receptors belong to G protein coupled receptor (GPCR) family.

History

Bradykinin was discovered in 1948 by three Brazilian physiologists and pharmacologists working at the Instituto Biológico, in São Paulo, Brazil, led by Dr. Maurício Rocha e Silva. Together with colleagues Wilson Teixeira Beraldo and Gastão Rosenfeld, they discovered the powerful hypotensive effects of bradykinin in animal preparations. Bradykinin was detected in the blood plasma of animals after the addition of venom extracted from the Bothrops jararaca (Brazilian lancehead snake), brought by Rosenfeld from the Butantan Institute. The discovery was part of a continuing study on circulatory shock and proteolytic enzymes related to the toxicology of snake bites, started by Rocha e Silva as early as 1939. Bradykinin was to prove a new autopharmacological principle, i.e., a substance that is released in the body by a metabolic modification from precursors, which are pharmacologically active. According to B.J. Hagwood, Rocha e Silva's biographer, "The discovery of bradykinin has led to a new understanding of many physiological and pathological phenomena including circulatory shock induced by venoms and toxins."

Applications

The practical importance of the discovery of bradykinin became apparent when one of his collaborators at the Medical School of Ribeirão Preto at the University of São Paulo, Dr. Sérgio Henrique Ferreira, discovered a bradykinin potentiating factor (BPF) in the bothropic venom which increases powerfully both the duration and magnitude of its effects on vasodilation and the consequent fall in blood pressure. On the basis of this finding, Squibb scientists developed the first of a new generation of highly-effective anti-hypertensive drugs, the so-called ACE inhibitors, such as captopril (trademarked Capoten).

References