Bradykinin
Role in Inflammation
Inflammation occurs in response to an external pathogen or in response to
noxious stimuli; immunological responses are either innate reactions or specific
cellular reactions and they act to protect the body’s systems. If healing
does not occur then the result may be chronic inflammation. Many illnesses
involving necessary drug treatment involve inflammation and hence the use
of anti-inflammatory drugs. Inflammation involves a number of cascades, which
result in the production of complement components that act to release histamine
and to stimulate processes such as activation of phagocytic cells. One of
these cascades is the kinin cascade, which produces bradykinin from kallikrein
from its interaction with plasma 
–globulin.
In this setting bradykinin acts to cause vasodilation, increased vascular
permeability, pain, Nitric Oxide (NO) synthesis, spasmogen and generation
of eicosanoids. As such, bradykinin acts as a mediator between the initial
compounds and causes and the final responses. Eicosanoids, such as prostanoids
and arachidonic acid, are important in the inflammatory process; prostanoids
(prostaglandins and thromboxanes) are a result of a reaction between COX (cyclo-oxygenase)
and arachidonate. Prostanoids have a variety of actions ranging from vasodilation
and platelet aggregation inhibition to smooth muscle relaxation and inhibition
of neurotransmitter release.
Bradykinin admits its effects through two receptors: BK1 and BK2; the effects mediated by these receptors are very similar. [1, 17, 34]
B2 receptors are G-Protein coupled receptors that are naturally present in tissues and are the predominant mode of BK’s actions. They are rapidly desensitised after activation and are not significantly activated by des-Arg-BK (BK1-8, a product of kinase I action) but compounds, such as Hoe 140 (the peptide icatibant), which have been developed do effectively act as BK2 antagonists. [34, 41]
BK1 receptors, however, are not initially expressed in tissues but are synthesised and expressed, following a stimulus, over a number of hours. The stimulus of the receptor development is thought to be sustained and persistent conditions of inflammation, and hence BK1 receptors are thought to be involved in persistent inflammatory hyperalgesia. Whilst BK is active at the BK1 receptor it’s affinity is lower than at BK2, des-Arg-BK has a higher affinity for this receptor and is thought to be it’s primary natural substrate. Again antagonists of the BK receptor are in the case of BK1 peptides; des-Arg Hoe140 and Leu8BK1-8 are effective BK1 antagonists.
The BK2 receptor is coupled to a G-Protein or either the Gi or Gq family, both of which can activate the production of phosphoinositide-specific phospholipase C. This phospholipase C mobilizes intracellular calcium via hydrolysis of phosphatidylinositol 4,5-bisphosphate, this signal is necessary for many BK elicited vascular responses, including the release of endothelial nitric oxide (NO). In addition to this the stimulation of Gi proteins and phospholipase A2 by BK leads to the production of arachidonic acids and leukotrienes, which are important in mediating the inflammatory response and it can also cause a decrease in cAMP production via inhibition of adenylyl cyclase activity, which can counteract symptoms associated with immune hypersensitivity reactions. Thus, factors that modulate BK2 receptor-coupled G-proteins may influence the course and outcome of BK-mediated inflammatory processes. [34, 41]
BK’s actions in inflammation are partly due to its stimulation of the production of PGI2 (Prostacyclin) and NO, these are both potent direct vasodilators and largely how BK indirectly brings about the vasodilation observed in inflammation (Other mediators also act to stimulate NO particularly to contribute to these effects). BK is also a potent pain-producing agent, specifically through sensitisation and this is also potentiated by the development of prostaglandins. [1, 17]
BK also acts as a spasmogenic, meaning that it causes slow and sustained contraction of many smooth muscle types; in particular this occurs in the intestine and the uterus and can also take effect in the bronchial muscle. This is similar to the actions of histamine but within a slower time frame.
Due to the complicated system of events within inflammation BK’s individual contribution is not fully known other than that it can produce many of the symptoms of inflammation observed. It’s other pathophysiological functions may be to control blood flow to exocrine organs and hence control their releases and also in control of ion and fluid movement by epithelia of various locations, such as the intestines (which may account for diarrhoea in gastrointestinal conditions).
