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1.
Behav Brain Res ; 336: 77-84, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-28864205

RESUMO

We previously reported that systemic administration of the selective delta opioid receptor (DOP) agonist KNT-127 produces potent anxiolytic-like effects in rats. Although a higher distribution pattern of DOPs was reported in the prelimbic medial prefrontal cortex (PL-PFC) of rodents, the role of DOPs in PL-PFC and in anxiolytic-like effects have not been well examined. Recently, we demonstrated that activation of PL-PFC with the sodium channel activator veratrine increases glutamatergic neurotransmission and produces anxiety-like behaviors in mice. Therefore, we investigated the effects of co-perfusion with KNT-127 in PL-PFC on veratrine-induced anxiety-like behaviors in mice. We also simultaneously measured extracellular glutamate and GABA levels. In addition, we assessed the effect of KNT-127 on the expression of c-Fos in sub-regions of the amygdala. Extracellular glutamate levels were measured in seven-week-old male C57BL/6N mice using an in vivo microdialysis-HPLC/ECD system, and behaviors were assessed simultaneously in an open field test. Basal levels of glutamate were measured by collecting samples every 10min for 60min. The drug-containing medium was perfused for 30min, and the open field test was performed during the last 10min of drug perfusion. After drug treatments, the perfusion was switched from drug-containing medium to control medium without drugs and samples were collected for another 90min. KNT-127 co-perfusion completely diminished veratrine-induced anxiety-like behaviors and attenuated the veratrine-induced increase in extracellular glutamate levels in PL-PFC. Interestingly, KNT-127 perfusion alone in PL-PFC did not affect anxiety-like behaviors. Local perfusion of veratrine in PL-PFC induced c-Fos immunoreactivity in sub-regions of amygdala. Co-perfusion of KNT-127 diminished c-Fos expression. Here we demonstrate that the DOP agonist KNT-127 in PL-PFC attenuates veratrine-induced anxiety-like behaviors in mice. These effects may be caused by the presynaptic suppression of activated glutamatergic transmission in PL-PFC, which projects to sub-regions of the amygdala. We propose that compounds like KNT-127, which inhibit glutamatergic transmission in PL-PFC, are candidates for novel anxiolytics.


Assuntos
Morfinanos/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Receptores Opioides delta/metabolismo , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Ansiolíticos/farmacologia , Ansiedade/induzido quimicamente , Ansiedade/metabolismo , Ansiedade/patologia , Comportamento Animal/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Córtex Pré-Frontal/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptores Opioides delta/agonistas , Transmissão Sináptica/efeitos dos fármacos , Veratrina/farmacologia
2.
Behav Brain Res ; 304: 120-4, 2016 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-26802727

RESUMO

The medial prefrontal cortex is a heterogeneous cortical structure composed of several nuclei, including the prelimbic (PL) and infralimbic (IL) cortices. We previously demonstrated in mice that PL activation with the sodium channel activator veratrine induces anxiety-like behaviors. However, the role of IL in the regulation of anxiety-like behaviors remained unclear. Therefore, in the present study, we investigated the role of the IL in the regulation of anxiety-like behaviors using pharmacological activation model with veratrine, and compared it with the role of the PL. Extracellular glutamate levels were measured by in vivo microdialysis-HPLC with an electrochemical detector, and behaviors were assessed using the open field test. In this study, extracellular glutamate levels rose significantly after perfusion of veratrine in the IL and PL. Interestingly, the PL activation produced anxiety-like behaviors, whereas the activation of the IL produced no anxiety-like behavior in mice. Although the IL is adjacent to the PL, these two regions of the brain have differential functions in the expression of anxiety-like behaviors.


Assuntos
Ansiedade/patologia , Ansiedade/fisiopatologia , Líquido Extracelular/metabolismo , Atividade Motora/fisiologia , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/metabolismo , Análise de Variância , Animais , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Líquido Extracelular/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microdiálise , Atividade Motora/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Veratrina/farmacologia
3.
Behav Brain Res ; 292: 316-22, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26099814

RESUMO

In this study, we investigated the anxiogenic-like effects of systemically administered veratrine in rat models of anxiety. In the light/dark test, veratrine (0.6 mg/kg, s.c.) significantly and dose-dependently decreased the time rats spent in and the number of entries into a light box 30 min after administration, suggesting that veratrine increases anxiety-like behaviors. These findings were also supported by results from the elevated-plus maze test and the tail-swing behavior test. In addition, veratrine (0.6 mg/kg, s.c.) significantly increased the plasma concentration of corticosterone, an endogenous biomarker for anxiety, compared to vehicle. On the basis of these results, we conclude that veratrine induces anxiogenic-like behaviors in rats. The anxiogenic-like behaviors induced by veratrine (0.6 mg/kg, s.c.) were completely abolished by co-treatment with the typical benzodiazepine anxiolytic diazepam (1 mg/kg, s.c.), when assessed in the elevated-plus maze test. Similar results were obtained with co-treatment with riluzole (10 mg/kg, p.o.), which directly affects the glutamatergic system and has recently been suggested to have anxiolytic-like effects. In conclusion, this study provides evidence that systemically administered veratrine induces anxiogenic-like behaviors in rats. We propose the veratrine model as a novel pathological animal model to explore possible candidate drugs for anxiolytics.


