Bradykinin

High-dose ACEi might be harmful in COVID-19 patients with serious respiratory distress syndrome by leading to excessive bradykinin receptor activation.

B Székács, S Várbíró, L Debreczeni

We aimed to critically review the available information on the potential contribution of excessive kallikrein-kinin systems (KKSs) activation to severe respiratory inflammation in SARS-CoV-2 infection, and the likely consequence of ACE inhibition in seriously affected patients.

Pathophysiology of COVID-19: A Post Hoc Analysis of the ICAT-COVID Clinical Trial of the Bradykinin Antagonist Icatibant.

Pierre Malchair, Jordi Giol, Javier Jacob +3 more

We used the data from a successful therapeutic assay that used icatibant in patients with hypoxemic COVID-19 pneumonia (the ICAT·COVID trial) to explore pathophysiological mechanisms. We performed concurrent-type, criterion-related validity analyses to assess the discriminative ability of a panel of nine potential serum markers (interleukin 6, ferritin, lactate dehydrogenase, C reactive protein, fibrin fragment D (D-dimer), complement 1 esterase inhibitor (antigenic and functional), complement 4 factor, and lymphocyte count) to predict the clinical milestones. Consistent with previous research, we evidenced a significant relationship between interleukin 6, lactate dehydrogenase and the lymphocyte count, and the clinical events. Furthermore, exposure to icatibant, a bradykinin B2 receptor antagonist (which improved pneumonia and mortality in the aforementioned randomised trial), attenuated this relationship, although this effect faded over time. The results reinforce the key role that the angiotensin-converting enzyme 2 has on COVID-19 pathophysiology as a point of convergence between the renin-angiotensin and kallikrein-kinin systems. This was shown clinically by the successful blocking of inflammatory pathways by icatibant at the bradykinin effector loop level early during the acute hyperinflammatory stage of the disease.

Kinin-kallikrein system: New perspectives in heart failure.

Keivan Mohammadi, Davood Shafie, Newsha Ghomashi +2 more

Heart failure (HF) is a pervasive clinical challenge characterized by compromised cardiac function and reduced quality of life. The kinin-kallikrein system (KSS), a multifaceted peptide cascade, has garnered substantial attention due to its potential role in HF. Through activation of B1 and/or B2 receptors and downstream signaling, kinins modulate various physiological processes, including inflammation, coagulation, pain, blood pressure control, and vascular permeability. Notably, aberrations in KKS components have been linked to HF risk. The elevation of vasodilatory bradykinin (BK) due to kallikrein activity reduces preload and afterload, while concurrently fostering sodium reabsorption inhibition. However, kallikrein's conversion of prorenin to renin leads to angiotensinsII upregulation, resulting in vasoconstriction and fluid retention, alongside increased immune cell activity that fuels inflammation and cardiac remodeling. Importantly, prolonged KKS activation resulting from volume overload and tissue stretch contributes to cardiac collagen loss. The conventional renin-angiotensin-aldosterone system (RAAS) inhibitors used in HF management may inadvertently intensify KKS activity, exacerbating collagen depletion and cardiac remodeling. It is crucial to balance the KKS's role in acute cardiac damage, which may temporarily enhance function and metabolic parameters against its detrimental long-term effects. Thus, KKS blockade emerges as a promising strategy to impede HF progression. By attenuating the link between immune system function and tissue damage, KKS inhibition can potentially reduce cardiac remodeling and alleviate HF symptoms. However, the nuanced roles of BK in various acute conditions necessitate further investigation into the sustained benefits of kallikrein inhibitors in patients with chronic HF.

Meta-analysis of ACE inhibitor-induced angioedema identifies novel risk locus.

Carina M Mathey, Carlo Maj, Niclas Eriksson +48 more

Angioedema is a rare but potentially life-threatening adverse drug reaction in patients receiving angiotensin-converting enzyme inhibitors (ACEis). Research suggests that susceptibility to ACEi-induced angioedema (ACEi-AE) involves both genetic and nongenetic risk factors. Genome- and exome-wide studies of ACEi-AE have identified the first genetic risk loci. However, understanding of the underlying pathophysiology remains limited.

