ABSTRACT
O tratamento do angioedema hereditário tem início com a educação dos pacientes e familiares sobre a doença, pois é fundamental o conhecimento da imprevisibilidade das crises, assim como os seus fatores desencadeantes. O tratamento medicamentoso se divide em terapia das crises e profilaxia das manifestações clínicas. As crises devem ser tratadas o mais precocemente possível com o uso do antagonista do receptor de bradicinina, o icatibanto ou o concentrado de C1-inibidor. É necessário estabeler um plano de ação em caso de crises para todos os pacientes. A profilaxia de longo prazo dos sintomas deve ser realizada preferencialmente com medicamentos de primeira linha, como concentrado do C1-inibidor ou o anticorpo monoclonal anti-calicreína, lanadelumabe. Como segunda linha de tratamento temos os andrógenos atenuados. Na profilaxia de curto prazo, antes de procedimentos que podem desencadear crises, o uso do concentrado de C1-inibidor é preconizado. Existem algumas restrições para uso desses tratamentos em crianças e gestantes que devem ser consideradas. Novos medicamentos baseados nos avanços do conhecimento da fisiopatologia do angioedema hereditário estão em desenvolvimento, devendo melhorar a qualidade de vida dos pacientes. O uso de ferramentas padronizadas para monitorização da qualidade de vida, do controle e da atividade da doença são fundamentais no acompanhamento destes pacientes. A criação de associações de pacientes e familiares de pacientes com angioedema hereditário tem desempenhado um papel muito importante no cuidado destes pacientes no nosso país.
The treatment of hereditary angioedema begins with the education of patients and their families about the disease, as it is essential to know the unpredictability of attacks as well as their triggering factors. Drug treatment is divided into attack therapy and prophylaxis of clinical manifestations. Attacks should be treated as early as possible with the bradykinin receptor antagonist icatibant or C1-inhibitor concentrate. An action plan needs to be established for all patients with attacks. Long-term prophylaxis of symptoms should preferably be performed with first-line drugs such as C1-inhibitor concentrate or the anti-kallikrein monoclonal antibody lanadelumab. Attenuated androgens are the second line of treatment. In short-term prophylaxis, before procedures that can trigger attacks, the use of C1-inhibitor concentrate is recommended. There are some restrictions for the use of these treatments in children and pregnant women that should be considered. New drugs based on advances in knowledge of the pathophysiology of hereditary angioedema are under development and are expected to improve patient quality of life. The use of standardized tools for monitoring quality of life and controlling disease activity is essential in the follow-up of these patients. The creation of associations of patients and families of patients with hereditary angioedema has played a very important role in the care of these patients in Brazil.
Subject(s)
Humans , Drug Therapy , Angioedemas, Hereditary , Antibodies, Monoclonal, Humanized , Bradykinin Receptor Antagonists , Patients , Quality of Life , Therapeutics , Bradykinin , Pharmaceutical Preparations , Kallikreins , Reference DrugsABSTRACT
Abstract Objectives: To describe the hereditary angioedema to improve awareness of this condition and reduce diagnostic delay. Data sources: Relevant articles in the MEDLINE database through PubMed. Data synthesis: Hereditary angioedema is rare and has an autosomal dominant pattern of inheritance. Its onset occurs mainly in childhood, but there is an important delay in the diagnosis. In the most frequent phenotype, there is a quantitative and/or functional deficiency in the C1esterase inhibitor protein, which regulates the activation of the complement, contact and fibrinolysis systems with greater formation of bradykinin, the main mediator of angioedema. There is a third type, the hereditary angioedema with a normal C1 inhibitor level, which is rare in children. Clinical manifestations are characterized by recurrent angioedema attacks, mainly in the extremities, abdomen and upper airways, which can progress to asphyxia and death. The main triggers are mechanical trauma, infections and stress. The diagnosis is attained by patient clinical picture and decreased serum levels of C4 and C1esterase inhibitor or its function. In hereditary angioedema with a normal C1 inhibitor, there is no change in these parameters, thus requiring a genetic study. Treatment is based on the use of attack medications and long and short-term prophylaxis. Conclusions: Hereditary angioedema is little known by pediatricians due to the significant delay in diagnosis of this condition, whose onset usually begins in childhood. The presence of recurrent angioedema that does not respond to treatment with antihistamines, corticosteroids and adrenaline should increase the diagnostic suspicion.
Subject(s)
Humans , Child , Angioedemas, Hereditary/diagnosis , Angioedemas, Hereditary/genetics , Angioedema , Bradykinin , Delayed Diagnosis , PediatriciansABSTRACT
Abstract This second joint document, written by experts from the Brazilian Association of Allergy and Immunology (ASBAI) and Brazilian Society of Anesthesiology (SBA) concerned with perioperative anaphylaxis, aims to review the pathophysiological reaction mechanisms, triggering agents (in adults and children), and the approach for diagnosis during and after an episode of anaphylaxis. As anaphylaxis assessment is extensive, the identification of medications, antiseptics and other substances used at each setting, the comprehensive data documentation, and the use of standardized nomenclature are key points for obtaining more consistent epidemiological information on perioperative anaphylaxis.
