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1.
Br J Anaesth ; 122(4): 437-447, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30857600

RESUMO

BACKGROUND: A pulmonary hypertensive crisis (PHC) can be a life-threatening condition. We established a PHC model by exposing rats with monocrotaline (MCT)-induced pulmonary hypertension to acute hypoxia, and investigated the effects of vasopressin, phenylephrine, and norepinephrine on the PHC. METHODS: Four weeks after MCT 60 mg kg-1 administration i.v., right ventricular systolic pressure (RVSP), systolic BP (SBP), mean BP (MBP), cardiac index (CI), and pulmonary vascular resistance index (PVRI) were measured. PHC defined as an RVSP exceeding or equal to SBP was induced by changing the fraction of inspiratory oxygen to 0.1. Rats were subsequently treated by vasopressin, phenylephrine, or norepinephrine, followed by assessment of systemic haemodynamics, isometric tension of femoral and pulmonary arteries, cardiac function, blood gas composition, and survival. RESULTS: PHC was associated with increased RV dilatation and paradoxical septal motion. Vasopressin increased MBP [mean (standard error)] from 52.6 (3.8) to 125.0 (8.9) mm Hg and CI from 25.4 (2.3) to 40.6 (1.8) ml min-1 100 g-1 while decreasing PVRI. Vasopressin also improved RV dilatation, oxygenation, and survival in PHC. In contrast, phenylephrine increased MBP from 54.8 (2.3) to 96.8 (3.2) mm Hg without improving cardiac pump function. Norepinephrine did not alter MBP. Vasopressin contracted femoral but not pulmonary arteries, whereas phenylephrine contracted both arterial beds. Hence, improvements with vasopressin in PHC might be associated with decreased PVRI and selective systemic vasoconstriction. CONCLUSIONS: In this rat model of a PHC, vasopressin, but not phenylephrine or norepinephrine, resulted in better haemodynamic and vascular recovery.


Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/etiologia , Hipóxia/complicações , Vasoconstritores/uso terapêutico , Vasopressinas/uso terapêutico , Doença Aguda , Animais , Avaliação Pré-Clínica de Medicamentos/métodos , Ecocardiografia , Hemodinâmica/efeitos dos fármacos , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/fisiopatologia , Hipóxia/fisiopatologia , Masculino , Monocrotalina , Nordefrin/farmacologia , Oxigênio/sangue , Pressão Parcial , Fenilefrina/farmacologia , Ratos Sprague-Dawley , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Vasopressinas/farmacologia
2.
Cell Physiol Biochem ; 47(2): 800-816, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29807365

RESUMO

BACKGROUND/AIMS: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a basic leucine-zipper transcription factor essential for cellular responses to oxidative stress. Degradation of Nrf2 in the cytoplasm, mediated by Keap1-Cullin3/RING box1 (Cul3-Rbx1) E3 ubiquitin ligase and the proteasome, is considered the primary pathway controlling the cellular abundance of Nrf2. Although the nucleus has been implicated in the degradation of Nrf2, little information is available on how this compartment participates in degrading Nrf2. METHODS: Here, we fused the photoconvertible fluorescent protein Dendra2 to Nrf2 and capitalized on the irreversible change in color (green to red) that occurs when Dendra2 undergoes photoconversion to study degradation of Dendra2-Nrf2 in single live cells. RESULTS: Using this approach, we show that the half-life (t1/2) of Dendra2-Nrf2 in the whole cell, under homeostatic conditions, is 35 min. Inhibition of the proteasome with MG-132 or induction of oxidative stress with tert-butylhydroquinone (tBHQ) extended the half-life of Dendra2-Nrf2 by 6- and 28-fold, respectively. By inhibiting nuclear export using Leptomycin B, we provide direct evidence that degradation of Nrf2 also occurs in the nucleus and involves PML-NBs (Promyelocytic Leukemia-nuclear bodies). We further demonstrate that co-expression of Dendra2-Nrf2 and Crimson-PML-I lacking two PML-I sumoylation sites (K65R and K490R) changed the decay rate of Dendra2-Nrf2 in the nucleus and stabilized the nuclear derived Nrf2 levels in whole cells. CONCLUSION: Altogether, our findings provide direct evidence for degradation of Nrf2 in the nucleus and suggest that modification of Nrf2 in PML nuclear bodies contributes to its degradation in intact cells.


