RESUMO
Nociceptin/orphanin FQ (N/OFQ) and its receptor, nociceptin opioid peptide (NOP) receptor, are localized in brain areas implicated in depression including the amygdala, bed nucleus of the stria terminalis, habenula, and monoaminergic nuclei in the brain stem. N/OFQ inhibits neuronal excitability of monoaminergic neurons and monoamine release from their terminals by activation of G protein-coupled inwardly rectifying K⁺ channels and inhibition of voltage sensitive calcium channels, respectively. Therefore, NOP receptor antagonists have been proposed as a potential antidepressant. Indeed, mounting evidence shows that NOP receptor antagonists have antidepressant-like effects in various preclinical animal models of depression, and recent clinical studies again confirmed the idea that blockade of NOP receptor signaling could provide a novel strategy for the treatment of depression. In this review, we describe the pharmacological effects of N/OFQ in relation to depression and explore the possible mechanism of NOP receptor antagonists as potential antidepressants.
Assuntos
Tonsila do Cerebelo , Antidepressivos , Encéfalo , Tronco Encefálico , Canais de Cálcio , Depressão , Habenula , Modelos Animais , Neurônios , Neuropeptídeos , Peptídeos Opioides , Receptores de Droga , Núcleos SeptaisRESUMO
Objective To understand the experiences and expectations of nurses in the treatment of women with chronic venous ulcers. Method Phenomenological research was based on Alfred Schütz, whose statements were obtained in January, 2012, through semi-structured interviews with seven nurses. Results The nurse reveals the difficulties presented by the woman in performing self-care, the perceived limitations in the treatment anchored in motivation, and the values and beliefs of women. It showed professional frustration because venous leg ulcer recurrence, lack of inputs, interdisciplinary work and training of nursing staff. There was an expected adherence to the treatment of women, and it emphasized the need for ongoing care, supported self-care and standard practices in treatment. Conclusion That treatment of chronic venous leg ulcers constitutes a challenge that requires collective investment, involving women, professionals, managers and health institutions. .
Objetivo Comprender las experiencias y expectativas de enfermeras en el tratamiento de mujeres con úlcera venosa crónica. Método Investigación fenomenológica fundamentada en Alfred Schutz, que buscó Se realizó entrevista semiestructurada con siete enfermeras, en enero del 2012. Resultados La enfermera revela dificultades presentadas por la mujer para realizar el autocuidado, percibe limitaciones en el tratamiento relacionadas con la desmotivación, los valores y las creencias de las mujeres. Refiere frustración profesional debido a la recidiva de la lesión, a la falta de insumos, al deficiente trabajo interdisciplinar y a la limitada capacitación del equipo de enfermeras. Espera la adhesión de la mujer al tratamiento y resalta la necesidad del cuidado continuo, del autocuidado apoyado y de estandarizar conductas de tratamiento. Conclusión El tratamiento de la úlcera venosa crónica es un desafío que requiere contribución colectiva, involucrando a las mujeres, a los profesionales, a los gestores y a las instituciones de salud. .
Objetivo Compreender as experiências e expectativas de enfermeiras no tratamento de mulheres com úlcera venosa crônica na Atenção Primária à Saúde. Método Pesquisa fundamentada na fenomenologia social de Alfred Schütz, com depoimentos obtidos em janeiro de 2012, por meio de entrevista semiestruturada com sete enfermeiras. Resultados As enfermeiras revelam dificuldades apresentadas pelas mulheres com úlcera venosa crônica para realizar o autocuidado, percebem limitações na terapêutica ancoradas na desmotivação e nos valores e crenças das mulheres. Referem frustração profissional em razão da recidiva da lesão, falta de insumos e tecnologia, de trabalho interdisciplinar e da capacitação da equipe de enfermagem. Esperam a adesão das mulheres ao tratamento e ressaltam a necessidade do cuidado contínuo, do autocuidado apoiado e da padronização de condutas no tratamento. Conclusão O tratamento da úlcera venosa crônica constitui-se em um desafio que requer investimento coletivo, envolvendo a mulher, os profissionais, os gestores e as instituições de saúde. .