Review of icatibant use in the Winnipeg Regional Health Authority.

George Cai, Colin Barber, Chrystyna Kalicinsky

This is a retrospective review of the Winnipeg Regional Health Authority's (WRHA) angioedema patients who were dispensed icatibant in hospital. Icatibant is a bradykinin B2 receptor antagonist indicated for Hereditary Angioedema (HAE) types I and II and is used off-label for HAE with normal C1INH (HAE-nC1INH) and ACE-inhibitor induced angioedema (ACEIIAE). The WRHA's use of icatibant is regulated by the Allergist on call. We characterized icatibant's use and the timeline from patient presentation, compared the real-world experience with the FAST-3 trial and hypothesized the factors which may affect response to icatibant.

Potential Pathways and Pathophysiological Implications of Viral Infection-Driven Activation of Kallikrein-Kinin System (KKS).

Sharton Vinícius Antunes Coelho, Fabiane Messner Augusto, Luciana Barros de Arruda

Microcirculatory and coagulation disturbances commonly occur as pathological manifestations of systemic viral infections. Research exploring the role of the kallikrein-kinin system (KKS) in flavivirus infections has recently linked microvascular dysfunctions to bradykinin (BK)-induced signaling of B2R, a G protein-coupled receptor (GPCR) constitutively expressed by endothelial cells. The relevance of KKS activation as an innate response to viral infections has gained increasing attention, particularly after the reports regarding thrombogenic events during COVID-19. BK receptor (B2R and B1R) signal transduction results in vascular permeability, edema formation, angiogenesis, and pain. Recent findings unveiling the role of KKS in viral pathogenesis include evidence of increased activation of KKS with elevated levels of BK and its metabolites in both intravascular and tissue milieu, as well as reports demonstrating that virus replication stimulates BKR expression. In this review, we will discuss the mechanisms triggered by virus replication and by virus-induced inflammatory responses that may stimulate KKS. We also explore how KKS activation and BK signaling may impact virus pathogenesis and further discuss the potential therapeutic application of BKR antagonists in the treatment of hemorrhagic and respiratory diseases.

CAN'T INTUBATE, CAN'T OXYGENATE: 
A RARE CASE OF A DIFFICULT AIRWAY DUE TO NONHEREDITARY ANGIOEDEMA.

Điđi Delalić, Vinko Borčić, Ingrid Prkačin

Angioedema is a form of allergic mediated by histamine and non-allergic mediated by bradykinin and can be lethal if not recognized and treated promptly. This case demonstrates the proper diagnosis of and intervention in rapid onset severe angioedema. A 68-year-old male came to the emergency department with a complaint of dyspnea that started two hours before. He had type II diabetes, chronic kidney disease and several different antihypertensive medications, including an ACE inhibitor for hypertension. During physical examination, the patient was hypertensive, tachycardic, tachypnoic, and edematous. During his stay in the ED he was treated with a combination of corticosteroids, antihistamines and epinephrine, but the patient's edema and dyspnea worsened and his oxygen saturation started to deteriorate with a progression of skin edema. Intubation was not possible due to the large edema of the tongue, so a tracheotomy was done. An ampule of icatibant was administered and rapid regression of the edema, along with the stabilization of the patient's vital signs, followed after five minutes. The patient was discharged home after five days with a recommendation of discontinuing the ACE inhibitor. While non-hereditary angioedema is not a rare condition, emergency physicians should be adequately educated about it.

Pharmacological suppression of the kallikrein kinin system with KVD900: An orally available plasma kallikrein inhibitor for the on-demand treatment of hereditary angioedema.

Edward J Duckworth, Nivetha Murugesan, Lily Li +7 more

Hereditary angioedema (HAE) is a rare genetic disease that leads to recurrent episodes of swelling and pain caused by uncontrolled plasma kallikrein (PKa) activity. Current guidelines recommend ready availability of on-demand HAE treatments that can be administered early upon attack onset. This report describes the pharmacological and pharmacodynamic properties of the novel oral small-molecule PKa inhibitor KVD900 as a potential on-demand treatment for HAE.

