Bradykinin Receptor Antagonist Research Articles

Modular Hub Genes in DNA Microarray Suggest Potential Signaling Pathway Interconnectivity in Various Glioma Grades.

Gliomas have displayed significant challenges in oncology due to their high degree of invasiveness, recurrence, and resistance to treatment strategies. In this work, the key hub genes mainly associated with different grades of glioma, which were represented by pilocytic astrocytoma (PA), oligodendroglioma (OG), anaplastic astrocytoma (AA), and glioblastoma multiforme (GBM), were identified through weighted gene co-expression network analysis (WGCNA) of microarray datasets retrieved from the Gene Expression Omnibus (GEO) database. Through this, four highly correlated modules were observed to be present across the PA (GSE50161), OG (GSE4290), AA (GSE43378), and GBM (GSE36245) datasets. The functional annotation and pathway enrichment analysis done through the Database for Annotation, Visualization, and Integrated Discovery (DAVID) showed that the modules and hub genes identified were mainly involved in signal transduction, transcription regulation, and protein binding, which collectively deregulate several signaling pathways, mainly PI3K/Akt and metabolic pathways. The involvement of several hub genes primarily linked to other signaling pathways, including the cAMP, MAPK/ERK, Wnt/β-catenin, and calcium signaling pathways, indicates potential interconnectivity and influence on the PI3K/Akt pathway and, subsequently, glioma severity. The Drug Repurposing Encyclopedia (DRE) was used to screen for potential drugs based on the up- and downregulated hub genes, wherein the synthetic progestin hormones norgestimate and ethisterone were the top drug candidates. This shows the potential neuroprotective effect of progesterone against glioma due to its influence on EGFR expression and other signaling pathways. Aside from these, several experimental and approved drug candidates were also identified, which include an adrenergic receptor antagonist, a PPAR-γ receptor agonist, a CDK inhibitor, a sodium channel blocker, a bradykinin receptor antagonist, and a dopamine receptor agonist, which further highlights the gene network as a potential therapeutic avenue for glioma.

ACE2/ACE imbalance mediates bisphenol A-induced lung injury in Wistar rats: Results from captopril versus losartan histo-biochemical study

Bisphenol-A (BPA) is a synthetic chemical compound broadly used in the plastic and epoxy resin industries with a considerable potential for food contamination. Literary reports have suggested that the altered renin-angiotensin system (RAS) is a mechanism for lung injury and inflammation caused by variable agents. The current study sought to investigate the contribution of RAS to BPA-induced lung damage. Moreover, the study assessed whether angiotensin II and/or bradykinin pathways were involved. For this aim, the angiotensin-converting enzyme (ACE) inhibitor captopril (Cap), either alone or combined with bradykinin receptor antagonist icatibant (Icat), was attempted versus the angiotensin receptor blocker losartan (Los). An eight-week study was conducted on forty Wistar male albino rats randomly divided into five equal groups: control, BPA, BPA/Cap, BPA/Los, and BPA/Cap/Icat groups. Captopril (100 mg/mL) and losartan (200 mg/mL) were given orally in drinking water, but icatibant (Icat) was injected subcutaneously (250 μg/kg) during the last two weeks of captopril treatment. Biochemical analysis of bronchoalveolar lavage fluid (BALF) and lung tissues, polymerase chain reaction (PCR) assay for ACE, ACE2, and caspase-3 genes expression, and histological and immunohistochemical studies were carried out to evaluate BPA-mediated pulmonary inflammation/apoptosis. BPA impaired the histological structure of the lungs, increased ACE, ACE2, and caspase-3 expressions at both gene/protein levels, and increased BALF inflammatory cytokines and lung oxidative markers. Inhibiting the ACE activity by captopril maintained the histological lung injury score, restored inflammation and the ACE2/ACE balance, and decreased apoptosis. Further improvement was obtained by the angiotensin II receptor (ATR1) blocker losartan. Icatibant (bradykinin B2 receptor blocker) didn't counteract the observed captopril effects. It was strongly suggested that RAS contributed to BPA-induced lung damage via alteration of ACE2 and ACE expression mediating angiotensin II generation rather than bradykinin.

Pathophysiology of bradykinin and histamine mediated angioedema.