Assuntos
Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Veratrina/farmacologia , Agonistas do Canal de Sódio Disparado por Voltagem/farmacologia , Animais , Ansiolíticos/farmacologia , Diazepam/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Ratos Wistar
4.
J Neural Transm (Vienna) ; 122(8): 1203-7, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25645866

RESUMO

Local perfusion of the sodium channel activator veratrine in mouse prelimbic medial prefrontal cortex (PL) induced c-Fos immunoreactivity in the sub-regions of amygdala. Co-perfusion of the NMDA receptor antagonist MK-801 diminished the c-Fos expression. Significant correlations were observed between c-Fos immunoreactivity and behavioral measures in the open-field test. The PL stimulation activates a neural network projecting to the amygdala via NMDA receptor-mediated glutamatergic neurotransmission. Anxiety-like behavior induced after the PL stimulation may be partly mediated through the activation of amygdala.


Assuntos
Tonsila do Cerebelo/metabolismo , Ansiedade/metabolismo , Córtex Pré-Frontal/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Ansiedade/tratamento farmacológico , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Imuno-Histoquímica , Masculino , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Fotomicrografia , Córtex Pré-Frontal/efeitos dos fármacos , Agonistas de Canais de Sódio/administração & dosagem , Veratrina/administração & dosagem
5.
Psychopharmacology (Berl) ; 232(2): 391-8, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25127925

RESUMO

RATIONALE: We previously demonstrated in mice that the activation of prelimbic medial prefrontal cortex (PL) with the sodium channel activator veratrine induces anxiety-like behaviors via NMDA receptor-mediated glutamatergic neurotransmission. Riluzole directly affects the glutamatergic system and has recently been suggested to have an anxiolytic-like effect in both experimental animals and patients with anxiety disorders. OBJECTIVES: We investigated the effects of co-perfusion of riluzole on veratrine-induced anxiety-like behaviors in mice. METHODS: Extracellular glutamate levels were measured in 7-week-old male C57BL6 mice by using an in vivo microdialysis-HPLC/ECD system, and behaviors were assessed simultaneously in an open field (OF) test. Basal levels of glutamate were measured by collecting samples every 10 min for 60 min. The medium containing drugs was perfused for 30 min, and the OF test was performed during the last 10 min of drug perfusion. After the drug treatments, the drug-containing medium was switched to perfusion of control medium lacking drugs, and then samples were collected for another 90 min. RESULTS: Riluzole co-perfusion attenuated veratrine-induced increase in extracellular glutamate levels in the PL and completely diminished veratrine-induced anxiety-like behaviors. Interestingly, riluzole perfusion alone in the PL did not affect the basal levels of glutamate and anxiety-like behaviors. CONCLUSIONS: Our results suggest that compounds like riluzole that inhibit glutamatergic function in the PL are possible candidates for novel anxiolytics.


Assuntos
Ansiolíticos/farmacologia , Ansiedade/induzido quimicamente , Ansiedade/tratamento farmacológico , Córtex Pré-Frontal/efeitos dos fármacos , Riluzol/farmacologia , Veratrina/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Interações Medicamentosas , Ácido Glutâmico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microdiálise , Receptores de N-Metil-D-Aspartato/metabolismo , Transmissão Sináptica/efeitos dos fármacos
6.
Eur Neuropsychopharmacol ; 24(8): 1405-14, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24846538

RESUMO

Epilepsy is recognized as one of the most common and serious neurological disorder affecting 1-2% of the world׳s population. The present study demonstrates that systemic administration of 3-butyl-5,5-dimethyl-1,2,3-oxathiazolidine-4-one-2,2-dioxide (DIOXIDE), a synthetic compound bioisoster of trimethadione and phenytoin (classical anticonvulsants), elicits a dose dependent anticonvulsant response in mice submitted to the subcutaneous pentylenetetrazole seizure test (scPTZ). Among various factors supposed to play role in epilepsy, oxidative stress and reactive species have strongly emerged. The protection exerted by DIOXIDE over the extent of brain oxidative damage produced by PTZ was determined, by measuring the levels of lipid peroxidation and reduced glutathione and the activity of Na(+)/K(+)-ATPase. Psychiatric disorders represent frequent comorbidities in persons with epilepsy. In this report, the potential anxiolytic and antidepressant activities of DIOXIDE were evaluated in several widely used models for assessing anxiolytic and antidepressant activities in rodents. Although DIOXIDE did not evidence anxiolytic activity at the doses tested, it revealed a significant antidepressant-like effect. Preliminary studies of its mechanism of action, by means of its capacity to act via the GABAA receptor (using the [(3)H]flunitrazepam binding assay in vitro and the picrotoxin test in vivo) and the Na(+) channel (using the alkaloid veratrine, a voltage-Na(+) channel agonist) demonstrated that the anticonvulsant effect is not likely related to the GABAergic pathway and the antidepressant-like effect could be due to its Na(+) channel blocking properties. The results for DIOXIDE suggested it as a new anticonvulsant-antioxidant and antidepressant compound that deserves further development.


