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1.
Mol Biol Rep ; 49(10): 9915-9927, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35596055

RESUMO

Bradykinin, a member of the kallikrein-kinin system (KKS), is a potent, short-lived vasoactive peptide that acts as a vasodilator and an inflammatory mediator in a number of signaling mechanisms. Bradykinin induced signaling is mediated through kinin B1 (BDKRB1) and B2 (BDKRB2) transmembrane receptors coupled with different subunits of G proteins (Gαi/Gα0, Gαq and Gß1γ2). The bradykinin-mediated signaling mechanism activates excessive pro-inflammatory cytokines, including IL-6, IL-1ß, IL-8 and IL-2. Upregulation of these cytokines has implications in a wide range of clinical conditions such as inflammation leading to fibrosis, cardiovascular diseases, and most recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In SARS-CoV-2 infection, bradykinin is found to be at raised levels and is reported to trigger a diverse array of symptoms. All of this brings bradykinin to the core point as a molecule of immense therapeutic value. Our understanding of its involvement in various pathways has expanded with time. Therefore, there is a need to look at the overall picture that emerges from the developments made by deciphering the bradykinin mediated signaling mechanisms involved in the pathological conditions. It will help devise strategies for developing better treatment modalities in the implicated diseases. This review summarizes the current state of knowledge on bradykinin mediated signaling in the diverse conditions described above, with a marked emphasis on the therapeutic potential of targeting the bradykinin receptor.


Assuntos
Bradicinina , COVID-19 , Humanos , Interleucina-2 , Interleucina-6 , Interleucina-8 , Receptores da Bradicinina/fisiologia , SARS-CoV-2 , Vasodilatadores
2.
Mediators Inflamm ; 2022: 7423537, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35153624

RESUMO

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


Assuntos
Bradicinina/fisiologia , COVID-19/etiologia , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2/fisiologia , Humanos , Sistema Calicreína-Cinina/fisiologia , Receptores da Bradicinina/fisiologia , Tratamento Farmacológico da COVID-19
3.
Br J Pharmacol ; 179(12): 3061-3077, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-34978069

RESUMO

BACKGROUND AND PURPOSE: Bradykinin (BK-(1-9)) is an endogenous nonapeptide involved in multiple physiological and pathological processes. Peptide fragments of bradykinin are believed to be biologically inactive. We have now tested the two major peptide fragments of bradykinin in human and animals. EXPERIMENTAL APPROACH: BK peptides were quantified by MS in male rats. NO release was quantified from human, mouse and rat cells loaded with DAF-FM. Rat aortic rings were used to measure vascular reactivity. Changes in BP and HR were measured in conscious male rats. To evaluate pro-inflammatory effects both vascular permeability and nociception were measured in adult mice. KEY RESULTS: BK-(1-7) and BK-(1-5) are produced in vivo from BK-(1-9). Both peptides induced NO production in all cell types tested. However, unlike BK-(1-9), NO production elicited by BK-(1-7) or BK-(1-5) was not inhibited by B1 or B2 receptor antagonists. BK-(1-7) and BK-(1-5) induced concentration-dependent vasorelaxation of aortic rings, without involvement of B1 or B2 receptors. Intravenous or intra-arterial administration of BK-(1-7) or BK-(1-5) induced similar hypotensive response in vivo. Nociceptive responses of BK-(1-7) and BK-(1-5) were reduced compared to BK-(1-9), and no increase in vascular permeability was observed for BK-(1-9) fragments. CONCLUSIONS AND IMPLICATIONS: BK-(1-7) and BK-(1-5) are endogenous peptides present in plasma. BK-related peptide fragments show biological activity, not mediated by B1 or B2 receptors. These BK fragments could constitute new, active components of the kallikrein-kinin system.