Angioedema is characterized by swelling localized to the subcutaneous and submucosal tissues. This review provides an overview of angioedema, including the different types, triggers, and underlying pathophysiologic mechanisms. Hereditary and acquired angioedema are caused by dysregulation of the complement and kinin pathways. In contrast, drug-induced and allergic angioedema involve the activation of the immune system and release of vasoactive mediators. Recent advances in the understanding of the pathophysiology of angioedema have led to the development of targeted therapies, such as monoclonal antibodies, bradykinin receptor antagonists, and complement inhibitors, which promise to improve clinical outcomes in patients with this challenging condition. To accurately diagnose and manage angioedema, an understanding of this condition's complex and varied pathophysiology is both necessary and critical.

Pseudo-Allergies in the Emergency Department: A Common Misdiagnosis of Hypersensitivity Type 1 Allergic Reaction.

Type-1 hypersensitivity reaction represents an acute IgE-mediated reaction that can cause life-threatening conditions, such as anaphylactic shock, angioedema, and airway obstruction. Other reactions that can mimic type-1 hypersensitivity reactions include IgE-independentmast cell degranulation, bradykinin-mediated reactions, leukotrienes-mediated reactions, and pseudo-allergies. We use the term pseudo-allergy in this article for histamine-mediated reactions that are mast cell-independent. We did not discuss pseudo-allergic reactions that are not acute or life-threatening, such as celiac disease, Heiner's syndrome, eosinophilic esophagitis, and food protein-induced enterocolitis in our article because the emergency department is not the primary location to diagnose or treat these reactions. Herein, we present some allergic-like reactions that can be life-threatening, such as scombroid food poisoning (SFP), bradykinin-induced angioedema, IgE-independent angioedema, opioid-induced angioedema, and non-steroidal anti-inflammatory drug (NSAID)-induced hypersensitivity and angioedema. These reactions may have different treatments based on their mechanism of reaction. Histamine-mediated reactions, such as SFP, histamine-mediated angioedema, and mast cell degranulation induced by NSAIDs, and opioids can be treated with antihistamines, epinephrine, and corticosteroids. Bradykinin-induced angioedema, including hereditary angioedema and acquired angioedema, can be treated with fresh frozen plasma. Hereditary angioedema can be treated withmany FDA-approved targeted medications, such asplasma-derived C1-INH,plasma kallikrein inhibitor (Ecallantide), and selective bradykinin-2 receptor antagonist (Icatibant).However, these targeted agents are not well-studied enough to be used for acquired angioedema.It is crucial for emergency medicine physicians to be familiar with and predict these reactions to prevent misdiagnosis, be prepared to treat these life-threatening conditions appropriately without delay and eliminate patients' exposure to any unnecessary investigations or treatments.

Angiotensin receptor-neprilysin inhibitor improves coronary collateral perfusion.

We investigated the pleiotropic effects of an angiotensin receptor-neprilysin inhibitor (ARNi) on collateral-dependent myocardial perfusion in a rat model of coronary arteriogenesis, and performed comprehensive analyses to uncover the underlying molecular mechanisms. A rat model of coronary arteriogenesis was established by implanting an inflatable occluder on the left anterior descending coronary artery followed by a 7-day repetitive occlusion procedure (ROP). Coronary collateral perfusion was measured by using a myocardial particle infusion technique. The putative ARNi-induced pro-arteriogenic effects were further investigated and compared with an angiotensin-converting enzyme inhibitor (ACEi). Expression of the membrane receptors and key enzymes in the natriuretic peptide system (NPS), renin-angiotensin-aldosterone system (RAAS) and kallikrein-kinin system (KKS) were analyzed by quantitative polymerase chain reaction (qPCR) and immunoblot assay, respectively. Protein levels of pro-arteriogenic cytokines were measured by enzyme-linked immunosorbent assay, and mitochondrial DNA copy number was assessed by qPCR due to their roles in arteriogenesis. Furthermore, murine heart endothelial cells (MHEC5-T) were treated with a neprilysin inhibitor (NEPi) alone, or in combination with bradykinin receptor antagonists. MHEC5-T proliferation was analyzed by colorimetric assay. The in vivo study showed that ARNis markedly improved coronary collateral perfusion, regulated the gene expression of KKS, and increased the concentrations of relevant pro-arteriogenic cytokines. The in vitro study demonstrated that NEPis significantly promoted MHEC5-T proliferation, which was diminished by bradykinin receptor antagonists. ARNis improve coronary collateral perfusion and exert pro-arteriogenic effects via the bradykinin receptor signaling pathway.