Assuntos
Animais , Proteínas de Caenorhabditis elegans/isolamento & purificação , Caenorhabditis elegans/metabolismo , Membrana Celular/metabolismo , Canais Iônicos/isolamento & purificação , Canais Iônicos/metabolismo , Proteínas do Tecido Nervoso/isolamento & purificação , Proteínas do Tecido Nervoso/metabolismo , Sistema Nervoso/metabolismo , Neurônios Aferentes/metabolismo , Sensação/genética , Sequência de Aminoácidos/genética , Sequência de Bases/genética , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/citologia , Capsaicina/farmacologia , Compartimento Celular/genética , Membrana Celular/efeitos dos fármacos , Membrana Celular/ultraestrutura , Regulação da Expressão Gênica/fisiologia , Canais Iônicos/genética , Canais Iônicos/ultraestrutura , Dados de Sequência Molecular , Mutação/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/ultraestrutura , Sistema Nervoso/citologia , Sistema Nervoso/efeitos dos fármacos , Neurônios Aferentes/citologia , Neurônios Aferentes/efeitos dos fármacos , Dor/genética , Dor/metabolismo , Dor/fisiopatologia , Filogenia , Receptores de Droga/efeitos dos fármacos , Receptores de Droga/metabolismo , Receptores de Droga/ultraestrutura , Sensação/efeitos dos fármacos , Transdução de Sinais/genética , Canais de Cátion TRPV , Canais de Potencial de Receptor TransitórioRESUMO
No obstante los adelantos en el conocimiento y tratamiento del dolor agudo y del dolor crónico, esta entidad continúa siendo un azote para la humanidad. Se ha considerado que más de 1500,000000,000 de seres humanos sufren de dolor crónicomoderado a severo, lo que significa un elevado costo económico y de salud, aun en los países más desarrollados. Por siglos la humanidad ha utilizado remedios para aliviar este sufrimiento y aunque el uso de opioides y de analgésicos antiinflamatoriosno esteroideos transformó el manejo racional del dolor, sus efectos secundarios son una restricción que limita su uso y eficacia terapéutica. El conocimiento de novedosos nociceptores y de sus ligandos revolucionó el conocimiento del dolor, facilitando tanto su prevención como su tratamiento. El uso de fármacos con acción analgésica en diversos receptores específicos de las múltiples y complejas vías dolorosas se fundamenta en el conocimiento de los mecanismos de interacción molecular involucrados en diversos nociceptores como por ejemplo los canales de sodio y potasio, los receptores purinérgicos, los receptores NMDA, los receptorescannabinoides, entre otros muchos. El redescubrimiento de las características analgésicas de antiguos fármacos y el desarrollo de nuevas moléculas con efectos antinociceptivos específicos ha revolucionado el manejo del dolor, creando el concepto de analgesiadirigida al órgano blanco (at-site pain targets). En esta breve revisión se discuten algunos de los mecanismos de acción analgésica de antiguos y de nuevos medicamentos que podemos utilizar en las personas con dolor agudo postoperatorio, con dolor crónicono oncológico y en dolor secundario al cáncer.
Despite major advances in the understanding and treatment of acute and chronic pain, this entity continues to be a plague to mankind. It was considered that more than 1500,000000,000 human beings suffer from moderate to severe chronic pain, which means a high health and economic costs, even in the most developed countries. For centuries mankind has used remedies to relieve pain suffering and although the use of opioids and nonsteroidal anti-inflamma tory drugs revolutionized the management of pain, their side effects are a restriction limiting its use and therapeutic efficacy. The knowledge of novel nociceptors and their ligands revolutionized our understanding of pain, facilitating its prevention and treatment. The proper use of analgesic and co-adyuvant drugs with selective actions on specific receptors of the multiple and complex pain pathways is based on the understanding of the pain mechanisms involved in molecular interaction on nociceptor receptors such as sodium and potassium membrane channels, purinergic, NMDA, and cannabinoid receptors, among many others. The rediscovery of the ancient analgesic properties of drugs and development of new molecules with specific antinociceptive effects has revolutionized pain management, creating the concept of analgesia addressed to the target organ (at-site pain targets). In this brief review we discuss some of the mechanisms of analgesic action of old and new drugs that can be used in people with acute postoperative pain, chronic noncancer pain and pain secondary to cancer.
Assuntos
Adjuvantes Anestésicos , Analgesia , Analgésicos/uso terapêutico , Receptores de DrogaRESUMO
Pharmacological activity and druggability are two pivotal factors in drug innovation, which are respectively determined by the microscopic structure and macroscopic property of a molecule. Since structural optimization consists in a molecular operation in the space with multi-dimensions, and there exists a body of uncertainties for transduction from in vitro activity into in vivo pharmacological response. It is necessary for early stage in lead optimization to evaluate compound quality or efficiency using a kind of metrics containing multi-parameters. On the basis of the describing parameters of activity and druggability, this overview deals with the roles of thermodynamic signatures and binding kinetics of drug-receptor interactions in optimizing quality of compounds, signifying the significance in optimization of microscopic structures for drug discovery.
