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.