Slučaj angioedema hereditarnog porekla u seoskoj ambulanti nadomak Subotice

Introduction: Hereditary angioedema (HAE) is inherited in an autosomal dominant manner. It manifests with bradykinin-mediated swelling due to a deficiency of C1 inhibitor. Managing these patients is challenging during acute edema and the onset of asphyxiation. Transportation to the hospital takes 25 minutes. Objective: To present a patient with HAE for whom specific therapy has only recently become available. Case Presentation: A female patient presented with difficulty breathing, swelling of the lips, and periorbital edema. Status: visibly distressed, talkative, facial and lip swelling, visible mucosa without edema, uvula and pharynx calm. Respiratory movements symmetric, without the use of accessory muscles. Auscultation revealed normal breath sounds, tachycardic heart action, clear tones without murmurs, and no urticaria. Blood pressure 120/70 mmHg, heart rate 100/min., respiratory rate 30/min., SpO2 98%, capillary refill time (CRT) 2 sec. Treatment: infusion, Methylprednisolone 40 mg IV. She was transported with monitoring. During transport, the condition worsened: blood pressure 105/60 mmHg, heart rate 130/min., respiratory rate 40/min., SpO2 94%, CRT 2 sec. Oxygen at 15 L/min. was initiated, an additional IV line was opened, and capnography showed ETCO2 of 36 mmHg. Methylprednisolone was increased to 80 mg. Preparation for difficult intubation was initiated. Parameters did not worsen, and the patient was transferred to the emergency department of the General Hospital Subotica. Conclusion: Since specific therapies, such as human C1 inhibitor concentrate or bradykinin receptor antagonists, have been approved for self-administration at home during acute attacks, the treatment of these patients has been facilitated, minimizing the potential fatal outcomes and morbidity.

Bradykinin 2 receptors contribute to the exaggerated exercise pressor reflex in a rat model of simulated peripheral artery disease.

We investigated the role played by bradykinin 2 (B2) receptors in the exaggerated exercise pressor reflex in rats with a femoral artery ligated for 72 h to induce simulated peripheral artery disease (PAD). We hypothesized that in decerebrate, unanesthetized rats with a ligated femoral artery, hindlimb arterial injection of HOE-140 (100 ng, B2 receptor antagonist) would reduce the pressor response to 30 s of electrically induced 1 Hz hindlimb skeletal muscle contraction, and 30 s of 1 Hz hindlimb skeletal muscle stretch (a model of mechanoreflex activation isolated from contraction-induced metabolite production). We hypothesized no effect of HOE-140 in sham-operated "freely perfused" rats. In both freely perfused (n = 4) and "ligated" (n = 4) rats, we first confirmed efficacious B2 receptor blockade by demonstrating that HOE-140 injection significantly reduced (P < 0.05) the peak increase in mean arterial pressure (peak ΔMAP) in response to hindlimb arterial injection of bradykinin. In subsequent experiments, we found that HOE-140 reduced the peak ΔMAP response to muscle contraction in ligated (n = 14; control: 23 ± 2; HOE-140: 17 ± 2 mmHg; P = 0.03) but not freely perfused rats (n = 7; control: 17 ± 3; HOE-140: 18 ± 4 mmHg; P = 0.65). Furthermore, HOE-140 had no effect on the peak ΔMAP response to stretch in ligated rats (n = 14; control: 37 ± 4; HOE-140: 32 ± 5 mmHg; P = 0.13) but reduced the integrated area under the blood pressure signal over the final ∼20 s of the maneuver. The data suggest that B2 receptors contribute to the exaggerated exercise pressor reflex in rats with simulated PAD, and that contribution includes a modest role in the chronic sensitization of the mechanically activated channels/afferents that underlie mechanoreflex activation.

