The role of vasoactive peptides in skin homeostasis-focus on adiponectin and the kallikrein-kinin system.

Vasoactive peptides often serve a multitude of functions aside from their direct effects on vasodynamics. This article will review the existing literature on two vasoactive peptides and their involvement in skin homeostasis: adiponectin and-as the main representative of the kallikrein-kinin system-bradykinin. Adiponectin is the most abundantly expressed adipokine in the human organism, where it is mainly localized in fat depots including subcutaneous adipose tissue, from where adiponectin can exert paracrine effects. The involvement of adiponectin in skin homeostasis is supported by a number of studies reporting the effects of adiponectin in isolated human keratinocytes, sebocytes, fibroblasts, melanocytes, and immune cells. Regarding skin pathology, the potential involvement of adiponectin in psoriasis, atopic dermatitis, scleroderma, keloid, and melanogenesis is discussed in this article. The kallikrein-kinin system is composed of a variety of enzymes and peptides, most of which have been identified to be expressed in the skin. This also includes the expression of bradykinin receptors on most skin cells. Bradykinin is one of the very few hormones that is targeted by treatment in routine clinical use in dermatology-in this case for the treatment of hereditary angioedema. The potential involvement of bradykinin in wound healing, psoriasis, and melanoma is further discussed in this article. This review concludes with a call for additional preclinical and clinical studies to further explore the therapeutic potential of adiponectin supplementation (for psoriasis, atopic dermatitis, wound healing, scleroderma, and keloid) or pharmacological interference with the kallikrein-kinin system (for wound healing, psoriasis, and melanoma).

Kinins: Locally formed peptides during inflammation with potential use in tissue regeneration.

Kinins are a set of peptides present in tissues and involved in cardiovascular regulation, inflammation, and pain. Here, we briefly comment on recent key findings on the use of kinins in regenerative medicine.

Dysregulated Bradykinin: Mystery in the Pathogenesis of COVID-19.

The COVID-19 pandemic is rapidly spreading, and health care systems are being overwhelmed with the huge number of cases, with a good number of cases requiring intensive care. It has become imperative to develop safe and effective treatment strategies to improve survival. In this regard, understanding the pathogenesis of COVID-19 is highly important. Many hypotheses have been proposed, including the ACE/angiotensin-II/angiotensin receptor 1 pathway, the complement pathway, and the angiotensin-converting enzyme 2/mitochondrial assembly receptor (ACE2/MasR) pathway. SARS-CoV-2 binds to the ACE2 on the cell surface, downregulating the ACE2, and thus impairs the inactivation of bradykinin and des-Arg9-bradykinin. Bradykinin, a linear nonapeptide, is extensively distributed in plasma and different tissues. Kininogens in plasma and tissue are the main sources of the two vasoactive peptides called bradykinin and kallidin. However, the role of the dysregulated bradykinin pathway is less explored in the pathogenesis of COVID-19. Understanding the pathogenesis of COVID-19 is crucial for the development of new effective treatment approaches which interfere with these pathways. In this review, we have tried to explore the interaction between SARS-CoV-2, ACE2, bradykinin, and its metabolite des-Arg9-bradykinin in the pathogenesis of COVID-19.

Plasma kallikrein modulates immune cell trafficking during neuroinflammation via PAR2 and bradykinin release.

Blood-brain barrier (BBB) disruption and transendothelial trafficking of immune cells into the central nervous system (CNS) are pathophysiological hallmarks of neuroinflammatory disorders like multiple sclerosis (MS). Recent evidence suggests that the kallikrein-kinin and coagulation system might participate in this process. Here, we identify plasma kallikrein (KK) as a specific direct modulator of BBB integrity. Levels of plasma prekallikrein (PK), the precursor of KK, were markedly enhanced in active CNS lesions of MS patients. Deficiency or pharmacologic blockade of PK renders mice less susceptible to experimental autoimmune encephalomyelitis (a model of MS) and is accompanied by a remarkable reduction of BBB disruption and CNS inflammation. In vitro analysis revealed that KK modulates endothelial cell function in a protease-activated receptor-2-dependent manner, leading to an up-regulation of the cellular adhesion molecules Intercellular Adhesion Molecule 1 and Vascular Cell Adhesion Molecule 1, thereby amplifying leukocyte trafficking. Our study demonstrates that PK is an important direct regulator of BBB integrity as a result of its protease function. Therefore, KK inhibition can decrease BBB damage and cell invasion during neuroinflammation and may offer a strategy for the treatment of MS.