Assuntos
Bradicinina , Receptores da Bradicinina , Animais , Bradicinina/farmacologia , Masculino , Camundongos , Fragmentos de Peptídeos , Ratos , Receptor B1 da Bradicinina , Receptor B2 da Bradicinina , Receptores da Bradicinina/fisiologia
4.
FASEB J ; 34(6): 7265-7269, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32359101

RESUMO

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


Assuntos
Betacoronavirus , Antagonistas de Receptor B2 da Bradicinina/uso terapêutico , Bradicinina/análogos & derivados , Infecções por Coronavirus/fisiopatologia , Modelos Biológicos , Peptidil Dipeptidase A/fisiologia , Pneumonia Viral/fisiopatologia , Receptores Virais/fisiologia , Enzima de Conversão de Angiotensina 2 , Bradicinina/farmacologia , Bradicinina/fisiologia , Bradicinina/uso terapêutico , Antagonistas de Receptor B2 da Bradicinina/farmacologia , COVID-19 , Ensaios de Uso Compassivo , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Dispneia/etiologia , Dispneia/fisiopatologia , Retroalimentação Fisiológica/efeitos dos fármacos , Humanos , Inflamação , Uso Off-Label , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Receptores da Bradicinina/efeitos dos fármacos , Receptores da Bradicinina/fisiologia , SARS-CoV-2 , Tratamento Farmacológico da COVID-19
5.
Dis Model Mech ; 7(6): 701-10, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24742784

RESUMO

Focal and segmental glomerulosclerosis (FSGS) is one of the most important renal diseases related to end-stage renal failure. Bradykinin has been implicated in the pathogenesis of renal inflammation, whereas the role of its receptor 2 (B2RBK; also known as BDKRB2) in FSGS has not been studied. FSGS was induced in wild-type and B2RBK-knockout mice by a single intravenous injection of Adriamycin (ADM). In order to further modulate the kinin receptors, the animals were also treated with the B2RBK antagonist HOE-140 and the B1RBK antagonist DALBK. Here, we show that the blockage of B2RBK with HOE-140 protects mice from the development of FSGS, including podocyte foot process effacement and the re-establishment of slit-diaphragm-related proteins. However, B2RBK-knockout mice were not protected from FSGS. These opposite results were due to B1RBK expression. B1RBK was upregulated after the injection of ADM and this upregulation was exacerbated in B2RBK-knockout animals. Furthermore, treatment with HOE-140 downregulated the B1RBK receptor. The blockage of B1RBK in B2RBK-knockout animals promoted FSGS regression, with a less-inflammatory phenotype. These results indicate a deleterious role of both kinin receptors in an FSGS model and suggest a possible cross-talk between them in the progression of disease.


Assuntos
Glomerulosclerose Segmentar e Focal/patologia , Receptores da Bradicinina/fisiologia , Animais , Bradicinina/análogos & derivados , Bradicinina/farmacologia , Glomerulosclerose Segmentar e Focal/metabolismo , Camundongos , Camundongos Knockout , Receptores da Bradicinina/efeitos dos fármacos , Receptores da Bradicinina/genética
6.
Rheumatology (Oxford) ; 53(7): 1301-6, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24599920

RESUMO

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


Assuntos
Artrite Experimental/imunologia , Artrite Experimental/fisiopatologia , Bradicinina/fisiologia , Receptores da Bradicinina/fisiologia , Animais , Anticorpos Anti-Idiotípicos/efeitos adversos , Artrite Experimental/metabolismo , Colágeno/efeitos adversos , Colágeno/imunologia , Modelos Animais de Doenças , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Articulações/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores da Bradicinina/deficiência , Receptores da Bradicinina/genética
7.
Curr Vasc Pharmacol ; 12(2): 223-48, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24568157