A case of acquired angioedema.

Arielle D Zwanziger

Acquired angioedema is a rare disorder characterized by nonurticarial angioedema secondary to deficiency or altered activity of C1-esterase inhibitor protein. This article describes a patient whose recurrent angioedema was initially diagnosed as angiotensin-converting enzyme (ACE) inhibitor-induced angioedema. However, after further testing, she was diagnosed with acquired angioedema and subsequently treated with a synthetic bradykinin B2-receptor antagonist.

Association of Variants Near the Bradykinin Receptor B2 Gene With Angioedema in Patients Taking ACE Inhibitors.

Jonas Ghouse, Gustav Ahlberg, Laura Andreasen +13 more

Angioedema is a rare but potentially life-threatening adverse reaction associated with angiotensin-converting enzyme (ACE) inhibitors. Identification of potential genetic factors related to this adverse event may help identify at-risk patients.

Novel Pharmacogenomic Locus Implicated in Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema.

Stuart A Scott, Paola Nicoletti

Angiotensin-converting enzyme inhibitor induced angioedema: not always a class effect? A case report and short narrative review.

Guillaume Becker, Fabien Rougerie, Amelia-Naomi Sabo +3 more

Bradykinin-mediated angioedema is a rare but potentially fatal adverse event. Angioedema induced by angiotensin-converting enzyme (ACE) inhibitors is generally attributed to an inhibition of bradykinin degradation following ACE inhibition. Clinical studies on ACE inhibitors mainly focus on their efficacy. Few examine their potential to generate undesirable adverse effects, particularly with regard to angioedema.

Molecular basis for kinin selectivity and activation of the human bradykinin receptors.

Yu-Ling Yin, Chenyu Ye, Fulai Zhou +6 more

Bradykinin and kallidin are endogenous kinin peptide hormones that belong to the kallikrein-kinin system and are essential to the regulation of blood pressure, inflammation, coagulation and pain control. Des-Arg10-kallidin, the carboxy-terminal des-Arg metabolite of kallidin, and bradykinin selectively activate two G protein-coupled receptors, type 1 and type 2 bradykinin receptors (B1R and B2R), respectively. The hyperactivation of bradykinin receptors, termed 'bradykinin storm', is associated with pulmonary edema in COVID-19 patients, suggesting that bradykinin receptors are important targets for COVID-19 intervention. Here we report two G protein-coupled complex structures of human B1R and B2R bound to des-Arg10-kallidin and bradykinin, respectively. Combined with functional analysis, our structures reveal the mechanism of ligand selectivity and specific activation of the bradykinin receptor. These findings also provide a framework for guiding drug design targeting bradykinin receptors for the treatment of inflammation, cardiovascular disorders and COVID-19.

Real-world off-label use of icatibant for acute management of non-hereditary angioedema.

Thanh-Thao Adriana Le, William Smith, Pravin Hissaria

We retrospectively examined the indications and efficacy of off-label use of the bradykinin B2 receptor antagonist icatibant. The clinical heterogeneity, variability of response to icatibant and lack of efficacy of adrenaline described in this audit highlights both the need for biomarkers that can rapidly distinguish between histaminergic and non-histaminergic angioedema, and for guidelines to improve the utility of icatibant in the non-hereditary angioedema setting.

Blockade of bradykinin receptors or angiotensin II type 2 receptor prevents paclitaxel-associated acute pain syndrome in mice.

Graziele C Zanata, Larissa G Pinto, Nicole R da Silva +7 more

Paclitaxel (PCX) is the first-line choice for the treatment of several types of cancer, including breast, ovarian, and lung cancers. However, patients who receive even a single dose with PCX commonly develop mechanical and cold allodynia, a symptom known as PCX-associated acute pain syndrome (P-APS). Here, we assessed possible involvement of kinin-kallikrein and renin-angiotensin systems in P-APS in mice.

