RESUMEN
Endometriosis is a gynecological condition characterized by the growth of endometrium-like tissues outside of the uterine cavity. Currently available drugs are efficacious in treating endometriosis-related pain, however it's not a targeted treatment. The aim of this work is to evaluate the effects of R-954, a bradykinin B1 receptor antagonist, in a murine model of endometriosis. The model was induced in animals through autologous transplantation of part of the uterine horn. After 51 days, it was observed that implants developed into endometriotic lesions. The administration of R-954 or progesterone, for 15 consecutive days, prevented the progression of cyst development, reduced the size and weight of the cysts. Both treatments also reduced cellular infiltrate and production of inflammatory mediators (interleukin-1ß, interleukin-6, tumor necrosis factor). However, only R-954 decreased angiogenic factors (VEGF and VEGF receptor). In addition, treatment with the antagonist did not interfere in the females' estrous cycle, as well as prevented gestational losses (reduction in the number of intermediate resorptions in pregnant females with endometriosis). Data suggested that R-954 has anti-inflammatory and anti-angiogenic effects; does not influence the estrous cycle; and prevents the number of gestational losses suggesting it as a good candidate for endometriosis treatment.
Asunto(s)
Antagonistas del Receptor de Bradiquinina B1 , Modelos Animales de Enfermedad , Endometriosis , Endometriosis/tratamiento farmacológico , Endometriosis/patología , Femenino , Animales , Antagonistas del Receptor de Bradiquinina B1/farmacología , Antagonistas del Receptor de Bradiquinina B1/uso terapéutico , Ratones , Humanos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , EmbarazoRESUMEN
Tumour necrosis factor (TNF) and kinins have been associated with neuropathic pain-like behaviour in numerous animal models. However, the way that they interact to cause neuron sensitisation remains unclear. This study assessed the interaction of kinin receptors and TNF receptor TNFR1/p55 in mechanical hypersensitivity induced by an intraneural (i.n.) injection of rm-TNF into the lower trunk of brachial plexus in mice. The i.n. injection of rm-TNF reduced the mechanical withdrawal threshold of the right forepaw from the 3rd to the 10th day after the injection, indicating that TNF1/p55 displays a critical role in the onset of TNF-elicited neuropathic pain. The connection between TNF1/p55 and kinin B1 and B2 receptors (B1R and B2R) was confirmed using both knockout mice and mRNAs quantification in the injected nerve, DRG and spinal cord. The treatment with the B2R antagonist HOE 140 or with B1R antagonist des-Arg9-Leu8-BK reduced both BK- and DABK-induced hypersensitivity. The experiments using kinin receptor antagonists and CPM inhibitor (thiorphan) suggest that BK does not only activate B2R as an orthosteric agonist, but also seems to be converted into DABK that consequently activates B1R. These results indicate a connection between TNF and the kinin system, suggesting a relevant role for B1R and B2R in the process of sensitisation of the central nervous systems by the cross talk between the receptor and CPM after i.n. injection of rm-TNF.
Asunto(s)
Plexo Braquial/metabolismo , Neuralgia/metabolismo , Receptor de Bradiquinina B1/metabolismo , Receptor de Bradiquinina B2/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Plexo Braquial/efectos de los fármacos , Antagonistas del Receptor de Bradiquinina B1/farmacología , Antagonistas del Receptor de Bradiquinina B2/farmacología , Modelos Animales de Enfermedad , Femenino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuralgia/tratamiento farmacológicoRESUMEN
Muscle pain is an important health issue and frequently related to static force exertion. The aim of this study is to evaluate whether peripheral inflammatory mechanisms are involved with static contraction-induced muscle pain in rats. To this end, we developed a model of muscle pain induced by static contraction performed by applying electrical pulses through electrodes inserted into muscle. We also evaluated the involvement of neutrophil migration, bradykinin, sympathetic amines and prostanoids. A single session of sustained static contraction of gastrocnemius muscle induced acute mechanical muscle hyperalgesia without affecting locomotor activity and with no evidence of structural damage in muscle tissue. Static contraction increased levels of creatine kinase but not lactate dehydrogenase, and induced neutrophil migration. Dexamethasone (glucocorticoid anti-inflammatory agent), DALBK (bradykinin B1 antagonist), Atenolol (ß1 adrenoceptor antagonist), ICI 118,551 (ß2 adrenoceptor antagonist), indomethacin (cyclooxygenase inhibitor), and fucoidan (non-specific selectin inhibitor) all reduced static contraction-induced muscle hyperalgesia; however, the bradykinin B2 antagonist, bradyzide, did not have an effect on static contraction-induced muscle hyperalgesia. Furthermore, an increased hyperalgesic response was observed when the selective bradykinin B1 agonist des-Arg9-bradykinin was injected into the previously stimulated muscle. Together, these findings demonstrate that static contraction induced mechanical muscle hyperalgesia in gastrocnemius muscle of rats is modulated through peripheral inflammatory mechanisms that are dependent on neutrophil migration, bradykinin, sympathetic amines and prostanoids. Considering the clinical relevance of muscle pain, we propose the present model of static contraction-induced mechanical muscle hyperalgesia as a useful tool for the study of mechanisms underlying static contraction-induced muscle pain.