Resumo Este segundo documento, escrito por especialistas da Associação Brasileira de Alergia e Imunologia (ASBAI) e da Sociedade Brasileira de Anestesiologia (SBA) interessados no tema anafilaxia perioperatória, tem por objetivo revisar os mecanismos fisiopatológicos, agentes desencadeantes (em adultos e crianças), assim como a abordagem diagnóstica durante e após o episódio. Por se tratar de uma avaliação abrangente, a identificação das medicações, antissépticos e outras substâncias usadas em cada região, registros detalhados, e nomenclatura padronizada são pontos fundamentais para a obtenção de dados epidemiológicos mais fidedignos sobre a anafilaxia perioperatória.
Subject(s)
Humans , Child , Adult , Drug Hypersensitivity/diagnosis , Drug Hypersensitivity/etiology , Perioperative Period , Anaphylaxis/diagnosis , Anaphylaxis/etiology , Societies, Medical , Vasodilator Agents/adverse effects , In Vitro Techniques , Mastocytosis/complications , Brazil , Preoperative Care , Immunoglobulin E/immunology , Bradykinin/adverse effects , Skin Tests/methods , Risk Factors , IgA Deficiency/complications , Drug Hypersensitivity/physiopathology , Allergy and Immunology , Symptom Assessment , Anaphylaxis/physiopathology , Anesthesiology , Angioedema/chemically induced , Terminology as TopicABSTRACT
Abstract Experts from the Brazilian Association of Allergy and Immunology (ASBAI) and the Brazilian Society of Anesthesiology (SBA) interested in the issue of perioperative anaphylaxis, and aiming to strengthen the collaboration between the two societies, combined efforts to study the topic and to prepare a joint document to guide specialists in both areas. The purpose of the present series of two articles was to report the most recent evidence based on the collaborative assessment between both societies. This first article will consider the updated definitions, treatment and guidelines after a perioperative crisis. The following article will discuss the major etiologic agents, how to proceed with the investigation, and the appropriate tests.
Resumo Especialistas da Associação Brasileira de Alergia e Imunologia (ASBAI) e da Sociedade Brasileira de Anestesiologia (SBA) interessados no tema anafilaxia perioperatória reuniram-se com o objetivo de intensificar a colaboração entre as duas sociedades no estudo desse tema e elaborar um documento conjunto que possa guiar os especialistas de ambas as áreas. O objetivo desta série de dois artigos foi mostrar as evidências mais recentes alicerçadas na visão colaborativa entre as sociedades. Este primeiro artigo versará sobre as definições mais atuais, formas de tratamento e as orientações após a crise no perioperatório. No próximo artigo serão discutidos os principais agentes causais e a condução da investigação com testes apropriados.
Subject(s)
Humans , Child , Adult , Drug Hypersensitivity/diagnosis , Drug Hypersensitivity/etiology , Perioperative Period , Anaphylaxis/diagnosis , Anaphylaxis/etiology , Societies, Medical , Vasodilator Agents/adverse effects , In Vitro Techniques , Mastocytosis/complications , Brazil , Preoperative Care , Immunoglobulin E/immunology , Bradykinin/adverse effects , Skin Tests/methods , Risk Factors , IgA Deficiency/complications , Drug Hypersensitivity/physiopathology , Allergy and Immunology , Symptom Assessment , Anaphylaxis/physiopathology , Anesthesiology , Angioedema/chemically induced , Terminology as TopicABSTRACT
ABSTRACT: COVID-19 is a new disease, whose several atypical clinical manifestations began to be observed with the evolution of the pandemic, and have been investigated to understand the pathophysiology of the disease. In this article, the objective is to describe a case of angioedema in COVID-19, considered an atypical manifestation, and rarely described in the literature. The case is of a 55-year-old patient who sought medical attention for a complaint of intermittent fever for four days. On the seventh day, he manifested angioedema in the left zygomatic projection and the right subpalpebral region. The patient had no history of angioedema earlier in life. The following day, he presented a regression of the angioedema concerning the previous day. After this period, the patient progressed well and became asymptomatic. The RT-PCR laboratory test performed on the first days of manifesting symptoms was positive for SARS-CoV-2. We correlate the onset of angioedema with the possible endotheliitis present in the disease, which has been evidenced by the observation of severe endothelial injury associated with the intracellular presence of the virus in several histopathological studies of patients with COVID-19. Also, possible deregulation of the Kininogen-Kallikrein-Kinin System (KKKS) could explain this manifestation, as SARS-CoV-2 binds to the ACE2 receptor, which is responsible for degrading kinins, such as bradykinin. (AU)
RESUMO: A COVID-19 é uma doença nova, cujas diversas manifestações clínicas atípicas começaram a ser observadas com a evolução da pandemia e foram investigadas com o objetivo de compreender a fisiopatologia da doença. Neste artigo, o objetivo é descrever um caso de angioedema no COVID-19, considerado manifestação atípica e raramente descrito na literatura. O caso é de um paciente de 55 anos que procurou atendimento médico por uma queixa de febre intermitente há quatro dias. No sétimo dia, manifestou angioedema na projeção zigomática esquerda e na região subpalpebral direita. Não tinha histórico de apresentar angioedema. No dia seguinte, ele apresentou regressão do angioedema em relação ao dia anterior. Após esse período, o paciente progrediu bem e tornou-se assintomático. O teste laboratorial de RT-PCR realizado nos primeiros dias de manifestação dos sintomas foi positivo para SARS-CoV-2. Correlacionamos o início do angioedema com a possível endotelite presente na doença, o que foi evidenciado pela observação de lesão endotelial grave associada à presença intracelular do vírus em vários estudos histopatológicos de pacientes com COVID-19. Além disso, uma possível desregulação do sistema Cininogênio-Calicreína-Cinina poderia explicar essa manifestação, já que o SARS-CoV-2 se liga ao receptor ACE2, responsável pela degradação de cininas, como a bradicinina. (AU)
