New topics in bradykinin research

Abstract

The kinins are a family of vasoactive peptides including bradykinin, kallidin and methionyl-lysyl-bradykinin, the latter two compounds being converted very rapidly to bradykinin by aminopeptidases. Bradykinin is a low molecular weight (1060.21 Da; C 50 H 73 N 15 O 11 ) nonapeptide, which is rapidly metabolized by endogenous metalloproteases including angiotensin-converting enzyme (ACE or kininase II), neutral endopeptidase (NEP or neprilysin), carboxypeptidase N (CPN or kininase I) and aminopeptidase P (1). Bradykinin has only a short plasma half-life of 15 s, and circulating levels are usually relatively low (0.2-7.1 pM) (2, 3).Much progress was made in understanding the physiological role of kinins with the development of selective antagonists for endothelial B 1 and B 2 receptors (4) and of C1 esterase inhibitor (C1-INH)-and B 2 -receptor-transgenic mice (5, 6). Bradykinin binds these receptors, exerting potent effects in different pathophysiological states (7) (Fig. 1). For example, bradykinin exerts potent antihypertensive, antithrombogenic, antiproliferative and antifibrogenic effects (8) as summarised in Table 1. Bradykinin also participates in inflammatory processes by activating endothelial cells to promote vasodilation and increased vascular permeability, producing classical symptoms of inflammation such as redness, heat, swelling and pain (1, 9). Specifically, bradykinin contributes to tissue hyper-responsiveness and local inflammation in allergic rhinitis, asthma and anaphylaxis, while bradykinin-dependent angioedema can result from hereditary or acquired C1-INH deficiency or the use of ACE inhibitors (ACEi) to treat hypertension, heart failure, diabetes or scleroderma. AbstractBradykinin has been implicated to contribute to allergic inflammation and the pathogenesis of allergic conditions. It binds to endothelial B 1 and B 2 receptors and exerts potent pharmacological and physiological effects, notably, decreased blood pressure, increased vascular permeability and the promotion of classical symptoms of inflammation such as vasodilation, hyperthermia, oedema and pain. Towards potential clinical benefit, bradykinin has also been shown to exert potent antithrombogenic, antiproliferative and antifibrogenic effects. The development of pharmacologically active substances, such as bradykinin receptor blockers, opens up new therapeutic options that require further research into bradykinin. This review presents current understanding surrounding the role of bradykinin in nonallergic angioedema and other conditions seen by allergists and emergency physicians, and its potential role as a therapeutic target.

C-reactive protein levels in hereditary angioedema

“…These receptors occur on vascular endothelium, primary sensory afferent neurones and vascular and non-vascular smooth muscle cells [7][8][9]. B2R is expressed constitutively, while B1R is absent in most tissues under physiological conditions [7,8].…”

“…BK is cleaved off from high-molecular-weight kininogen (HK) by kallikrein, which is generated from prekallikrein by activated factor XII (factor XIIa). C1INH regulates the activity of kallikrein as well as that of factor XIIa [7][8][9]. Hence, a lack of C1INH, as occurs in HAE, results in enhanced BK formation, which presumably explains why C1INH deficiency leads to angioedema [1][2][3]5,6].…”

Cysteine proteases of human hookwormNecator Americanus as virulencefactors and implications for drug design with anti-heparin and heparin analogs: A bioinformatics study

“…Such kininogencleaving activity of cruzain and cathepsin B generates bradykinin, a potent vasodilator that releases PGI 2 -which inhibits platelet activation and degranulation [42] . As NA larvae too traces migratory route through blood capillaries of human hosts, the cathepsin B-like cysteine proteases of the human hookworm were scrutinized for molecular features which could be responsible for kallikrein-like activity.…”

“…However, in the dynamic NA CP proteins, the side chains of the charged acidic residues could probably move closer (more so Glu245 of CP6, because of its longer side chain) to make the salt-bridge interaction with charged Arg 381 of HMWK substrate. Human plasma kallikrein (pKal) is a component of the anticoagulation pathway that cleaves HMWK -a protein involved in blood coagulation and fibrinolysis -to produce a potent vasodilator bradykinin [42] that stimulates prostacyclin (PGI 2 ) release from .…”

“…17, 2017; endothelial cells. PGI 2 in turn is an inhibitor of platelet activation and degranulation pathway [42] . Emulation of plasma kallikrein activity has been reported for cruzain [40] [41] -a cysteine protease from T.Cruzi that traverses blood capillary vessels.…”