A hypothesized role for dysregulated bradykinin signaling in COVID-19 respiratory complications.

As of April 20, 2020, over time, the COVID-19 pandemic has resulted in 157 970 deaths out of 2 319 066 confirmed cases, at a Case Fatality Rate of ~6.8%. With the pandemic rapidly spreading, and health delivery systems being overwhelmed, it is imperative that safe and effective pharmacotherapeutic strategies are rapidly explored to improve survival. In this paper, we use established and emerging evidence to propose a testable hypothesis that, a vicious positive feedback loop of des-Arg(9)-bradykinin- and bradykinin-mediated inflammation â†’ injury â†’ inflammation, likely precipitates life threatening respiratory complications in COVID-19. Through our hypothesis, we make the prediction that the FDA-approved molecule, icatibant, might be able to interrupt this feedback loop and, thereby, improve the clinical outcomes. This hypothesis could lead to basic, translational, and clinical studies aimed at reducing COVID-19 morbidity and mortality.

Establishing low-density lipoprotein apheresis tolerability in patients with prior anaphylactoid reactions to lipoprotein apheresis using magnesium sulfate.

BACKGROUND: Lipoprotein apheresis (LA) tolerability is a key factor for the utilization of this therapy. Common reactions to LA are hypotension and nausea. Serious reactions include severe hypotension and anaphylactoid reactions (0.13%-1.3% and 0.2%-0.4%, respectively). The bradykinin response drives these reactions and can worsen with the use of angiotensin-converting-enzyme inhibitors. Efforts to mitigate these reactions are necessary for the tolerability of LA with a dextran sulfate-adsorption (DSA) system. MATERIALS AND METHODS: In an effort to increase apheresis tolerability, seven patients at The University of Kansas, Department of Clinical Pharmacology, who had prior anaphylactoid reactions (defined as general cutaneous flushing, nausea/vomiting, tongue swelling, lightheadedness, and hypotension) to the DSA despite pharmacologic intervention, were treated with pre-LA intravenous magnesium adapted from a protocol developed by co-author Eliaz. This protocol consists of 1.5 g of magnesium sulfate administered over 45 minutes. All seven patients were treated with intravenous magnesium sulfate immediately before LA. RESULTS: No episodes of anaphylactoid reactions during LA have been reported to date. CONCLUSIONS: Magnesium infusion before DSA can be utilized to establish tolerability in patients with prior anaphylactoid reactions to LA. Proposed mechanisms include temporary stabilization of the negative-positive interactions of the dextran sulfate filter leading to a reduction of circulating bradykinin, reduction of nitric oxide, and reduction of the sympathetic response to LA.

Hyperfibrinolysis increases blood-brain barrier permeability by a plasmin- and bradykinin-dependent mechanism.

Hyperfibrinolysis is a systemic condition occurring in various clinical disorders such as trauma, liver cirrhosis, and leukemia. Apart from increased bleeding tendency, the pathophysiological consequences of hyperfibrinolysis remain largely unknown. Our aim was to develop an experimental model of hyperfibrinolysis and to study its effects on the homeostasis of the blood-brain barrier (BBB). We induced a sustained hyperfibrinolytic state in mice by hydrodynamic transfection of a plasmid encoding for tissue-type plasminogen activator (tPA). As revealed by near-infrared fluorescence imaging, hyperfibrinolytic mice presented a significant increase in BBB permeability. Using a set of deletion variants of tPA and pharmacological approaches, we demonstrated that this effect was independent of N-methyl-D-aspartate receptor, low-density lipoprotein-related protein, protease-activated receptor-1, or matrix metalloproteinases. In contrast, we provide evidence that hyperfibrinolysis-induced BBB leakage is dependent on plasmin-mediated generation of bradykinin and subsequent activation of bradykinin B2 receptors. Accordingly, this effect was prevented by icatibant, a clinically available B2 receptor antagonist. In agreement with these preclinical data, bradykinin generation was also observed in humans in a context of acute pharmacological hyperfibrinolysis. Altogether, these results suggest that B2 receptor blockade may be a promising strategy to prevent the deleterious effects of hyperfibrinolysis on the homeostasis of the BBB.