Assuntos
Desenho de Fármacos , Descoberta de Drogas , Métodos , Ligantes , Estrutura Molecular , Preparações Farmacêuticas , Química , Farmacocinética , Farmacologia , Ligação Proteica , Receptores de Droga , Química , Relação Estrutura-Atividade , TermodinâmicaRESUMO
Neonatal diabetes mellitus (DM) is defined as insulin-requiring DM in the first six months of life. Unlike type 1 DM, it is a monogenic disorder resulting from a de novo mutation in the genes involved in the development of the pancreas, β-cell mass or secretory function. The majority of neonatal DM cases are caused by a heterozygous activating mutation in the KCNJ11 or ABCC8 genes that encode the Kir6.2 and SUR1 protein subunits, respectively, in the KATP channel. Sulphonylurea, a KATP channel inhibitor, can restore insulin secretion, hence offering an attractive alternative to insulin therapy. We report three cases of neonatal DM and their genetic mutations. Two patients were successfully switched over to sulphonylurea monotherapy with resultant improvement in the quality of life and a more stable blood glucose profile. Patients with neonatal DM should undergo genetic evaluation. For patients with KCNJ11 and ABCC8 gene mutation, oral sulphonylurea should be considered.
Assuntos
Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Transportadores de Cassetes de Ligação de ATP , Genética , Glicemia , Metabolismo , Diabetes Mellitus , Genética , Terapêutica , Genótipo , Heterozigoto , Modelos Biológicos , Modelos Genéticos , Biologia Molecular , Mutação , Pâncreas , Fisiologia , Canais de Potássio Corretores do Fluxo de Internalização , Genética , Qualidade de Vida , Receptores de Droga , Genética , Compostos de Sulfonilureia , Usos Terapêuticos , Receptores de SulfonilureiasRESUMO
ATP-sensitive potassium (K(ATP)) channels are widely distributed in vasculatures, and play an important role in the vascular tone regulation. The K(ATP) channels consist of 4 pore-forming inward rectifier K(+) channel (Kir) subunits and 4 regulatory sulfonylurea receptors (SUR). The major vascular isoform of K(ATP) channels is composed of Kir6.1/SUR2B, although low levels of other subunits are also present in vascular beds. The observation from transgenic mice and humans carrying Kir6.1/SUR2B channel mutations strongly supports that normal activity of the Kir6.1/SUR2B channel is critical for cardiovascular function. The Kir6.1/SUR2B channel is regulated by intracellular ATP and ADP. The channel is a common target of several vasodilators and vasoconstrictors. Endogenous vasopressors such as arginine vasopressin and α-adrenoceptor agonists stimulate protein kinase C (PKC) and inhibit the K(ATP) channels, while vasodilators such as β-adrenoceptor agonists and vasoactive intestinal polypeptide increase K(ATP) channel activity by activating the adenylate cyclase-cAMP-protein kinase A (PKA) pathway. PKC phosphorylates a cluster of 4 serine residues at C-terminus of Kir6.1, whereas PKA acts on Ser1387 in the nucleotide binding domain 2 of SUR2B. The Kir6.1/SUR2B channel is also inhibited by oxidants including reactive oxygen species allowing vascular regulation in oxidative stress. The molecular basis underlying such a channel inhibition is likely to be mediated by S-glutathionylation at a few cysteine residues, especially Cys176, in Kir6.1. Furthermore, the channel activity is augmented in endotoxemia or septic shock, as a result of the upregulation of Kir6.1/SUR2B expression. Activation of the nuclear factor-κB dependent transcriptional mechanism contributes to the Kir6.1/SUR2B channel upregulation by lipopolysaccharides and perhaps other toll-like receptor ligands as well. In this review, we summarize the vascular K(ATP) channel regulation under physiological and pathophysiological conditions, and discuss the importance of K(ATP) channel as a potentially useful target in the treatment and prevention of cardiovascular diseases.
