The kinin system-bradykinin: Biological effects and clinical implications. Multiple role of the kinin system-bradykinin (original) (raw)
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New topics in bradykinin research
Allergy, 2011
Bradykinin 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.
Inflammation Research, 2014
The following summarises the plenary lectures of the 'Bradykinin Symposium 2012' held on 23-24 August 2012 at Charité-Universitätsmedizin Berlin, Germany. The summary begins with bradykinin activation, examines the effects of bradykinin in different organs of the body, provides an update on the role and regulation of bradykinin receptors, introduces the effects of oestrogens on bradykinin-mediated angioedema and concludes with models that may lead to new therapies.
British Journal of Pharmacology, 1993
1 The effects of intrathecal (i.t.) pretreatment with selective B1 or B2 kinin receptor antagonists were studied on the cardiovascular response to i.t. injection of bradykinin (BK) in conscious freely moving rats. 2 BK (81 pmol) produced an increase in mean arterial pressure (MAP: 9-13 mmHg) and decrease in heart rate (HR: 20-30 beats min-') that reached a maximum 2min after injection. 3 The BK-induced cardiovascular responses were dose-dependently and reversibly reduced by four antagonists with the following rank order of potency: Tyr, D-Arg[Hyp3,D-Phe7,Leu8]-BK = D-Arg[Tyr3,D-Phe7,Leul-BK = D-Arg[Hyp3,D-Phe7,Leul-BK > D-Arg[Hyp3,Thi1,D_Tic7 OicJ-PK (Hoe 140). These compounds failed to alter the cardiovascular response to i.t. injection of 8.1 nmol of substance P. 4 Other compounds acting on the B2 receptor, namely D-Arg[Hyp3,Gly6,Leu8]-BK, D-Arg[Hyp3,D-Phe7]-BK, D-Arg[Hyp2,Thi5'8,D-Phe7]-BK and D-Arg[Hyp3,Gly6,D-Phe7,Leu8]-BK or on the B1 receptor, [Leu8]-
Vascular and sympathoadrenal responses to bradykinin and a bradykinin analogue
Hypertension, 1988
These experiments were designed to assess the interaction of bradykinin and its antagonist (Arg-Pro-Hyp-Gly-Phe-Ser-DPhe-Phe-Arg-trifluoroacetic acid) with the sympathoadrenal system. Three groups of male Wistar rats received 5-minute intra-arterial infusions of either dextrose (Group 1, n = 6), bradykinin, 250 /ig/min (Group 2, n = 5), or bradykinin, 25 /ig/min (Group 3, n = 4). Six other groups received a similar infusion of the bradykinin antagonist at 250 /xg/min. They Were either intact rats (Group 4, n = 10) or rats previously submitted to chemical sympathectomy (Group 5, n-17), to adrenal enucleation (Group 6, n = 8), to combined a-adrenergic and /3-adrenergic blockade (Group 7, n = 7), to a r adrenergic receptor blockade (Group 8, n = 8), or to a 2adrenergic receptor blockade (Group 9, n = 8). Bradykinin infusion produced a sustained fall in mean arterial pressure (MAP) in Groups 2 and 3 (by-48 ± 3 and-36 ± 7 mm Hg, respectively) associated with similar increases in plasma epinephrine levels (100-fold), and norepinephrine (sevenfold) as compared with Group 1. The bradykinin antagonist infusion in intact rats produced a 23 ± 4 mm Hg rise in MAP associated with a sixfold increase in epinephrine and a twofold increase in norepinephrine. Group 5 rats with lower baseline catecholamine levels had an even larger MAP rise (30 ± 6 mm Hg) accompanied by a rise in epinephrine and norepinephrine proportionally similar to that of intact animals. Groups 6 to 8, which lacked either epinephrine or available c«i-adrenergic receptors, had no increase in MAP. We conclude that, while bradykinin produces a MAP fall with sharp stimulation of epinephrine release, the bradykinin antagonist raises MAP and also produces a direct adrenomedullary stimulation; its hypertensive response apparently depends on the a,-agonistic properties of epinephrine.