RESUMO

Endogenous kinins are important vasoactive peptides whose effects are mediated by two G-Protein-coupled receptors (R), named B2R (constitutive) and B1R (inducible). They are involved in vascular homeostasis, ischemic pre- and post- conditioning, but also in cardiovascular diseases. They contribute to the therapeutic effects of angiotensin-1 converting enzyme inhibitors (ACEI) and angiotensin AT1 receptor blockers. Benefits derive primarily from vasodilatory, antiproliferative, antihypertrophic, antifibrotic, antithrombic and antioxidant properties, which are associated with the release of endothelial factors such as nitric oxide, prostacyclin and tissue plasminogen activator. Uncontrolled production of kinins or the inhibition of their metabolism may lead to unwanted pro-inflammatory side effects. Thus, B2R antagonism is salutary in angioedema, septic shock, stroke, and Chagas vasculopathy. B1R is virtually absent in healthy tissues, yet this receptor is induced by the cytokine pathway and the oxidative stress via the transcriptional nuclear factor NF-κB. The B1R may play a compensatory role for the lack of B2R, and its up-regulation during tissue damage may be a useful mechanism of host defense. Activation of both receptors may be beneficial, notably in neovascularisation, angiogenesis, heart ischemia and diabetic nephropathy. At the same time, B1R is a potent activator of inducible nitric oxide and NADPH oxidase, which are associated with vascular inflammation, increased permeability, insulin resistance, endothelial dysfunction and diabetic complications. The dual beneficial and deleterious effects of kinin receptors and, particularly B1R, raise an unsettled issue on the therapeutic value of B1R/B2R agonists versus antagonists in cardiovascular diseases. Hence, the Janus-face of kinin receptors needs to be seriously addressed in the upcoming clinical trials for each pathological setting.


Assuntos
Receptores da Bradicinina/fisiologia , Doenças Vasculares/etiologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Apoptose , Doenças Cardiovasculares/etiologia , Homeostase , Humanos , Cininas/fisiologia , Óxido Nítrico Sintase Tipo III/fisiologia , Sistema Renina-Angiotensina/fisiologia , Doenças Vasculares/patologia , Doenças Vasculares/fisiopatologia
8.
Curr Cardiol Rev ; 10(1): 29-37, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23638831

RESUMO

The formation of collateral vessels (arteriogenesis) to sustain perfusion in ischemic tissue is native to the body and can compensate for coronary stenosis. However, arteriogenesis is a complex process and is dependent on many different factors. Although animal studies on collateral formation and stimulation show promising data, clinical trials have failed to replicate these results. Further research to the exact mechanisms is needed in order to develop a pharmalogical stimulant. This review gives an overview of recent data in the field of arteriogenesis.


Assuntos
Circulação Colateral/fisiologia , Doença da Artéria Coronariana/fisiopatologia , Neovascularização Fisiológica/fisiologia , Indutores da Angiogênese/uso terapêutico , Inibidores da Angiogênese/uso terapêutico , Animais , Bradicinina/fisiologia , Circulação Coronária/fisiologia , Vasos Coronários/fisiologia , Modelos Animais de Doenças , Fator Estimulador de Colônias de Granulócitos/fisiologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/fisiologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Macrófagos/fisiologia , Camundongos , Monócitos/fisiologia , Músculo Liso Vascular/fisiologia , Neurregulinas/fisiologia , Plasma Rico em Plaquetas/fisiologia , Receptores da Bradicinina/fisiologia , Transdução de Sinais/fisiologia , Células-Tronco/fisiologia , Fator A de Crescimento do Endotélio Vascular/fisiologia , Vasodilatadores/uso terapêutico
10.
Sheng Li Ke Xue Jin Zhan ; 43(3): 177-82, 2012 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-23019919

RESUMO

Bradykinin receptors are an important member of the G protein-coupled receptors family. Bradykinin receptor-mediated signal transductions play a significant role in maintaining cardiovascular homeostasis, regulating pain and inflammation. In recent years, the introduction of fluorescence resonance energy transfer, bioluminescence resonance energy transfer and their extended technologies, confirmed that bradykinin receptors can exist in the formation of dimerizations or even high-order oligomers. Compared with the monomer, its signal transduction and pathological features have changed accordingly. In this paper, we overview how bradykinin receptor monomeric and dimers regulate physiological and pathological processes as well as the latest research techniques.