Assuntos
Animais , Humanos , Camundongos , Transportadores de Cassetes de Ligação de ATP , Genética , Fisiologia , Endotoxemia , Metabolismo , Canais KATP , Genética , Fisiologia , Camundongos Transgênicos , Músculo Liso Vascular , Metabolismo , Fisiologia , Canais de Potássio Corretores do Fluxo de Internalização , Genética , Fisiologia , Receptores de Droga , Genética , Fisiologia , Choque Séptico , Metabolismo , Receptores de Sulfonilureias , Vasoconstrição , Fisiologia , Vasodilatação , Fisiologia , Sistema Vasomotor , FisiologiaRESUMO
Gitelman's syndrome is an autosomal recessive disorder characterized by hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalciuria that has recently been reported to be linked to thiazide-sensitive Na-Cl cotransporter gene mutation. We have experienced one patient whose initial complaint was paresthesia of hand and feet, who had hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalciuria. We report the case of Gitelman's syndrome with a brief review of related literature.
Assuntos
Humanos , Alcalose , Pé , Síndrome de Gitelman , Mãos , Hipopotassemia , Parestesia , Receptores de Droga , Simportadores de Cloreto de SódioRESUMO
Transient neonatal diabetes mellitus (TNDM) is a rare form of diabetes mellitus that presents within the first 6 months of life with remission in infancy or early childhood. TNDM is mainly caused by anomalies in the imprinted region on chromosome 6q24; however, recently, mutations in the ABCC8 gene, which encodes sulfonylurea receptor 1 (SUR1), have also been implicated in TNDM. Herein, we present the case of a male child with TNDM whose mutational analysis revealed a heterozygous c.3547C>T substitution in the ABCC8 gene, leading to an Arg1183Trp mutation in the SUR1 protein. The parents were clinically unaffected and did not show a mutation in the ABCC8 gene. This is the first case of a de novo ABCC8 gene mutation in a Korean patient with TNDM. The patient was initially treated with insulin and successfully switched to sulfonylurea therapy at 14 months of age. Remission of diabetes had occurred at the age of 16 months. Currently, the patient is 21 months old and is euglycemic without any insulin or oral hypoglycemic agents. His growth and physical development are normal, and there are no delays in achieving neurological and developmental milestones.
Assuntos
Criança , Humanos , Lactente , Masculino , Transportadores de Cassetes de Ligação de ATP , Diabetes Mellitus , Hipoglicemiantes , Insulina , Pais , Canais de Potássio Corretores do Fluxo de Internalização , Receptores de DrogaRESUMO
<p><b>BACKGROUND</b>Type 2 diabetes mellitus (T2DM) results from the complex association of insulin resistance and pancreatic β-cell failure. Recent studies have shown that patients diagnosed with T2DM present with a significant decrease in β-cell function, which can be further compromised during the progression of the disease. Several mechanisms have been shown to play a role in this process such as glucotoxicity and lipotoxicity, which contribute to accelerating insulin secretion. In this regard, Chinese medicine has a certain advantage. This experiment was performed to observe the effect of a Chinese medicine named Kaiyuqingre formula (KYQRF) on β-cell function and its mechanisms of action therein.</p><p><b>METHODS</b>High glucose was used to set up a model of β-cell function failure. At the same time, medicated serum of KYQRF with different doses were administered to the cells. Rosiglitazone was taken as a control to observe the changes in insulin secretion, ATP-sensitive K(+) channels (K(ATP) channel) and uncoupling protein-2 (UCP-2) in each group.</p><p><b>RESULTS</b>KYQRF had some effects on the insulin secretion. In a low glucose environment, no effective change in insulin secretion was observed (P > 0.05). However, insulin levels increased significantly when INS-1 cells were exposed to a high glucose environment (P < 0.05). KYQRF could also enhance cell viability (P < 0.05) in an effect similar to rosiglitazone. Although KYQRF had no effect on inwardly rectifying potassium channels (Kir6.2) (P > 0.05), it could decrease the overexpression of both UCP-2 and sulfonylurea receptor 1 (P < 0.05).</p><p><b>CONCLUSION</b>KYQRF can protect islet function by decreasing UCP-2 and sulfonylurea receptor 1.</p>
Assuntos
Animais , Masculino , Ratos , Transportadores de Cassetes de Ligação de ATP , Genética , Sobrevivência Celular , Medicamentos de Ervas Chinesas , Farmacologia , Glucose , Farmacologia , Insulina , Secreções Corporais , Células Secretoras de Insulina , Biologia Celular , Metabolismo , Canais Iônicos , Genética , Proteínas Mitocondriais , Genética , Canais de Potássio Corretores do Fluxo de Internalização , Genética , Ratos Sprague-Dawley , Receptores de Droga , Genética , Receptores de Sulfonilureias , Tiazolidinedionas , Farmacologia , Proteína Desacopladora 2RESUMO