Unilateral orolingual angioedema in a patient with sarcoidosis after intravenous thrombolysis due to acute stroke without improvement after treatment with icatibant.

Anna Daniela Wollmach, Daniel Zehnder, Markus Schwendinger +1 more

A potential complication after intravenous administration of recombinant tissue plasminogen activators (rtPAs) for thrombolysis in acute ischaemic stroke is orolingual angioedema, with an incidence of 0.4%-7.9%. In the herewith reported case, we discuss potential links between a history of sarcoidosis and the occurrence of orolingual angioedema after rtPA administration. Sarcoidosis is often accompanied by an elevated ACE level. In contrast, low ACE levels appear to play a role in the pathomechanism currently assumed to trigger angioedema, that is, the activation of the bradykinin and complement pathways. Medication with ACE inhibitors is considered a risk factor for angioedema. Based on these considerations, the patient was also treated with icatibant, a bradykinin B2-receptor antagonist, which has been found useful in recent publications on treating orolingual angioedema after intravenous lysis in ischaemic stroke.

A randomized, open-label, adaptive, proof-of-concept clinical trial of modulation of host thromboinflammatory response in patients with COVID-19: the DAWn-Antico study.

T Vanassche, M M Engelen, Q Van Thillo +31 more

The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19.

Does hereditary angioedema make COVID-19 worse?

Yingyang Xu, Shuang Liu, Yan Zhang +1 more

The coronavirus disease 2019 (COVID-19) pandemic has spread rapidly worldwide. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent for COVID-19, enters host cells via angiotensin-converting enzyme 2 (ACE2) and depletes ACE2, which is necessary for bradykinin metabolism. The depletion of ACE2 results in the accumulation of des-Arg (9)-bradykinin and possible bradykinin, both of which bind to bradykinin receptors and induce vasodilation, lung injury, and inflammation. It is well known that an overactivated contact system and excessive production of bradykinin comprise the key mechanisms that drive the pathogenesis of hereditary angioedema (HAE). It is reasonable to speculate that COVID-19 may increase disease activity in patients with HAE and vice versa. In this review, we explore the potential interactions between COVID-19 and HAE in terms of the contact system, the complement system, cytokine release, increased T helper 17 cells, and hematologic abnormalities. We conclude with the hypothesis that comorbidity with HAE might favor COVID-19 progression and may worsen its outcomes, while COVID-19 might in turn aggravate pre-existing HAE and prompt the onset of HAE in asymptomatic carriers of HAE-related mutations. Based on the pathophysiologic links, we suggest that long-term prophylaxis should be considered in patients with HAE at risk of SARS-CoV-2 infection, especially the prophylactic use of C1 inhibitor and lanadelumab and that HAE patients must have medications for acute attacks of angioedema. Additionally, therapeutic strategies employed in HAE should be considered for the treatment of COVID-19, and clinical trials should be performed.

In Vitro Modeling of Bradykinin-Mediated Angioedema States.

François Marceau, Hélène Bachelard, Xavier Charest-Morin +2 more

Kinins (peptides related to bradykinin, BK) are formed from circulating substrates, the kininogens, by the action of two proteases, the kallikreins. The only clinical application of a BK receptor ligand, the B2 receptor antagonist icatibant, is the treatment of the rare hereditary angioedema (HAE) caused by the deficiency of C1-esterase inhibitor (C1-INH). Less common forms of HAE (genetic variants of factor XII, plasminogen, kininogen) are presumably mediated by increased BK formation. Acquired forms of BK-mediated angioedema, such as that associated with angiotensin-I converting enzyme (ACE) inhibition, are also known. Antibody-based analytical techniques are briefly reviewed, and support that kinins are extremely short-lived, prominently cleared by ACE. Despite evidence of continuous activation of the kallikrein-kinin system in HAE, patients are not symptomatic most of the time and their blood or plasma obtained during remission does not generate excessive immunoreactive BK (iBK), suggesting effective homeostatic mechanisms. HAE-C1-INH and HAE-FXII plasmas are both hyperresponsive to fibrinolysis activation. On another hand, we suggested a role for the alternate tissue kallikrein-kinin system in patients with a plasminogen mutation. The role of the BK B1 receptor is still uncertain in angioedema states. iBK profiles under in vitro stimulation provide fresh insight into the physiopathology of angioedema.

