RESUMO
Recent studies have shown that the innate and adaptive immune system, together with low-grade inflammation, may play an important role in essential hypertension. In this work, to verify the importance of selected factors for the development of essential hypertension, we created a Petri net-based model and analyzed it. The analysis was based mainly on t-invariants, knockouts of selected fragments of the net and its simulations. The blockade of the renin-angiotensin (RAA) system revealed that the most significant effect on the emergence of essential hypertension has RAA activation. This blockade affects: (1) the formation of angiotensin II, (2) inflammatory process (by influencing C-reactive protein (CRP)), (3) the initiation of blood coagulation, (4) bradykinin generation via the kallikrein-kinin system, (5) activation of lymphocytes in hypertension, (6) the participation of TNF alpha in the activation of the acute phase response, and (7) activation of NADPH oxidase-a key enzyme of oxidative stress. On the other hand, we found that the blockade of the activation of the RAA system may not eliminate hypertension that can occur due to disturbances associated with the osmotically independent binding of Na in the interstitium. Moreover, we revealed that inflammation alone is not enough to trigger primary hypertension, but it can coexist with it. We believe that our research may contribute to a better understanding of the pathology of hypertension. It can help identify potential subprocesses, which blocking will allow better control of essential hypertension.
Assuntos
Hipertensão Essencial/fisiopatologia , Inflamação/fisiopatologia , Modelos Biológicos , Angiotensina II/fisiologia , Autoantígenos/imunologia , Coagulação Sanguínea , Bradicinina/biossíntese , Proteína C-Reativa/fisiologia , Endotélio Vascular/imunologia , Hipertensão Essencial/etiologia , Hipertensão Essencial/imunologia , Humanos , Inflamação/imunologia , Sistema Calicreína-Cinina/fisiologia , Ativação Linfocitária , NADPH Oxidases/fisiologia , Natriurese/fisiologia , Óxido Nítrico/fisiologia , Óxido Nítrico Sintase Tipo III/fisiologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Pele/fisiopatologia , Sódio/metabolismo , Cloreto de Sódio na Dieta/farmacocinética , Fator de Necrose Tumoral alfa/fisiologiaRESUMO
The aims of this study were to assess whether ischemic preconditioning (PC) induces bradykinin (Bk) synthesis in bovine aortic endothelial cells (bAECs) and, if so, to explore the molecular mechanisms by which this peptide provides cytoprotection against hypoxia. PC was induced by exposing bAECs to three cycles of 15 min of hypoxia followed by 15 min of reoxygenation. Bk synthesis peaked in correspondence to the early and late phases of PC (10-12 M and 10-11 M, respectively) and was abolished by a selective tissue kallikrein inhibitor, aprotinin. Stimulation with exogenous Bk at concentrations of 10-12 M and 10-11 M reduced the cell death induced by 12 h of hypoxia by 50%. Pretreatment with HOE-140, a Bk receptor 2 (BKR2) inhibitor, in bAECs exposed to 12 h of hypoxia, abrogated the cytoprotective effect of early and late PC, whereas des-Arg-HOE-140, a Bk receptor 1 (BKR1) inhibitor, affected only the late PC. In addition, we found that PC evoked endocytosis and the recycling of BKR2 during both the early and late phases, and that inhibition of these pathways affected PC-mediated cytoprotection. Finally, we evaluated the activation of PKA and Akt in the presence or absence of BKR2 inhibitor. HOE-140 abrogated PKA and Akt activation during both early and late PC. Consistently, BKR2 inhibition abolished cross-talk between PKA and Akt in PC. In bAECs, Bk-synthesis evoked by PC mediates the protection against both apoptotic and necrotic hypoxia-induced cell death in an autocrine manner, by both BKR2- and BKR1-dependent mechanisms.