We report a 2 month male child presenting with diabetic ketoacidosis (DKA) and seizures treated with intravenous fluids and intravenous insulin infusion till the ketoacidosis was reversed, thereafter responding well to sulphonylureas and at age of 13 months going into complete remission. At age of 11 mo developmental delay in the form of negative neck holding and inability to sit without support was seen. The child is 3 yr of age now ,euglycemic without any insulin or oral hypoglycemic agents but has severe developmental delay. Genetic analysis was negative for mutations of KCNJ11, 6q24, Glucokinase and IPF-1 genes. A mutation R1183W was found in the ABCC8 gene encoding SUR1, which was the cause of neonatal diabetes in this case.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Cromossomos Humanos Par 6/genética , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/genética , Cetoacidose Diabética/tratamento farmacológico , Cetoacidose Diabética/genética , Humanos , Hipoglicemiantes/uso terapêutico , Lactente , Insulina/uso terapêutico , Masculino , Mutação Puntual/genética , Canais de Potássio Corretores do Fluxo de Internalização/genética , Receptores de Droga/genética , Compostos de Sulfonilureia/uso terapêuticoRESUMO
<p><b>BACKGROUND</b>KCNJ11, ABCC8, PPARG, and HNF4A have been found to be associated with type 2 diabetes in populations with different genetic backgrounds. The aim of this study was to test, in a Chinese Han population from Beijing, whether the genetic variants in these four genes were associated with genetic predisposition to type 2 diabetes.</p><p><b>METHODS</b>We studied the association of four representative SNPs in KCNJ11, ABCC8, PPARG, and HNF4A by genotyping them using ABI SNaPshot Multiplex System in 400 unrelated type 2 diabetic patients and 400 unrelated normoglycaemic subjects.</p><p><b>RESULTS</b>rs5219 (E23K) in KCNJ11 was associated with genetic susceptibility to type 2 diabetes (OR = 1.400 with 95% CI 1.117 1.755, P = 0.004 under an additive model, OR = 1.652 with 95% CI 1.086 2.513, P = 0.019 under a recessive model, and OR = 1.521 with 95% CI 1.089 2.123, P = 0.014 under a dominant model) after adjusting for sex and body mass index (BMI). We did not find evidence of association for ABCC8 rs1799854, PPARG rs1801282 (Pro12Ala) and HNF4A rs2144908. Genotype-phenotype correlation analysis revealed that rs1799854 in ABCC8 was associated with 2-hour postprandial insulin secretion (P = 0.005) after adjusting for sex, age and BMI. Although no interactions between the four variants on the risk of type 2 diabetes were detected, the multiplicative interaction between PPARG Pro12Ala and HNF4A rs2144908 was found to be associated with 2-hour postprandial insulin (P = 0.004 under an additive model for rs2144908; and P = 0.001 under a dominant model for rs2144908) after adjusting for age, sex and BMI, assuming a dominant model for PPARG Pro12Ala.</p><p><b>CONCLUSIONS</b>Our study replicated the association of rs5219 in KCNJ11 with type 2 diabetes in Chinese Han population in Beijing. And we also observed that ABCC8 as well as the interaction between PPARG and HNF4A may contribute to post-challenge insulin secretion.</p>
Assuntos
Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transportadores de Cassetes de Ligação de ATP , Genética , Índice de Massa Corporal , Diabetes Mellitus Tipo 2 , Genética , Predisposição Genética para Doença , Genética , Genótipo , Fator 4 Nuclear de Hepatócito , Genética , PPAR gama , Genética , Polimorfismo de Nucleotídeo Único , Genética , Canais de Potássio Corretores do Fluxo de Internalização , Genética , Receptores de Droga , Genética , Receptores de SulfonilureiasRESUMO
Existe evidencia que señala que las claves pareadas con drogas no sólo son asociadas con los efectos de éstas, sino que también adquieren propiedades modulatorias de la asociación entre otras claves y los efectos de la droga, contribuyendo así al desarrollo de la tolerancia asociativa (Ramos, Siegel & Bueno, 2002). Utilizando un procedimiento de discriminación derasgo positivo, en la presente investigación evaluamos la contribución de los contextos como moduladores del efecto atáxico del etanol en ratas. Los resultados sugieren que el contexto adquiere propiedades modulatorias de la tolerancia a las drogas y que estas propiedades puedenser extinguidas.