Asunto(s)
Bradiquinina/metabolismo , Hiperalgesia/fisiopatología , Contracción Muscular/fisiología , Mialgia/etiología , Neutrófilos/fisiología , Análisis de Varianza , Animales , Antiarrítmicos/farmacología , Antiinflamatorios/farmacología , Atenolol/farmacología , Antagonistas del Receptor de Bradiquinina B1/farmacología , Creatina Quinasa/metabolismo , Dexametasona/farmacología , Modelos Animales de Enfermedad , Estimulación Eléctrica/efectos adversos , Hiperalgesia/inducido químicamente , L-Lactato Deshidrogenasa/metabolismo , Locomoción/efectos de los fármacos , Masculino , Neutrófilos/efectos de los fármacos , Propanolaminas/farmacología , Prostaglandinas , Ratas , Ratas WistarRESUMEN
Cisplatin is a drug widely used in chemotherapy that frequently causes severe renal dysfunction. Organic transporters have an important role to control the absorption and excretion of cisplatin in renal cells. Deletion and blockage of kinin B1 receptor has already been show to protect against cisplatin-induced acute kidney injury. To test whether it exerts its protective function by modulating the organic transporters in kidney, we studied kinin B1 receptor knockout mice and treatment with a receptor antagonist at basal state and in presence of cisplatin. Cisplatin administration caused downregulation of renal organic transporters; in B1 receptor knockout mice, this downregulation of organic transporters in kidney was absent; and treatment by a B1 receptor antagonist attenuated the downregulation of the transporter MATE-1. Moreover, kinin B1 receptor deletion and blockage at basal state resulted in higher renal expression of MATE-1. Moreover we observed that kinin B1 receptor deletion and blockage result in less accumulation of platinum in renal tissue. Thus, we propose that B1 receptor deletion and blockage protect the kidney from cisplatin-induced acute kidney injury by upregulating the expression of MATE-1, thereby increasing the efflux of cisplatin from renal cells.
Asunto(s)
Lesión Renal Aguda/prevención & control , Antagonistas del Receptor de Bradiquinina B1/farmacología , Cisplatino/farmacocinética , Proteínas de Transporte de Catión Orgánico/genética , Receptor de Bradiquinina B1/genética , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/genética , Animales , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Técnicas de Inactivación de Genes , Riñón/efectos de los fármacos , Riñón/metabolismo , Masculino , Ratones , Proteínas de Transporte de Catión Orgánico/metabolismo , Receptor de Bradiquinina B1/metabolismoRESUMEN
Previous studies have demonstrated that targeting bradykinin receptors is a promising strategy to counteract the cognitive impairment related with aging and Alzheimer's disease (AD). The hippocampus is critical for cognition, and abnormalities in this brain region are linked to the decline in mental ability. Nevertheless, the impact of bradykinin signaling on hippocampal function is unknown. Therefore, we sought to determine the role of hippocampal bradykinin receptors B1R and B2R on the cognitive decline of middle-aged rats. Twelve-month-old rats exhibited impaired ability to acquire and retrieve spatial information in the Morris water maze task. A single intra-hippocampal injection of the selective B1R antagonist des-Arg9-[Leu8]-bradykinin (DALBK, 3 nmol), but not the selective B2R antagonist D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]-BK (Hoe 140, 3 nmol), reversed the spatial learning and memory deficits on these animals. However, both drugs did not affect the cognitive function in 3-month-old rats, suggesting absence of nootropic properties. Molecular biology analysis revealed an up-regulation of B1R expression in the hippocampal CA1 sub-region and in the pre-frontal cortex of 12-month-old rats, whereas no changes in the B2R expression were observed in middle-aged rats. These findings provide new evidence that inappropriate hippocampal B1R expression and activation exert a critical role on the spatial learning and memory deficits in middle-aged rats. Therefore, selective B1R antagonists, especially orally active non-peptide antagonists, may represent drugs of potential interest to counteract the age-related cognitive decline.
Asunto(s)
Hipocampo/metabolismo , Trastornos de la Memoria/patología , Receptor de Bradiquinina B1/metabolismo , Aprendizaje Espacial/efectos de los fármacos , Envejecimiento/efectos de los fármacos , Animales , Bradiquinina/análogos & derivados , Bradiquinina/farmacología , Antagonistas del Receptor de Bradiquinina B1/farmacología , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/tratamiento farmacológico , Ratas , Ratas Wistar , Regulación hacia Arriba/efectos de los fármacosRESUMEN
OBJECTIVE: Verify the role of the kinin B1 receptors (B1R) and the effect of ACE inhibitors (ACEi) on acute gout induced by monosodium urate (MSU) crystals in rodents. METHODS: Painful (overt pain and allodynia) and inflammatory parameters (joint oedema, leukocyte trafficking, interleukin-1ß levels) of acute gout attacks were assessed several hours after an intra-articular injection of MSU (1.25 or 0.5 mg/articulation) into the ankle of rats or mice, respectively. The role of B1R was investigated using pharmacological antagonism or gene deletion. Additionally, B1R immunoreactivity in ankle tissue and sensory neurons, kininase I activity and des-Arg(9)-bradykinin synovial levels were also measured. Similar tools were used to investigate the effects of ACEi on a low dose of MSU (0.0125 mg/articulation)-induced inflammation. RESULTS: Kinin B1R antagonism or gene deletion largely reduced all painful and inflammatory signs of gout. Furthermore, MSU increased B1R expression in articular tissues, the content of the B1 agonist des-Arg(9)-bradykinin and the activity of the B1 agonist-forming enzyme kininase I. A low dose of MSU crystals, which did not induce inflammation in control animals, caused signs of acute gout attacks in ACEi-treated animals that were B1R-dependent. CONCLUSIONS: Kinin B1R contributes to acute gouty attacks, including the ones facilitated by ACEi. Therefore, B1R is a potential therapeutic target for the treatment and prophylaxis of gout, especially in patients taking ACEi.