Assuntos
Aorta/citologia , Aorta/metabolismo , Comunicação Autócrina , Bradicinina/biossíntese , Citoproteção , Células Endoteliais/metabolismo , Precondicionamento Isquêmico , Animais , Apoptose , Bovinos , Endocitose , Hipóxia/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de SinaisRESUMO
Hereditary angioedema (HAE) is a genetic disorder mostly caused by mutations in the C1 esterase inhibitor gene (C1INH) that results in poor control of contact pathway activation and excess bradykinin generation. Bradykinin increases vascular permeability and is ultimately responsible for the episodes of swelling characteristic of HAE. We hypothesized that the use of RNA interference (RNAi) to reduce plasma Factor XII (FXII), which initiates the contact pathway signaling cascade, would reduce contact pathway activation and prevent excessive bradykinin generation. A subcutaneously administered GalNAc-conjugated small-interfering RNA (siRNA) targeting F12 mRNA (ALN-F12) was developed, and potency was evaluated in mice, rats, and cynomolgus monkeys. The effect of FXII reduction by ALN-F12 administration was evaluated in two different vascular leakage mouse models. An ex vivo assay was developed to evaluate the correlation between human plasma FXII levels and high-molecular weight kininogen (HK) cleavage. A single subcutaneous dose of ALN-F12 led to potent, dose-dependent reduction of plasma FXII in mice, rats, and NHP. In cynomolgus monkeys, a single subcutaneous dose of ALN-F12 at 3 mg/kg resulted in >85% reduction of plasma FXII. Administration of ALN-F12 resulted in dose-dependent reduction of vascular permeability in two different mouse models of bradykinin-driven vascular leakage, demonstrating that RNAi-mediated reduction of FXII can potentially mitigate excess bradykinin stimulation. Lastly, ex vivo human plasma HK cleavage assay indicated FXII-dependent bradykinin generation. Together, these data suggest that RNAi-mediated knockdown of FXII by ALN-F12 is a potentially promising approach for the prophylactic treatment of HAE.
Assuntos
Angioedemas Hereditários/tratamento farmacológico , Bradicinina/biossíntese , Fator XII/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/uso terapêutico , Animais , Permeabilidade Capilar/efeitos dos fármacos , Proteína Inibidora do Complemento C1/genética , Fator XII/análise , Feminino , Humanos , Cininogênios/metabolismo , Macaca fascicularis , Camundongos , Camundongos Endogâmicos C57BL , Interferência de RNA , RatosRESUMO
The plasma contact system contributes to thrombosis in experimental models. Even though our standard blood coagulation tests are prolonged when plasma lacks contact factors, this enzyme system appears to have a minor (if any) role in hemostasis. In this review, we explore the clinical phenotype of C1 esterase inhibitor (C1-INH) deficiency. C1-INH is the key plasma inhibitor of the contact system enzymes, and its deficiency causes hereditary angioedema (HAE). This inflammatory disorder is characterized by recurrent aggressive attacks of tissue swelling that occur at unpredictable locations throughout the body. Bradykinin, which is considered to be a byproduct of the plasma contact system during in vitro coagulation, is the main disease mediator in HAE. Surprisingly, there is little evidence for thrombotic events in HAE patients, suggesting mechanistic uncoupling from the intrinsic pathway of coagulation. In addition, it is questionable whether a surface is responsible for contact system activation in HAE. In this review, we discuss the clinical phenotype, disease modifiers and diagnostic challenges of HAE. We subsequently describe the underlying biochemical mechanisms and contributing disease mediators. Furthermore, we review three types of HAE that are not caused by C1-INH inhibitor deficiency. Finally, we propose a central enzymatic axis that we hypothesize to be responsible for bradykinin production in health and disease.
Assuntos
Angioedemas Hereditários/sangue , Coagulação Sanguínea/fisiologia , Bradicinina/fisiologia , Idade de Início , Angioedemas Hereditários/enzimologia , Angioedemas Hereditários/etiologia , Angioedemas Hereditários/fisiopatologia , Bradicinina/biossíntese , Permeabilidade Capilar , Ativação do Complemento , Proteína Inibidora do Complemento C1/fisiologia , Fator XIIa/fisiologia , Feminino , Angioedema Hereditário Tipos I e II/sangue , Angioedema Hereditário Tipos I e II/enzimologia , Angioedema Hereditário Tipos I e II/fisiopatologia , Humanos , Inflamação , Calidina/metabolismo , Calicreínas/fisiologia , Cininogênio de Alto Peso Molecular/metabolismo , Masculino , Modelos Biológicos , Fenótipo , Polifosfatos/metabolismo , Inibidores de Serina Proteinase/deficiência , Inibidores de Serina Proteinase/fisiologiaRESUMO
BACKGROUND: Angiotensin-converting enzyme inhibitor-induced angioedema (ACEI-AE) is mediated by bradykinin. There remains an unmet treatment need because these patients, when presenting to the emergency department (ED), do not respond to conventional therapies, such as antihistamines and corticosteroids. OBJECTIVE: To estimate the treatment effect of ecallantide, a recombinant plasma kallikrein inhibitor, in ED patients with ACEI-AE in whom conventional therapy fails. METHODS: This was a triple-blind (patient, physician, and statistician), randomized, controlled, phase 2 study to estimate the magnitude of safety and efficacy signals for designing a definitive phase 3 trial comparing conventional therapy with ecallantide to conventional therapy with placebo. Patients were enrolled from April 1, 2010, through January 31, 2013. The primary efficacy study end point was achieving discharge criteria from the ED within 4 hours after initiating study-related treatment. RESULTS: Discharge criteria from the ED was met in 4 hours or less for 8 (31%) of 26 patients receiving ecallantide vs 5 of (21%) 24 patients receiving placebo (difference in proportions, 10%; 95% confidence interval, -14% to 34%). Ecallantide was well tolerated in both groups. CONCLUSION: The results from this preliminary study reveal that ecallantide is safe to use and may increase the proportion of patients who meet early discharge criteria by approximately10%. A larger phase 3 study is necessary to confirm the efficacy and evaluate the cost-effectiveness of ecallantide use for ACEI-AE in the ED setting. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01036659.