HEALTHCARE RESOURCE UTILIZATION AMONG LANADELUMAB AND SUBCUTANEOUS C1-INHIBITOR CONCENTRATE NEW USERS - RETROSPECTIVE DATABASE STUDY

<h3>Introduction</h3> Three long-term prophylactic therapies (LTPs) have become available in the past five years for hereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency, including two subcutaneous (SC) options: a monoclonal antibody (lanadelumab) and a plasma-derived C1-INH concentrate (SC-C1-INH). However, limited real-world data on these therapies have been reported. <h3>Methods</h3> Annualized healthcare resource utilization (HCRU), including medication use, and costs of SC-LTP are described among adults starting lanadelumab or SC-C1-INH based on the 180 days before (baseline) and up to 365 days of continuous use after (follow-up) starting therapy, from the IBM MarketScan US insurance claims database. The study population was required to continuously use lanadelumab or SC-C1-INH for=180 days to be in the analysis. <h3>Results</h3> 47 lanadelumab and 38 SC-C1-INH subjects were identified. Bradykinin receptor antagonists (∼50% in both cohorts) and intravenous-C1-INH (40% and 58%, respectively) were the most frequent HAE medications filled during baseline. 20–30% of each cohort had no baseline HAE medication fills. Annualized HCRU, including but not limited to acute medication fills and angioedema-associated emergency department (ED) visits/hospitalizations, decreased by >50% between baseline and follow-up (∼10 to 3–4 for acute medication fills; 1–2 to ∼0.5 for ED visits/hospitalizations) [Figure]. Total estimated annualized healthcare costs were $866,639 and $734,460 for the lanadelumab and SC-C1-INH cohorts respectively, with pharmacy costs accounting for >95% of total costs. <h3>Conclusion</h3> HAE SC-LTP reduced HCRU by >50%, though did not eliminate prescription fills for acute HAE medication nor angioedema-associated ED/hospital utilization, indicating burden of disease persists despite newer treatments.

A CASE OF DIFFICULT TO DIAGNOSE C1INH NORMAL HAE

<h3>Introduction</h3> Hereditary Angioedema (HAE) is characterized by recurrent swellings of the face, tongue, oropharynx, extremities, and abdomen. Typically beginning in the second decade of life, these swells often require emergent treatment and may result in intubation. Unchecked production of bradykinin, typically due to low levels of C1 esterase inhibitor (C1INH), results in bradykinin mediated vascular leakage and swelling. Type I and II can be diagnosed by checking C1INH levels and function but C1INH Normal continues to be difficult to diagnose. We present a challenging case detailing the diagnosis and management of probable C1INH normal HAE in a 42-year-old female. <h3>Case Description</h3> A 42-year-old woman with a history of hypothyroidism, GERD, migraine, obesity, and borderline personality disorder, presented to our clinic with a 10-year history of three or more weekly episodes of throat and eyelid angioedema, accompanied by intermittent urticaria. Her controller therapy included montelukast, fexofenadine, cetirizine, zyflo, famotidine, and cromolyn. Despite this regimen, she continued her thrice weekly episodes, so cyclosporine was added without improvement in flare frequency or severity. C1INH level and function, along with her physical exam, were unremarkable. A trial of recombinant C1INH resolved an acute swell, so she was started on C1INH replacement, with significant reduction in her swell frequency. <h3>Discussion</h3> C1INH normal HAE continues to be difficult to diagnose with currently available assays. For patients with recurrent swells, not responding to mast cell stabilizers or antihistamines, a trial of recombinant C1INH or a bradykinin receptor antagonist, may aid in the diagnosis of C1INH Normal HAE.

Functionalized Nanogels with Endothelin-1 and Bradykinin Receptor Antagonist Peptides Decrease Inflammatory and Cartilage Degradation Markers of Osteoarthritis in a Horse Organoid Model of Cartilage.

Osteoarthritis (OA) is a degenerative and heterogeneous disease that affects all types of joint structures. Current clinical treatments are only symptomatic and do not manage the degenerative process in animals or humans. One of the new orthobiological treatment strategies being developed to treat OA is the use of drug delivery systems (DDS) to release bioactive molecules over a long period of time directly into the joint to limit inflammation, control pain, and reduce cartilage degradation. Two vasoactive peptides, endothelin-1 and bradykinin, play important roles in OA pathogenesis. In this study, we investigated the effects of two functionalized nanogels as DDS. We assessed the effect of chitosan functionalized with a type A endothelin receptor antagonist (BQ-123-CHI) and/or hyaluronic acid functionalized with a type B1 bradykinin receptor antagonist (R-954-HA). The biocompatibility of these nanogels, alone or in combination, was first validated on equine articular chondrocytes cultured under different oxic conditions. Further, in an OA equine organoid model via induction with interleukin-1 beta (IL-1β), a combination of BQ-123-CHI and R-954-HA (BR5) triggered the greatest decrease in inflammatory and catabolic markers. In basal and OA conditions, BQ-123-CHI alone or in equimolar combinations with R-954-HA had weak pro-anabolic effects on collagens synthesis. These new nanogels, as part of a composite DDS, show promising attributes for treating OA.