Subject(s)
Humans , Male , Middle Aged , Bradykinin , Coronavirus Infections , Endothelium , Pandemics , SARS-CoV-2 , AngioedemaABSTRACT
Abstract Purpose To investigate the effects of bradykinin on reperfusion injury in an experimental intestinal ischemia reperfusion model. Methods We used 32 Wistar-Albino rats. We composed 4 groups each containing 8 rats. Rats in sham group were sacrified at 100 minutes observation after laparotomy. Thirty minutes reperfusion was performed following 50 minutes ischaemia in control group after observing 20 minutes. Ischaemic preconditioning was performed in one group of the study. We performed the other study group pharmacologic preconditioning by infusional administration of 10 μg/kg/minute bradykinin intravenously. We sacrified all of the rats by taking blood samples to evaluate the lactate and lactate dehydrogenase (LDH) after resection of jejunum for detecting tissue myeloperoxidase (MPO) activity. Results Lactate and LDH levels were significantly higher in control and study groups than the sham group (P<0.001). There is no difference between the study groups statistically. (P>0.05). The results were the same for MPO levels. Although definitive cell damage was determinated in the control group by hystopatological evaluation, the damage in the study groups observed was lower in different levels. However, there was no significant difference between the study groups statistically (P>0.05). Conclusion Either ischeamic preconditioning or pharmacologic preconditioning made by bradykinin reduced the ischemia reperfusion injury at jejunum.
Subject(s)
Animals , Female , Vasodilator Agents/pharmacology , Bradykinin/pharmacology , Reperfusion Injury/prevention & control , Ischemic Preconditioning/methods , Disease Models, Animal , Intestine, Small/drug effects , Reference Values , Time Factors , Random Allocation , Reproducibility of Results , Treatment Outcome , Rats, Wistar , Peroxidase/analysis , LaparotomyABSTRACT
Introdução: Tradução e adaptação transcultural do instrumento Escore de Atividade do Angioedema (Angioedema Activity Score - AAS) para o idioma português do Brasil. Métodos: O documento original em alemão foi traduzido para o português (cultura brasileira) e posteriormente retrovertido para a língua alemã. As traduções foram analisadas pelos pesquisadores brasileiros e alemães para definição da versão final em português. A versão final foi respondida por 10 pacientes com angioedema recorrente, com o intuito de identificar possíveis dificuldades na compreensão e nos termos utilizados. Resultados: Todos os pacientes compreenderam as perguntas, embora apenas a metade tenha preenchido adequadamente o questionário. Conclusões: O documento do Escore de Atividade do Angioedema adaptado para a cultura brasileira se mostrou um instrumento fidedigno à versão alemã original.
Introduction: To translate and validate the Angioedema Activity Score to Brazilian Portuguese aiming further use of this tool in patients with recurrent angioedema. Methods: The original questionnaire in German was translated into Portuguese (Brazilian culture) and subsequently back translated into the German language. The translations were analyzed by Brazilian and German researchers to define the final version in Portuguese. The final version was administered to 10 patients with recurrent angioedema in order to identify possible issues in understanding the terms used. Results: All patients had a good comprehension of the questions, but only half of them completed the questionnaire properly. Conclusions: The Angioedema Activity Score adapted to the Brazilian culture proved to be a reliable instrument to the original German version.
Subject(s)
Humans , Translations , Surveys and Questionnaires , Angioedema , Patients , Urticaria , Bradykinin , Histamine , Language , MethodsABSTRACT
Inflammation is one of the main causes of pathologic pain. Knowledge of the molecular links between inflammatory signals and pain-mediating neuronal signals is essential for understanding the mechanisms behind pain exacerbation. Some inflammatory mediators directly modulate the excitability of pain-mediating neurons by contacting the receptor molecules expressed in those neurons. For decades, many discoveries have accumulated regarding intraneuronal signals from receptor activation through electrical depolarization for bradykinin, a major inflammatory mediator that is able to both excite and sensitize pain-mediating nociceptor neurons. Here, we focus on the final effectors of depolarization, the neuronal ion channels, whose functionalities are specifically affected by bradykinin stimulation. Particular G-protein coupled signaling cascades specialized for each specific depolarizer ion channels are summarized. Some of these ion channels not only serve as downstream effectors but also play critical roles in relaying specific pain modalities such as thermal or mechanical pain. Accordingly, specific pain phenotypes altered by bradykinin stimulation are also discussed. Some members of the effector ion channels are both activated and sensitized by bradykinin-induced neuronal signaling, while others only sensitized or inhibited, which are also introduced. The present overview of the effect of bradykinin on nociceptor neuronal excitability at the molecular level may contribute to better understanding of an important aspect of inflammatory pain and help future design of further research on the components involved and pain modulating strategies.