Assuntos
Angioedema/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Peptídeos/uso terapêutico , Angioedema/induzido quimicamente , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Bradicinina/biossíntese , Método Duplo-Cego , Serviço Hospitalar de Emergência , Feminino , Humanos , Calicreínas/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Peptídeos/efeitos adversos , Placebos/administração & dosagemAssuntos
Angioedema/diagnóstico , Angioedema/tratamento farmacológico , Face , Peptídeos/administração & dosagem , Dor Abdominal/diagnóstico , Dor Abdominal/tratamento farmacológico , Dor Abdominal/etiologia , Adolescente , Angioedema/etiologia , Bradicinina/antagonistas & inibidores , Bradicinina/biossíntese , Proteína Inibidora do Complemento C1/biossíntese , Proteína Inibidora do Complemento C1/fisiologia , Feminino , Humanos , Peptídeos/uso terapêutico , Radiografia Torácica , Tomografia Computadorizada por Raios XRESUMO
Hereditary angio-oedema (HAE) is a rare but potentially life-threatening condition. Three types are now recognized. Types I and II HAE involve mutations in the C1NH (SERPING1) gene, encoding the C1 inhibitor protein, whereas type III HAE involves mutations in the F12 gene, encoding coagulation factor XII (Hageman factor). They share a common final pathway leading to increased bradykinin formation. HAE must be distinguished from acquired angio-oedema with C1 esterase inhibitor deficiency, angiotensin-converting enzyme inhibitor-induced angio-oedema and the much more common histaminergic angio-oedema, occurring with or without weals. Understanding the pathogenesis of HAE is leading to the introduction of new therapies that target the bradykinin receptor or inhibit kallikrein activity, innovations that will hopefully reduce morbidity and mortality in this group of severe genetic disease.
Assuntos
Angioedemas Hereditários/diagnóstico , Angioedemas Hereditários/tratamento farmacológico , Angioedemas Hereditários/classificação , Angioedemas Hereditários/genética , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Bradicinina/biossíntese , Antagonistas dos Receptores da Bradicinina , Proteínas Inativadoras do Complemento 1/genética , Proteína Inibidora do Complemento C1 , Estrogênios/efeitos adversos , Fator XII/genética , Feminino , Humanos , Calicreínas/antagonistas & inibidores , MutaçãoRESUMO
OBJECTIVE: To review the available evidence on the pathophysiologic mechanism of episodes of edema in hereditary angioedema (HAE). DATA SOURCES: MEDLINE and PubMed were searched using the following keywords: hereditary angioedema, C1 inhibitor, complement system, contact system, and bradykinin. STUDY SELECTION: Studies were selected based on their relevance to the pathophysiologic features of HAE. RESULTS: Early studies from the 1970s and 1980s disagreed as to whether the symptoms in HAE were mediated via complement or contact system activation. Studies have demonstrated that, in vitro, in C1 inhibitor (C1-INH)-deficient plasma, only contact system activation results in generation of a vascular permeability enhancing factor. Furthermore, individuals who express a variant C1-INH that is a normal inhibitor of contact system proteases but is deficient in the ability to inactivate complement system proteases do not develop angioedema. The blood of patients with HAE, during attacks, contains elevated levels of cleaved high-molecular-weight kininogen and bradykinin. Last, C1-INH-deficient mice develop increased vascular permeability that is mediated via contact system activation. CONCLUSIONS: Hereditary angioedema attacks are mediated by bradykinin generated via contact system activation. The specific factors that trigger attacks remain unclear.