ALTEPLASE-ASSOCIATED ANGIOEDEMA: NEW TREATMENT OPTIONS

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Alteplase (recombinant tissue plasminogen activator or tPA) has revolutionized the management of acute ischemic stroke since its FDA approval in 1995. Intracerebral bleed is the most known and feared complication after tPA administration. tPA-associated orolingual angioedema (TAOA) is a less common but potentially fatal complication of tPA. We report a patient who developed hemi-orolingual angioedema after receiving tPA. CASE PRESENTATION: A 79-year-old female presented with sudden onset right-sided weakness with initial National Institutes of Health Stroke Scale score of 4. CT head was negative for intracranial bleed and a CT angiogram with perfusion of the head showed occlusion of P2 segment of the left posterior cerebral artery. She received tPA bolus followed by infusion and was transferred to the intensive care unit. She developed right hemi-orolingual angioedema without evidence of airway compromise one and half hours after tPA initiation. Administration of intravenous corticosteroids and antihistamines failed to improve angioedema. She was subsequently treated with 2 units of fresh frozen plasma (FFP) with complete resolution of swelling within 2 hours. DISCUSSION: Alteplase cleaves plasminogen to plasmin which degrades thrombus-bound fibrin. Plasmin also activates the kinin and complement pathways causing increased bradykinin and histamine release respectively. Bradykinin-mediated vasodilation appears to be the primary cause of TAOA. TAOA has an incidence of 0.2-5.1%. It usually develops hemi-lingually and tends to be contralateral to the ischemic side possibly due to autonomic dysfunction from insular cortex ischemia. However, this may not always be true since our patient had contralateral angioedema without insular cortex involvement. Initial management includes corticosteroids and antihistamines which are less effective for bradykinin-mediated angioedema. FFP contains kininase 2 which degrades bradykinin and hence is effectively used off label for angiotensin-converting enzyme inhibitor-induced angioedema. As TAOA also follows the bradykinin pathway, we treated our patient with FFP. To our knowledge, this is the first-ever case of TAOA treated with FFP. Other potential treatment options include C1 esterase inhibitor, icatibant (bradykinin receptor antagonist), and ecallantide (kallikrein inhibitor) which are being used for hereditary angioedema and need to be studied for TAOA. CONCLUSIONS: TAOA is a life-threatening complication that typically occurs in the first 4 hours after tPA administration. Physicians should be aware of this uncommon side effect for early recognition and treatment. Treatment targeting the bradykinin pathway like FFP might be more effective and needs further investigation. REFERENCE #1: Rathbun KM. Angioedema after thrombolysis with tissue plasminogen activator: an airway emergency. Oxf Med Case Reports. 2019;2019(1):omy112. Published 2019 Jan 24. doi:10.1093/omcr/omy11 REFERENCE #2: Hemi-orolingual angioedema and ACE inhibition after alteplase treatment of stroke. M. D. Hill, T. Lye, H. Moss, P. A. Barber, A. M. Demchuk, N. J. Newcommon, T. L. Green, C. Kenney, A. Cole–Haskayne, A. M. Buchan. Neurology May 2003, 60 (9) 1525-1527; DOI: 10.1212/01.WNL.0000058840.66596.1A DISCLOSURES: No relevant relationships by Robert Caldera, source=Web Response No relevant relationships by Kristin Fless, source=Web Response No relevant relationships by Bilal Khan, source=Web Response No relevant relationships by Nirav Mistry, source=Web Response No relevant relationships by Vagram Ovnanian, source=Web Response No relevant relationships by Fariborz Rezai, source=Web Response No relevant relationships by Aditi Saha, source=Web Response No relevant relationships by Sohaib Tariq, source=Web Response No relevant relationships by Lalithaa Thirunavukarasu Murugan, source=Web Response No relevant relationships by Paul Yodice, source=Web Response

Recognition and Management of Hereditary Angioedema: Best Practices for Dermatologists.

