Bradykinin is a potent endothelium-dependent vasodilator and mild diuretic, which may cause a lowering of the blood pressure. It also causes contraction of non-vascular smooth muscle in the bronchus and gut, increases vascular permeability and is also involved in the mechanism of pain. During inflammation, it is released locally from mast cells and basophils during tissue damage. Specifically in relation to pain, bradykinin has been shown to sensitize TRPV1 receptors, thus lowering the temperature threshold at which they activate, thus presumably contributing to allodynia. Initial secretion of bradykinin post-natally causes constriction and eventual atrophy of the ductus arteriosus, forming the ligamentum arteriosum between the pulmonary trunk and aortic arch. It also plays a role in the constriction and eventual occlusion of a number of other fetal vessels, including the umbilical arteries and vein. The differential vasoconstriction of these fetal vessels compared to the vasodilator response of other vessels suggest that the walls of these fetal vessels are different than other vessels.
Receptors
The B1 receptor is expressed only 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. 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.
The B2 receptor is constitutively expressed and participates in bradykinin's vasodilatory role.
Bradykinin is also thought to be the cause of the dry cough in some patients on widely prescribed angiotensin-converting enzyme inhibitor drugs. It is thought that bradykinin is converted to inactive metabolites by ACE, therefore inhibition of this enzyme leads to increased levels of bradykinin; increased bradykinin sensitizes somatosensory fibers and thus causes hyperalgesia. Bradykinin may mediate this via pro-inflammatory peptides and a local release of histamine. In severe cases, the elevation of bradykinin may result in angioedema, a medical emergency. People of African descent have up to 5x increased risk of ACE inhibitor induced angioedema due to hereditary predisposing risk factors such as hereditary angioedema. This refractory cough is a common cause for stopping ACE inhibitor therapy. Overactivation of bradykinin is thought to play a role in a rare disease called hereditary angioedema.
Therapeutic implications
A bradykinin-potentiating factor which increases both the duration and magnitude of the effects of bradykinin on vasodilation and the consequent fall in blood pressure, was discovered in Bothrops jararacavenom. On the basis of this finding, a non-protein analog of BPF which was effective orally was developed: the first angiotensin converting enzyme inhibitorcaptopril. It was approved by the FDA for the treatment of hypertension in 1981. Currently, bradykinin inhibitors are being developed as potential therapies for hereditary angioedema. Icatibant is one such inhibitor. Additional bradykinin inhibitors exist. It has long been known in animal studies that bromelain, a substance obtained from the stems and leaves of the pineapple plant, suppresses trauma-induced swelling caused by the release of bradykinin into the bloodstream and tissues. Other substances that act as bradykinin inhibitors include aloe and polyphenols, substances found in red wine and green tea.
Role in carcinogenesis and progression
Bradykinins have been implicated in a number of cancer progression processes. Increased levels of bradykinins resulting from ACE inhibitor use have been associated with increased lung cancer risks Bradykinins have been implicated in cell proliferation and migration in gastric cancers, and bradykinin antagonists have been investigated as anti-cancer agents.
History
Bradykinin was discovered in 1948 by three Brazilian physiologists and pharmacologists working at the Biochemistry and Pharmacology department of the Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, in Ribeirão Preto, 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, 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." Etymology: brady slow, kinin kīn to move, set in motion, ? from the effect of snake venom on intestinal smooth muscle, which was noted to slowly contract.