Assuntos
Anticonvulsivantes/uso terapêutico , Antidepressivos/uso terapêutico , Lesões Encefálicas/prevenção & controle , Fenitoína/uso terapêutico , Convulsões/tratamento farmacológico , Convulsões/patologia , Trimetadiona/uso terapêutico , Animais , Lesões Encefálicas/metabolismo , Modelos Animais de Doenças , Flunitrazepam/farmacocinética , Glutationa/metabolismo , Elevação dos Membros Posteriores/psicologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Atividade Motora/efeitos dos fármacos , Pentilenotetrazol/toxicidade , Fenitoína/química , Convulsões/induzido quimicamente , ATPase Trocadora de Sódio-Potássio/metabolismo , Fatores de Tempo , Trimetadiona/química , Veratrina/farmacologia
7.
J Neurosci Res ; 92(8): 1044-53, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24752881

RESUMO

We investigated the possible roles of the prelimbic medial prefrontal cortex (PL) in the regulation of anxiety-like behaviors by pharmacologically activating the terminals of neuronal inputs or postsynaptic efferent neurons with a sodium channel activator veratrine. The extracellular glutamate levels were measured by in vivo microdialysis, and the behaviors were assessed with the open field (OF) test in mice simultaneously. The samples were collected every 10 min for 60 min, as basal levels of glutamate. The medium containing drugs were perfused for 30 min. The OF test was performed in the last 10 min of drug perfusion. After the drug treatments, the perfusion medium containing drugs was switched back to perfusion medium without drugs, and then samples were collected for another 90 min. The extracellular glutamate levels were significantly elevated after local perfusion of veratrine in the PL. At the same time, perfusion of veratrine in the PL produced anxiety-like behaviors in mice. Local coperfusion of a sodium channel blocker, lamotrigine, completely diminished the veratrine-induced elevated extracellular glutamate levels and the behavioral changes. Local coperfusion of an NMDA receptor antagonist, MK-801, but not a non-NMDA (AMPA/kainate) receptor antagonist, CNQX, completely diminished the behavioral changes without any effects on the veratrine-induced elevated extracellular glutamate levels. This study demonstrates that the activation of the PL with veratrine induces anxiety-like behaviors via NMDA receptor-mediated glutamatergic neurotransmission in mice.


Assuntos
Ansiedade/metabolismo , Comportamento Animal/fisiologia , Ácido Glutâmico/metabolismo , Córtex Pré-Frontal/metabolismo , Transmissão Sináptica/fisiologia , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Lamotrigina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microdiálise , Córtex Pré-Frontal/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Bloqueadores dos Canais de Sódio/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Triazinas/farmacologia , Veratrina/farmacologia
8.
Pharm Biol ; 52(1): 105-10, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24102122

RESUMO

CONTEXT: Hypericum caprifoliatum Cham & Schlecht (Guttiferae) extracts have a potential antidepressant-like effect in rodents. However, the molecular mechanisms by which these extracts exert this effect remain unclear. OBJECTIVE: This study evaluated the effect of HC1, a fraction obtained from H. caprifoliatum enriched in phloroglucinol derivatives, on the Na⁺, K⁺ ATPase activity in mouse brain and verified the influence of veratrine on the effect of HC1 in the forced swimming test (FST). MATERIALS AND METHODS: Veratrine (0.06 mg/kg) and HC1 (360 mg/kg) were given alone or combined i.p. 60 and p.o. 30 min, respectively, before FST. The effect of single and repeated administration (once a day for 3 consecutive days) of HC1 (360 mg/kg) on Na⁺, K⁺ ATPase activity was evaluated ex vivo in the cerebral cortex and hippocampus of mice subjected or not to FST. RESULTS: HC1 reduced the immobility time (103.15 ± 18.67 s), when compared to the control group (183.6 ± 9.51 s). This effect was prevented by veratrine (151.75 ± 22.19 s). Mice repeatedly treated with HC1 presented a significant increase in Na⁺, K⁺ ATPase activity, both in cerebral cortex (46 ± 2.41 nmol Pi/min·mg protein) and hippocampus (49.83 ± 2.31 nmol Pi/min·mg protein), in relation to the respective controls (30 ± 2.66 and 29.83 ± 2.31 nmol Pi/min·mg protein respectively). DISCUSSION AND CONCLUSION: The HC1 antidepressant-like effect on FST might be related to its capacity to inhibit Na⁺ influx. HC1 increases hippocampal and cortical Na⁺, K⁺ ATPase activities possibly through long-term regulatory mechanisms.


Assuntos
Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Floroglucinol/farmacologia , Extratos Vegetais/farmacologia , Animais , Antidepressivos/administração & dosagem , Antidepressivos/isolamento & purificação , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hypericum , Masculino , Camundongos , Floroglucinol/administração & dosagem , Floroglucinol/isolamento & purificação , Extratos Vegetais/administração & dosagem , Sódio/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Natação , Veratrina/administração & dosagem , Veratrina/farmacologia
9.
Fundam Clin Pharmacol ; 27(6): 650-5, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23437921

RESUMO

The objective of this study was to verify whether phenytoin modifies methylphenidate-induced hyperlocomotion, an animal model for screening antimanic-like drugs, and also evaluate the effect of veratrine, a voltage-gated sodium channel opener, pretreatment on the effect of phenytoin in this model. Carbamazepine was used as a positive control. Methylphenidate (5 mg/kg, s.c.) increased open-field locomotion, and phenytoin (5-10 mg/kg, i.p.) and carbamazepine (20 mg/kg, i.p.) blocked this effect. Veratrine (0.4 mg/kg, s.c.) pretreatment reversed the effects of phenytoin (10 mg/kg, i.p.) and carbamazepine (20 mg/kg, i.p.). Phenytoin (1-50 mg/kg, i.p.) and carbamazepine (10-20 mg/kg i.p.) alone did not change spontaneous locomotor activity. These results indicate that voltage-gated sodium channels play an important role in antimanic-like effects of phenytoin and carbamazepine on psychostimulant-induced hyperlocomotion model.