Assuntos
Angioedemas Hereditários/fisiopatologia , Animais , Bradicinina/biossíntese , Bradicinina/sangue , Proteína Inibidora do Complemento C1/genética , Proteína Inibidora do Complemento C1/metabolismo , Complemento C1r/metabolismo , Complemento C1s/metabolismo , Humanos , Calicreínas/metabolismo , Cininogênios/sangue , Camundongos , Camundongos KnockoutRESUMO
The kallikrein-kinin system (KKS) is a complex system produced in various organs. This system includes kininogen (precursor for kinin), kallikreins, and pharmacologically active bradykinin (BK), which is considered to be proinflammatory and/or cardioprotective. It is a proinflammatory polypeptide that is involved in many pathological conditions and can cause pain, inflammation, increased vascular permeability, vasodilation, contraction of various smooth muscles, as well as cell proliferation. On the other hand, it has been shown that BK has cardioprotective effects, as all components of KKS are located in the cardiac muscles. Numerous observations have indicated that decreased activity of this system may lead to cardiovascular diseases, such as hypertension, cardiac failure, and myocardial infarction. BK acts on two receptors, B1 and B2, which are linked physiologically through their natural stimuli and their common participation in a variety of inflammatory responses. Recently, numerous BK antagonists have been developed in order to treat several diseases that are due to excessive BK formation. Although BK has many beneficial effects, it has been recognized to have some undesirable effects that can be reversed with BK antagonists. In addition, products of this system have multiple interactions with other important metabolic pathways, such as the renin-angiotensin system.
Assuntos
Antagonistas dos Receptores da Bradicinina , Bradicinina/metabolismo , Sistema Calicreína-Cinina/efeitos dos fármacos , Sistema Calicreína-Cinina/fisiologia , Receptores da Bradicinina/agonistas , Bradicinina/biossíntese , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/prevenção & controle , Gastroenteropatias/fisiopatologia , Humanos , Inflamação , Cininas/efeitos adversos , Cininas/fisiologia , Receptores da Bradicinina/fisiologia , Sistema Renina-Angiotensina/fisiologiaRESUMO
Blood coagulation factor XII (FXII, Hageman factor) is a plasma serine protease which is autoactivated following contact with negatively charged surfaces in a reaction involving plasma kallikrein and high-molecular-weight kininogen (contact phase activation). Active FXII has the ability to initiate blood clotting via the intrinsic pathway of coagulation and inflammatory reactions via the kallikrein-kinin system. Here we have determined FXII-mediated bradykinin formation and clotting in plasma. Western blotting analysis with specific antibodies against various parts of the contact factors revealed that limited activation of FXII is sufficient to promote plasma kallikrein activation, resulting in the conversion of high-molecular-weight kininogen and bradykinin generation. The presence of platelets significantly promoted FXII-initiated bradykinin formation. Similarly, in vitro clotting assays revealed that platelets critically promoted FXII-driven thrombin and fibrin formation. In summary, our data suggest that FXII-initiated protease cascades may proceed on platelet surfaces, with implications for inflammation and clotting.
Assuntos
Coagulação Sanguínea/fisiologia , Plaquetas/fisiologia , Fator XII/fisiologia , Sistema Calicreína-Cinina/fisiologia , Bradicinina/biossíntese , Humanos , Cininogênios/biossíntese , Peso Molecular , Valores de Referência , Trombina/biossíntese , Fatores de TempoRESUMO
Kinins are vasoactive oligopeptides generated upon proteolytic cleavage of low and high molecular weight kininogens by kallikreins. These peptides have a well established signaling role in inflammation and homeostasis. Nevertheless, emerging evidence suggests that bradykinin and other kinins are stored in the central nervous system and may act as neuromediators in the control of nociceptive response. Here we show that the kinin-B2 receptor (B2BKR) is differentially expressed during in vitro neuronal differentiation of P19 cells. Following induction by retinoic acid, cells form embryonic bodies and then undergo neuronal differentiation, which is complete after 8 and 9 days. Immunochemical staining revealed that B2BKR protein expression was below detection limits in nondifferentiated P19 cells but increased during the course of neuronal differentiation and peaked on days 8 and 9. Measurement of [Ca(2+)](i) in the absence and presence of bradykinin showed that most undifferentiated cells are unresponsive to bradykinin application, but following differentiation, P19 cells express high molecular weight neurofilaments, secrete bradykinin into the culture medium, and respond to bradykinin application with a transient increase in [Ca(2+)](i). However, inhibition of B2BKR activity with HOE-140 during early differentiation led to a decrease in the size of embryonic bodies formed. Pretreatment of differentiating P19 cells with HOE-140 on day 5 resulted in a reduction of the calcium response induced by the cholinergic agonist carbamoylcholine and decreased expression levels of M1-M3 muscarinic acetylcholine receptors, indicating crucial functions of the B2BKR during neuronal differentiation.