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Gota/metabolismo , Receptor de Bradiquinina B1/fisiología , Enfermedad Aguda , Animales , Antagonistas del Receptor de Bradiquinina B1/uso terapéutico , Dioxoles/uso terapéutico , Edema/inducido químicamente , Edema/metabolismo , Gota/inducido químicamente , Gota/tratamiento farmacológico , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Dolor/inducido químicamente , Dolor/metabolismo , Ratas Wistar , Sulfonamidas/uso terapéutico , Ácido ÚricoRESUMEN
The kallikrein-kinin and renin-angiotensin systems interact at multiple levels. In the present study, we tested the hypothesis that the B1 kinin receptor (B1R) contributes to vascular hypertrophy in angiotensin II (ANG II)-induced hypertension, through a mechanism involving reactive oxygen species (ROS) generation and extracellular signal-regulated kinase (ERK1/2) activation. Male Wistar rats were infused with vehicle (control rats), 400 ng/Kg/min ANG II (ANG II rats) or 400 ng/Kg/min ANG II plus B1 receptor antagonist, 350 ng/Kg/min des-Arg(9)-Leu(8)-bradykinin (ANGII+DAL rats), via osmotic mini-pumps (14 days) or received ANG II plus losartan (10 mg/Kg, 14 days, gavage - ANG II+LOS rats). After 14 days, ANG II rats exhibited increased systolic arterial pressure [(mmHg) 184 ± 5.9 vs 115 ± 2.3], aortic hypertrophy; increased ROS generation [2-hydroxyethidium/dihydroethidium (EOH/DHE): 21.8 ± 2.7 vs 6.0 ± 1.8] and ERK1/2 phosphorylation (% of control: 218.3 ± 29.4 vs 100 ± 0.25]. B1R expression was increased in aortas from ANG II and ANG II+DAL rats than in aortas from the ANG II+LOS and control groups. B1R antagonism reduced aorta hypertrophy, prevented ROS generation (EOH/DHE: 9.17 ± 3.1) and ERK1/2 phosphorylation (137 ± 20.7%) in ANG II rats. Cultured aortic vascular smooth muscle cells (VSMC) stimulated with low concentrations (0.1 nM) of ANG II plus B1R agonist exhibited increased ROS generation, ERK1/2 phosphorylation, proliferating-cell nuclear antigen expression and [H3]leucine incorporation. At this concentration, neither ANG II nor the B1R agonist produced any effects when tested individually. The ANG II/B1R agonist synergism was inhibited by losartan (AT1 blocker, 10 µM), B1R antagonist (10 µM) and Tiron (superoxide anion scavenger, 10 mM). These data suggest that B1R activation contributes to ANG II-induced aortic hypertrophy. This is associated with activation of redox-regulated ERK1/2 pathway that controls aortic smooth muscle cells growth. Our findings highlight an important cross-talk between the DABK and ANG II in the vascular system and contribute to a better understanding of the mechanisms involved in vascular remodeling in hypertension.
Asunto(s)
Hipertensión/patología , Sistema Calicreína-Quinina/fisiología , Sistema Renina-Angiotensina/fisiología , Angiotensina II/toxicidad , Animales , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Aorta/metabolismo , Aorta/patología , Presión Sanguínea/efectos de los fármacos , Antagonistas del Receptor de Bradiquinina B1/farmacología , Células Cultivadas , Sinergismo Farmacológico , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Hipertrofia/metabolismo , Sistema Calicreína-Quinina/efectos de los fármacos , Losartán/farmacología , Losartán/uso terapéutico , Masculino , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/metabolismo , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Receptor de Bradiquinina B1/agonistas , Receptor de Bradiquinina B1/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos , Superóxidos/metabolismoRESUMEN
Gliomas are the most common malignant brain tumors in adults. Bradykinin (BK) displays an important role in cancer, although the exact role of kinin receptors in the glioma biology remains unclear. This study investigated the role of kinin B1 and B2 receptors (B1R and B2R) on cell proliferation in human glioblastoma cell lineages. The mRNA expression of B1R and B2R was verified by RT-qPCR, whereas the effects of kinin agonists (des-Arg(9)-BK and BK) were analyzed by cell counting, MTT assay and annexin-V/PI determination. The PI3K/Akt and ERK1/2 signaling activation was assessed by flow cytometry. Our results demonstrated that both human glioblastoma cell lines U-138MG and U-251MG express functional B1R and B2R. The proliferative effects induced by the incubation of des-Arg(9)-BK and BK are likely related to the activation of PI3K/Akt and ERK 1/2 pathways. Moreover, the pre-incubation of the selective PI3Kγ blocker AS252424 markedly prevented kinin-induced AKT phosphorylation. Noteworthy, the selective B1R and B2R antagonists SSR240612 and HOE-140 were able to induce cell death of either lineages, with mixed apoptosis/necrosis characteristics. Taken together, the present results show that activation of B1R and B2R might contribute to glioblastoma progression in vitro. Furthermore, PI3K/Akt and ERK 1/2 signaling may be a target for adjuvant treatment of glioblastoma with a possible impact on tumor proliferation.
