Trends in Pharmacological Sciences
ReviewTargeting kinin receptors for the treatment of tissue ischaemia
Section snippets
Expression of the endogenous kallikrein–kinin system in ischaemia
All of the key components of the KKS are present in the vasculature, where it can function by an autocrine and/or paracrine mechanism. TK expression and activity is documented in both human and rat cardiovascular tissue 4, 6. Kinins released from the vascular endothelium activate bradykinin (BK) B1 and B2 receptors on endothelial and vascular smooth muscle cells 4, 7, 8. Binding to B1 and B2 receptors conjointly promotes the formation of prostaglandins and NO, which increases intracellular cAMP
Therapeutic angiogenesis with TK in peripheral ischaemia
Vascular endothelial cells are crucial components of postnatal angiogenesis (Box 2). Because ACE inhibitors can affect endothelial function favourably, it has been hypothesized that their administration might enhance the spontaneous angiogenic response to ischaemia. With this in mind, Fabre et al.22 employed two ACE inhibitors, quinaprilat and captopril, in a rabbit model of limb ischaemia. Although both achieve equivalent levels of ACE inhibition in plasma, only quinaprilat inhibits ACE
Putative mechanisms of TK-induced neoangiogenesis
Various mechanisms that are intrinsic to the biological activities of the KKS are implicated in TK-induced angiogenesis (Fig. 3).
The proteinase activity of TK could activate metalloproteinases type IV collagenase 43 and favour the degradation of the vascular basal membrane and extracellular matrix proteins, an essential step for detachment, invasion and migration of endothelial cells.
TK-generated kinins could evoke plasma-protein extravasation and proliferation of endothelial cells 5, 44, two
Concluding remarks
Recent studies indicate that the KKS has a role in reparative and therapeutic angiogenesis. Thus, local supplementation with TK could benefit the treatment of myocardial and peripheral ischaemia, although additional information regarding the biological impact and safety of TK is necessary before this is applied clinically. For example, although evidence has been provided regarding the magnitude and stability of TK-generated neovascularization, given the complexity of vascular-endothelial-cell
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2012, Cellular SignallingCitation Excerpt :The kB1R and kB2R have 36% sequence identity in humans and belong to the family of seven transmembrane receptors, coupling to G protein subtypes Gαq and Gαi [2,7]. kB1R and kB2R play key roles in many pathological or physiological processes including nociception, inflammation, and cardiovascular and renal diseases [2,8–11]. For example, kB2R knockout mice have hypertension and exaggerated blood pressure increases induced by angiotensin II and chronic salt loading [12].
Kininogens: More than cysteine protease inhibitors and kinin precursors
2010, BiochimieCitation Excerpt :These features support the evidence that endogenous kinins have hypotensive properties and can challenge the effects of the antidiuretic vasopressin [73,74]. In contrast, des-Arg9-BK (and to a lesser extent des-Arg10-kallidin) binds with high affinity to B1 receptors, which are generally absent from normal tissues but are induced during inflammatory episodes [75]. Following the original work of Stewart dedicated to the design of BK receptor antagonists (see e.g. [76,77], it has been proposed that kinin B1 receptors represent innovative and alternative targets for the treatment of chronic pain and inflammation (e.g. severe synovitis) as well as of some infectious diseases (e.g. endotoxic shock) [78].
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