Subject(s)
Bradykinin , GTP-Binding Proteins , Inflammation , Ion Channels , Neurons , Nociceptors , Pain Perception , PhenotypeABSTRACT
Cardiovascular diseases are responsible for almost one third of all global deaths yearly, and therefore are largely studied. Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CM) have emerged as an exciting technology for cardiac disease modelling and personalised therapy. Nevertheless, issues concerning functional and molecular maturation are still faced. In addition to this, differentiation protocols generally yield a heterogeneous mixed population comprised of nodal, atrial and ventricular-like subtypes, being unsuitable for therapeutic purposes. Bradykinin (BK) is a vasoactive peptide which exerts important physiological roles in the cardiovascular system, having been previously described as important for cellular, keratinocyte and skeletal muscle differentiation. This project performed in cooperation with PluriCell Biotech, a startup specialized in the production and differentiation of hiPSC-CM, has sought (1) characterizing gene and protein expression of molecular markers of maturation and of subtype specification throughout of differentiation; (2) Assessing the electrical functionality of hiPSC-CM through the characterization of subtype-specific action potentials (APs) and (3) Investigating whether the progress of hiPSCCM maturation is regulated by BK through kinin-B2 receptors (B2R). Our results have validated the model that proposes a developmental-dependent switch between skeletal (ssTnI) and cardiac (cTnI) isoforms of troponin I as differentiation progresses, at least to some extent. Furthermore, prolonged time in culture has resulted in higher levels of expression of the ventricular marker MLC2v and in increased rates of ventricular-like action APs. Electrophysiological analysis of hiPSC-CM reveals a mixed population with AP morphologies correspondent to nodal, atrial and ventricular subtypes, all showing pronounced automaticity as well as other features of immature cardiomyocytes, such as low amplitude and depolarization velocity. Such findings are coherent with those from other groups who have attempted to differentiate mature native-like cardiac cells from pluripotent stem cells sources, without fully succeeding. After showing that differentiating hiPSC-CM express a functional and responsive B2R, the receptor was subjected to chronic activation with 10µM BK and 1µM BK or inhibition with 5µM Firazyr+BK. Even though B2R modulation has not interfered negatively with differentiation yields nor cell morphology, analysis of gene andprotein expression of ssTnI or cTnI and of the ventricular marker MLC2v, have revealed no significant results in comparison to untreated controls. This suggests that BK does not interfere on hiPSC-CM maturation nor subtype specification, although we cannot rule out that it could be leading to other unexplored effects. We recommend a closer look into which intracellular signalling pathways become active upon B2R stimulation in hiPSC-CM, in order to narrow down cellular processes for further investigation
Doenças cardiovasculares são responsáveis por quase um terço de todas as mortes globais anualmente, e por isto o sistema cardiovascular é amplamente estudado. Cardiomiócitos derivados a partir de células-tronco pluripotentes induzidas humanas (hiPSCCM) emergiram como uma promissora tecnologia para modelagem de doenças cardíacas e terapia personalizada. No entanto, desafios acerca de sua maturação funcional e molecular ainda são enfrentados. Além disso, protocolos de diferenciação geralmente levam à obtenção de populações heterogêneas contendo células com fenótipos similares aos de cardiomiócitos nodais, atriais e ventriculares sendo, portanto, inapropriadas para fins terapêuticos. A bradicinina (BK) é um peptídio vasoativo que exerce importantes papeis fisiológicos no sistema cardiovascular, além de ter sido previamente descrita como importante para a diferenciação neuronal, de queratinócitos e de músculo esquelético. Este projeto foi realizado em colaboração com a empresa PluriCell Biotech, uma startup especializada na produção e diferenciação de hiPSC-CM, e buscou (1) caracterizar a expressão gênica e proteíca de marcadores moleculares de maturação e de especificação de subtipos cardíacos durante a diferenciação; (2) avaliar a funcionalidade elétrica de hiPSC-CM por meio da caracterização de seus potenciais de ação (PAs) e (3) Investigar se o progresso da diferenciação de hiPSCCM é regulado por bradicinina por meio do receptor B2 (B2R). Nossos resultados validaram o modelo que propõe um switch na expressão das isoformas funcionais de troponina I esquelética (ssTnI) e cardíaca (cTnI), durante o desenvolvimento e diferenciação celular, pelo menos parcialmente. Além disso, tempo prolongado em cultura resultou em maiores níveis de expressão do marcador ventricular MLC2v, assim como maiores frequências de PAs com morfologias similares