Asunto(s)
Proliferación Celular , Glioma/metabolismo , Glioma/patología , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor de Bradiquinina B1/metabolismo , Receptor de Bradiquinina B2/metabolismo , Apoptosis , Western Blotting , Bradiquinina/análogos & derivados , Bradiquinina/farmacología , Antagonistas del Receptor de Bradiquinina B1/farmacología , Antagonistas del Receptor de Bradiquinina B2/farmacología , Dioxoles/farmacología , Citometría de Flujo , Glioma/tratamiento farmacológico , Humanos , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/genética , Fosfatidilinositol 3-Quinasas/genética , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/genética , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor de Bradiquinina B1/química , Receptor de Bradiquinina B1/genética , Receptor de Bradiquinina B2/química , Receptor de Bradiquinina B2/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sulfonamidas/farmacología , Células Tumorales CultivadasRESUMEN
The biological and pharmacological effects of BK (bradykinin) are mediated by two receptors: the constitutive B2R (B2 receptor) and the inducible B1R (B1 receptor). BK plays a role in the hepatic microcirculation by inducing the PHR (portal hypertensive response) via B2R, whereas DABK (des-Arg9-BK), a B1R agonist, does not elicit the response. During IRI (ischaemia/reperfusion injury), important changes occur in the microcirculation, and cell death by necrosis and apoptosis is involved in poor graft function. The aim of the present study was to analyse the role of B1R and B2R in liver cell death induced by IRI. Livers from Wistar rats were submitted to ischaemia (4°C) for 4 or 24 h. After this period, livers were reperfused ex vivo with Krebs-Henseleit solution (37°C). BK or DABK was then injected as a bolus during reperfusion in the absence or presence of HOE-140 (a B2R antagonist) or DALBK (des-Arg(9)-Leu(8)-BK) (a B1R antagonist) respectively. Liver viability was analysed by glucose release and bile secretion. The PHR to kinins did not change. Cell death was higher in the DABK group and its antagonist significantly decreased cell death. Interestingly, the B1R antagonist did not alter the number of necrotic cells, but it decreased the number of apoptotic cells. On the other hand, the B2R antagonist decreased the number of necrotic cells, but did not alter the number of apoptotic cells. Therefore B1R may participate in apoptotic cell death signalling, and B2R may be involved in necrotic cell death.
Asunto(s)
Hígado/metabolismo , Receptor de Bradiquinina B1/metabolismo , Receptor de Bradiquinina B2/metabolismo , Daño por Reperfusión/metabolismo , Animales , Antagonistas del Receptor de Bradiquinina B1 , Antagonistas del Receptor de Bradiquinina B2 , Muerte Celular , Modelos Animales de Enfermedad , Masculino , Ratas , Ratas WistarRESUMEN
UNLABELLED: Cisplatin is a chemotherapeutic agent that causes severe renal dysfunction. The kinin B1 receptor has been associated with the migration of immune cells to injured tissue as well as with renal inflammation. To examine the role of the kinin B1 receptor in cisplatin-induced acute kidney injury, we used kinin B1 receptor knockout mice and treatment with a receptor antagonist before and after cisplatin administration. Cisplatin injection caused exacerbation of renal macrophage and neutrophil migration, higher levels of serum creatinine and blood urea, upregulation of B1 receptor mRNA and an increase in pro-inflammatory cytokines expression. B1 receptor knockout mice exhibited a reduction in serum creatinine and blood urea levels, diminished apoptosis, and decreased cisplatin-induced upregulation of inflammatory components. Moreover, treatment with the B1 receptor antagonist prior to cisplatin administration normalized serum creatinine, blood urea levels, protected from acute tubular necrosis, apoptosis-related genes, and prevented upregulation of pro-inflammatory cytokines. Thus, we propose that kinins have an important role in cisplatin-induced acute kidney injury by impairing immune cells migration to renal tissue during cisplatin nephrotoxicity. KEY MESSAGE: Kinin B1 receptor is upregulated after cisplatin exposure. Kinin B1 receptor deficiency diminishes the nephrotoxicity caused by cisplatin. Kinin B1 receptor deficiency ameliorates the inflammatory response. Kinin B1 receptor deficiency diminishes apoptosis caused by cisplatin. Kinin B1 receptor antagonism ameliorates renal function after cisplatin injection.