A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm.

Michael R Garvin, Christiane Alvarez, J Izaak Miller +7 more

Neither the disease mechanism nor treatments for COVID-19 are currently known. Here, we present a novel molecular mechanism for COVID-19 that provides therapeutic intervention points that can be addressed with existing FDA-approved pharmaceuticals. The entry point for the virus is ACE2, which is a component of the counteracting hypotensive axis of RAS. Bradykinin is a potent part of the vasopressor system that induces hypotension and vasodilation and is degraded by ACE and enhanced by the angiotensin1-9 produced by ACE2. Here, we perform a new analysis on gene expression data from cells in bronchoalveolar lavage fluid (BALF) from COVID-19 patients that were used to sequence the virus. Comparison with BALF from controls identifies a critical imbalance in RAS represented by decreased expression of ACE in combination with increases in ACE2, renin, angiotensin, key RAS receptors, kinogen and many kallikrein enzymes that activate it, and both bradykinin receptors. This very atypical pattern of the RAS is predicted to elevate bradykinin levels in multiple tissues and systems that will likely cause increases in vascular dilation, vascular permeability and hypotension. These bradykinin-driven outcomes explain many of the symptoms being observed in COVID-19.

ACE inhibitor-mediated angioedema.

Vincenzo Montinaro, Marco Cicardi

Angioedema (AE) occurring during ACE inhibitor therapy (ACEi-AE) is a rare complication involving between 0.1 and 0.7% of treated patients. AE can also complicate other therapeutic regimens that block the renin-angiotensin aldosterone system. Other drugs, such as immune suppressors, some type of antidiabetics or calcium antagonists, can increase the likelihood of ACEi-AE when associated to ACEi. There is a clear ethnic predisposition, since African-Americans or Hispanics show a higher prevalence of this condition compared to Caucasians. At least in African-Americans the genetic predisposition accounts for a general higher prevalence of AE, independently from the cause. People that experience ACEi-AE may have some recurrence when they are switched to an angiotensin-receptor blocker (ARB); however, epidemiological studies on large cohorts have shown that angiotensin receptor blockers (ARB) do not increase the likelihood of AE compared to other antihypertensives. Clinical manifestations consist of edema of face, lips, tongue, uvula and upper airways, requiring intubation or tracheotomy in severe cases. Attacks last for 48-72 h and require hospital admission in most cases. Intestinal involvement with sub-occlusive symptoms has also been reported. The pathogenesis of ACEi-AE depends mainly on a reduced catabolism and accumulation of bradykinin, which is normally metabolized by ACE. Genetic studies have shown that some single nucleotide polymorphisms at genes encoding relevant molecules for bradykinin metabolism and action may be involved in ACEi-AE, giving a basis for the ethnic predisposition. Treatment of ACEi-AE is still a matter of debate. Corticosteroids and antihistamines do not show efficacy. Some therapeutic attempts have shown some efficacy for fresh frozen plasma or C1 inhibitor concentrate infusion. Interventional studies with the specific bradykinin receptor antagonist icatibant have shown conflicting results; there might be a different ethnic predisposition to icatibant efficacy which has been proven in caucasian but not in black patients.

[ACE-inhibition and bradykinin-mediated angioedema].