[Acquired C1 esterase inhibitor deficiency via bradykinin-mediated angioedema: Four cases]. / Angiœdème bradykinique par déficit en C1 Inhibiteur acquis : quatre cas.

BACKGROUND: Acquired C1-esterase inhibitor (C1-INH) deficiency angioedema (C1-INH-AAE) is a form of bradykinin-mediated angioedema. This rare disorder is due to acquired consumption of C1-INH, hyperactivation of the classic pathway of human complement, and potentially fatal recurrent angioedema symptoms. Clinical symptoms of C1-INH-AAE are very similar to those of hereditary angioedema (HAE) but usually appear after the fourth decade of life and induce abdominal pain less frequently. Laboratory tests are essential in establishing the diagnosis with low levels or abnormal structure and function of C1-INH. Most patients present C1-INH autoantibodies. Furthermore, C1q is reduced in AAE, contrary to HAE. The long-term prognosis is determined by associated hematologic malignancies. PATIENTS AND METHODS: We report 4 cases of C1-INH-AAE associated with lymphoproliferative disorders referred to the Reference Centre for Angioedema of Besançon, France. The patients were aged between 60 and 77 years. C1 INH antibodies were found in three patients. Symptoms were triggered by angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) in 3 patients. Hematologic malignancy was present at diagnosis (one case of chronic lymphoid leukemia) or was diagnosed during follow-up (one case of indolent marginal zone non-Hodgkin lymphoma and two cases of monoclonal gammopathy). DISCUSSION: C1-INH-AAE induced by ACE inhibitors or ARBs may be associated with hematologic malignancies. This form of revelation does not necessarily indicate a diagnosis of ACE or ARBs angioedema, and screening should therefore be performed for C1 Inh and C1q. An underlying hematologic malignancy should be routinely sought and the long-term prognosis determined.

Angiotensin-converting enzyme inhibitor-induced angioedema: epidemiology, pathogenesis and management.

Angiotensin-converting enzyme-induced angioedema occurs in 0.1-0.7 % of recipients. Swelling often affects head and neck and makes it an extremely dangerous adverse effect. Bradykinin is considered to be the main mediator of edema in these cases. There is currently no specific treatment for angioedema of this etiology. Drugs used for treatment of attacks in hereditary angioedema with C1 inhibitor deficiency are tried also in this indication, but there are currently no clinical studies available supporting their effectiveness. Patients using angiotensin-converting enzyme inhibitors with angioedemas of unknown etiology must discontinue using this drug. Swelling episodes may appear even after this arrangement. Key words: angioedema - angiotensin-converting enzyme inhibitors - bradykinin.

Genetic determination of the vascular reactions in humans in response to the diving reflex.

The purpose of this study was to investigate the genetic mechanisms of the defense vascular reactions in response to the diving reflex in humans with polymorphisms in the genes ADBR2, ACE, AGTR1, BDKRB2, and REN We hypothesized that protective vascular reactions, in response to the diving reflex, are genetically determined and are distinguished in humans with gene polymorphisms of the renin-angiotensin and kinin-bradykinin system. A total of 80 subjects (19 ± 1.4 yr) participated in the study. The intensity of the vascular response was estimated using photoplethysmogram. The I/D polymorphism (rs4340) of ACE was analyzed by PCR. REN (G/A, rs2368564), AGTR1 (A/C, rs5186), BDKRB2 (T/C, rs1799722), and ADBR2 (A/G, rs1042713) polymorphisms were examined using the two-step multiplex PCR followed by carrying allele hybridization on the biochip. Subjects with the BDKRB2 (C/C), ACE (D/D), and ADBR2 (G/G, G/A) genotypes exhibited the strongest peripheral vasoconstriction in response to diving. In subjects with a combination of the BDKRB2 (C/C) plus ACE (D/D) genotypes, we observed the lowest pulse wave amplitude and pulse transit time values and the highest arterial blood pressure during face immersion compared with the heterozygous individuals, suggesting that these subjects are more susceptible to diving hypoxia. This study observed that humans with gene polymorphisms of the renin-angiotensin and kinin-bradykinin systems demonstrate various expressions of protective vascular reactions in response to the diving reflex. The obtained results might be used in estimation of resistance to hypoxia of any origin in human beings or in a medical practice.NEW & NOTEWORTHY Our study demonstrates that the vascular reactions in response to the diving reflex are genetically determined and depend on gene polymorphisms of the kinin-bradykinin and the renin-angiotensin systems.