Assuntos
Doenças Cardiovasculares/fisiopatologia , Receptores da Bradicinina/fisiologia , Transdução de Sinais/fisiologia , Animais , Técnicas de Transferência de Energia por Ressonância de Bioluminescência , Transferência Ressonante de Energia de Fluorescência , Humanos , Multimerização Proteica/fisiologia
11.
Contrib Nephrol ; 170: 145-155, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21659767

RESUMO

Emerging evidence suggests a role of the kallikrein-kinin system (KKS) in the pathogenesis of diabetic nephropathy (DN). Tissue kallikrein 1 is a member of the tissue kallikrein family that is mainly responsible for the generation of kinins, and bradykinin (BK) is the principal kinin responsible for the biologic actions of the KKS that acts through the ubiquitous BK 2receptor (B2R) and the inducible B1R. In the kidney, all KKS components are expressed. In particular, kallikrein 1 that is traditionally thought to be solely confined to the distal nephron has recently been identified in the proximal tubule of the human diabetic kidney. Current evidence suggests conflicting roles of the KKS in DN. For a renoprotective role of the KKS, BK reduces mesangial cell proliferation under the diabetic milieu; Akita B2R-/- or STZ-induced KLK-/- mice (T1DM) have more severe albuminuria and glomerulosclerosis, while antagonizing the B2R with icatibant attenuates the antiproteinuric effect of ramiprilin db/db mice (T2DM). For a detrimental role of the KKS, BK upregulates tubular cell IL-6, CCL-2, and TGF-ß expression via ERK1/2 activation; the B2R-/- status protects against the development of DN lesions in STZ-injected mice, while blocking B2R with icatibant alleviates biochemical and histologic injuries in uninephrectomized db/db mice. These opposite findings may arise from multiple factors and call for further evaluation to clarify the role of the KKS in DN and diabetic tubulopathy.


Assuntos
Nefropatias Diabéticas/etiologia , Sistema Calicreína-Cinina/fisiologia , Animais , MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Humanos , Calicreínas/análise , Túbulos Renais Proximais/metabolismo , Receptores da Bradicinina/fisiologia
12.
CNS Neurosci Ther ; 17(6): 742-9, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20950328

RESUMO

Targets for antipruritic therapies are now expanding from the skin to the central nervous system. Recent studies demonstrate that various neuronal receptors in the spinal cord are involved in pruritus. The spinal opioid receptor is one of the best-known examples. Spinal administration of morphine is frequently accompanied by segmental pruritus. In addition to µ-opioid receptor antagonists, κ-opioid receptor agonists have recently come into usage as novel antipruritic drugs, and are expected to suppress certain subtypes of itch such as hemodialysis- and cholestasis-associated itch that are difficult to treat with antihistamines. The gastrin-releasing peptide receptor in the superficial dorsal horn of the spinal cord has also received recent attention as a novel pathway of itch-selective neural transmission. The NMDA glutamate receptor appears to be another potential target for the treatment of itch, especially in terms of central sensitization. The development of NMDA receptor antagonists with less undesirable side effects on the central nervous system might be beneficial for antipruritic therapies. Drugs suppressing presynaptic glutamate-release such as gabapentin and pregabalin also reportedly inhibit certain subtypes of itch such as brachioradial pruritus. Spinal receptors of other neuromediators such as bradykinin, substance P, serotonin, and histamine may also be potential targets for antipruritic therapies, given that most of these molecules interfere not only with pain, but also with itch transmission or regulation. Thus, the identification of itch-specific receptors and understanding itch-related circuits in the spinal cord may be innovative strategies for the development of novel antipruritic drugs.


Assuntos
Neurotransmissores/fisiologia , Prurido/tratamento farmacológico , Prurido/fisiopatologia , Medula Espinal/fisiologia , Animais , Desenho de Fármacos , Células Secretoras de Gastrina/efeitos dos fármacos , Células Secretoras de Gastrina/fisiologia , Humanos , Receptores da Bradicinina/efeitos dos fármacos , Receptores da Bradicinina/fisiologia , Receptores de Glutamato/efeitos dos fármacos , Receptores de Glutamato/fisiologia , Receptores Histamínicos/efeitos dos fármacos , Receptores Histamínicos/fisiologia , Receptores da Neurocinina-1/efeitos dos fármacos , Receptores da Neurocinina-1/fisiologia , Receptores Opioides/efeitos dos fármacos , Receptores Opioides/fisiologia , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/fisiologia
13.
Cell Calcium ; 48(2-3): 114-23, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20728215