ObjectiveThe goal of this article is to discuss the importance of differentiating hereditary angioedema (HAE) from other types of angioedema, describe advances in HAE management, especially long-term prophylaxis (LTP), and offer practical recommendations for dermatologists.CommentaryWhile HAE is rare, dermatologists are likely to encounter patients with this condition at some point over the course of their clinical practice due to the fact that HAE episodes typically involve subcutaneous swelling and sometimes erythema marginatum. HAE is characterized by recurrent episodes of painful and/or disabling bradykinin-mediated angioedema. Unfortunately, HAE is commonly mistaken for other conditions such as allergic and other mast cell-mediated angioedema, but has very different treatment requirements. Delayed diagnosis of HAE can result in years of avoidable debilitating symptoms, inappropriate treatment, potentially unnecessary invasive intervention, and reduced quality of life, and can be life threatening. Thus, timely identification of HAE is essential to ensure appropriate clinical management. Patients with HAE have either deficiency or dysfunction of the C1 inhibitor (C1INH) protein that inhibits proteases in the contact, complement, and fibrinolytic systems. Pathway-specific HAE treatments include C1INH replacement, kallikrein inhibitors, and bradykinin receptor antagonists. Treatment options for managing acute attacks include C1INH replacement (plasma-derived or recombinant formulations), icatibant (kallikrein inhibitor), and ecallantide (bradykinin B2 receptor antagonist). In the past 5 years, several new options for LTP have been approved, including a subcutaneous plasma-derived C1INH formulation and two kallikrein inhibitors (lanadelumab; berotralstat). Optimal management of HAE entails the creation of a comprehensive management plan that addresses both acute and long-term patient needs and includes input from an HAE expert and the patient/caregivers.

The Toxicology of Native Fucosylated Glycosaminoglycans and the Safety of Their Depolymerized Products as Anticoagulants.

Fucosylated glycosaminoglycan (FG) from sea cucumber is a potent anticoagulant by inhibiting intrinsic coagulation tenase (iXase). However, high-molecular-weight FGs can activate platelets and plasma contact system, and induce hypotension in rats, which limits its application. Herein, we found that FG from T. ananas (TaFG) and FG from H. fuscopunctata (HfFG) at 4.0 mg/kg (i.v.) could cause significant cardiovascular and respiratory dysfunction in rats, even lethality, while their depolymerized products had no obvious side effects. After injection, native FG increased rat plasma kallikrein activity and levels of the vasoactive peptide bradykinin (BK), consistent with their contact activation activity, which was assumed to be the cause of hypotension in rats. However, the hemodynamic effects of native FG cannot be prevented by the BK receptor antagonist. Further study showed that native FG induced in vivo procoagulation, thrombocytopenia, and pulmonary embolism. Additionally, its lethal effect could be prevented by anticoagulant combined with antiplatelet drugs. In summary, the acute toxicity of native FG is mainly ascribed to pulmonary microvessel embolism due to platelet aggregation and contact activation-mediated coagulation, while depolymerized FG is a safe anticoagulant candidate by selectively targeting iXase.

Age-dependent possible role of contact-activated blood coagulation factor XII as a potential contributor to the “bradykinin storm” in COVID-19 patients

Bradykinin was implicated in a new complex model of pathomechanism leading to the symptoms of COVID-19 created by a computer-assisted association analysis. According to this model, the decrease in angiotensin-converting enzyme expression leads to impaired bradykinin elimination and subsequent enrichment in the lungs. However, there is no mentioning of the importance of blood coagulation factor XII in increased bradykinin production, in spite of its age-dependent activation and the lower level of C1-esterase inhibitor (C1INH). Activated factor XII may be an important contributor to the "bradykinin storm" in elder cardiovascular patients. Literature review. 1) Activation of the coagulation factor XII on the surface of SARS-CoV-2 infected endothelial cells may trigger the prekallikrein/kallikrein/kinin system producing bradykinin. Such process is taking place in hantavirus infections causing severe lung and kidney damages. 2) The endothelial system is dysregulated in elderly patients, resulting in potentially higher factor XII activities on the surface of damaged endothelial cells in the stiffened arteries. This can contribute to the higher mortality rates in the elderly. The targeted inhibition of activated blood coagulation factor XII may represent a new therapeutic target for COVID-19, especially for elder patients. Recently, beneficial results have already been observed by the clinical applications of recombinant C1INH and bradykinin receptor antagonists. Orv Hetil. 2020; 161(50): 2099-2103.