Assuntos
Núcleo Celular/metabolismo , Proteínas Luminescentes/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Proteína da Leucemia Promielocítica/metabolismo , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Animais , Ácidos Graxos Insaturados/farmacologia , Meia-Vida , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Células Hep G2 , Humanos , Leupeptinas/farmacologia , Luz , Proteínas Luminescentes/genética , Camundongos , Microscopia de Fluorescência , Fator 2 Relacionado a NF-E2/genética , Nordefrin/análogos & derivados , Nordefrin/farmacologia , Proteínas Nucleares/metabolismo , Proteína da Leucemia Promielocítica/genética , Estabilidade Proteica/efeitos dos fármacos , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/genética , Sumoilação
3.
Semin Thorac Cardiovasc Surg ; 30(1): 62-68, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29360599

RESUMO

We aimed to empirically derive an inotrope score to predict real-time outcomes using the doses of inotropes after pediatric cardiac surgery. The outcomes evaluated included in-hospital mortality, prolonged hospital length of stay, and composite poor outcome (mortality or prolonged hospital length of stay). The study population included patients <18 years of age undergoing heart operations (with or without cardiopulmonary bypass) of varying complexity. To create this novel pediatric cardiac inotrope score (PCIS), we collected the data on the highest doses of 4 commonly used inotropes (epinephrine, norepinephrine, dopamine, and milrinone) in the first 24 hours after heart operation. We employed a hierarchical framework by representing discrete probability models with continuous latent variables that depended on the dosage of drugs for a particular patient. We used Bayesian conditional probit regression to model the effects of the inotropes on the mean of the latent variables. We then used Markov chain Monte Carlo simulations for simulating posterior samples to create a score function for each of the study outcomes. The training dataset utilized 1030 patients to make the scientific model. An online calculator for the tool can be accessed at https://soipredictiontool.shinyapps.io/InotropeScoreApp. The newly proposed empiric PCIS demonstrated a high degree of discrimination for predicting study outcomes in children undergoing heart operations. The newly proposed empiric PCIS provides a novel measure to predict real-time outcomes using the doses of inotropes among children undergoing heart operations of varying complexity.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Cardiotônicos/administração & dosagem , Técnicas de Apoio para a Decisão , Cálculos da Dosagem de Medicamento , Cardiopatias Congênitas/cirurgia , Hemodinâmica/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Fatores Etários , Teorema de Bayes , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Procedimentos Cirúrgicos Cardíacos/mortalidade , Cardiotônicos/efeitos adversos , Pré-Escolar , Tomada de Decisão Clínica , Simulação por Computador , Dopamina/administração & dosagem , Epinefrina/administração & dosagem , Feminino , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/mortalidade , Cardiopatias Congênitas/fisiopatologia , Mortalidade Hospitalar , Humanos , Lactente , Recém-Nascido , Tempo de Internação , Masculino , Cadeias de Markov , Milrinona/administração & dosagem , Método de Monte Carlo , Nordefrin/administração & dosagem , Razão de Chances , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
4.
Life Sci ; 193: 1-8, 2018 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-29208463