Assuntos
Antimaníacos/farmacologia , Carbamazepina/farmacologia , Atividade Motora/efeitos dos fármacos , Fenitoína/farmacologia , Animais , Antimaníacos/administração & dosagem , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/fisiopatologia , Carbamazepina/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Metilfenidato/farmacologia , Camundongos , Fenitoína/administração & dosagem , Veratrina/farmacologia , Canais de Sódio Disparados por Voltagem/efeitos dos fármacos , Canais de Sódio Disparados por Voltagem/metabolismo
10.
Br J Pharmacol ; 161(2): 405-15, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20735424

RESUMO

BACKGROUND AND PURPOSE: The persistent sodium current is involved in myocardial ischaemia and is selectively inhibited by the newly described 3-(R)-[3-(2-methoxyphenylthio-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine bromhydrate (F 15845). Here, we describe the pharmacological profile of F 15845 against the effects of hypoxia in femoral arteries in vitro. EXPERIMENTAL APPROACH: Isometric tension measurement of rat isolated femoral arteries was used to characterize the protective effect of F 15845 against contraction of the vessels induced by veratrine (100 microg.mL(-1)) or hypoxia. KEY RESULTS: Rat femoral artery expressed the Na(v)1.5 channel isoform. When exposed to veratrine (100 microg.mL(-1)), vessels developed a rapid and strong contraction that was abolished by both absence of sodium and blockade of the Na(+)/Ca(++) exchanger by KB-R7943 (10 and 32 micromol.L(-1)) or treatment with F 15845. When used before veratrine exposure, the potency of F 15845 depended on the extracellular K(+) concentration (IC(50)= 11 and 0.77 micromol.L(-1) for 5 and 20 mmol.L(-1) KCl, respectively), whereas its potency was unaffected by extracellular K(+) concentration when given after veratrine. F 15845 did not affect either KCl (80 mmol.L(-1)) or phenylephrine-induced femoral artery contraction. Moreover, endothelium disruption did not affect the protective effect of F 15845 against veratrine-induced femoral artery contraction, suggesting a mechanism of action dependent on smooth muscle cells. Finally, F 15845 prevented in a concentration-dependent manner rat femoral artery contraction induced by hypoxia. CONCLUSION AND IMPLICATIONS: F 15845, a selective blocker of the persistent sodium current prevented vascular contraction induced by hypoxic conditions.


Assuntos
Benzotiepinas/farmacologia , Artéria Femoral/efeitos dos fármacos , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/biossíntese , Sódio/metabolismo , Animais , Hipóxia Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Artéria Femoral/metabolismo , Imunofluorescência , Técnicas In Vitro , Transporte de Íons/efeitos dos fármacos , Contração Isométrica/efeitos dos fármacos , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Canal de Sódio Disparado por Voltagem NAV1.5 , Ratos , Ratos Endogâmicos , Trocador de Sódio e Cálcio/metabolismo , Veratrina/farmacologia
11.
Circ Res ; 106(3): 593-600, 2010 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-20007914

RESUMO

RATIONALE: Patients on a low salt (LS) diet have increased mortality. OBJECTIVE: To determine whether reduction in NO bioactivity may contribute to the LS-induced cardiac dysfunction and mortality. METHODS AND RESULTS: Adult male mongrel dogs were placed on LS (0.05% sodium chloride) for 2 weeks. Body weight (25.4 + or - 0.4 to 23.6 + or - 0.4 kg), left ventricular systolic pressure (137.0 + or - 3.4 to 124.0 + or - 6.7 mm Hg), and mean aortic pressure (111 + or - 3.1 to 98 + or - 4.3 mm Hg) decreased. Plasma angiotensin II concentration increased (4.4 + or - 0.7 to 14.8 + or - 3.7 pg/mL). Veratrine-induced (5 microg/kg) NO-mediated vasodilation was inhibited by 44% in LS; however, the simultaneous intravenous infusion of ascorbic acid or apocynin acutely and completely reversed this inhibition. In LS heart tissues, lucigenin chemiluminescence was increased 2.3-fold to angiotensin II (10(-8) mol/L), and bradykinin (10(-4) mol/L) induced reduction of myocardial oxygen consumption in vitro was decreased (40 + or - 1.3% to 16 + or - 6.3%) and completely restored by coincubation with tiron, tempol or apocynin. Switching of substrate uptake from free fatty acid to glucose by the heart was observed (free fatty acid: 8.97 + or - 1.39 to 4.53 + or - 1.12 micromol/min; glucose: 1.31 + or - 0.52 to 6.86 + or - 1.78 micromol/min). Western blotting indicated an increase in both p47(phox) (121%) and gp91(phox) (44%) as did RNA microarray analysis (433 genes changed) showed an increase in p47(phox) (1.6-fold) and gp91(phox) (2.0 fold) in the LS heart tissue. CONCLUSIONS: LS diet induces the activation of the renin-angiotensin system, which increases oxidative stress via the NADPH oxidase and attenuates NO bioavailability in the heart.