Assuntos
Bradicinina/análogos & derivados , Neurônios/citologia , Neurônios/metabolismo , Receptor B2 da Bradicinina/genética , Receptor B2 da Bradicinina/metabolismo , Animais , Sequência de Bases , Bradicinina/biossíntese , Bradicinina/farmacologia , Antagonistas de Receptor B2 da Bradicinina , Sinalização do Cálcio/efeitos dos fármacos , Carbacol/farmacologia , Diferenciação Celular , Linhagem Celular Tumoral , DNA Complementar/genética , Regulação para Baixo/efeitos dos fármacos , Expressão Gênica , Cininogênios/metabolismo , Camundongos , Modelos Neurológicos , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Muscarínicos/genéticaRESUMO
In diabetes, mesangial cell proliferation and extracellular matrix expansion are critical components in the development of glomerulosclerosis. We reported that diabetes alters the activity of the kallikrein-kinin system and that these alterations contribute to the development of diabetic nephropathy. The present study examined the influence of streptozotocin-induced diabetes on the renal expression of bradykinin (BK) B2 receptors (B2KR), connective tissue growth factor (CTGF), transforming growth factor-beta (TGF-beta), and TGF-beta type II receptor (TGF-betaRII) and assessed the signaling mechanisms through which B2KR activation may promote glomerular injury. Eight weeks after the induction of diabetes, renal mRNA levels of B2KR, CTGF, and TGF-beta as well as protein levels of CTGF and TGF-betaRII were measured in control (C), diabetic (D), and insulin-treated diabetic (D+I) rats. Renal B2KR and TGF-beta mRNA levels expressed relative to beta-actin mRNA levels and CTGF and TGF-betaRII protein levels were significantly increased in D and D+I rats compared with C rats (P < 0.03, n = 5). To assess the contribution of B2KR activation on modulating the expression of CTGF, TGF-betaRII, and collagen I, mesangial cells (MC) were treated with BK (10(-8) M) for 24 h and CTGF and TGF-betaRII protein levels were measured by Western blots and collagen I mRNA levels were measured by RT-PCR. A two- to threefold increase in CTGF and TGF-betaRII protein levels was observed in response to BK stimulation (P < 0.001, n = 6). In addition, a marked increase in collagen I mRNA levels was observed in response to BK stimulation. Treatment of MC with BK (10(-8) M) for 5 min significantly increased the tyrosine phosphorylation of p60src kinase and of p42/p44 MAPK (P < 0.05, n = 4). Inhibition of src kinase by PP1 (10 microM) inhibited the increase in p42/p44 MAPK activation in response to BK. Finally, to determine whether BK stimulates CTGF, TGF-betaRII, and collagen I expression via activation of MAPK pathways, MC were pretreated with an inhibitor of p42/p44 MAPK (PD-98059) for 45 min, followed by BK (10(-8) M) stimulation for 24 h. Selective inhibition of p42/p44 MAPK significantly inhibited the BK-induced increase in CTGF, TGF-betaRII, and collagen I levels. These findings are the first to demonstrate that BK regulates the expression of CTGF, TGF-betaRII, and collagen I in MC and provide a mechanistic pathway through which B2KR activation may contribute to the development of diabetic nephropathy.