RESUMO

TRPC channels play significant roles in the regulation of neuronal plasticity and development. The mechanism by which these nonselective cation channels exert their trophic actions appears to involve entry of Ca(2+) into the cells. Using a neuronal cell model (differentiated human IMR32 neuroblastoma cells), we demonstrate a central role for sodium entry via TRPC3/6 channels in receptor-mediated increases in intracellular calcium. These Na(+)-dependent Ca(2+) influxes, which were observed in a subpopulation of cells, were efficiently blocked by protein kinase C activation, by the Na(+)/Ca(2+) exchanger inhibitors, and by molecular disruption of TRPC3/6 channel function. On the other hand, another subpopulation of cells showed a Na(+)-independent Ca(2+) entry upon stimulation of the same receptors, orexin/hypocretin and bradykinin receptors. This second type of response was not affected by the above mentioned treatments, but it was sensitive to polyvalent cations, such as ruthenium red, spermine and Gd(3+). The data suggest that a NCX-TRPC channel interaction constitutes an important functional unit in receptor-mediated Ca(2+) influx in neuronal cells.


Assuntos
Sinalização do Cálcio/fisiologia , Cálcio/fisiologia , Proteínas de Homeodomínio/fisiologia , Receptores Acoplados a Proteínas G/fisiologia , Receptores de Neuropeptídeos/fisiologia , Canais de Cátion TRPC/fisiologia , Cálcio/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Humanos , Neuroblastoma/química , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Neurônios/metabolismo , Neurônios/patologia , Receptores de Orexina , Proteína Quinase C/fisiologia , Receptores da Bradicinina/fisiologia , Receptores Acoplados a Proteínas G/genética , Receptores de Neuropeptídeos/genética , Rutênio Vermelho/farmacologia , Trocador de Sódio e Cálcio/genética , Trocador de Sódio e Cálcio/fisiologia , Espermina/fisiologia , Canais de Cátion TRPC/antagonistas & inibidores , Canal de Cátion TRPC6
14.
Pharmacol Rep ; 61(4): 631-40, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19815945

RESUMO

Pain that accompanies neuropathy is difficult to treat. Analgesics administered as monotherapies possess low activities in relieving this kind of pain. The effect of the simultaneous administration of indomethacin (a preferential inhibitor of cyclooxygenase-1; COX-1) or celecoxib (a relatively selective inhibitor of cyclooxygenase-2; COX-2), with selective antagonists of bradykinin(2) (B(2)) bradykinin(1) (B(1)) receptors (HOE 140 or des-Arg(10)-HOE 140) on the alleviation of diabetic and toxic neuropathic pain was investigated. Pretreatment with indomethacin (0.1 mg/kg, sc) increased the antihyperalgesic activity of low daily doses of HOE 140 or des-Arg(10)HOE 140 (70 nmol/kg, ip) in a diabetic (streptozotocin(STZ)-induced) neuropathy/hyperalgesia experimental model. Premedication with celecoxib before HOE 140 or des-Arg(10)HOE 140 administration resulted in a gradual reduction of STZ hyperalgesia. Furthermore, on days 23-24, almost complete abolishment of STZ hyperalgesia was observed. After cessation of drug administration, hyperalgesia quickly returned to the baseline threshold. The results of this study suggest that inhibitors of cyclooxygenases can increase the antihyperalgesic activity of selective antagonists of B(2) and B(1) receptors in diabetic and toxic neuropathic pain models. These observations may be clinically relevant.


Assuntos
Antagonistas dos Receptores da Bradicinina , Bradicinina/análogos & derivados , Inibidores de Ciclo-Oxigenase/uso terapêutico , Hiperalgesia/tratamento farmacológico , Estreptozocina/toxicidade , Vincristina/toxicidade , Animais , Bradicinina/farmacologia , Bradicinina/uso terapêutico , Sinergismo Farmacológico , Hiperalgesia/induzido quimicamente , Hiperalgesia/fisiopatologia , Masculino , Estimulação Física/métodos , Ratos , Ratos Wistar , Receptores da Bradicinina/fisiologia
15.
Neuro Endocrinol Lett ; 30(1): 144-52, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19300402