There is evidence that drug-paired cues not only become associated with the drug effects but also become occasion setters that modulate the association of other cues with the drug effects,contributing to the development of associative tolerance (Ramos, Siegel, & Bueno, 2002). Using a feature-positive discrimination training, we evaluated the contribution of contexts asoccasion setters of the ataxic effect of ethanol in rats. The results suggest that the context acquire occasion setter properties of the drug tolerance, and that these properties can be extinguished.
Assuntos
Animais , Etanol , Extinção Psicológica , Receptores de DrogaRESUMO
Gitelman's syndrome [GS] is an autosomal recessive disorder caused by a defect of the thiazide-sensitive NaCl cotransporter [TSC] at the distal tubule, characterized by hypomagnesemia, hypokalemic alkalosis and hypocalciuria. This condition was previously confused with Bartter's syndrome [BS]. The documentation of hypocalciuria helps to differentiate this syndrome from BS. We report a 35-year-old female patient presented to our hospital with a history of muscle weakness and carpal spasm. She showed hypokalemia, hypocalcemia, hypomagnesemia and hypocalciuria. She was treated with electrolyte supplements
Assuntos
Humanos , Feminino , Hipocalcemia , Receptores de Droga , NefropatiasRESUMO
<p><b>OBJECTIVE</b>To investigate the association of thiazide-sensitive Na+ -Cl* cotransporter (TSC) gene 1784C/T and 2736G/A polymorphisms with the risk of essential hypertension (EH) in a Han nationality population.</p><p><b>METHODS</b>A community-based, case-control study including 190 EH patients and 94 sex- and age-matched controls was conducted. Genotypes of TSC gene 1784C/T and 2736G/A polymorphisms were analyzed by gene chip technology.</p><p><b>RESULTS</b>The genotype (1784C/T CC, CT, TT:87, 88, 15 vs 36, 52, 6û2736G/A GG, AG, AA:167, 22, 1 vs 83, 10, 1) and alleles frequency (1784C/T C, T:68.9%, 31.1% vs 66.0%, 34.0%; 2736G/A G,A:93.7%, 6.3% vs 93.6%, 6.4%) distribution of 1784C/T and 2736G/A showed no significant difference between the EH group and the control group (P >0.05). Moreover, no significant difference was observed in the frequencies distribution of four haplotypes (P > 0.05); Logistic regression analysis of haplotypes showed that the risk of EH had no significant difference in the population with different haplotypes (P > 0.05).</p><p><b>CONCLUSION</b>The 1784C/T and 2736G/A polymorphisms of TSC gene may not play an important role in the etiology of EH in a Han nationality population. The studies in the future are warranted to validate our findings.</p>
Assuntos
Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Hipertensão , Epidemiologia , Genética , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Receptores de Droga , Genética , Risco , Simportadores de Cloreto de Sódio , GenéticaRESUMO
This paper was aimed to investigate the effects of ATP-sensitive potassium channels on the proliferation and differentiation of rat preadipocytes. We examined the expression of sulphonylurea receptor 2 (SUR2) mRNA in preadipocytes and adipocytes obtained by inducing for 5 d and the effects of the inhibitor (glibenclamide) and opener (diazoxide) of ATP-sensitive potassium channels on the expression of SUR2 mRNA in preadipocytes by real-time PCR. Preadipocyte proliferation and cell cycle were measured by MTT spectrophotometry and flow cytometer. The content of intracellular lipid was measured by oil red O staining, cell diameter was determined by Image-Pro Plus 5.0 software and the expression of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) mRNA was estimated by RT-PCR. SUR2 mRNA was expressed in both preadipocytes and adipocytes obtained by inducing for 5 d, and the expression in adipocytes was obviously higher than that in preadipocytes. Glibenclamide inhibited the expression of SUR2 mRNA in preadipocyte, promoted preadipocyte proliferation in a dose-dependent manner, increased the cell percentages in G(2)/M + S phase, increased lipid content, augmented adipocyte diameter, and promoted the expression of PPAR-gamma mRNA. But the actions of diazoxide were contrary to those of glibenclamide. These results suggest that ATP-sensitive potassium channels regulate the proliferation and differentiation of preadipocytes, and PPAR-gamma is probably involved in the effect of ATP-sensitive potassium channels.