D Ndjekembo Shango, O Simonet, F Vallot +2 more

Angiotensin converting enzyme inhibitors (ACE-i) are the most common cause of bradykininin angioedema. These bradykinin-mediated angioedemas are sometimes confused with histamine-induced angioedema, which may cause a late diagnosis and hence poor initial management, deleterious to the patient. This report describes a patient with a bradykinin-mediated angioedema soon after the initiation of perindopril, with laryngeal involvement requiring orotracheal intubation in emergency. The diagnosis was confirmed later and the assay of the activity of the enzymes involved in the catabolism of kinins - aminopeptidase P (APP), carboxypeptidase N (CPN) and Angiotensin-Converting Enzyme (ACE) - demonstrated a decrease of activity of both APP and ACE. As the diagnosis was not made initially, the specific treatments - concentrate of C1 inhibitor or antagonist of the B2 receptor of bradykinin (Icatibant) - were not administered. Any angioedema occurring during a treatment with ACE-i should be considered as a bradykinin-mediated angioedema.

[The ulm emergency algorithm for the acute treatment of drug-induced, bradykinin-mediated angioedema].

J Hahn, B Bock, C-M Muth +4 more

Bradykinin-mediated, drug-induced edema like ACE-inhibitor-induced angioedema (ACEi AE) is almost exclusively located in the head and neck region and is potentially life threatening. To date, there are no guidelines or officially-approved treatments available for this pathology.

Angioedema and emergency medicine: From pathophysiology to diagnosis and treatment.

Federica Depetri, Alberto Tedeschi, Massimo Cugno

Angioedema is a self-limiting edema of the subcutaneous or submucosal tissues due to localised increase of microvascular permeability whose mediator may be histamine or bradykinin. Patients present to emergency department when angioedema involves oral cavity and larynx (life-threatening conditions) or gut (mimicking an acute abdomen). After initial evaluation of consciousness and vital signs to manage breathing and to support circulation if necessary, a simple approach can be applied for a correct diagnosis and treatment. Forms of edema such as anasarca, myxedema, superior vena cava syndrome and acute dermatitis should be ruled out. Then, effort should be done to differentiate histaminergic from non-histaminergic angioedema. Concomitant urticaria and pruritus suggest a histaminergic origin. Exposure to allergens and drugs (mainly ACE inhibitors and non steroidal anti-inflammatory drugs) should be investigated as well as a family history of similar symptoms. Allergic histaminergic angioedema has a rapid course (minutes) whereas non histaminergic angioedema is slower (hours). Since frequently the intervention needs to be immediate, the initial diagnosis is only clinical. However, laboratory tests can be subsequently confirmatory. Allergic angioedema is sensitive to standard therapies such as epinephrine, glucocorticoids and antihistamines whereas non histaminergic angioedema is often resistant to these drugs. Therapeutic options for angioedema due C1-inhibitor deficiencies are C1-inhibitor concentrates, icatibant and ecallantide. If these drugs are not available, fresh frozen plasma can be considered. All these medications have been used also in ACE inhibitor-induced angioedema with variable results thus they are not currently recommended whereas experts agree on the discontinuation of the causative drug.

Stable and Long-Lasting, Novel Bicyclic Peptide Plasma Kallikrein Inhibitors for the Treatment of Diabetic Macular Edema.

Daniel P Teufel, Gavin Bennett, Helen Harrison +10 more

Plasma kallikrein, a member of the kallikrein-kinin system, catalyzes the release of the bioactive peptide bradykinin, which induces inflammation, vasodilation, vessel permeability, and pain. Preclinical evidence implicates the activity of plasma kallikrein in diabetic retinopathy, which is a leading cause of visual loss in patients suffering from diabetes mellitus. Employing a technology based on phage-display combined with chemical cyclization, we have identified highly selective bicyclic peptide inhibitors with nano- and picomolar potencies toward plasma kallikrein. Stability in biological matrices was either intrinsic to the peptide or engineered via the introduction of non-natural amino acids and nonpeptidic bonds. The peptides prevented bradykinin release in vitro, and in vivo efficacy was demonstrated in both a rat paw edema model and in rodent models of diabetes-induced retinal permeability. With a highly extended half-life of ∼40 h in rabbit eyes following intravitreal administration, the bicyclic peptides are promising novel agents for the treatment of diabetic retinopathy and diabetic macular edema.