Characterisation of cough evoked by inhaled treprostinil and treprostinil palmitil

Cough is induced by inhaled prostacyclin analogues including treprostinil (TRE), and, at higher doses, treprostinil palmitil (TP), a prodrug of TRE. In this report, we have investigated mechanisms involved in TRE- and TP-induced cough, using a dry powder formulation of TP (TPIP) to supplement previous data obtained with an aqueous suspension formulation of TP (TPIS).Experiments in guinea pigs and rats investigated the prostanoid receptor subtype producing cough and whether it involved activation of sensory nerves in the airways and vasculature. Experiments involved treatment with prostanoid, tachykinin and bradykinin receptor antagonists, a cyclooxygenase inhibitor and TRE administration to the isolated larynx or intravenously.In guinea pigs, cough with inhaled TRE (1.23 µg·kg−1) was not observed with an equivalent dose of TPIP and required higher inhaled doses (12.8 and 35.8 µg·kg−1) to induce cough. TRE cough was blocked with IP and tachykinin NK1 receptor antagonists but not with EP1, EP2, EP3, DP1 or bradykinin B2 antagonists or a cyclooxygenase inhibitor. TRE administered to the isolated larynx or intravenously in rats produced no apnoea or swallowing, whereas citric acid, capsaicin and hypertonic saline had significant effects.The mechanisms inducing cough with inhaled TRE likely involves the activation of prostanoid IP receptors on jugular C-fibres in the tracheobronchial airways. Cough induced by inhaled dry powder and nebulised formulations of TP occurs at higher inhaled doses than TRE, presumably due to the slow, sustained release of TRE from the prodrug resulting in lower concentrations of TRE at the airway sensory nerves.

Spinal and Peripheral Mechanisms Individually Lead to the Development of Remifentanil-induced Hyperalgesia

The present study was performed to determine neuronal loci and individual molecular mechanisms responsible for remifentanil-induced hyperalgesia. The effect of methylnaltrexone (MNX) on remifentanil-induced behavioral hyperalgesia was assessed to distinguish contributions of the peripheral and/or central nervous system to remifentanil-induced hyperalgesia. Phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) in the dorsal root ganglion (DRG) neurons after remifentanil infusion, and the effect of a p38MAPK inhibitor on remifentanil-induced hyperalgesia were analyzed to investigate involvement of p38MAPK in the peripheral mechanisms of remifentanil-induced hyperalgesia. Spinal levels of prodynorphin mRNA after remifentanil infusion, and the effect of the BK2 bradykinin receptor antagonist on remifentanil-induced hyperalgesia were investigated to assess potential spinal mechanisms. The effects of MNX and BK2 antagonists on remifentanil-induced exacerbation of post-incisional hyperalgesia were also investigated using behavioral analysis. Remifentanil infusion induced hyperalgesia in the early (4 h to 2 days) and late (8–14 days) post-infusion periods. MNX inhibited hyperalgesia only during the early post-infusion period. p38MAPK phosphorylation was observed in the DRG neuron, and the p38MAPK inhibitor inhibited hyperalgesia during the early post-infusion period. Prodynorphin expression increased in the spinal cord, and a BK2 antagonist inhibited hyperalgesia during the late post-infusion period. Remifentanil-induced exacerbation of incisional hyperalgesia was inhibited by MNX and the BK2 antagonist. The present study demonstrated that remifentanil activates peripheral and spinal neurons to promote chronologically distinctive hyperalgesia. p38MAPK phosphorylation in the DRG neuron leads to peripherally-driven hyperalgesia during the early post-infusion period, while spinal dynorphin-bradykinin signaling promotes hyperalgesia during the late post-infusion period.

Outcomes Associated With Use of a Kinin B2 Receptor Antagonist Among Patients With COVID-19

This case-control study examines the association between receipt of the bradykinin 2 (B2) receptor antagonist icatibant and improved oxygenation in patients with coronavirus disease 2019 (COVID-19).

Hereditary angioedema in children and adolescents - A consensus update on therapeutic strategies for German-speaking countries.