a de cardiomiócitos ventriculares. Análise eletrofisiológica de hiPSCCM revelam a existência de uma população mista contendo PAs correspondentes aos subtipos nodais, atriais e ventriculares, assim como pronunciada automaticidade e outros atributos típicos de cardiomiócitos imaturos, como baixa amplitude e devagar velocidade de despolarização. Estes resultados são coerentes com os de outros grupos que ainda não foram totalmente bem-sucedidos em diferenciar células cardíacas maduras similares acardiomiócitos nativos a partir de células-troncos pluripotentes. Após mostrar que as hiPSCCM expressam receptores B2 funcionais e responsivos, submetemos o receptor a uma ativação crônica com BK 10µM e BK 1µM ou inibição crônica com Firazyr 5µM + BK. Apesar da modulação do B2R não ter interferido de forma negativa no rendimento da diferenciação ou na morfologia celular, análise de expressão gênica e proteica de ssTnI e cTnI e do marcador ventricular MLC2v não revelou resultados significativos em comparação aos controles não-tratados. Isto sugere que a BK não interfere na maturação e especificação de subtipos cardíacos em hiPSC-CM, apesar de não podermos ignorar o fato de que ela poderia estar desencadeando outros efeitos inexplorados. Nós recomendamos um estudo mais aprofundado acerca de quais vias de sinalização se tornam ativas após estimulação do receptor B2 em hiPSC-CM, com o objetivo de afunilar quais processos celulares poderiam ser investigados em uma próxima etapa deste estudo
Subject(s)
Myocytes, Cardiac/chemistry , Receptor, Bradykinin B2/analysis , Kinins/adverse effects , Bradykinin/physiology , Cardiovascular Diseases/pathology , Cardiovascular System , Electrophysiology/instrumentation , Induced Pluripotent Stem CellsABSTRACT
The benefits of the worldwide approval of new drugs for the treatment of acute C1-INH-HAE attacks may still not reach all patients. Identifying the current barriers in the access to medication, as well as conducting a detailed assessment of the progress in this area, is essential to achieve universal treatment. Two hundred and twenty five patients registered in the Argentina Hereditary Angioedema Patient Association (AHAEPA) were randomly selected and invited to participate in a web based questionnaire on accessibility to icatibant and pdC1-INH, self-treatment, delay to treatment, and coverage. The data retrieved was compared to our previous reports in 2008 and 2013. We collected 156/225 answers. One hundred and eighteen (76%) patients have either pdC1-INH (n = 86), icatibant (n = 10) or both (n = 22), while 38 (24%) do not have access to treatment. In 2008, 26% had access while 82% had it in 2013. Thirty-two subjects (22%) self-inject themselves, similar to 29% in 2013, even though between studies, widespread self-injection training activities have taken place. However, considering injections by proxy, home treatment reached 56%. Only half of the patients decide to receive treatment early during the attack. Ninety-nine patients (63%) have full coverage, thirty (19%) have no coverage at all and the rest only obtain partial reimbursement. Twenty-nine families (31%) share a single treatment dose of the medication, better than 36% in 2013. Argentina's C1-INH-HAE patients had a sustained improvement in their access to medication. Efforts should continue to further improve accessibility and optimal management of HAE acute attacks to all patients in the country.
La aprobación mundial de los medicamentos para el ataque agudo del angioedema hereditario (HAE) no beneficia a todos los pacientes. Es necesario conocer las barreras de acceso a la medicación para el tratamiento universal. Doscientos veinticinco pacientes, registrados en la Asociación de Pacientes con Angioedema Hereditario (AHAEPA), fueron encuestados por internet acerca de su accesibilidad al icatibant y al concentrado del inhibidor de C1 (pdC1-INH), a la auto inyección de la medicación, al retraso del tratamiento y a la cobertura del medicamento. Comparamos esta información con la obtenida en nuestros estudios de 2008 y 2013. Recolectamos 156/225 respuestas. Ciento dieciocho (76%) pacientes tienen pdC1-INH (n = 86), icatibant (n = 10) o ambos (n = 22), mientras que 38 (24%) no tienen medicación. En 2008, 26% tenían acceso y en 2013, 82%. Treinta y dos (22%) se autoinyectan la medicación, similar al 29% en 2013. Sumando las aplicaciones por profesionales de la salud o familiares en la casa, el tratamiento fuera de las instituciones médicas alcanza el 56%. Solo la mitad decide tratarse tempranamente. Noventa y nueve (63%) tiene cobertura del 100%, 30 (19%) no tiene ningún tipo de cobertura, y el resto la tiene en forma parcial. Veintinueve familias (31%), solo tienen una dosis de tratamiento para todos, mejor que el 36% en 2013. Los pacientes con C1-INH-HAE han tenido una mejoría sustancial en el acceso a la medicación. Igualmente, los esfuerzos deben continuar para mejorar la accesibilidad y tratamiento óptimo de todos.