Assuntos
Animais , Masculino , Ratos , Transportadores de Cassetes de Ligação de ATP , Genética , Metabolismo , Adipócitos , Biologia Celular , Diferenciação Celular , Fisiologia , Proliferação de Células , Células Cultivadas , Canais KATP , Fisiologia , Obesidade , Patologia , PPAR gama , Metabolismo , Canais de Potássio Corretores do Fluxo de Internalização , Genética , Metabolismo , RNA Mensageiro , Genética , Metabolismo , Ratos Sprague-Dawley , Receptores de Droga , Genética , Metabolismo , Receptores de SulfonilureiasRESUMO
The present study was done to determine whether endogenous nitric oxide (NO) plays a role in the regulation of sodium transporters in the kidney. Male Sprague-Dawley rats were treated with NG-nitro-L-arginine methyl ester (L-NAME, 100 mg/L drinking water) for 4 weeks. Control rats were supplied with tap water without drugs. Expression of Na, K-ATPase, type 3 Na/H exchanger (NHE3), Na/K/2Cl cotransporter (BSC1), and thiazide-sensitive Na/Cl cotransporter (TSC) proteins was determined in the kidney by Western blot analysis. Catalytic activity of Na,K-ATPase was also determined. The treatment with L-NAME significantly and steadily increased the systemic blood pressure. Total and fractional excretion of urinary sodium decreased significantly, while creatinine clearance remained unaltered. Neither plasma renin activity nor aldosterone concentration was significantly altered. The alpha1 subunit expression and the catalytic activity of Na, K-ATPase were increased in the kidney. The expression of NHE3, BSC1 and TSC was also increased significantly. These results suggest that endogenously-derived NO exerts a tonic inhibitory effect on the expression of sodium transporters, including Na, K-ATPase, NHE3, BSC1, and TSC, in the kidney.
Assuntos
Animais , Masculino , Ratos , Western Blotting , Proteínas de Transporte/biossíntese , Inibidores Enzimáticos/farmacologia , Rim/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , ATPase Trocadora de Sódio-Potássio/biossíntese , Óxido Nítrico Sintase/antagonistas & inibidores , Ratos Sprague-Dawley , Receptores de Droga/biossíntese , Sódio/metabolismo , Simportadores de Cloreto de Sódio/biossíntese , Trocadores de Sódio-Hidrogênio/biossíntese , Simportadores de Cloreto de Sódio-Potássio/biossínteseRESUMO
The present study was carried out to elucidate the main difference between the various types of imidazoline receptors in the CNS and pancreas. The second generation selective imidazoline receptor agonist rilmenidine was used as a tool in the present study to demonstrate the difference of action on imidazoline receptors in these sites. An animal model of fructose induced insulin resistance in rats, similar to the metabolic syndrome X in human was adopted in the present work. The present study proved the ability of imidazoline receptor agonist rilmenidine to block ATP sensitive K+ channels, involved in the release of insulin in the pancreas via stimulation of 13 receptors. It also proved the ability of rilmenidine to normalize metabolic changes on lipid profile and to correct dyslipidemia that occurred in this condition. Moreover, rilmenidine lowered raised systolic blood pressure in fructose induced insulin resistant rats; due to additional effect on imidazoline I1 receptors in kidney, besides the main action on RVLM [rostral ventrolateral medulla] the final common pathway for sympathetic vasomotor outflow. The results revealed highly significant reduction of plasma glucose by 40.02%*, plasma insulin by 25.45%* and lipid profile [cholesterol by 25.42%*, triglycerides by 24.86%* and LDL by 44.92%*], while HDL was increased by 57.92%* [p<0.001] in insulin resistant group treated with rilmenidine. It also produced significant drop in the systolic blood pressure [p<0.001]. The difference in this action amounted to 30.91%* drop in BP with rilmenidine, compared with non-treated fructose induced insulin resistant group and insignificant change from normal control group [p>0.05]. In conclusion, the present work proved the presence of imidazoline binding site I3 in pancreas, previously called non I1 or I2. It also proved the effect of imidazoline receptor agonist rilmenidine to normalize the metabolic and haemodynamic effects that occur in fructose induced insulin resistant rats, supporting its use in diabetic hypertensive patients and in the metabolic syndrome X
Assuntos
Animais de Laboratório , Receptores de Droga , Pâncreas , Sistema Nervoso Central , Glicemia , Insulina/sangue , Lipídeos/sangue , Pressão Sanguínea , Resistência à Insulina , Ratos , FrutoseRESUMO
Bioactive small molecules play a crucial role in maintaining structural and functional homeostasis of cardiovascular system. However, systemic research pattern is rare because of the multiple forms, diverse effects and complicated interaction of these molecules. Therefore firstly, they can be classified into different single 'families' according to their internal relationships. Secondly, studies may be focused on the network of members within each 'family' as well as network among different 'families', especially the physiological and pathological significance of each member in the cardiovascular diseases. Lastly, efforts should be made to establish a primary and simple regulation network as the strategy of researches on biology of cardiovascular systems, and to promote the transition to a network covering more complicated multiplex 'families', even the whole body.