RESUMO

PURPOSE: The influence of an irreversible inhibitor of constitutive NO synthase (L-NOArg; 1.0 mg/kg ip), a relatively selective inhibitor of inducible NO synthase (L-NIL; 1.0 mg/kg ip) and a relatively specific inhibitor of neuronal NO synthase (7-NI; 0.1 mg/kg ip), on antihyperalgesic action of selective antagonists of B2 and B1 receptors: D-Arg-[Hyp3,Thi5,D-Tic7,Oic8] bradykinin (HOE 140; 70 nmol/kg ip) or des Arg10 HOE 140 (70 nmol/kg ip) respectively, in model of diabetic (streptozotocin-induced) and toxic (vincristine-induced) neuropathy was investigated. METHODS: The changes in pain thresholds were determined using mechanical stimuli--the modification of the classic paw withdrawal test described by Randall-Selitto. RESULTS: The results of this paper confirm that inhibition of bradykinin receptors and inducible NO synthase but not neuronal NO synthase activity reduces diabetic hyperalgesia. Pretreatment with L-NOArg and L-NIL but not 7-NI, significantly increases antihyperalgesic activity both HOE 140 and des Arg10 HOE 140. It was also shown that both products of inducible NO synthase and neuronal NO synthase activation as well as bradykinin are involved in hyperalgesia produced by vincristine. Moreover, L-NOArg and 7-NI but not L-NIL intensify antihyperalgesic activity of HOE 140 or des-Arg10HOE 140 in toxic neuropathy. CONCLUSIONS: Results of these studies suggest that B1 and B2 receptors are engaged in transmission of nociceptive stimuli in both diabetic and toxic neuropathy. In streptozotocin-induced hyperalgesia, inducible NO synthase participates in pronociceptive activity of bradykinin, whereas in vincristine-induced hyperalgesia bradykinin seemed to activate neuronal NO synthase pathway. Therefore, concomitant administration of small doses of bradykinin receptor antagonists and NO synthase inhibitors can be effective in alleviation of neuropathic pain, even in hospital care.


Assuntos
Antagonistas dos Receptores da Bradicinina , Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Óxido Nítrico Sintase/antagonistas & inibidores , Animais , Bradicinina/administração & dosagem , Bradicinina/análogos & derivados , Bradicinina/uso terapêutico , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Neuropatias Diabéticas/induzido quimicamente , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/uso terapêutico , Hiperalgesia/induzido quimicamente , Hiperalgesia/etiologia , Hipoglicemiantes/administração & dosagem , Indazóis/administração & dosagem , Indazóis/uso terapêutico , Lisina/administração & dosagem , Lisina/análogos & derivados , Lisina/uso terapêutico , Masculino , Nitroarginina/administração & dosagem , Nitroarginina/uso terapêutico , Medição da Dor , Ratos , Ratos Wistar , Receptores da Bradicinina/fisiologia , Estreptozocina , Tetra-Hidroisoquinolinas/administração & dosagem , Tetra-Hidroisoquinolinas/uso terapêutico , Vincristina
16.
Clin Sci (Lond) ; 116(5): 443-50, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18798730

RESUMO

In the present study, we investigated the effects of basal and intra-arterial infusion of bradykinin on unstressed forearm vascular volume (a measure of venous tone) and blood flow in healthy volunteers (n=20) and in chronic heart failure patients treated with ACEIs [ACE (angiotensin-converting enzyme) inhibitors] (n=16) and ARBs (angiotensin receptor blockers) (n=14). We used radionuclide plethysmography to examine the effects of bradykinin and of the bradykinin antagonists B9340 [B1 (type 1)/B2 (type 2) receptor antagonist] and HOE140 (B2 antagonist). Bradykinin infusion increased unstressed forearm vascular volume in a similar dose-dependent manner in healthy volunteers and ARB-treated CHF patients (healthy volunteers maximum 12.3+/-2.1%, P<0.001 compared with baseline; ARB-treated CHF patients maximum 9.3+/-3.3%, P<0.05 compared with baseline; P=not significant for difference between groups), but the increase in unstressed volume in ACEI-treated CHF patients was higher (maximum 28.8+/-7.8%, P<0.001 compared with baseline; P<0.05 for the difference between groups). In contrast, while the increase in blood flow in healthy volunteers (maximum 362+/-9%, P<0.001) and in ACEI-treated CHF patients (maximum 376+/-12%, P<0.001) was similar (P=not significant for the difference between groups), the increase in ARB-treated CHF patients was less (maximum 335+/-7%, P<0.001; P<0.05 for the difference between groups). Infusion of each receptor antagonist alone similarly reduced basal unstressed volume and blood flow in ACEI-treated CHF patients, but not in healthy volunteers or ARB-treated CHF patients. In conclusion, bradykinin does not contribute to basal venous tone in health, but in ACEI-treated chronic heart failure it does. In ARB-treated heart failure, venous responses to bradykinin are preserved but arterial responses are reduced compared with healthy controls. Bradykinin-mediated vascular responses in both health and heart failure are mediated by the B2, rather than the B1, receptor.