Assuntos
Dieta Hipossódica/efeitos adversos , Miocárdio/metabolismo , Óxido Nítrico/metabolismo , Sistema Renina-Angiotensina/fisiologia , Superóxidos/metabolismo , Acetofenonas/administração & dosagem , Acetofenonas/uso terapêutico , Angiotensina II/sangue , Animais , Ácido Ascórbico/administração & dosagem , Ácido Ascórbico/uso terapêutico , Vasos Coronários/metabolismo , Cães , Ácidos Graxos/metabolismo , Perfilação da Expressão Gênica , Glucose/metabolismo , Hemodinâmica , Infusões Intravenosas , Lactatos/metabolismo , Masculino , NADPH Oxidases/biossíntese , NADPH Oxidases/genética , Óxido Nítrico/deficiência , Análise de Sequência com Séries de Oligonucleotídeos , Estresse Oxidativo , Consumo de Oxigênio , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia , Veratrina/farmacologia , Perda de Peso
12.
Behav Brain Res ; 205(2): 421-5, 2009 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-19660501

RESUMO

UNLABELLED: Topiramate and phenytoin possess mood stabilizing properties. The mechanism of action of anticonvulsants used in the treatment of bipolar depression is complex and still not completely elucidated. Na(+) channels are present at distinct sites in neurons, where they sub serve different functions and play distinct roles. The fact that most of the anticonvulsants used in the treatment of bipolar disorders are blockers of voltage-gated Na channels has determined our interest in evaluating the role of ion channels in bipolar disorders. OBJECTIVES: The scope of this study was to determinate if sodium channels are important for topiramate and phenytoin to exert their antidepressant-like functioning. METHODS: The role of Na(+) channels in the mechanism of action of the anticonvulsants was investigated by using veratrine a selective activator of Na channels in a mice model of depression, the forced swimming test. Veratrine 0.125 mg/kg and topiramate or phenytoin (16 and 32 mg/kg) were given IP 45 and 30 min, respectively, before the test. RESULTS: The administration of topiramate and phenytoin induce a decrease in the immobility time on the FST which can be considered as an antidepressant-like activity. The antidepressant-like effect of the anticonvulsants was completely reversed by veratrine suggesting that the antidepressant-like effect of topiramate and phenytoin on the FST might be due to their Na(+) channels blocking properties.


Assuntos
Antidepressivos/farmacologia , Transtorno Depressivo/tratamento farmacológico , Frutose/análogos & derivados , Moduladores de Transporte de Membrana/farmacologia , Fenitoína/farmacologia , Veratrina/farmacologia , Animais , Antidepressivos/administração & dosagem , Transtorno Bipolar , Transtorno Depressivo/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Frutose/administração & dosagem , Frutose/farmacologia , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Testes Neuropsicológicos , Fenitoína/administração & dosagem , Distribuição Aleatória , Agonistas de Canais de Sódio , Canais de Sódio/metabolismo , Natação , Fatores de Tempo , Topiramato
13.
J Pharmacol Exp Ther ; 330(3): 696-703, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19515969

RESUMO

The present study investigates whether 3-(R)-[3-(2-methoxyphenylthio-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine bromhydrate (F 15845), a new, persistent sodium current blocker, can reduce the ischemic Na(+) accumulation and exert short- and long-term cardioprotection after myocardial infarction. First, F 15845 concentration-dependently reduced veratrine-induced diastolic contracture (IC(50) = 0.14 microM) in isolated atria. Second, F 15845 from 1 microM preserved viability in 54.2 +/- 12.5% of isolated cardiomyocytes exposed to lysophosphatidylcholine. Third, the effect of F 15845 on intracellular Na(+) of isolated hearts from control and diabetic db/db mice was monitored using (23)Na-nuclear magnetic resonance spectroscopy. F 15845 (0.3 microM) significantly counteracted [Na(+)](i) increase during no-flow ischemia in control mouse hearts. In diabetic db/db mouse hearts, the reduction in [Na(+)](i) was delayed relative to control. However, it was more marked and maintained upon reperfusion. The cardioprotective properties after myocardial infarction associated with short- (24-h) and long-term (14-day) reperfusion were measured in anesthetized rats. After 24-h reperfusion, F 15845 (5 mg/kg) significantly reduced infarct size (32.4 +/- 1.7% with vehicle and 24.2 +/- 3.4% with F 15845; P < 0.05) and decrease of troponin I levels (524 +/- 93 microg/l with vehicle versus 271 +/- 63 microg/l with F 15845; P < 0.05). It is important that F 15845 limits the long-term expansion of infarct size (35.2 +/- 2.6%, n = 19 versus 46.7 +/- 1.6%, n = 27 in the vehicle group; P < 0.001). Overall, F 15845 attenuates [Na(+)](i) and prevents (or reverses) contractile and biochemical dysfunction in ischemic and remodeling heart. F 15845 constitutes a new generation of cardioprotective agent.