Asunto(s)
Lesión Renal Aguda/inmunología , Antineoplásicos/efectos adversos , Movimiento Celular , Cisplatino/efectos adversos , Receptor de Bradiquinina B1/genética , Lesión Renal Aguda/sangre , Lesión Renal Aguda/inducido químicamente , Animales , Apoptosis , Nitrógeno de la Urea Sanguínea , Bradiquinina/análogos & derivados , Bradiquinina/farmacología , Antagonistas del Receptor de Bradiquinina B1/farmacología , Proliferación Celular , Creatinina/sangre , Citocinas/genética , Citocinas/metabolismo , Riñón/efectos de los fármacos , Riñón/inmunología , Riñón/patología , Macrófagos/inmunología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Receptor de Bradiquinina B1/metabolismoRESUMEN
RATIONALE: There are evidences indicating the role of kinins in pathophysiology of traumatic brain injury, but little is known about their action on memory deficits. OBJECTIVES: Our aim was to establish the role of bradykinin receptors B1 (B1R) and B2 (B2R) on the behavioral, biochemical, and histologic features elicited by moderate lateral fluid percussion injury (mLFPI) in mice. METHODS: The role of kinin B1 and B2 receptors in brain damage, neuromotor, and cognitive deficits induced by mLFPI, was evaluated by means of subcutaneous injection of B2R antagonist (HOE-140; 1 or 10 nmol/kg) or B1R antagonist (des-Arg9-[Leu8]-bradykinin (DAL-Bk; 1 or 10 nmol/kg) 30 min and 24 h after brain injury. Brain damage was evaluated in the cortex, being considered as lesion volume, inflammatory, and oxidative damage. The open field and elevated plus maze tests were performed to exclude the nonspecific effects on object recognition memory test. RESULTS: Our data revealed that HOE-140 (10 nmol/kg) protected against memory impairment. This treatment attenuated the brain edema, interleukin-1ß, tumor necrosis factor-α, and nitric oxide metabolites content elicited by mLFPI. Accordingly, HOE-140 administration protected against the increase of nicotinamide adenine dinucleotide phosphate oxidase activity, thiobarbituric-acid-reactive species, protein carbonylation generation, and Na⺠K⺠ATPase inhibition induced by trauma. Histologic analysis showed that HOE-140 reduced lesion volume when analyzed 7 days after brain injury. CONCLUSIONS: This study suggests the involvement of the B2 receptor in memory deficits and brain damage caused by mLFPI in mice.
Asunto(s)
Bradiquinina/análogos & derivados , Lesiones Encefálicas/complicaciones , Lesiones Encefálicas/tratamiento farmacológico , Trastornos de la Memoria/etiología , Trastornos de la Memoria/prevención & control , Fármacos Neuroprotectores/farmacología , Animales , Bradiquinina/metabolismo , Bradiquinina/farmacología , Antagonistas del Receptor de Bradiquinina B1/farmacología , Antagonistas del Receptor de Bradiquinina B2/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Edema Encefálico/etiología , Edema Encefálico/metabolismo , Edema Encefálico/patología , Edema Encefálico/prevención & control , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/patología , Modelos Animales de Enfermedad , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/patología , Ratones , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , NADPH Oxidasas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Reconocimiento en Psicología/efectos de los fármacos , Reconocimiento en Psicología/fisiología , Factores de TiempoRESUMEN
Kinins are generated within inflammatory tissue microenvironments, where they exert diverse functions, including cell proliferation, leukocyte activation, cell migration, endothelial cell activation and nociception. These pleiotropic functions depend on signaling through two cross talking receptors, the constitutively expressed kinin receptor 2 (B2R) and the inducible kinin receptor 1 (B1R). We have reviewed evidence, which supports the concept that kinin receptors, especially kinin receptor 1, are promising targets for cancer therapy, since (1) many tumor cells express aberrantly high levels of these receptors; (2) some cancers produce kinins and use them as autocrine factors to stimulate their growth; (3) activation of kinin receptors leads to activation of macrophages, dendritic cells and other cells from the tumor microenvironment; (4) kinins have pro-angiogenic properties; (5) kinin receptors have been implicated in cancer migration, invasion and metastasis; and (6) selective antagonists for either B1R or B2R have shown anti-proliferative, anti-inflammatory, anti-angiogenic and anti-migratory properties. The multiple cross talks between kinin receptors and renin-angiotensin system (RAS) as well as its implications for targeting KKS or RAS for the treatment of malignancies are also discussed. It is expected that B1R antagonists would interfere less with housekeeping functions and therefore would be attractive compounds to treat selected types of cancer. Reliable clinical studies are needed to establish the translatability of these data to human settings and the usefulness of kinin receptor antagonists.
Asunto(s)
Antagonistas del Receptor de Bradiquinina B1 , Antagonistas del Receptor de Bradiquinina B2 , Neoplasias/tratamiento farmacológico , Receptor de Bradiquinina B1/metabolismo , Receptor de Bradiquinina B2/metabolismo , Animales , Humanos , Terapia Molecular Dirigida , Transducción de SeñalRESUMEN
Diabetic peripheral neuropathy is one the most common complications of diabetes mellitus and frequently results in clinically significant morbidities such as pain, foot ulcers and amputations. The diabetic condition progresses from early functional changes to late, poorly reversible structural changes. The chronic hyperglycemia measured alongside diabetes development is associated with significant damage and failure of various organs. In the present study diabetes was induced in male Wistar rats by a single dose of streptozotocin (STZ) and the association between the BKB1-R and the oxidative stress and Na+-K+ ATPase activity in nervous tissues was analysed. The results showed that the resulting hyperglycemia induced a reduction of the neuronal electrical function integrity and increased oxidative stress in the sciatic nerve homogenates of 30 days diabetic rats. Malondialdehyde (MDA) used as a marker of oxidative stress was elevated whereas Biological Antioxidant Potential (BAP), glutathion (GSH) levels and superoxide dismutase (SOD) activity were decreased. Treatment of the rats 3 days before the end of the 4 week period with the BKB1 antagonist R-954 restored the neuronal activity and significantly attenuated the oxidative stress as shown by the level of the various markers returning close to levels found in control rats. Our results suggest that the BKB1-R subtype is overexpressed in sciatic nerve during the STZ-induced diabetes development as evidenced by inhibitory effects of the BKB1-R antagonist R-954. The beneficial role of BKB1-R antagonist R-954 for the treatment of diabetic neuropathy is also suggested.