Bradykinin stimulates protein kinase D-mediated colonic myofibroblast migration via cyclooxygenase-2 and heat shock protein 27.

BACKGROUND: Inflammatory bowel disease is characterized by episodic intestinal injury and repair. Myofibroblasts are gastrointestinal tract stromal cells that regulate the reparative process and are known targets of inflammatory mediators including bradykinin (BK). However, the mechanisms through which inflammation regulates myofibroblast-induced wound healing remain incompletely understood. Here, we demonstrate, for the first time, that BK stimulates myofibroblast migration through protein kinase D (PKD)-mediated activation of the cyclooxygenase-2 (COX-2) and heat shock protein 27 (Hsp27) pathways. MATERIALS AND METHODS: CCD-18Co is a human colonic myofibroblast cell line used from passages 8 to 14. An in vitro scratch assay assessed the effect of BK (100 nM) on myofibroblast migration over 24 h in the presence or absence of several inhibitors (CID755673 [10 µM] and NS398 [10 µM]). Hsp27 small interfering RNA evaluated the effect of Hsp27 on colonic myofibroblast migration. Antibodies to pPKD, pHsp27, and COX-2 evaluated expression levels by Western blot. RESULTS: BK stimulated myofibroblast migration over 24 h. BK also led to rapid and sustained phosphorylation of PKD at Ser-916, rapid phosphorylation of Hsp27 at Ser-82, and increased COX-2 expression over 4 h. BK-mediated COX-2 expression and Hsp27 phosphorylation were both inhibited by the PKD inhibitor CID755673. Similarly, BK-induced myofibroblast migration was significantly inhibited by CID755673 (P < 0.05), by the direct COX-2 inhibitor NS398 (P < 0.05), and by Hsp27 small interfering RNA (P < 0.05). CONCLUSIONS: BK stimulates myofibroblast migration through PKD-mediated activation of COX-2 and Hsp27. PKD, COX-2, and Hsp27 all appear to regulate myofibroblast cell migration, a stromal population that may play an important role in mucosal healing in the setting of inflammation.

Human airway smooth muscle cells secrete amphiregulin via bradykinin/COX-2/PGE2, inducing COX-2, CXCL8, and VEGF expression in airway epithelial cells.

Human airway smooth muscle cells (HASMC) contribute to asthma pathophysiology through an increased smooth muscle mass and elevated cytokine/chemokine output. Little is known about how HASMC and the airway epithelium interact to regulate chronic airway inflammation and remodeling. Amphiregulin is a member of the family of epidermal growth factor receptor (EGFR) agonists with cell growth and proinflammatory roles and increased expression in the lungs of asthma patients. Here we show that bradykinin (BK) stimulation of HASMC increases amphiregulin secretion in a mechanism dependent on BK-induced COX-2 expression, increased PGE2 output, and the stimulation of HASMC EP2 and EP4 receptors. Conditioned medium from BK treated HASMC induced CXCL8, VEGF, and COX-2 mRNA and protein accumulation in airway epithelial cells, which were blocked by anti-amphiregulin antibodies and amphiregulin siRNA, suggesting a paracrine effect of HASMC-derived amphiregulin on airway epithelial cells. Consistent with this, recombinant amphiregulin induced CXCL8, VEGF, and COX-2 in airway epithelial cells. Finally, we found that conditioned media from amphiregulin-stimulated airway epithelial cells induced amphiregulin expression in HASMC and that this was dependent on airway epithelial cell COX-2 activity. Our study provides evidence of a dynamic axis of interaction between HASMC and epithelial cells that amplifies CXCL8, VEGF, COX-2, and amphiregulin production.