Subject(s)
Humans , Male , Bradykinin/analogs & derivatives , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Complement C1 Inhibitor Protein/administration & dosage , Complement Inactivating Agents/administration & dosage , Angioedemas, Hereditary/drug therapy , Argentina , Bradykinin/administration & dosage , Surveys and Questionnaires , Health Services Accessibility/statistics & numerical dataABSTRACT
Background: Angiotensin I-converting enzyme [ACE] has two homologous catalytic domains, the N- and C-domains. Our previous study suggested that Alu insertion [I allele] in the intron 16 of ACE resulted in premature codon termination. The I allele has only one active site in the N-domain while the Alu deletion [D allele] still has two active sites of ACE. Therefore the effect of I/ D polymorphism of ACE on the enzyme's ability to catalyse bradykinin is still not widely known
Aims: This study aimed to examine the serum bradykinin level in hypertensive patients with I/D polymorphism of ACE, who were treated with ACE inhibitor
Subjects and methods: The serum bradykinin and I/D polymorphism have been detected in 64 hypertensive patients taking ACE inhibitor [lisinopril or captopril] for at least eight weeks with good medication adherence. The binding affinity of ACE with its receptor was calculated by molecular docking
Results: The findings show that genotype II is more frequent in the population the researchers observed [53.12%] compared to ID [23.44%] and DD [23.44%] variances. On the other hand, the bradykinin level is not affected by genotype of the ACE genes on the population. Bradykinin increases in patients with genotype II who are given captopril, but decreases in patients treated with lisinopril. Nevertheless, there is no statistically significant difference
Conclusion: This study suggests that the polymorphism might not significantly affect the serum bra-dykinin level in hypertensive patients taking ACE inhibitors
Subject(s)
Humans , Female , Male , Adult , Middle Aged , Aged , Aged, 80 and over , Peptidyl-Dipeptidase A , Polymorphism, Genetic , Alu Elements , INDEL Mutation , Angiotensin-Converting Enzyme Inhibitors , Bradykinin , AngiotensinsABSTRACT
Hereditary angioedema is a disease of congenital deficiency or functional defect in the C1 esterase inhibitor (C1-INH) consequent to mutation in the SERPING1 gene, which encodes C1-INH. This disease manifests as recurrent, non-pitting, non-pruritic subcutaneous, or submucosal edema as well as an erythematous rash in some cases. These symptoms result from the uncontrolled localized production of bradykinin. The most commonly affected sites are the extremities, face, gastrointestinal tract, and respiratory system. When the respiratory system is affected by hereditary angioedema, swelling of the airway can restrict breathing and lead to life-threatening obstruction. Herein, we report a case of a 24-year-old woman with type 2 hereditary angioedema who presented with recurrent episodic abdominal pain and swelling of the extremities. She had no family history of angioedema. Although her C4 level was markedly decreased (3.40 mg/dL; normal range: 10-40 mg/dL), she presented with a very high C1-INH level (81.0 mg/dL; normal range: 21.0-39.0 mg/dL) and abnormally low C1-INH activity (less than 25%; normal range: 70%-130%). The SERPING1 gene mutation was confirmed in this patient. She was treated with prophylactic tranexamic acid, as needed, and subsequently reported fewer and less severe episodes. To our knowledge, this is the first reported case of type 2 hereditary angioedema in Korea that was consequent to SERPING1 mutation and involved a significantly elevated level of C1-INH as well as a low level of C1-INH activity.
Subject(s)
Female , Humans , Young Adult , Abdominal Pain , Angioedema , Angioedemas, Hereditary , Bradykinin , Complement C1 Inhibitor Protein , Edema , Exanthema , Extremities , Gastrointestinal Tract , Korea , Reference Values , Respiration , Respiratory System , Tranexamic AcidABSTRACT
Bradykinin-potentiating peptides (BPPs) are molecules discovered by Sergio Ferreira - who found them in the venom of Bothrops jararaca in the 1960s - that literally potentiate the action of bradykinin in vivo by, allegedly, inhibiting the angiotensin-converting enzymes. After administration, the global physiological effect of BPP is the decrease of the blood pressure. Due to this interesting effect, one of these peptides was used by David Cushman and Miguel Ondetti to develop a hypotensive drug, the widely known captopril, vastly employed on hypertension treatment. From that time on, many studies on BPPs have been conducted, basically describing new peptides and assaying their pharmacological effects, mostly in comparison to captopryl. After compiling most of these data, we are proposing that snake BPPs are 'modular' peptidic molecules, in which the combination of given amino acid 'blocks' results in the different existing peptides (BPPs), commonly found in snake venom. We have observed that there would be mandatory modules (present in all snake BPPs), such as the N-terminal pyroglutamic acid and C-terminal QIPP, and optionalmodules (amino acid blocks present in some of them), such as AP or WAQ. Scattered between these modules, there might be other amino acids that would 'complete' the peptide, without disrupting the signature of the classical BPP. This modular arrangement would represent an important evolutionary advantage in terms of biological diversity that might have its origins either at the genomic or at the post-translational modification levels. Regardless of the modules' origin, the increase in the diversity of peptides has definitely been essential for snakes' success on nature.(AU)