Assuntos
Bradicinina/fisiologia , Nefropatias Diabéticas/patologia , Glomérulos Renais/patologia , Animais , Western Blotting , Bradicinina/biossíntese , Bradicinina/farmacologia , Células Cultivadas , Colágeno Tipo I/biossíntese , Colágeno Tipo II/biossíntese , Fator de Crescimento do Tecido Conjuntivo , DNA Complementar/biossíntese , DNA Complementar/genética , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/metabolismo , Mesângio Glomerular/citologia , Mesângio Glomerular/efeitos dos fármacos , Mesângio Glomerular/metabolismo , Proteínas Imediatamente Precoces/biossíntese , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Glomérulos Renais/metabolismo , Masculino , Proteínas Quinases Ativadas por Mitógeno/biossíntese , Proteína Oncogênica pp60(v-src)/metabolismo , RNA/biossíntese , RNA/isolamento & purificação , Ratos , Ratos Sprague-Dawley , Receptor B2 da Bradicinina/biossíntese , Receptores de Fatores de Crescimento Transformadores beta/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/fisiologia , Regulação para Cima/fisiologiaRESUMO
BACKGROUND: Cardiopulmonary bypass (CPB) induces derangements in physiology characterized by activation of blood pathways that may contribute to multiorgan dysfunction. This trial addresses the efficacy of a biocompatible surface alone and in combination with steroids in inhibiting these changes. METHODS: In a factorial design, patients undergoing coronary artery bypass grafting were randomized (four groups; n = 17 per group) to CPB utilizing control circuits or a circuit prepared with a surface modifying active copolymer (SMA-CPB), with or without methylprednisolone (MPSS, 1 g intravenous). Leukocyte and complement activation, cytokine release, and bradykinin generation were measured. Clinical outcomes (blood loss, transfusion, arterial pressure response, and postoperative cardiac and pulmonary functions) were also examined. RESULTS: The SMA-CPB was associated with a significant inhibition of elastase release (p = 0.026) and bradykinin generation (p = 0.027) during CPB. Terminal complement complex (TCC) generation was inhibited as an effect of SMA-CPB (p = 0.047). There was an interaction of SMA-CPB and MPSS to decrease both TCC (p = 0.042) and bradykinin generation (p = 0.028). There were strong effects of MPSS in inhibiting release of interleukin 6 (IL-6) (p = 0.007) and IL-8 (p < 0.001) and tissue plasminogen activator over time (p = 0.009) as well as decreasing peak day 1 creatine kinase (CK, p = 0.015) levels. Clinical effects of MPSS included decreased atrial fibrillation (p = 0.02), improved cardiac index over time, increased pulmonary compliance, and increased insulin need. CONCLUSIONS: This trial suggests a potential beneficial effect for combined strategies to minimize inflammation after CPB. The specific effect of MPSS in decreasing postoperative atrial fibrillation and CK warrants further investigation of its role as a potential myocardial protective agent.
Assuntos
Fenômenos Fisiológicos Sanguíneos/efeitos dos fármacos , Ponte Cardiopulmonar/instrumentação , Materiais Revestidos Biocompatíveis/farmacologia , Ativação do Complemento/efeitos dos fármacos , Inflamação/metabolismo , Leucócitos/imunologia , Metilprednisolona/farmacologia , Polímeros/farmacologia , Biomarcadores/metabolismo , Bradicinina/biossíntese , Ponte Cardiopulmonar/efeitos adversos , Ponte Cardiopulmonar/métodos , Ativação do Complemento/fisiologia , Citocinas/metabolismo , Feminino , Humanos , Inflamação/etiologia , Interleucinas/metabolismo , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/prevenção & controle , Elastase Pancreática/metabolismoRESUMO
Bradykinin and Lys-bradykinin are potent peptide mediators implicated in several physiopathological effects in mammals. They act through activation of G-protein-coupled constitutive B(2) or inducible kinin B(1) receptors linked to signaling pathways involving increased intracellular Ca(++) concentrations and/or release of mediators including arachidonic acid metabolites, NO and EDHF. In the cardiovascular system, the kallikrein-kinin system exerts a fine control of vascular smooth muscle tone and arterial blood pressure, and plays a significant cardioprotective effect. This has been lately confirmed in experimental studies employing transgenic mice overexpressing human tissue kallikrein and animals with knockout of kinin B(1) and B(2) receptor gene. Disturbances in this system are associated with arterial hypertension, myocardial ischaemia and other clinical complications. Inhibitors of kininase II (angiotensin-converting enzyme) have been prescribed successfully to patients with cardiovascular diseases, but there is still a great interest in developing drugs or pharmacological strategies that augment the activity of kininogen-kallikrein-kinin system in pathological conditions. Delivery of adenovirus vector containing the human tissue kallikrein gene (gene kallikrein therapy) has emerged as a great potential to satisfy these conditions. This review provides a summary of plasma and tissue kallikrein-kinin system, focusing on the pharmacological properties, kinin receptors and drugs reported to interfere with their actions. The modulatory effects of the kallikrein-kinin system on cardiovascular system, particularly in regulating smooth muscle tone and arterial blood pressure and in preventing myocardium ischaemia have also been explored in the review.