Novel insights into the critical role of bradykinin and the kinin B2 receptor for vascular recruitment of circulating endothelial repair-promoting mononuclear cell subsets: alterations in patients with coronary disease.

BACKGROUND: Endothelial injury is considered critical for progression of atherosclerosis and its complications in coronary artery disease (CAD). The endothelial-supportive effects of bradykinin have mainly been attributed to activation of the resident endothelium. Here we newly investigate the role of bradykinin and its B2 receptor for the recruitment and functional activation of circulating mononuclear cell subsets with endothelial-repair promoting capacity, such as CD34(+)CXCR4(+)cells, at sites of arterial injury. METHODS AND RESULTS: Bradykinin-B2-receptor (B2R) blockade by icatibant substantially impaired recruitment of circulating CD34(+)CXCR4(+) mononuclear cells (expressing high levels of B2R) to endothelial cells in vitro and to injured arterial wall in vivo, whereas recruitment of CD14(hi) monocytes (expressing low levels of B2R) was unchanged. Moreover, the capacity of genetically B2R-deficient bone marrow cells to promote endothelial repair in vivo was markedly impaired as compared with wild-type bone marrow cells. B2R expression was reduced on CD34(+)CXCR4(+)mononuclear cells and endothelial repair-promoting early outgrowth cells, but not on CD14(hi)monocytes, from CAD patients as compared with healthy subjects. B2R stimulation induced CD18 activation in early outgrowth cells of healthy subjects, but not in early outgrowth cells of CAD patients. Adenoviral B2R overexpression enhanced in vivo vascular recruitment and rescued impaired endothelial repair capacity of early outgrowth cells from CAD patients. CONCLUSIONS: We newly report that bradykinin/B2R signaling may promote endothelial repair after arterial injury by selective recruitment and functional activation of B2R-expressing circulating mononuclear cell subsets. In CAD patients, B2R downregulation on endothelial repair-promoting circulating mononuclear cells substantially impairs the bradykinin-dependent endothelial repair, representing a novel mechanism promoting endothelial injury in CAD patients.

Bradykinin contracts rat urinary bladder largely independently of phospholipase C.

Several receptor systems in the bladder causing detrusor smooth muscle contraction stimulate phospholipase C (PLC). PLC inhibition abolishes bladder contraction via P2Y6 but not that via M3 muscarinic receptors, indicating a receptor-dependent role of PLC. Therefore, we explored the role of PLC in rat bladder contraction by bradykinin. The PLC inhibitor U 73,122 [1-(6-[([17ß]-3-methoxyestra-1,3,5[10]-trien-17-yl)-amino]hexyl)-1H-pyrrole-2,5-dione] did not affect the bradykinin response to a significantly greater degree than its inactive analog U 73,343 [10 µM each; 1-(6-[-([17ß]-3-methoxyestra-1,3,5[10]-trien-17-yl)-amino]hexyl)-2,5-pyrrolidinedione], whereas the phospholipase D inhibitor butan-1-ol relative to its inactive control butan-2-ol caused a weak but significant inhibition (0.3% each). The cytosolic phospholipase A2 inhibitor arachidonyltrifluoromethyl ketone (300 µM) and the cyclooxygenase inhibitor indomethacin (10 µM) caused strong inhibition of the bradykinin response. The L-type Ca(2+) channel blocker nifedipine (10-100 nM) concentration-dependently caused strong inhibition, whereas only a small but significant inhibition was seen with SK&F 96,365 [10 µM; 1-[ß-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole HCl], an inhibitor of receptor-operated Ca(2+) channels. Several protein kinase C inhibitors yielded an equivocal picture (inhibition by 10 µM bisindolylmaleimide I and 1 µM calphostin but not by 10 µM chelerythrine). The rho kinase inhibitor Y 27,632 [1-10 µM; trans-4-[(1R)-1-aminoethyl]-N-4-pyridinylcyclohexanecarboxamide] caused a strong and concentration-dependent inhibition of the bradykinin response. Our data support that not only M3 but also bradykinin receptors cause bladder contraction by a largely PLC-independent mechanism. Both responses strongly involve L-type Ca(2+) channels and rho kinase, whereas only the bradykinin response additionally involves the phospholipase A2/cyclooxygenase pathway.