Assuntos
Humanos , Produtos Biológicos , Química , Genética , Metabolismo , Doenças Cardiovasculares , Tratamento Farmacológico , Fenômenos Fisiológicos Cardiovasculares , Homeostase , Peptídeos e Proteínas de Sinalização Intercelular , Química , Genética , Metabolismo , Neuroimunomodulação , Ligação Proteica , Proteínas , Química , Receptores de DrogaRESUMO
We aimed to examine the effects of angiotensin II AT1 receptor blocker on the expression of major renal sodium transporters and aquaporin-2 (AQP2) in rats with chronic renal failure (CRF). During 2 wks after 5/6 nephrectomy or sham operation, both CRF rats (n=10) and sham-operated control rats (n=7) received a fixed amount of low sodium diet and had free access to water. CRF rats (n=10) were divided into two groups which were either candesartan-treated (CRF-C, n=4) or vehicletreated (CRF-V, n=6). Both CRF-C and CRF-V demonstrated azotemia, decreased GFR, polyuria, and decreased urine osmolality compared with sham-operated rats. When compared with CRF-V, CRF-C was associated with significantly higher BUN levels and lower remnant kidney weight. Semiquantitative immunoblotting demonstrated decreased AQP2 expression in both CRF-C (54% of control levels) and CRF-V (57%), whereas BSC-1 expression was increased in both CRF groups. Particularly, CRF-C was associated with higher BSC-1 expression (611%) compared with CRF-V (289%). In contrast, the expression of NHE3 (25%) and TSC (27%) was decreased in CRF-C, whereas no changes were observed in CRF-V. In conclusion, 1) candesartan treatment in an early phase of CRF is associated with decreased renal hypertrophy and increased BUN level; 2) decreased AQP2 level in CRF is likely to play a role in the decreased urine concentration, and the downregulation is not altered in response to candesartan treatment; 3) candesartan treatment decreases NHE3 and TSC expression; and 4) an increase of BSC-1 is prominent in candesartan-treated CRF rats, which could be associated with the increased delivery of sodium and water to the thick ascending limb.
Assuntos
Animais , Masculino , Ratos , Bloqueadores do Receptor Tipo 1 de Angiotensina II , Aquaporinas/genética , Benzimidazóis/farmacologia , Nitrogênio da Ureia Sanguínea , Falência Renal Crônica/tratamento farmacológico , Tamanho do Órgão/efeitos dos fármacos , Ratos Sprague-Dawley , Receptores de Droga/genética , Trocadores de Sódio-Hidrogênio/genética , Simportadores de Cloreto de Sódio-Potássio/genética , Simportadores/genética , Tetrazóis/farmacologiaRESUMO
To study the effects of free fatty acids on insulin secretion and expression of SUR1 gene in rat pancreatic B cells in vitro, and to explore the molecular mechanisms in lipotoxicity inducing insulin secretion dysfunction, pancreatic islet cells were isolated and digested from male SD rats. Purified islets were incubated with either 0.25 mmol/L palmitate or 0.125 mmol/L oleate for 48 h in vitro. Then islets were stimulated with either 5.6 mmol/L or 16.7 mmol/L glucose for 1 h. Insulin release was measured by using radioimmunoassay, and the expression of SUR1 gene mRNA was quantified by reserve transcription-polymerase chain reaction (RT-PCR). The islets exposed to both palmitate and oleate for 48 h showed an increased basal and a decreased glucose-indused insulin release as compared with control islets. Palmitate increased basal insulin secretion by 110% (P< 0.01), decreased glucose stimulated insulin secretion by 43% (P<0.01); while oleate increased basal insulin secretion by 80% (P<0.01) and decreased glucose stimulated insulin secretion by 32 % (P<0.05). RT-PCR showed that oleate significantly suppressed SUR1 gene expression by 64 % (P<0.01) as compared with the control group, while palmitate group manifested a light decrease of 15% (P>0.05) of SUR1 gene expression. Our results suggested that chronic exposure to free fatty acids of pancreatic beta cells inhibited glucose stimulated insulin secretion. Regulation of SUR1 gene expression may be involved in such effects, which may also be one of the molecular mechanisms in lipotoxocity inducing beta cells secretion dysfunction.