Assuntos
Benzotiepinas/farmacologia , Benzotiepinas/uso terapêutico , Isquemia Miocárdica/tratamento farmacológico , Bloqueadores dos Canais de Sódio/farmacologia , Bloqueadores dos Canais de Sódio/uso terapêutico , Sódio/metabolismo , Remodelação Ventricular/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/metabolismo , Cobaias , Técnicas In Vitro , Lisofosfatidilcolinas/antagonistas & inibidores , Lisofosfatidilcolinas/toxicidade , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Contração Miocárdica/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Isquemia Miocárdica/patologia , Miócitos Cardíacos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Radioisótopos de Sódio , Veratrina/farmacologia
14.
Cardiovasc Res ; 84(2): 237-44, 2009 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-19556280

RESUMO

AIMS: Class III antiarrhythmic agents exhibit reverse rate-dependent lengthening of the action potential duration (APD). In spite of the several theories developed so far to explain this reverse rate dependency (RRD), its mechanism has not yet been clarified. The aim of the present work was to further elucidate the mechanisms responsible for reverse rate-dependent drug effects. METHODS AND RESULTS: Action potentials were recorded from multicellular canine ventricular preparations and isolated cardiomyocytes, at cycle lengths (CLs) varying from 0.3 to 5 s, using conventional sharp microelectrodes. APD was either modified by applying inward and outward current pulses, or by superfusion of agents known to lengthen and shorten APD. Net membrane current (I(m)) was calculated from action potential waveforms. The hypothesis that RRD may be implicit in the relationship between I(m) and APD was tested by numerical modelling. Both drug-induced lengthening (by veratrine, BAY-K 8644, dofetilide, and BaCl(2)) and shortening (by lidocaine and nicorandil) of action potentials displayed RRD, i.e. changes in APD were greater at longer than at shorter CL. A similar dependency of effect on CL was found when repolarization was modified by injection of inward or outward current pulses. I(m) measured at various points during repolarization was inversely proportional to APD and to CL. Model simulations showed that RRD is expected as a consequence of the non-linearity of the relationship between I(m) and APD. CONCLUSION: RRD of APD modulation is shared, although with differences in magnitude, by interventions of very different nature. RRD can be interpreted as a consequence of the relationship between I(m) and APD and, as such, is expected in all species having positive APD-CL relationship. This implies that the development of agents prolonging APD with direct rate dependency, or even completely devoid of RRD, may be difficult to achieve.


Assuntos
Antiarrítmicos/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Ramos Subendocárdicos/efeitos dos fármacos , Éster Metílico do Ácido 3-Piridinacarboxílico, 1,4-Di-Hidro-2,6-Dimetil-5-Nitro-4-(2-(Trifluormetil)fenil)/farmacologia , Potenciais de Ação , Animais , Compostos de Bário/farmacologia , Estimulação Cardíaca Artificial , Cloretos/farmacologia , Simulação por Computador , Cães , Feminino , Ventrículos do Coração/citologia , Ventrículos do Coração/efeitos dos fármacos , Técnicas In Vitro , Masculino , Modelos Cardiovasculares , Miócitos Cardíacos/fisiologia , Dinâmica não Linear , Fenetilaminas/farmacologia , Ramos Subendocárdicos/fisiologia , Sulfonamidas/farmacologia , Fatores de Tempo , Veratrina/farmacologia
15.
Behav Brain Res ; 191(1): 49-54, 2008 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-18433891

RESUMO

UNLABELLED: Lamotrigine has been found to be efficacious in the acute management of bipolar depression and long-term management of bipolar disorder, especially in delaying depressive recurrence, either as monotherapy or as adjunctive therapy. Lamotrigine is also an antiepileptic drug, and is efficient in the treatment of focal epilepsies. It is thought to act by inhibition of glutamate release through blockade of voltage-sensitivity sodium channels and stabilization of the neuronal membrane. OBJECTIVES: The scope of this study was to determinate if sodium channels are important for lamotrigine and other antidepressant to exert their antidepressant-like function. METHODS: This study assessed the effects of veratrine, a Na(+) channel opener on antidepressant effect of lamotrigine and others antidepressants: two tricyclic antidepressants (TCAs): imipramine, a mixed serotonergic noradrenergic reuptake inhibitor, desipramine, a specific noradrenergic reuptake inhibitor and a SSRI: paroxetine, the most potent selective serotonergic reuptake inhibitor, using an animal model of depression, the forced swimming test. Veratrine (0.125 mg/kg) and lamotrigine (16, 32 mg/kg) or antidepressants (16, 32 mg/kg) were given i.p. 45 and 30 min, respectively, before the test. RESULTS: We observed that when combined with veratrine the antidepressant-like effect of lamotrigine was reversed, but the antidepressant-like effect of the imipramine, desipramine and paroxetine was not changed, indicating that the mechanism of action of lamotrigine is different from that of antidepressants.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Triazinas/uso terapêutico , Veratrina/farmacologia , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações Medicamentosas , Resposta de Imobilidade Tônica/efeitos dos fármacos , Lamotrigina , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Wistar , Natação
16.
Am J Physiol Heart Circ Physiol ; 294(6): H2516-23, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18424630