Assuntos
Bradicinina/fisiologia , Sistema Cardiovascular/metabolismo , Sistema Calicreína-Cinina/fisiologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Bradicinina/biossíntese , Bradicinina/metabolismo , Cardiotônicos/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Sistema Cardiovascular/efeitos dos fármacos , Terapia Genética , Humanos , Calidina/biossíntese , Calidina/metabolismo , Sistema Calicreína-Cinina/efeitos dos fármacos , Cininogênios/metabolismo , Cininas/antagonistas & inibidores , Cininas/genética , Cininas/metabolismo , Calicreína Plasmática/antagonistas & inibidores , Calicreína Plasmática/metabolismo , Inibidores de Proteases/uso terapêutico , Calicreínas Teciduais/antagonistas & inibidores , Calicreínas Teciduais/metabolismoRESUMO
We have previously demonstrated that both n-3 and n-6 polyunsaturated fatty acids (PUFA)-rich diets decrease the acute inflammatory response partially explained by the high corticosterone basal levels. The present study aimed to determine the effect of hyperlipidic diets (PUFA n-3 or n-6) on phagocytosis, hydrogen peroxide (H(2)O(2)) and nitric oxide (NO) release by macrophages, bradykinin (BK) and NO release in the paw inflammatory perfusate and Kallikrein (KK), corticosterone and leptin blood levels. Hyperlipidic diets decreased H(2)O(2) release from macrophages stimulated by carrageenan or phorbol-miristate-acetate (PMA), NO release from macrophage stimulated by carrageenan, BK and NO release in the edema perfusate, KK plasma levels and the increase of serum leptin after carrageenan stimulus. These data show that both fish and soybean oil-rich diets promote similar alterations on inflammatory mediators of carrageenan edema and a causal association with the anti-inflammatory effect of these diets.
Assuntos
Bradicinina/biossíntese , Carragenina/farmacologia , Corticosterona/metabolismo , Óleos de Peixe/metabolismo , Calicreínas/metabolismo , Leptina/metabolismo , Macrófagos/metabolismo , Óxido Nítrico/metabolismo , Óleo de Soja/metabolismo , Animais , Bradicinina/metabolismo , Peixes , Peróxido de Hidrogênio/metabolismo , Peróxido de Hidrogênio/farmacologia , Leptina/sangue , Masculino , Óxido Nítrico/farmacologia , Ratos , Ratos WistarRESUMO
Bradykinin has been implicated in the pathogenesis of inflammatory arthritis by virtue of the potent pro-inflammatory properties. The purpose of this study is to investigate the expression of bradykinin in patients with internal derangement of the temporomandibular joint (TMJ). We examined 33 TMJ synovial biopsy specimens from 31 patients with internal derangement of the TMJ by an immunohistochemical technique using specific antibodies. We also determined the concentration of bradykinin in 20 synovial fluids from 18 patients with TMJ internal derangement by enzyme-linked immunosorbent assay. These data were compared with those of the control subjects. Bradykinin was predominantly localized in the synovial lining cell layer of TMJ samples obtained from patients with TMJ internal derangement. Bradykinin was also detected in 19 patients' TMJ synovial fluids and the average of bradykinin concentration in the synovial fluids of patients was higher than that of the healthy controls. Although a statistically significant correlation was not observed, these findings support the hypothesis that bradykinin may also be involved in the pathogenesis of TMJ pain and synovitis.
Assuntos
Bradicinina/biossíntese , Líquido Sinovial/metabolismo , Membrana Sinovial/metabolismo , Transtornos da Articulação Temporomandibular/metabolismo , Adulto , Bradicinina/análise , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Luxações Articulares/metabolismo , Masculino , Pessoa de Meia-Idade , Medição da Dor , Líquido Sinovial/químicaRESUMO
Diabetes mellitus impairs the cardiac kallikrein-kinin system by reducing cardiac kallikrein (KLK) and kininogen levels, a mechanism that may contribute to the deleterious outcome of cardiac ischemia in this disease. We studied left ventricular (LV) function and bradykinin (BK) coronary outflow in buffer-perfused, isolated working hearts (n = 7) of controls and streptozotocin (STZ)-induced diabetic rats before and after global ischemia. With the use of selective kininase inhibitors, the activities of angiotensin I-converting enzyme, aminopeptidase P, and neutral endopeptidase were determined by analyzing the degradation kinetics of exogenously administered BK during sequential coronary passages. Basal LV function and coronary flow were impaired in STZ-induced diabetic rats. Neither basal nor postischemic coronary BK outflow differed between control and diabetic hearts. Reperfusion after 15 min of ischemia induced a peak in coronary BK outflow that was of the same extent and duration in both groups. In diabetic hearts, total cardiac kininase activity was reduced by 41.4% with an unchanged relative kininase contribution compared with controls. In conclusion, despite reduced cardiac KLK synthesis, STZ-induced diabetic hearts are able to maintain kinin liberation under basal and ischemic conditions because of a primary impairment or a secondary downregulation of kinin-degrading enzymes.