Assuntos
Bradicinina/farmacologia , Insuficiência Cardíaca/fisiopatologia , Resistência Vascular/efeitos dos fármacos , Vasodilatadores/farmacologia , Idoso , Idoso de 80 Anos ou mais , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Bradicinina/análogos & derivados , Bradicinina/antagonistas & inibidores , Antagonistas dos Receptores da Bradicinina , Relação Dose-Resposta a Droga , Feminino , Antebraço/irrigação sanguínea , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Receptores da Bradicinina/fisiologia , Fluxo Sanguíneo Regional/efeitos dos fármacos , Vasodilatadores/antagonistas & inibidores
17.
Neurosci Lett ; 437(3): 175-9, 2008 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-18450375

RESUMO

The endogenous opioid peptide dynorphin A is distinct from other endogenous opioid peptides in having significant neuronal excitatory and neurotoxic effects that are not mediated by opioid receptors. Some of these non-opioid actions of dynorphin contribute to the development of abnormal pain resulting from a number of pathological conditions. Identifying the mechanisms and the sites of action of dynorphin is essential for understanding the pathophysiology of dynorphin and for exploring novel therapeutic targets for pain. This review will discuss the mechanisms that have been proposed and the recent finding that spinal dynorphin may be an endogenous ligand of bradykinin receptors under pathological conditions to promote pain.


Assuntos
Dinorfinas/metabolismo , Dor/metabolismo , Receptores da Bradicinina/fisiologia , Animais , Humanos , Dor/patologia , Dor/fisiopatologia , Medula Espinal/metabolismo
18.
Int Immunopharmacol ; 8(2): 155-60, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18182219

RESUMO

This review deals with the effects of kinins, a family of octa- to decapeptides structurally related to bradykinin (BK), in adaptive immune responses. Herein, we discuss the experimental evidence that kinins may exert influence on multiple players of the immune system (i.e. macrophages, dendritic cells, T and B lymphocytes), and modulate the activation, proliferation, migration and effector functions of these cells. We also give an overview of the possible impact of kinins in human autoimmune diseases and corresponding animal models, with special emphasis on autoimmune neuroinflammation and arthritis. These studies indicate a possible immunomodulatory capacity of kinins beyond our current knowledge of kinin actions regarding the vascular system, and thus the way towards future therapeutic approaches.


Assuntos
Sistema Imunitário/fisiologia , Sistema Calicreína-Cinina/fisiologia , Receptores da Bradicinina/fisiologia , Animais , Doenças Autoimunes/tratamento farmacológico , Células Dendríticas/fisiologia , Humanos , Linfócitos/fisiologia
19.
Pharmacology ; 81(2): 158-63, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-17989505

RESUMO

The role of bradykinin receptor blockade in the development of neuropathies caused by diabetes mellitus and vincristine was examined. The effects of a potent and selective B(1) receptor antagonist (des-Arg(10)-HOE 140) as well as a specific antagonist of B(2) receptors (HOE 140) were investigated. Both agents significantly decreased hyperalgesia caused otherwise by vincristine. In a diabetic neuropathy model, both agents almost completely suppressed hyperalgesia in the first 10 days of the study. However, from day 11 after administration of streptozotocin, the action of des-Arg(10)-HOE 140 was significantly weaker than that of HOE 140. The results of the study suggest involvement of both B(1) and B(2) receptors in transmission of nociceptive stimuli in the vincristine-induced as well as diabetic neuropathy model.