Enhancement of Bradykinin and Resensitization of Its B2 Receptor
Hypertension, 1999
We studied the enhancement of the effects of bradykinin B 2 receptor agonists by agents that react with active centers of angiotensin-converting enzyme (ACE) independent of enzymatic inactivation. The potentiation and the desensitization and resensitization of B 2 receptor were assessed by measuring [ 3 H]arachidonic acid release and [Ca 2ϩ ] i mobilization in Chinese hamster ovary cells transfected to express human ACE and B 2 receptor, or in endothelial cells with constitutively expressed ACE and receptor. Administration of bradykinin or its ACE-resistant analogue desensitized the receptor, but it was resensitized (arachidonic acid release or [Ca 2ϩ ] i mobilization) by agents such as enalaprilat (1 mol/L). Enalaprilat was inactive in the absence of ACE expression. La 3ϩ (100 mol/L) inhibited the apparent resensitization, probably by blocking the entry of extracellular calcium. Enalaprilat resensitized the receptor via ACE to release arachidonic acid by bradykinin at a lower concentration (5 nmol/L) than required to mobilize [Ca 2ϩ ] i (1 mol/L). Monoclonal antibodies inhibiting the ACE N-domain active center and polyclonal antiserum potentiated bradykinin. The snake venom peptide BPP5a and metabolites of angiotensin and bradykinin (angiotensin-[1-9], angiotensin-[1-7], bradykinin-[1-8]; 1 mol/L) enhanced arachidonic acid release by bradykinin. Angiotensin-(1-9) and -(1-7) also resensitized the receptor. Enalaprilat potentiated the bradykinin effect in cells expressing a mutant ACE with a single N-domain active site. Agents that reacted with a single active site, on the N-domain or on the C-domain, potentiated bradykinin not by blocking its inactivation but by inducing crosstalk between ACE and the receptor. Enalaprilat enhanced signaling via ACE by G␣ i in lower concentration than by G␣ q -coupled receptor. (Hypertension. 1999;33:835-843.) Key Words: angiotensin-converting enzyme inhibitors Ⅲ kininase II Ⅲ endothelial cells Ⅲ G proteins Ⅲ [Ca 2ϩ ] i Ⅲ arachidonic acid Ⅲ angiotensin-(1-9)
International Immunopharmacology
The Journal of Angioedemasit amet INTRODUCTION The pharmacology of bradykinin (BK)-related peptides, the kinins, has come a long way in recent decades, with the pharmacologic and then the molecular definition of 2 G protein-coupled receptors (GPCRs) that mediate their cellular actions, the B 1 and B 2 receptors (B 1 R, B 2 R). 1 Additional modern research tools include mouse strains in which one or both of the genes coding for kinin receptors have been deleted ("gene knockout" models). 2 The formation of kinins and their degradation by interesting peptidases, such as angiotensin-converting enzyme, will not be covered in the present text. The arduous nature of the analytic biochemistry of BK-related peptides is outlined elsewhere. 3 We rather propose an excursion into the pharmacology of kinins, the first author having been a spectator and an actor in the field for the past 35 years. There will be a strong autobiographic bias in the selection of the illustration material. We hope this partiality will be forgiven in light of the generous invitation he has received to summarize the field during an oral presentation at the 8th C1-Inhibitor Deficiency Workshop. BRADYKININ RECEPTOR LIGANDS: AGONISTS AND ANTAGONISTS The receptors for bradykinin were initially defined in the late 1970s and 1980s using pharmacologic criteria. The B 1 R was historically the first defined using both a typical potency order of agonists and a class of specific antagonists. This somewhat atypical receptor subtype is optimally responsive to fragments of the native kinins (BK and Lys-BK) in which the Arg 9 residue has been removed (des-Arg 9-BK, Lys-des-Arg 9-BK, respectively; Fig. 1). 