Assuntos
Aminopeptidases/metabolismo , Diabetes Mellitus Experimental/metabolismo , Cininas/metabolismo , Miocárdio/metabolismo , Neprilisina/metabolismo , Peptidil Dipeptidase A/metabolismo , Animais , Glicemia/metabolismo , Bradicinina/biossíntese , Diabetes Mellitus Experimental/enzimologia , Técnicas In Vitro , Sistema Calicreína-Cinina/efeitos dos fármacos , Masculino , Isquemia Miocárdica/metabolismo , Miocárdio/enzimologia , Perfusão , Ratos , Ratos Sprague-Dawley , Função Ventricular Esquerda/fisiologiaRESUMO
ACE inhibition protects the heart against ischemic injury by reducing angiotensin II and promoting bradykinin (BK) accumulation. Since neutral endopeptidase (NEP) metabolizes BK, we determined its activity after induction of myocardial infarction (MI) and examined whether it is influenced by treatment with an ACE inhibitor or AT1 receptor blocker. Rats were studied 6 days and 3 wk after coronary occlusion. Starting 48 h after MI induction, additional animals were treated with the ACE inhibitor quinapril (2 mg x kg(-1) x day-1) or the AT1 blocker irbesartan (50 mg x kg(-1) x day-1). Animals were hemodynamically characterized. Finally, NEP-specific activity and BK concentrations were detected in homogenates of heart compartments. Quinapril and irbesartan treatment improved left ventricular function 6 days and 3 wk after MI induction, and NEP activity was elevated only in the infarcted area of untreated compared with sham-operated rats. After 6 days, irbesartan reversed this increase by 80% and quinapril by 35%. Quinapril had no effect after 3 wk, whereas irbesartan almost completely blocked the increased NEP activity in the infarcted area and concomitantly induced a further rise in the BK concentrations. These results indicate mechanisms of NEP regulation influenced by the AT1 receptor. Our data suggest that NEP is more decisive than ACE in mediating BK degradation and may indicate BK involvement in the cardioprotective effects of AT1 antagonists.
Assuntos
Antagonistas de Receptores de Angiotensina , Compostos de Bifenilo/farmacologia , Bradicinina/biossíntese , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Neprilisina/metabolismo , Tetra-Hidroisoquinolinas , Tetrazóis/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Hemodinâmica , Irbesartana , Isoquinolinas/farmacologia , Masculino , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/enzimologia , Quinapril , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de AngiotensinaRESUMO
Physiological roles of angiotensin II type 2 receptor (AT(2)) are not well defined. This study was designed to investigate the mechanisms of AT(2)-dependent vascular relaxation by studying vasodilation in pressurized and perfused rat mesenteric arterial segments. Perfusion of angiotensin II in the presence of AT(1) antagonist elicited vascular relaxation, which was completely dependent on AT(2) receptors on endothelium. FR173657 (>1 microM), a bradykinin (BK) B(2)-specific antagonist, significantly suppressed AT(2)-dependent vasodilation (maximum inhibition: 68.5% at 10 microM). Kininogen-deficient Brown Norway Katholiek rats showed a significant reduction in AT(2)-mediated vasodilatory response compared with normal wild-type Brown Norway rats. Indomethacin (>1 microM), aprotinin (10 microM) and soybean trypsin inhibitor (10 microM) also reduced AT(2)-dependent vasodilation. Our results demonstrated that stimulation of AT(2) receptors caused a significant vasodilation through local production of BK in resistant arteries of rat mesentery in a flow-dependent manner. Such vasodilation counterbalances AT(1)-dependent vasoconstriction to regulate the vascular tone.