Subject(s)
Animals , Peptides , Snake Venoms , Bradykinin , Bothrops , Pyrrolidonecarboxylic Acid , BiodiversityABSTRACT
Background: Venoms represent a still underexplored reservoir of bioactive components that might mitigate or cure diseases in conditions in which conventional therapy is ineffective. The bradykinin-potentiating peptides (BPPs) comprise a class of angiotensin-I converting enzyme (ACE) inhibitors. The BPPs usually consist of oligopeptides with 5 to 13 residues with a high number of proline residues and the tripeptide Ile-Pro-Pro (IPP-tripeptide) in the C-terminus region and have a conserved N-terminal pyroglutamate residue. As a whole, the action of the BPPs on prey and snakebite victims results in the decrease of the blood pressure. The aim of this work was to isolate and characterize novel BPPs from the venom of Bitis gabonica rhinoceros. Methods: The crude venom of B. g. rhinoceros was fractionated by size exclusion chromatography and the peptide fraction (<7 kDa) was separated by reverse phase chromatography (RP-HPLC) and analyzed by ESI-IT-TOF-MS/MS. One new BPP was identified, synthetized and assayed for ACE inhibition and, in vivo, for edema potentiation. Results: Typical BPP signatures were identified in three RP-HPLC fractions. CID fragmentation presented the usual y-ion of the terminal P-P fragment as a predominant signal at m/z 213.1. De novo peptide sequencing identified one Bothrops-like BPP and one new BPP sequence. The new BPP was synthesized and showed poor inhibition over ACE, but displayed significant bradykinin-induced edema potentiation. Conclusions: So far, few BPPs are described in Viperinae, and based on the sequenced peptides, two non-canonical sequences were detected. The possible clinical role of this new peptides remains unclear.(AU)
Subject(s)
Animals , Oligopeptides , Peptides/isolation & purification , Biochemistry/classification , Bradykinin , Viperidae , BothropsABSTRACT
The aim of this study was to analyze the acute responses of bradykinin, insulin, and glycemia to exercise performed above and below lactate threshold (LT) in individuals with type 2 diabetes mellitus (T2D). Eleven participants with a diagnosis of T2D randomly underwent three experimental sessions 72 h apart: 1) 20 min of exercise performed at 120% of LT (120%LT), 2) 20 min of exercise performed at 80% of LT (80%LT), and 3) 20 min of control session. Blood glucose was analyzed before, during, and at 45 min post-exercise. Bradykinin and insulin were analyzed before and at 45 min post-exercise. Both exercise sessions elicited a parallel decrease in glucose level during exercise (P≤0.002), with a greater decrease being observed for 120%LT (P=0.005). Glucose decreased 22.7 mg/dL (95%CI=10.3 to 35, P=0.001) at the 45 min post-exercise recovery period for 80%LT and decreased 31.2 mg/dL (95%CI=18.1 to 44.4, P<0.001) for 120%LT (P=0.004). Insulin decreased at post-exercise for 80%LT (P=0.001) and control (P≤0.035). Bradykinin increased at 45 min post-exercise only for 80%LT (P=0.013), but was unrelated to the decrease in glucose (r=-0.16, P=0.642). In conclusion, exercise performed above and below LT reduced glycemia independently of insulin, but exercise above LT was more effective in individuals with T2D. However, these changes were unrelated to the increase in circulating bradykinin.
Subject(s)
Humans , Male , Female , Middle Aged , Aged , Blood Glucose/analysis , Bradykinin/blood , Exercise/physiology , Lactic Acid/blood , Diabetes Mellitus, Type 2/blood , Insulin/blood , Oxygen Consumption/physiology , Time Factors , Analysis of Variance , Treatment Outcome , Statistics, Nonparametric , Cross-Over Studies , Diabetes Mellitus, Type 2/physiopathology , Exercise Test , Heart Rate/physiologyABSTRACT
OBJECTIVE: Rebampide is a gastroprotective agent used to treat gastritis. It possesses anti-inflammatory and anti-arthritis effects, but the mechanisms of these effects are not well understood. The objective of this study was to explore mechanisms underlying the therapeutic effects of rebamipide in inflammatory arthritis. METHODS: Collagen-induced arthritis (CIA) was induced in DBA/1J mice. DBA/1J mice were immunized with chicken type II collagen, then treated intraperitoneally with rebamipide (10 mg/kg or 30 mg/kg) or vehicle (10% carboxymethylcellulose solution) alone. Seven weeks later, plasma samples were collected. Plasma metabolic profiles were analyzed using ultra performance liquid chromatography/quadrupole time-of-flight mass spectrometry-based metabolomics study and metabolite biomarkers were identified through multivariate data analysis. RESULTS: Low dose rebamipide treatment reduced the clinical arthritis score compared with vehicle treatment, whereas high dose rebamipide in CIA aggravated arthritis severity. Based on multivariate analysis, 17 metabolites were identified. The plasma levels of metabolites associated with fatty acids and phospholipid metabolism were significantly lower with rebamipide treatment than with vehicle. The levels of 15-deoxy-Δ¹²,¹⁴ prostaglandin J2 and thromboxane B3 decreased only in high dose-treated groups. Certain peptide molecules, including enterostatin (VPDPR) enterostatin and bradykinin dramatically increased in rebamipide-treated groups at both doses. Additionally, corticosterone increased in the low dose-treated group and decreased in the high dose-treated group. CONCLUSION: Metabolomics analysis revealed the anti-inflammatory effects of rebamipide and suggested the potential of the drug repositioning in metabolism- and lipid-associated diseases.