Asunto(s)
Antagonistas del Receptor de Bradiquinina B1 , Bradiquinina/análogos & derivados , Diabetes Mellitus Experimental/complicaciones , Neuropatías Diabéticas/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Nervio Ciático/enzimología , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Animales , Bradiquinina/farmacología , Neuropatías Diabéticas/enzimología , Neuropatías Diabéticas/etiología , Glutatión Reductasa/metabolismo , Masculino , Malondialdehído/metabolismo , Sistema Nervioso Periférico/efectos de los fármacos , Sistema Nervioso Periférico/enzimología , Ratas , Ratas Wistar , Nervio Ciático/efectos de los fármacos , Superóxido Dismutasa/metabolismoRESUMEN
Bradykinin (BK) and des-Arg(9)-bradykinin (DBK) of kallikrein-kinin system exert its effects mediated by the B2 (B2R) and B1 (B1R) receptors, respectively. It was already shown that the deletion of kinin B1R or of B2R induces upregulation of the remaining receptor subtype. However studies on overexpression of B1R or B2R in transgenic animals have supported the importance of the overexpressed receptor but the expression of another receptor subtype has not been determined. Previous study described a marked vasodilatation and increased susceptibility to endotoxic shock which was associated with increased mortality in response to DBK in thoracic aorta from transgenic rat overexpressing the kinin B1R (TGR(Tie2B1)) exclusively in the endothelium. In another study, mice overexpressing B1R in multiple tissues were shown to present high susceptibility to inflammation and to lipopolysaccharide-induced endotoxic shock. Therefore the role of B2R was investigated in the thoracic aorta isolated from TGR(Tie2B1) rats overexpressing the B1R exclusively in the vascular endothelium. Our findings provided evidence for highly increased expression level of the B2R in the transgenic rats. It was reported that under endotoxic shock, these rats exhibited exaggerated hypotension, bradycardia and mortality. It can be suggested that the high mortality during the pathogenesis of endotoxic shock provoked in the transgenic TGR(Tie2B1) rats could be due to the enhanced expression of B2R associated with the overexpression of the B1R.
Asunto(s)
Endotelio Vascular/fisiología , Receptor de Bradiquinina B1/metabolismo , Receptor de Bradiquinina B2/metabolismo , Acetilcolinesterasa/análisis , Acetilcolinesterasa/metabolismo , Angiotensina II/farmacología , Animales , Aorta/efectos de los fármacos , Bradiquinina/análogos & derivados , Bradiquinina/farmacología , Antagonistas del Receptor de Bradiquinina B1 , Regulación de la Expresión Génica , Técnicas In Vitro , Indometacina/farmacología , NG-Nitroarginina Metil Éster/farmacología , Ratas , Ratas Sprague-Dawley , Ratas Transgénicas , Receptor de Angiotensina Tipo 1/metabolismo , Receptor de Bradiquinina B1/genética , Receptor de Bradiquinina B2/genética , Regulación hacia Arriba , Vasodilatación/efectos de los fármacosRESUMEN
BACKGROUND AND PURPOSE: Kinins are pro-inflammatory peptides that are released during tissue injury, including that caused by inflammatory bowel disease. Herein, we assessed the role and underlying mechanisms through which the absence of kinin B(1) receptors exacerbates the development of dextran sulfate sodium (DSS)-induced colitis in mice. EXPERIMENTAL APPROACH: B(1) and B(2) receptor antagonists and B(1) receptor knockout mice (B1(-/-) ) were used to assess the involvement of B(1) and B(2) receptor signalling in a DSS-colitis. B(1) receptor, B(2) receptor, occludin and claudin-4 expression, cytokine levels and cell permeability were evaluated in colon from wild-type (WT) and B1(-/-) mice. KEY RESULTS: DSS-induced colitis was significantly exacerbated in B1(-/-) compared with WT mice. IL-1ß, IFN-γ, keratinocyte-derived chemokine and macrophage inflammatory protein-2 were markedly increased in the colon from DSS-treated B1(-/-) compared with DSS-treated WT mice. Treatment of WT mice with a selective B(1) receptor antagonist, DALBK or SSR240612, had no effect on DSS-induced colitis. Of note, B(2) receptor mRNA expression was significantly up-regulated in colonic tissue from the B1(-/-) mice after DSS administration. Moreover, treatment with a selective B(2) receptor antagonist prevented the exacerbation of colitis in B1(-/-) mice following DSS administration. The water- or DSS-treated B1(-/-) mice showed a decrease in occludin gene expression, which was partially prevented by the B(2) receptor antagonist. CONCLUSIONS AND IMPLICATIONS: A loss of B(1) receptors markedly exacerbates the severity of DSS-induced colitis in mice. The increased susceptibility of B1(-/-) may be associated with compensatory overexpression of B(2) receptors, which, in turn, modulates tight junction expression.
