Bradykinin is one of the plasma kinins along with kallidin. The name bradykinin is derived from the Greek word ‘bradys’ meaning slow and ‘kinein’ meaning ‘to move’. (Think of kinetics for example).
It was known before bradykinin was recognised that the protease trypsin and particular snake venoms will work on plasma based globulins which then produce a substance that lowers blood pressure and causes a slowly contraction of the gut. That substance was bradykinin.
Bradykinin and kallidin are relatively small peptides. Respectively, the first is a nonapeptide and the latter is a decapeptide- both discovered in the 1950s. They were called kinins because they were produced from proteolysis and triggered by inflammation, allergic reaction and tissue injury. These kinins then have a role as mediators in a host of acute conditions.
The source of both kinins is a kininogen. Bradykinin is derived from High Molecular Weight kininogen (HMW-kininogen) whilst kallidin is derived from Low Molecular Weight kininogen (LMW-kininogen).
These two proteins are α2 globulins which circulate in the plasma and which also contains an inactive kininogenase prekallikrein. Both kininogens are substrates for a kallikrein. The HMW-kininogen is hydrolysed to bradykinin by the plasma-borne kallikrein as well as trypsin and various snake venom. LMW-kininogen is hydrolysed to kallidin, by a tissue derived kallikrein which is located in various glands, the kidney and the central nervous system (CNS).
Kallidin can be reduced by a single amino acid from a decapeptide to bradykinin which is a nonapeptide by aminopeptidase. Both kinins are also hydrolysed by kininase II to form inactive peptides. Also, both kinins are acted upon by kininase I which produces either Des Arg Bradykinin or Des Arg Kallidin and then in turn are then converted to inactive peptides.
The Kallikreins
The kallikreins are glycoprotein enzyme that are produced in the liver as prekallikreins. They are present in the plasma and produced in other tissues including the intestine, kidney and pancreas.
Plasma kallikrein activates HMW-Kininogen. Prekallikrein is activated in turn using the Hageman factor (Factor XII) which in turn is activated on contact with damaged tissue and with surfaces having a negative charge. The tissue materials causing this activation include basement membrane, collagen, bacterial lipopolysaccharides and urate crystals as in gout. This activation in part relies on the enzyme plasmin.
The Kinin Receptors
There are two types of bradykinin receptor, the B1 and B2 receptor.
The B1 receptor is present in low levels. It is strongly induced when there is inflammation or their are damaged tissues. They respond to des-Arg9bradykinin and des-Arg9kallidin but actually not to bradykinin itself. The B1 receptor has a role in inflammation and hyperalgesia.
The B2 receptor is expressed in most normal tissues. It selectively binds bradykinin and kallidin and mediates the majority of actions. It activates PLA2 and PLC via interaction with distinct G protein.
The Actions of The Kinins
(1) Cardiovascular System (CVS)
The kinins are more potent vasodilators than acetylcholine and histamine. This dilation of mainly the arterioles is mediated through endothelial nitrous oxide and PGI2 (prostaglandin I2) generation. Of the larger arteries, most veins and vessels with damaged endothelium are constricted because of a direct action on the smooth muscle. There is no direct action on the heart but a reflex stimulation occurs due to a fall in blood pressure.
The kinins also release histamine and other mediators from mast cells. The kinins also increase capillary permeability which then causes the exudation and inflammation occurs.
(2) Smooth Muscles
The kinins cause a marked bronco constriction in guinea pigs and asthmatic patients.
(3) Neurons
The kinins are a potent pain producing agent and their action is potentiated by the prostaglandins. They alsa produce pain by stimulating the nocioceptive afferents in the viscera and skin.
(4) Kidney
The kinins facilitate salt and water excretion by the action of tubules. They also increase renal blood flow.
Pathophysiological Behaviour
The kinins are mediators of inflammation and all the signs of this are exudation of plasma, redness, pain and mobilization of leukocytes. The type of conditions they are associated with are asthma and rhinitis, and angioedema.
Localised tissue injury causes kinin production which then leads to both repair and defense processes. We see activation of B1 receptors on macrophages which induces production of IL-1, TNF-alpha and the other mediators of inflammation.
The mediation of pain occurs by direct stimulation of nerve endings and by increasing prostaglandin production.
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