Subject(s)
Animals , Mice , Arthritis , Arthritis, Experimental , Biomarkers , Bradykinin , Carboxymethylcellulose Sodium , Chickens , Collagen Type II , Corticosterone , Drug Repositioning , Fatty Acids , Gastritis , Mass Spectrometry , Metabolism , Metabolome , Metabolomics , Multivariate Analysis , Plasma , Statistics as Topic , Therapeutic UsesABSTRACT
ABSTRACT PURPOSE: To investigate the role of bradykinin in a rat lung transplantation (LTx) model and preliminarily discuss the relationship between bradykinin and CD26/DPP-4. METHODS: Rats were randomly divided into four groups: Control (CON), Sham, low potassium dextranglucose (LPD), and AB192 (n=15/group). Orthotopic single LTx was performed in the LPD and AB192 groups. The donor lungs were flush-perfused and preserved with low potassium dextranglucose (LPD) or LPD+CD26/DPP-4 catalytic inhibitor (AB192). LTx was performed after 18 h cold ischemia time and harvested two days post-LTx. Blood gas analysis (PO2), wet/dry weight ratio (W/D), myeloperoxidase activity (MPO), and lipid peroxidation (MDA) were analyzed at 48 hr after transplantation. Immunohistochemical (IHC) analysis was performed in the same sample and validated by Western-Blot. RESULTS: Compared to the LPD group, the AB192 group showed higher PO2, lower W/D ratio, and decreased MPO and MDA. IHC studies showed strong bradykinin β2 receptor (B2R) staining in the LPD group, especially in inflammatory cells, alveolar macrophages, and respiratory epithelial cells. Expression of B2R by Western-Blot was significantly different between the AB192 and LPD groups. CONCLUSION: Bradykinin may be a competitive substrate of DPP-4, and decreased bradykinin levels may enhance protective effects against ischemia/reperfusion injury during LTx.
Subject(s)
Animals , Male , Rats , Bradykinin/physiology , Reperfusion Injury/pathology , Lung Transplantation , Dipeptidyl Peptidase 4/physiology , Primary Graft Dysfunction/pathology , Lung/blood supply , Immunohistochemistry , Lipid Peroxidation , Reperfusion Injury/physiopathology , Reperfusion Injury/metabolism , Random Allocation , Blotting, Western , Disease Models, Animal , Primary Graft Dysfunction/physiopathology , Bradykinin B2 Receptor Antagonists/metabolism , Lung/drug effectsABSTRACT
Drospirenone (DRSP) is a progestin with anti-aldosterone properties and it reduces blood pressure in hypertensive women. However, the effects of DRSP on endothelium-dependent coronary vasodilation have not been evaluated. This study investigated the effects of combined therapy with estrogen (E2) and DRSP on endothelium-dependent vasodilation of the coronary bed of ovariectomized (OVX) spontaneously hypertensive rats. Female spontaneously hypertensive rats (n=87) at 12 weeks of age were randomly divided into sham operated (Sham), OVX, OVX treated with E2 (E2), and OVX treated with E2 and DRSP (E2+DRSP) groups. Hemodynamic parameters were directly evaluated by catheter insertion into the femoral artery. Endothelium-dependent vasodilation in response to bradykinin in the coronary arterial bed was assessed using isolated hearts according to a modified Langendorff method. Coronary protein expression of endothelial nitric oxide synthase and estrogen receptor alpha (ER-α) was assessed by Western blotting. Histological slices of coronary arteries were stained with hematoxylin and eosin, and morphometric parameters were analyzed. Oxidative stress was assessed in situ by dihydroethidium fluorescence. Ovariectomy increased systolic blood pressure, which was only prevented by E2+DRSP treatment. Estrogen deficiency caused endothelial dysfunction, which was prevented by both treatments. However, the vasodilator response in the E2+DRSP group was significantly higher at the three highest concentrations compared with the OVX group. Reduced ER-α expression in OVX rats was restored by both treatments. Morphometric parameters and oxidative stress were augmented by OVX and reduced by E2 and E2+DRSP treatments. Hormonal therapy with E2 and DRSP may be an important therapeutic option in the prevention of coronary heart disease in hypertensive post-menopausal women.
Subject(s)
Animals , Female , Rats , Androstenes/administration & dosage , Coronary Vessels/drug effects , Endothelium, Vascular/drug effects , Estradiol/administration & dosage , Hormone Replacement Therapy/methods , Hypertension/drug therapy , Vasodilation/drug effects , Blotting, Western , Bradykinin/pharmacology , Combined Modality Therapy , Coronary Vessels/pathology , Estrogen Receptor alpha/drug effects , Estrogens/administration & dosage , Ethidium/analogs & derivatives , Femoral Artery , Hemodynamics , Mineralocorticoid Receptor Antagonists/administration & dosage , Nitric Oxide Synthase Type III/drug effects , Ovariectomy , Oxidative Stress/drug effects , Random Allocation , Rats, Inbred SHR , Vasodilator Agents/pharmacologyABSTRACT
A pesar de que el angioedema hereditario es un padecimiento raro, tiene una amplia bibliografía que ratifica que la fisiopatología de esta enfermedad es compleja. La constante investigación de la industria farmacéutica no solo ha aportado nuevos recursos terapéuticos sino que ha logrado despertar un inusitado interés en la comunidad médica, permitiendo que tengamos una mayor comprensión sobre los mecanismos que presiden la aparición de las crisis. El Comité de Angioedema Hereditario de la AAAeIC ha desarrollado una puesta al día sobre esta entidad, que, por las características de sus síntomas, es abordada principalmente por los especialistas en alergia e inmunología clínica(AU)
Although hereditary angioedema is a rare condition, it has a large number of references that confirm that the pathophysiology of this disease is complex. The constant research of the pharmaceutical industry has not only brought new therapeutic resources, but also aroused an unusual interest in the medical community, allowing us to have a better understanding of the mechanisms that perform the onset of crises. The AAA e IC Hereditary Angioedema Committee has developed an update on this entity, which, due to the characteristics of its symptoms, is mainly addressed by specialists in allergy and clinical immunology.(AU)