Asunto(s)
Colitis/metabolismo , Receptor de Bradiquinina B1/metabolismo , Receptor de Bradiquinina B2/metabolismo , Animales , Bradiquinina/análogos & derivados , Bradiquinina/farmacología , Antagonistas del Receptor de Bradiquinina B1 , Antagonistas del Receptor de Bradiquinina B2 , Colitis/inducido químicamente , Colitis/patología , Citocinas/metabolismo , Sulfato de Dextran , Dioxoles/farmacología , Homeostasis , Mucosa Intestinal/metabolismo , Intestinos/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Peroxidasa/metabolismo , Receptor de Bradiquinina B1/genética , Sulfonamidas/farmacología , Uniones Estrechas/metabolismo , Regulación hacia ArribaRESUMEN
Kinins and their receptors have been recently implicated in cancer. Using functional and molecular approaches, we investigated the relevance of kinin B1 and B2 receptors in bladder cancer. Functional studies were conducted using bladder cancer cell lines, and human biopsies were employed for molecular studies. Both B1 des-Arg(9)-BK and B2 BK receptor agonists stimulated the proliferation of grade 3-derived T24 bladder cancer cells. Furthermore, treatment with B1 and B2 receptor antagonists (SSR240612 and HOE140) markedly inhibited the proliferation of T24 cells. Only higher concentrations of BK increased the proliferation of the grade 1 bladder cancer cell line RT4, while des-Arg(9)-BK completely failed to induce its proliferation. Real-time PCR revealed that the mRNA expression of kinin receptors, particularly B1 receptors, was increased in T24 cells relative to RT4 cells. Data from bladder cancer human biopsies revealed that B1 receptor expression was increased in all tumor samples and under conditions of chronic inflammation. We also show novel evidence demonstrating that the pharmacological inhibition of PI3Kγ (phosphatidylinositol 3-kinase) with AS252424, concentration-dependently reduced T24 cell proliferation induced by BK or des-Arg(9)-BK. Finally, the incubation of T24 cells with kinin agonists led to a marked activation of the PI3K/AKT and ERK 1/2 signaling pathways, whereas p38 MAP kinase remained unaffected. Kinin receptors, especially B1 receptors, appear to be implicated in bladder cancer progression. It is tempting to suggest that selective kinin antagonists might represent potential alternative therapies for bladder cancer.
Asunto(s)
Fosfatidilinositol 3-Quinasas/metabolismo , Receptor de Bradiquinina B1/metabolismo , Receptor de Bradiquinina B2/metabolismo , Neoplasias de la Vejiga Urinaria/enzimología , Anciano , Anciano de 80 o más Años , Biopsia , Antagonistas del Receptor de Bradiquinina B1 , Antagonistas del Receptor de Bradiquinina B2 , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Sistema de Señalización de MAP Quinasas , Persona de Mediana Edad , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor de Bradiquinina B1/agonistas , Receptor de Bradiquinina B1/genética , Receptor de Bradiquinina B2/agonistas , Receptor de Bradiquinina B2/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Tiazolidinedionas/farmacología , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/enzimología , Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
BACKGROUND AND PURPOSE: Kinin B(1) and B(2) receptors have been implicated in physiological and pathological conditions of the urinary bladder. However, their role in overactive urinary bladder (OAB) syndrome following spinal cord injury (SCI) remains elusive. EXPERIMENTAL APPROACH: We investigated the role of kinin B(1) and B(2) receptors in OAB after SCI in rats. KEY RESULTS: SCI was associated with a marked inflammatory response and functional changes in the urinary bladder. SCI resulted in an up-regulation of B(1) receptor mRNA in the urinary bladder, dorsal root ganglion and spinal cord, as well as in B(1) protein in the urinary bladder and B(1) and B(2) receptor protein in spinal cord. Interestingly, both B(1) and B(2) protein expression were similarly distributed in detrusor muscle and urothelium of animals with SCI. In vitro stimulation of urinary bladder with the selective B(1) or B(2) agonist elicited a higher concentration-response curve in the SCI urinary bladder than in naive or sham urinary bladders. Cystometry revealed that treatment of SCI animals with the B(2) selective antagonist icatibant reduced the amplitude and number of non-voiding contractions (NVCs). The B(1) antagonist des-Arg(9) -[Leu(8) ]-bradykinin reduced the number of NVCs while the non-peptide B(1) antagonist SSR240612 reduced the number of NVCs, the urinary bladder capacity and increased the voiding efficiency and voided volume. CONCLUSIONS AND IMPLICATIONS: Taken together, these data show the important roles of B(1) and B(2) receptors in OAB following SCI in rats and suggest that blockade of these receptors could be a potential therapeutic target for controlling OAB.
Asunto(s)
Receptor de Bradiquinina B1/fisiología , Receptor de Bradiquinina B2/fisiología , Traumatismos de la Médula Espinal/fisiopatología , Vejiga Urinaria Hiperactiva/fisiopatología , Animales , Antagonistas del Receptor de Bradiquinina B1 , Antagonistas del Receptor de Bradiquinina B2 , Ganglios Espinales/fisiología , Masculino , Contracción Muscular , Ratas , Ratas Wistar , Receptor de Bradiquinina B1/agonistas , Receptor de Bradiquinina B2/agonistas , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/metabolismo , Vejiga Urinaria/fisiología , Vejiga Urinaria Hiperactiva/etiología , Vejiga Urinaria Hiperactiva/metabolismoRESUMEN
The chronic hyperglycemia measured alongside diabetes development is associated with significant long-term damage and failure of various organs. In the present study it was shown that hyperglycemia induced early and long term increases in nitric oxide (NO) levels, kallikrein activity and vascular capillary permeability measured as plasma extravasation, and decreases of Na/K ATPase activity in diabetic rat retina 4 and 12 weeks after streptozotocin (STZ) injection. Treatment of the animals for 5 consecutive days with a novel selective bradykinin B(1) receptor (BKB(1)-R) antagonist R-954 (2mg/kg s.c) at the end of the 4 and 12 week periods highly reduced NO, kallikrein and capillary permeability and increased Na/K ATPase activity in the retina. These results suggest that the BKB(1)-R receptor subtype is over-expressed during the streptozotocin-induced development of diabetes in rat retina as evidenced by the inhibitory effects of the BKB(1)-R antagonist R-954 on NO, kallikrein and vascular permeability increases as well as Na/K ATPase decreases. The beneficial role of the BKB(1)-R antagonist R-954 for the treatment of the diabetic retinopathy is also suggested.