RESUMO

The aim of this study was to examine the role of nitric oxide (NO) in the control of cardiac metabolism at 60 days of pregnancy (P60) in the dog. There was a basal increase in diastolic coronary blood flow during pregnancy and a statistically significant increase in cardiac output (55 +/- 4%) and in cardiac NOx production (44 +/- 4 to 59 +/- 3 nmol/min, P < 0.05). Immunohistochemistry of the left ventricle showed an increase in endothelial nitric oxide synthase staining in the endothelial cells at P60. NO-dependent coronary vasodilation (Bezold-Jarisch reflex) was increased by 20% and blocked by N(G)-nitro-l-arginine methyl ester (l-NAME). Isotopically labeled substrates were infused to measure oleate, glucose uptake, and oxidation. Glucose oxidation was not significantly different in P60 hearts (5.4 +/- 0.5 vs. 6.2 +/- 0.4 micromol/min) but greatly increased in response to l-NAME injection (to 19.9 +/- 0.9 micromol/min, P < 0.05). Free fatty acid (FFA) oxidation was increased in P60 (from 5.3 +/- 0.6 to 10.4 +/- 0.5 micromol/min, P < 0.05) and decreased in response to l-NAME (to 4.5 +/- 0.5 micromol/min, P < 0.05). There was an increased oxidation of FFA for ATP production but no change in the respiratory quotient during pregnancy. Genes associated with glucose and glycogen metabolism were downregulated, whereas genes involved in FFA oxidation were elevated. The acute inhibition of NO shifts the heart away from FFA and toward glucose metabolism despite the downregulation of the carbohydrate oxidative pathway. The increase in endothelium-derived NO during pregnancy results in a tonic inhibition of glucose oxidation and reliance on FFA uptake and oxidation to support ATP synthesis in conjunction with upregulation of FFA metabolic enzymes.


Assuntos
Circulação Coronária , Vasos Coronários/metabolismo , Metabolismo Energético , Miocárdio/metabolismo , Óxido Nítrico/metabolismo , Vasodilatação , Trifosfato de Adenosina/metabolismo , Animais , Circulação Coronária/efeitos dos fármacos , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/enzimologia , Cães , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/genética , Inibidores Enzimáticos/farmacologia , Ácidos Graxos não Esterificados/metabolismo , Feminino , Glucose/metabolismo , Hemodinâmica , Imuno-Histoquímica , Ácido Láctico/metabolismo , Miocárdio/enzimologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/metabolismo , Oxirredução , Gravidez , RNA Mensageiro/metabolismo , Fatores de Tempo , Regulação para Cima , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Veratrina/farmacologia
17.
Bioorg Med Chem ; 16(6): 3025-31, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18191403

RESUMO

The lipid-soluble veratrum alkaloids, veratridine and cevadine, are plant neurotoxins that are agonists of voltage-gated sodium channel. Their conformations in a hydrophobic environment were analyzed by NMR spectroscopy in solution phase chloroform at low temperatures. The conformations around the 3-carboxylic esters which is essential for their neurotoxicity, was completely different from the previously reported X-ray crystallographic structure. The carbonyl oxygen atom (O28) of the carboxylic ester forms a weak intramolecular hydrogen bond with the OH proton at C4 (4-OH) that loosely restricts the conformation of the 3-veratroyl ester in veratridine and the 3-angeloyl ester in cevadine. Methylation at C4 hydroxyl group of veratridine had much reduced its neurotoxic activity relating to voltage-gated sodium channel. The results suggested that the loose conformational restrictions of the carboxylic esters are important for neurotoxicity of the veratrum alkaloids.


Assuntos
Alcaloides de Veratrum/química , Clorofórmio , Temperatura Baixa , Ésteres , Espectroscopia de Ressonância Magnética , Conformação Molecular , Neurotoxinas/química , Agonistas de Canais de Sódio , Veratridina/química , Veratrina/química
18.
J Neurochem ; 103(3): 1196-207, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17935604

RESUMO

Glutamate release induced by mild depolarization was studied in astroglial preparations from the adult rat cerebral cortex, that is acutely isolated glial sub-cellular particles (gliosomes), cultured adult or neonatal astrocytes, and neuron-conditioned astrocytes. K+ (15, 35 mmol/L), 4-aminopyridine (0.1, 1 mmol/L) or veratrine (1, 10 micromol/L) increased endogenous glutamate or [3H]D-aspartate release from gliosomes. Neurotransmitter release was partly dependent on external Ca2+, suggesting the involvement of exocytotic-like processes, and partly because of the reversal of glutamate transporters. K+ increased gliosomal membrane potential, cytosolic Ca2+ concentration [Ca2+]i, and vesicle fusion rate. Ca2+ entry into gliosomes and glutamate release were independent from voltage-sensitive Ca2+ channel opening; they were instead abolished by 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiurea (KB-R7943), suggesting a role for the Na+/Ca2+ exchanger working in reverse mode. K+ (15, 35 mmol/L) elicited increase of [Ca2+]i and Ca2+-dependent endogenous glutamate release in adult, not in neonatal, astrocytes in culture. Glutamate release was even more marked in in vitro neuron-conditioned adult astrocytes. As seen for gliosomes, K+-induced Ca2+ influx and glutamate release were abolished by KB-R7943 also in cultured adult astrocytes. To conclude, depolarization triggers in vitro glutamate exocytosis from in situ matured adult astrocytes; an aptitude grounding on Ca2+ influx driven by the Na+/Ca2+ exchanger working in the reverse mode.