A role for bradykinin in the development of anti-collagen antibody-induced arthritis.

OBJECTIVES: Clinical and experimental observations have suggested that bradykinin, a major activation product of the plasma kallikrein-kinin system, is involved in the pathogenesis of arthritis, but the pathogenic role of bradykinin receptors remains inconclusive. In this study we examined whether bradykinin receptors are important in the pathogenesis of anti-collagen antibody-induced arthritis (CAIA) using double receptor-deficient (B1RB2R(-/-)) mice. METHODS: CAIA was induced in B1RB2R(+/+) and B1RB2R(-/-) mice by injection of an anti-collagen antibody cocktail on day 0 and lipopolysaccharide on day 3. Severity of disease was evaluated by measurement of joint diameter and histological analysis. The expression of proinflammatory cytokines in joint tissue and peripheral mononuclear cells was determined by ELISA and real-time RT-PCR. RESULTS: The absent expression of B1R and B2R mRNA in B1RB2R(-/-) mice was confirmed by RT-PCR. Although B1RB2R(+/+) mice developed severe CAIA, the severity of the disease was significantly attenuated in B1RB2R(-/-) mice. In B1RB2R(+/+) mice bearing CAIA, both B1R and B2R mRNA levels were increased in joint tissue and peripheral mononuclear cells. Compared with B1RB2R(+/+) mice, the production of IL-1ß and IL-6 in joint tissue and their mRNA expression in peripheral mononuclear cells were remarkably reduced in B1RB2R(-/-) mice. CONCLUSION: These observations provide genetic evidence that bradykinin plays an important role in the pathogenesis of CAIA. B1R, whose expression is induced in inflamed joint tissue and peripheral inflammatory cells, is important in the development of CAIA.

Effect of bradykinin on renal mesangial cell proliferation and extracellular matrix secretion.

Recent studies have found that bradykinin (BK) plays a role in delaying glomerulosclerosis, although the mechanism of this phenomenon remains unclear. Mesangial cell proliferation (MCP) and extracellular matrix (ECM) secretion are important mechanisms for glomerulosclerosis. This study investigated the impact of BK on the platelet-derived growth factor (PDGF)-induced proliferation of mesangial cells, and evaluated its correlations with the extracellular signal-related kinase (ERK) signaling pathway. The results showed that on its own, 10-1000 mg/L BK promoted MCP and ECM secretion and induced ERK phosphorylation. However, BK administration after PDGF pre-incubation inhibited PDGF-induced MCP, ECM secretion, and ERK phosphorylation. The BK B2 receptor-specific antagonist, HOE-140, and tyrosine phosphatase inhibitor (OV) effectively blocked the function of BK. In summary, these results demonstrated that BK has a bidirectional effect on MCP and ECM secretion: when used alone, it promoted effects on these phenomena, but these effects were inhibited when combined with PDGF. This suggests that the role of BK might be achieved through inhibiting activation of the PDGF-induced ERK1/2 pathway.

Oral medicine case book 64: Some aspects of the pathophysiology of angioedema with special reference to the upper aerodigestive tract.

Angioedema refers to a localized oedematous swelling of subcutaneous or submucosal tissues, caused by dilatation and increased permeability of blood vessels, usually mediated either by histamine or by bradykinin. Deficiency or loss of functional activity of the complement component C1 esterase inhibitor (C1-INH) affects multiple systems, including the kallikrein-kinin, complement, coagulation and fibrinolytic pathways, and in the context of angioedema, the result is increased production and release of bradykinin and other vasoactive substances such as C3a. Owing to impairment of C1-INH, factors Xlla and kallikrein, by a positive feedback mechanism, bring about persistent activation of the kallikrein-kinin pathway with amplification of production of bradykinin, resulting in angioedema. Histamine can cause histaminergic angioedema. As the name implies, this oedema is caused by degranulation of mast cells/basophils as a result of an IgE-dependant allergic reaction to extracts of food, drugs, infectious agents, or to physical stimulation; or as the result of direct degranulation of mast cells/basophils independently of IgE, caused by releasing agents such as opiates, antibiotics or radiocontrast media. As dental, oral and maxillofacial operative procedures may trigger the development of angioederria in susceptible individuals, the dental practitioner should be familiar with its

Exercise training-enhanced, endothelium-dependent dilation mediated by altered regulation of BK(Ca) channels in collateral-dependent porcine coronary arterioles.