Angioedema: Systemic activation process during prodromes.

Samuel Luyasu, Delphine Charignon, Denise Ponard +2 more

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

Kerstin Göbel, Chloi-Magdalini Asaridou, Monika Merker +13 more

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.

Pharmacotherapy for Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema: A Systematic Review.

Claire M Lawlor, Ashwin Ananth, Blair M Barton +2 more

Objective Angioedema is a potentially life-threatening complication of angiotensin-converting enzyme inhibitor (ACEI) use, occurring in up to 0.5% of users. Although the pathophysiology of ACEI-induced angioedema is attributable to elevated serum bradykinin, standard management typically includes corticosteroids and antihistamines. We sought to summarize the evidence supporting pharmacotherapy for ACEI-induced angioedema. Data Sources PubMed, MEDLINE, and Embase portals. Methods A systematic literature review was conducted according to the PRISMA guidelines. Databases were queried by 3 independent reviewers for English-language studies published between 1980 and 2017. The initial search screened for all occurrences of "angioedema" and then was further refined to include studies of ACEI-related cases and exclude hereditary angioedema. Results Five articles representing 218 cases were identified, including 3 randomized controlled trials and 2 prospective case series with historical controls. One of 2 studies of icatibant (bradykinin B2 receptor antagonist) found more rapid symptom improvement than that with a control group of corticosteroids and antihistamines. Two studies of ecallantide (plasma kallikrein inhibitor) and 1 study of C1 inhibitor replacement found no significant benefit over control. No studies were identified that compared the efficacy of corticosteroids with antihistamines, of one dose with another, of fresh frozen plasma, or of combination therapy. Conclusion The efficacy of treatment of ACEI-induced angioedema with bradykinin antagonists, kallikrein inhibitor, and C1 inhibitor warrants further study. Although consistent benefit of these medications has not been demonstrated, their use has not caused harm. One study examining off-label use of icatibant has demonstrated efficacy over control. In addition, further study is needed to establish the efficacy and mechanism of action of standard pharmacotherapy such as corticosteroids and antihistamines in treatment of this condition.

Randomized Trial of Icatibant for Angiotensin-Converting Enzyme Inhibitor-Induced Upper Airway Angioedema.

Richard Sinert, Phillip Levy, Jonathan A Bernstein +7 more

Upper airway angioedema is a rare, unpredictable, and at times life-threatening adverse effect of angiotensin-converting enzyme inhibitors (ACE-Is) with no existing effective pharmacologic treatment. Icatibant is a bradykinin B2 receptor antagonist that may be beneficial in patients with ACE-I-induced angioedema.

Effect of 3-substituted 1,4-benzodiazepin-2-ones on bradykinin-induced smooth muscle contraction.

P A Virych, O V Shelyuk, T A Kabanova +4 more

Biochemical properties of 3-substituted 1,4-benzodiazepine determined by the characteristics of their chemical structure. Influence of 3-substituted 1,4-benzodiazepin-2-ones on maximal normalized rate and amplitudes of isometric smooth muscle contraction in rats was investigated. Compounds MX-1775 and MX-1828 demonstrated the similar inhibition effect on bradykinin-induced contraction of smooth muscle like competitive inhibitor des-arg9-bradykinin-acetate to bradykinin B2-receptors. MX-1626 demonstrated unidirectional changes of maximal normalized rate and force of smooth muscle that proportionally depended on bradykinin concentration in the range 10-10-10-6 M. MX-1828 has statistically significant decrease of normalized rate of smooth muscle contraction for bradykinin concentrations 10-10 and 10-9 M by 20.7 and 8.6%, respectively, but for agonist concentration 10-6 M, this parameter increased by 10.7% and amplitude was reduced by 29.5%. Compounds MX-2011, MX-1785 and MX-2004 showed no natural effect on bradykinin-induced smooth muscle contraction. Compounds MX-1775, MX-1828, MX-1626 were selected for further research of their influence on kinin-kallikrein system and pain perception.