At a consensus meeting in August 2018, pediatricians and dermatologists from German-speaking countries discussed the therapeutic strategy for the treatment of pediatric patients with type I and II hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) for Germany, Austria, and Switzerland, taking into account the current marketing approval status. HAE-C1-INH is a rare disease that usually presents during childhood or adolescence with intermittent episodes of potentially life-threatening angioedema. Diagnosis as early as possible and an optimal management of the disease are important to avoid ineffective therapies and to properly treat swelling attacks. This article provides recommendations for developing appropriate treatment strategies in the management of HAE-C1-INH in pediatric patients in German-speaking countries. An overview of available drugs in this age-group is provided, together with their approval status, and study results obtained in adults and pediatric patients. Currently, plasma-derived C1 inhibitor concentrates have the broadest approval status and are considered the best available option for on-demand treatment of HAE-C1-INH attacks and for short- and long-term prophylaxis across all pediatric age-groups in German-speaking countries. For on-demand treatment of children aged 2years and older, recombinant C1-INH and bradykinin-receptor antagonist icatibant are alternatives. For long-term prophylaxis in adolescents, the parenteral kallikrein inhibitor lanadelumab has recently been approved and can be recommended due to proven efficacy and safety.

Update on bradykinin-mediated angioedema in 2020

Bradykinin-mediated angioedema is a rare disease, due to vasodilation and increased vascular permeability resulting from bradykinin. This kind of angioedema affects abdominal and/or upper airways. It differs clinically from histamine-mediated angioedema by the absence of urticaria or skin rash. Antihistamines and corticosteroids are not effective. Delayed diagnosis can lead to inadequate and potentially fatal management by asphyxiation. Bradykinin-mediated angioedema results from either overproduction of bradykinin or inhibition of its degradation. Etiology can be hereditary or acquired. Deficiency of C1 inhibitor and drug induced are the main causes of bradykinin-mediated angioedema. Its diagnosis is clinical (presentation, family history, seriousness, frequency, etc.) and biological (dosage of C1-INH level, C1-INH activity, and complement protein 4 level). Acute attack treatment is based on C1-inhibitor concentrates and icatibant, a bradykinin receptor antagonist. Long-term prophylaxis can be necessary, especially before surgical and dental procedures. New drugs, including gene therapy, are being tested.

PIP2 Mediated Inhibition of TREK Potassium Currents by Bradykinin in Mouse Sympathetic Neurons.

Bradykinin (BK), a hormone inducing pain and inflammation, is known to inhibit potassium M-currents (IM) and to increase the excitability of the superior cervical ganglion (SCG) neurons by activating the Ca2+-calmodulin pathway. M-current is also reduced by muscarinic agonists through the depletion of membrane phosphatidylinositol 4,5-biphosphate (PIP2). Similarly, the activation of muscarinic receptors inhibits the current through two-pore domain potassium channels (K2P) of the “Tandem of pore-domains in a Weakly Inward rectifying K+ channel (TWIK)-related channels” (TREK) subfamily by reducing PIP2 in mouse SCG neurons (mSCG). The aim of this work was to test and characterize the modulation of TREK channels by bradykinin. We used the perforated-patch technique to investigate riluzole (RIL) activated currents in voltage- and current-clamp experiments. RIL is a drug used in the palliative treatment of amyotrophic lateral sclerosis and, in addition to blocking voltage-dependent sodium channels, it also selectively activates the K2P channels of the TREK subfamily. A cell-attached patch-clamp was also used to investigate TREK-2 single channel currents. We report here that BK reduces spike frequency adaptation (SFA), inhibits the riluzole-activated current (IRIL), which flows mainly through TREK-2 channels, by about 45%, and reduces the open probability of identified single TREK-2 channels in cultured mSCG cells. The effect of BK on IRIL was precluded by the bradykinin receptor (B2R) antagonist HOE-140 (d-Arg-[Hyp3, Thi5, d-Tic7, Oic8]BK) but also by diC8PIP2 which prevents PIP2 depletion when phospholipase C (PLC) is activated. On the contrary, antagonizing inositol triphosphate receptors (IP3R) using 2-aminoethoxydiphenylborane (2-APB) or inhibiting protein kinase C (PKC) with bisindolylmaleimide did not affect the inhibition of IRIL by BK. In conclusion, bradykinin inhibits TREK-2 channels through the activation of B2Rs resulting in PIP2 depletion, much like we have demonstrated for muscarinic agonists. This mechanism implies that TREK channels must be relevant for the capture of information about pain and visceral inflammation.