OBJECTIVE: Test the hypothesis that exercise training increases the contribution of BK(Ca) channels to endothelium-mediated dilation in coronary arterioles from collateral-dependent myocardial regions of chronically occluded pig hearts and may function downstream of H2O2. METHODS: An ameroid constrictor was placed around the proximal left circumflex coronary artery to induce gradual occlusion in Yucatan miniature swine. Eight weeks postoperatively, pigs were randomly assigned to sedentary or exercise training (treadmill; 14 week) regimens. RESULTS: Exercise training significantly enhanced bradykinin-mediated dilation in collateral-dependent arterioles (~125 µm diameter) compared with sedentary pigs. The BK(Ca) -channel blocker, iberiotoxin alone or in combination with the H2O2 scavenger, polyethylene glycol catalase, reversed exercise training-enhanced dilation in collateral-dependent arterioles. Iberiotoxin-sensitive whole-cell K+ currents (i.e., BK(Ca)-channel currents) were not different between smooth muscle cells of nonoccluded and collateral-dependent arterioles of sedentary and exercise trained groups. CONCLUSIONS: These data provide evidence that BK(Ca)-channel activity contributes to exercise training-enhanced endothelium-dependent dilation in collateral-dependent coronary arterioles despite no change in smooth muscle BK(Ca)-channel current. Taken together, our findings suggest that a component of the bradykinin signaling pathway, which stimulates BK(Ca) channels, is enhanced by exercise training in collateral-dependent arterioles and suggest a potential role for H2O2 as the mediator.

Bradykinin-mediated angioedema: factors prompting ED visits.

OBJECTIVE: Bradykinin-mediated angioedema (AE) is characterized by periodic subcutaneous or submucosal swelling, with the absence of urticaria and itching. It affects the face and extremities. Attacks of abdominal pain and obstruction of the upper airways are the hallmarks of disease severity. The aim of this study was to determine the factors prompting patients to turn up at the hospital emergency department (ED) in the event of an attack. METHODS: This was a retrospective review of attacks experienced by all patients with bradykinin-mediated AE (hereditary, acquired, or drug-induced) who visited our ED between January 2002 and March 2011. Characteristics of attacks prompting ED visits and attacks when patients stayed at home were compared using logistic regression with generalized estimating equations to take into account the correlation between multiple attacks from the same patient. RESULTS: A total of 55 patients were included, of whom 39 had hereditary AE; 13, drug-induced AE; and 3, acquired C1 inhibitor deficiency. The median follow-up was 32 months (interquartile range, 10-99 months). The attack was severe in 324 (58%) of 559 cases. Thirty-two patients (58%) visited the ED for a total of 75 attacks. First attack and laryngeal edema were significantly associated with more frequent ED visits (odds ratio, 5.28 [95% confidence interval, 2.42-11.5] and 4.83 [1.54-15.5], respectively]. C1 inhibitor concentrate and icatibant treatment was significantly more often administered in the ED than at home (odds ratio, 4.9 [2.43-9.88] and 8.25 [2.4-28.3], respectively). CONCLUSIONS: First attack of bradykinin AE and swelling of the larynx were significantly associated with visits to the ED.

Bradykinin and its role in osteoarthritis.

Osteoarthritis (OA), the most common joint disorder, is a disease involving all the articular structures. It presents both degenerative and inflammatory aspects. Recently, the important role of Bradykinin (BK), a phlogistic mediator, has been proposed in the pathophysiology of OA. In our review, we summarized the currently available information on the mechanisms of action of BK in OA by linking its B2 receptors. Then, we analyzed the data about the effects of BK in synoviocytes and chondrocytes cultures. Furthermore, we described the action of B2 receptor antagonists (Icatibant and Fasitibant), presenting them as new promising symptom-anddisease- modifying agents in the treatment of OA. However, more in vitro, animal model and clinical studies, are needed to better understand the mechanisms of action as well as the efficacy and tolerability of the B2 receptor antagonists in OA.