Assuntos
Astrócitos/metabolismo , Sinalização do Cálcio/fisiologia , Córtex Cerebral/metabolismo , Exocitose/fisiologia , Trocador de Sódio e Cálcio/metabolismo , Animais , Animais Recém-Nascidos , Astrócitos/efeitos dos fármacos , Cálcio/metabolismo , Canais de Cálcio/efeitos dos fármacos , Canais de Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Exocitose/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Fusão de Membrana/efeitos dos fármacos , Fusão de Membrana/fisiologia , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Potássio/metabolismo , Potássio/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Ratos , Ratos Sprague-Dawley , Trocador de Sódio e Cálcio/efeitos dos fármacos , Sinaptossomos , Vesículas Transportadoras/efeitos dos fármacos , Vesículas Transportadoras/metabolismo , Veratrina/farmacologia , Proteínas Vesiculares de Transporte de Glutamato/efeitos dos fármacos , Proteínas Vesiculares de Transporte de Glutamato/metabolismo
19.
Prog Neuropsychopharmacol Biol Psychiatry ; 31(6): 1307-11, 2007 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-17619070

RESUMO

Lamotrigine exhibits an anti-immobility effect in the modified forced swimming test, increasing swimming and climbing, behaviors that are related to serotonergic and noradrenergic effects, respectively. However, these effects could be secondary to lamotrigine blockade of Na(+) sensitive channel. Thus, this study investigated the influence of veratrine (0.1 mg/kg, ip, 10 min before each lamotrigine administration), an Na(+) channel activator, in the effect of lamotrigine (20 mg/kg, ip, 24, 5, 1 h before the test session) in the modified forced swimming test. Veratrine pre-treatment blocked lamotrigine-induced immobility decrease and swimming increase but it did not change the effect of lamotrigine on climbing. These results suggest that the serotonergic effect of lamotrigine in the modified forced swimming test is dependent on Na(+) voltage sensitive channel blockade, whereas its noradrenergic effect is not.


Assuntos
Anticonvulsivantes/farmacologia , Reação de Congelamento Cataléptica/efeitos dos fármacos , Natação/psicologia , Triazinas/farmacologia , Veratrina/farmacologia , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Interações Medicamentosas , Comportamento Exploratório/efeitos dos fármacos , Lamotrigina , Masculino , Ratos , Ratos Wistar
20.
Am J Physiol Heart Circ Physiol ; 292(2): H971-5, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17287453

RESUMO

Both enhanced sympathetic drive and altered autonomic control are involved in the pathogenesis of heart failure. The goal of the present study was to determine the extent to which chronically enhanced sympathetic drive, in the absence of heart failure, alters reflex autonomic control in conscious, transgenic (TG) rabbits with overexpressed cardiac Gsalpha. Nine TG rabbits and seven wild-type (WT) littermates were instrumented with a left ventricular (LV) pressure micromanometer and arterial catheters and studied in the conscious state. Compared with WT rabbits, LV function was enhanced in TG rabbits, as reflected by increased levels of LV dP/dt (5,600 +/- 413 vs. 3,933 +/- 161 mmHg/s). Baseline heart rate was also higher (P < 0.05) in conscious TG (247 +/- 10 beats/min) than in WT (207 +/- 10 beats/min) rabbits and was higher in TG after muscarinic blockade (281 +/- 9 vs. 259 +/- 8 beats/min) or combined beta-adrenergic receptor and muscarinic blockade (251 +/- 6 vs. 225 +/- 9 beats/min). Bradycardia was blunted (P < 0.05), whether induced by intravenous phenylephrine (arterial baroreflex), by cigarette smoke inhalation (nasopharyngeal reflex), or by veratrine administration (Bezold-Jarisch reflex). With veratrine administration, the bradycardia was enhanced in TG for any given decrease in arterial pressure. Thus the chronically enhanced sympathetic drive in TG rabbits with overexpressed cardiac Gsalpha resulted in enhanced LV function and heart rate and impaired reflex autonomic control. The impaired reflex control was generalized, not only affecting the high-pressure arterial baroreflex but also the low-pressure Bezold-Jarisch reflex and the nasopharyngeal reflex.


Assuntos
Bradicardia/fisiopatologia , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Miocárdio/metabolismo , Reflexo , Sistema Nervoso Simpático/fisiopatologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Animais Geneticamente Modificados , Atropina/farmacologia , Sistema Nervoso Autônomo/fisiopatologia , Barorreflexo , Pressão Sanguínea , Bradicardia/induzido quimicamente , Bradicardia/metabolismo , Estimulação Elétrica , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Frequência Cardíaca , Antagonistas Muscarínicos/farmacologia , Fenilefrina , Propranolol/farmacologia , Coelhos/genética , Fumaça/efeitos adversos , Sistema Nervoso Simpático/efeitos dos fármacos , Tabaco , Nervo Vago/fisiopatologia , Função Ventricular Esquerda , Veratrina
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