Asunto(s)
Antagonistas del Receptor de Bradiquinina B1 , Bradiquinina/análogos & derivados , Diabetes Mellitus Experimental/tratamiento farmacológico , Retinopatía Diabética/tratamiento farmacológico , Hiperglucemia/tratamiento farmacológico , Retina/efectos de los fármacos , Animales , Bradiquinina/administración & dosificación , Bradiquinina/uso terapéutico , Permeabilidad Capilar/efectos de los fármacos , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Retinopatía Diabética/complicaciones , Retinopatía Diabética/metabolismo , Expresión Génica/efectos de los fármacos , Hiperglucemia/complicaciones , Hiperglucemia/metabolismo , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/uso terapéutico , Inyecciones Subcutáneas , Calicreínas/antagonistas & inhibidores , Calicreínas/metabolismo , Masculino , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Ratas , Ratas Wistar , Receptor de Bradiquinina B1/genética , Receptor de Bradiquinina B1/metabolismo , Retina/metabolismo , Retina/patología , ATPasa Intercambiadora de Sodio-Potasio/metabolismoRESUMEN
BACKGROUND AND PURPOSE: B(1) and B(2) kinin receptors are involved in pain transmission but they may have different roles in the muscle pain induced by intense exercise or inflammation. We investigated the contribution of each of these receptors, and the intracellular pathways involved, in the initial development and maintenance of the muscle pain associated with inflammation-induced tissue damage. EXPERIMENTAL APPROACH: Mechanical hyperalgesia was measured using the Randall-Selitto apparatus after injecting 5% formalin solution into the gastrocnemius muscle in mice treated with selective antagonists for B(1) or B(2) receptors. The expression of kinin receptors and cytokines and the activation of intracellular kinases were monitored by real-time PCR and immunohistochemistry. KEY RESULTS: The i.m. injection of formalin induced an overexpression of B(1) and B(2) receptors. This overexpression was associated with the mechanical hyperalgesia induced by formalin because treatment with B(1) receptor antagonists (des-Arg(9) [Leu(8)]-BK, DALBK, and SSR240612) or B(2) receptor antagonists (HOE 140 and FR173657) prevented the hyperalgesia. Formalin increased myeloperoxidase activity, and up-regulated TNF-α, IL-1ß and IL-6 in gastrocnemius. Myeloperoxidase activity and TNF-α mRNA expression were inhibited by either DALBK or HOE 140, whereas IL-6 was inhibited only by HOE 140. The hyperalgesia induced by i.m. formalin was dependent on the activation of intracellular MAPKs p38, JNK and PKC. CONCLUSIONS AND IMPLICATIONS: Inflammatory muscle pain involves a cascade of events that is dependent on the activation of PKC, p38 and JNK, and the synthesis of IL-1ß, TNF-α and IL-6 associated with the up-regulation of both B(1) and B(2) kinin receptors.
Asunto(s)
Expresión Génica , Hiperalgesia/metabolismo , Sistema de Señalización de MAP Quinasas , Miositis/metabolismo , Receptor de Bradiquinina B1/genética , Receptor de Bradiquinina B2/genética , Animales , Antagonistas del Receptor de Bradiquinina B1 , Antagonistas del Receptor de Bradiquinina B2 , Citocinas/biosíntesis , Inhibidores Enzimáticos/farmacología , Formaldehído/farmacología , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/enzimología , Masculino , Ratones , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/enzimología , Músculo Esquelético/inmunología , Músculo Esquelético/metabolismo , Miositis/tratamiento farmacológico , Miositis/enzimología , Miositis/inmunología , Oligopéptidos/farmacología , Dimensión del Dolor , Reacción en Cadena en Tiempo Real de la Polimerasa , Regulación hacia ArribaRESUMEN
The present study investigated the effects of a new bradykinin B(1) receptor antagonist, R-954, on the development of Ehrlich ascitic tumor (EAT) induced by the intraperitoneal inoculation of EAT cells in mice and the formation of a solid tumor by the subcutaneous injection of the cells in rat paw. The development of the tumor was associated with an increase in mouse total cell counts in bone marrow (10.8-fold), ascitic fluid (14.6-fold), and blood (12.6-fold). R-954 (2mg/kg, s.c.) significantly reduced the ascitic fluid volume (63.7%) and the mouse weight gain (30.5%) after 10 consecutive days of treatment. The B(1) antagonist as well as the anti-neoplasic drug vincristine also significantly inhibited the increase in total cell count in bone marrow, ascitic fluid, and blood. R-954 reduced significantly the total protein extravasation (57.3%), the production of nitric oxide (56%), PGE(2) production (82%), and TNFα release (85.7%) in mice peritoneal cavity whereas vincristine reduced the release of these inflammatory mediators by 84-94%. The increase in paw edema after intraplantar injection of EAT cells was reduced by approximately 52% by either R-954 or vincristine treatment. In conclusion, this study presents for the first time the antitumoral activity of a new bradykinin B(1) receptor antagonist on ascitic and solid tumors induced by Ehrlich cell inoculation in mice and rats.