4 The early peptide antagonists were simply des-Arg 9 sequences in which Phe 8 was replaced with a residue possessing an aliphatic side chain, such as Leu. In retrospect, it is now clear that the native kinins produced by the kallikreins, either BK or Lys-BK (kallidin), are selective agonists of the physiologically prominent B 2 R subtype that has been consolidated with specific peptide antagonists in the 1980s by Professor John M. Stewart and colleagues. The B 2 R antagonists typically possess a constrained peptide backbone due to the inclusion of bulky nonnatural amino acids that also confer resistance ABSTRACT Bradykinin-related peptides, the kinins, are blood-derived peptides that stimulate 2 G protein-coupled receptors, the B 1 and B 2 receptors (B 1 R, B 2 R). The pharmacologic and molecular identities of these 2 receptor subtypes will be succinctly reviewed, with emphasis on drug development, receptor expression, signaling, and adaptation to persistent stimulation. Peptide and nonpeptide antagonists and fluorescent ligands have been produced for each receptor. The B 2 R is widely and constitutively expressed in mammalian tissues, whereas the B 1 R is mostly inducible under the effect of cytokines during infection and immunopathology. Both receptor subtypes mediate the vascular aspects of inflammation (vasodilation, edema formation). On this basis, icatibant, a peptide antagonist of the B 2 R, is approved in the management of hereditary angioedema attacks. Other clinical applications are still elusive despite the maturity of the medicinal chemistry efforts applied to kinin receptors. While both receptor subtypes are mainly coupled to the G q protein and related second messengers, the B 2 R is temporarily desensitized by a cycle of phosphorylation/endocytosis followed by recycling, whereas the nonphosphorylable B 1 R is relatively resistant to desensitization and translocated to caveolae on activation.
Fundamental & Clinical Pharmacology, 1999
Activation of the kinin-kallikrein system and stimulation of hradykinin (BK) B, receptors are thought to play an important role in the pathophysiology of inflammation and pain. In the present study, we report the pharmacological properties of a novel nonpeptide bradykinin B, receptor antagonist, L F 16-033SC, ( 1 -[[3-[(2,4-dimethylquinolin-8-yl)oxymethyl]-2,4-dichloro-phenyl]sulfonyl]-2(S)-[~4-~4-(aminoiminomethyl)-phenylcarbonyl]piperazin-1 -yl]carbonyl]pyrrolidine, 2HCI). In binding studies, L F 16-033SC competed with ['Hlbradykinin giving K, values of 1.65 f 0.36 nM and 2.20 t 0.30 nM in membrane preparations from rat uterus (RU) and guinea-pig ileum (GPI), respectively. In functional experiments, LF 16-033SC inhibited in a competitive manner BK-induced contractions of both isolated RU and GPI, leading to calculated PA, values of 7.70 k 0.70 and 8.30 k 0.30, respectively. The inhibitory effect of LF 16-033SC was
British Journal of Pharmacology, 2019
BACKGROUND AND PURPOSE: It has been shown that bradykinin may induce vasoconstriction in selected vessels or under specific experimental conditions. We hypothesized that inflammatory stimuli, such as endotoxin challenge, may induce the dimerization of AT1/B2 receptors, altering the vascular effects of bradykinin. EXPERIMENTAL APPROACH: Wistar rats received LPS (1 mg kg-1 , i.p.) and were anesthetized for assessment of blood pressure. Mesenteric resistance arteries were used in organ baths and subjected to co-immunoprecipitation and Western blot approaches. KEY RESULTS: At 24 and 48 h after LPS, bradykinin-induced hypotension was followed by a sustained increase in blood pressure, which was not found in non-endotoxemic animals.
2021
Background and purpose: Bradykinin [BK-(1-9)] is an endogenous nonapeptide involved in multiple physiological and pathological processes. A long-held belief is that peptide fragments of BK-(1-9) are biologically inactive. Here, we have tested the biological activities of BK-(1-9) and two major peptide fragments in human and animal systems. Experimental Approach: Levels of BK peptides in male Wistar rat plasma were quantified by mass spectrometric methods. Nitric oxide was quantified in human, mouse and rat cells, and loaded with DAF-FM. We used aortic rings from adult male Wistar rats to test vascular reactivity. Changes in blood pressure and heart rate were measured in conscious adult male Wistar rats. Key results: Plasma levels of BK-(1-7) and BK-(1-5) in rats were increased following infusion of BK-(1-9). All tested peptides induced NO production in all cell types tested. However, unlike BK-(1-9), NO production elicited by BK-(1-7) or BK-(1-5) was not inhibited by B1 or B2 recept...