Physiology of Bradykinin:
The synthesis of bradykinin takes place in plasma and tissues by
proteolytic cleavage of HMWK (High Molecular Weight Kininogen) and LMWK
(Low Molecular Weight Kininogen) respectively. The synthesis of Kinins
is triggered by various factors one of them includes endothelial injury
which is hence the name contact system which is accompanied by Factor
XII to XI. Factor XIIa converts pre-kallikrein into plasma kallikrein,
and they autoactivate through a positive feedback loop. Plasma
kallikrein cleaves high-molecular-weight kininogen (HMWK) into
bradykinin.3 Bradykinin then binds to B2-receptors,
inducing vasodilation and increased endothelial permeability, leading to
the characteristic swelling of an angioedema attack.4Their actions are mainly mediated through B1 and B2 receptors.
Bradykinin receptors are cell surface, G-protein coupled receptors of
the seven-transmembrane domain family. The existence of two subtypes of
bradykinin receptor, B1 and B2, has been confirmed through the use of
high affinity peptide and nonpeptide receptor antagonists, radioligand
binding studies and, recently, receptor cloning and expression
studies.5 For synthesis and functional roles
of bradykinin refer Figure 1 Appendix 1
In vitro studies show stimulation of endogenous B1R promotes cell
growth, migration, and invasion.6 A study found that,
when B2 is inhibited or absent, receptor B1 is upregulated and might
develop some B2 hemodynamic properties, which indicates that they both
play a role in the maintenance of normal Vaso regulation or the
development of hypertension.7 The vascular effects of
B1 receptor activation may be a result of the release of endothelial NO,
prostaglandins, and possibly endothelium-derived hyperpolarizing
factors.8,9
B2 bradykinin receptors are present in neurons of the
brain stem, basal nuclei, cerebral cortex, thalamus and hypothalamus.
B2 immunolabelling was also observed in the endothelial
lining of the superior sagittal Dural sinus and ependyma of the lateral
and third ventricles. B1 kinin receptors have been
localised on neurones of the thalamus, spinal cord and
hypothalamus.10 In studies that investigated the role
in FGF-2 pathway in the BK-mediated human endothelial cell permeability
and migration, and the role of the B2 receptor (B2R) of BK in this
cross-talk. Is established. B2R blockade by the selective antagonist,
fasitibant, significantly inhibited FGF-2/FGFR-1 signalling, and in
turn, BK-mediated endothelial cell permeability and
migration.11 The B2 receptor is
believed to play an important role in the beneficial effects of
angiotensin- 1 converting enzyme inhibitors used in the treatment of
cardiovascular diseases, yet it is involved in the acute phase of
inflammation and of somatic and visceral pain. An additional role was
introduced for B2 BK receptor demonstrating its
proliferative effects.10 Some studies also show that
bradykinin can also induce anti-mitogenic effects in proliferating cells
using an alternative signal transduction pathway involving a protein
tyrosine phosphatase.12 Thus the role of bradykinin as
a homeostatic plasma kinin is undeniable as suggested by the available
literature.