Assuntos
Antagonistas dos Receptores da Bradicinina , Bradicinina/análogos & derivados , Neuropatias Diabéticas/tratamento farmacológico , Modelos Animais de Doenças , Hiperalgesia/tratamento farmacológico , Estreptozocina/toxicidade , Vincristina/toxicidade , Animais , Antineoplásicos/toxicidade , Bradicinina/farmacologia , Bradicinina/uso terapêutico , Neuropatias Diabéticas/induzido quimicamente , Neuropatias Diabéticas/patologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/patologia , Masculino , Ratos , Ratos Wistar , Receptores da Bradicinina/fisiologia
20.
Eur J Pharmacol ; 573(1-3): 221-9, 2007 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-17669394

RESUMO

Kinin receptors are involved in the genesis of inflammatory pain. However, there is controversy concerning the mechanism by which B(1) and B(2) kinin receptors mediate inflammatory hypernociception. In the present study, the role of these receptors on inflammatory hypernociception in mice was addressed. Mechanical hypernociception was detected with an electronic pressure meter paw test in mice and cytokines were measured by ELISA. It was observed that in naïve mice a B(2) (d-Arg-Hyp(3), d-Phe(7)-bradykinin) but not a B(1) kinin receptor antagonist (des-Arg(9)-[Leu(8)]-bradykinin, DALBK) inhibited bradykinin- and carrageenin-induced hypernociception. Bradykinin-induced hypernociception was inhibited by indomethacin (5 mg/kg) and guanethidine (30 mg/kg), while not affected by IL-1ra (10 mg/kg) or antibody against keratinocyte-derived chemokine (KC/CXCL-1, 500 ng/paw) or in TNFR1 knockout mice. By contrast, in previously lipopolysaccharide (LPS)-primed mouse paw, B(1) but not B(2) kinin receptor antagonist inhibited bradykinin hypernociception. Furthermore, B(1) kinin receptor agonist induced mechanical hypernociception in LPS-primed mice, which was inhibited by indomethacin, guanethidine, antiserum against TNF-alpha or IL-1ra. This was corroborated by the induction of TNF-alpha and IL-1beta release by B(1) kinin receptor agonist in LPS-primed mouse paws. Moreover, B(1) but not B(2) kinin receptor antagonist inhibited carrageenin-induced hypernociception, and TNF-alpha and IL-1beta release as well, in LPS-primed mice. These results suggest that in naïve mice the B(2) kinin receptor mediates inflammatory hypernociception dependent on prostanoids and sympathetic amines, through a cytokine-independent mechanism. On the other hand, in LPS-primed mice, the B(1) kinin receptor mediates hypernociception by a mechanism dependent on TNF-alpha and IL-1beta, which could stimulate prostanoid and sympathetic amine production.


Assuntos
Hiperalgesia/fisiopatologia , Inflamação/fisiopatologia , Interleucina-1beta/fisiologia , Receptores da Bradicinina/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Animais , Anticorpos/farmacologia , Bradicinina/administração & dosagem , Bradicinina/análogos & derivados , Bradicinina/farmacologia , Antagonistas de Receptor B1 da Bradicinina , Antagonistas de Receptor B2 da Bradicinina , Antagonistas dos Receptores da Bradicinina , Carragenina/administração & dosagem , Carragenina/toxicidade , Relação Dose-Resposta a Droga , Guanetidina/farmacologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/prevenção & controle , Indometacina/farmacologia , Inflamação/induzido quimicamente , Inflamação/prevenção & controle , Interleucina-1beta/imunologia , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Prostaglandinas/fisiologia , Receptor B1 da Bradicinina/agonistas , Receptor B1 da Bradicinina/fisiologia , Receptor B2 da Bradicinina/fisiologia , Receptores da Bradicinina/agonistas , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/fisiologia , Fator de Necrose Tumoral alfa/imunologia
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