RESUMO

AIMS: Vascular calcification (VC) underlies substantial cardiovascular morbidity and mortality. No clinically therapies have emerged presently. Stellate ganglion block (SGB) is one of the most often used sympathetic blockade procedure, and regulates vascular dilation. However, the effect of SGB on VC is still unknown. Therefore, we aimed to identify the ameliorative effect of SGB on VC. KEY FINDING: In vivo VC was induced in rats by administering vitamin D3 plus nicotine (VDN), and in vitro calcification of rat aortic vascular smooth muscle cells (VSMC) was induced by ß-glycerophosphate. In VDN rats, alkaline phosphatase (ALP) activity and Calcium contents were higher than that in control rats. The transformation of VSMC from contractile to osteoblast-like phenotype was observed in calcified aorta. SGB ameliorated the increase of ALP activity and Calcium content, and the transformation of VSMC in calcified aorta. The stimulation of endoplasmic reticulum stress (ERS) in calcified aorta was also attenuated by SGB treatment. The inducer of ERS, tunicamycin could block the beneficial effect of SGB on VC, and the ERS inhibitor, 4-PBA could mimic the amelioration of SGB. Furthermore, SGB attenuated the increased plasma levels of norepinephrine in VDN rats. In vitro experiments, norepinephrine exaggerated VSMC calcification, phenotype transformation and ERS. SIGNIFICANCE: These results demonstrate that SGB could inhibit sympathetic nervous activity, and then prevent the activation of ERS followed by ameliorating VC. Sympathetic over-activation might play critical role in the pathogenesis of VC, which provides new strategy and target for therapy and prevention of VC.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Gânglio Estrelado/fisiologia , Calcificação Vascular/terapia , Animais , Aorta/patologia , Bloqueio Nervoso Autônomo/métodos , Cálcio/farmacologia , Colecalciferol/farmacologia , Modelos Animais de Doenças , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Glicerofosfatos , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Nicotina/farmacologia , Nordefrin , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Gânglio Estrelado/metabolismo
6.
Brain Res ; 1631: 46-52, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26607254

RESUMO

Predatory odors, which can induce innate fear and stress responses in prey species, are frequently used in the development of animal models for several psychiatric diseases including post-traumatic stress disorder (PTSD) following a life-threatening event. We have previously shown that odors can be divided into at least three types; odors that act as (1) innate stressors, (2) as innate relaxants, or (3) have no innate effects on stress responses. Here, we attempted to verify whether an artificial odor, which had no innate effect on predatory odor-induced stress, could alleviate stress if experienced in early life as a habitat odor. In the current study, we demonstrated that the innate responses were changed to counteract stress following a postnatal experience. Moreover, we suggest that inhibitory circuits involved in stress-related neuronal networks and the concentrations of norepinephrine in the hippocampus may be crucial in alleviating stress induced by the predatory odor. Overall, these findings may be important for understanding the mechanisms involved in differential odor responses and also for the development of pharmacotherapeutic interventions that can alleviate stress in illnesses like PTSD.


Assuntos
Ecossistema , Odorantes , Olfato/fisiologia , Estresse Psicológico/prevenção & controle , Animais , Encéfalo/metabolismo , Medo/fisiologia , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nordefrin/metabolismo , Bulbo Olfatório/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Núcleos Septais/metabolismo , Transtornos de Estresse Pós-Traumáticos/metabolismo , Transtornos de Estresse Pós-Traumáticos/prevenção & controle , Estresse Psicológico/metabolismo
7.
Crit Care ; 18(4): R158, 2014 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-25056510

RESUMO

INTRODUCTION: Circulatory failure during brain death organ donor resuscitation is a problem that compromises recovery of organs. Combined administration of steroid, thyroxine and vasopressin has been proposed to optimize the management of brain deceased donors before recovery of organs. However the single administration of hydrocortisone has not been rigorously evaluated in any trial. METHODS: In this prospective multicenter cluster study, 259 subjects were included. Administration of low-dose steroids composed the steroid group (n = 102). RESULTS: Although there were more patients in the steroid group who received norepinephrine before brain death (80% vs. 66%: P = 0.03), mean dose of vasopressor administered after brain death was significantly lower than in the control group (1.18 ± 0.92 mg/H vs. 1.49 ± 1.29 mg/H: P = 0.03), duration of vasopressor support use was shorter (874 min vs. 1160 min: P < 0.0001) and norepinephrine weaning before aortic clamping was more frequent (33.8% vs. 9.5%: P < 0.0001). Using a survival approach, probability of norepinephrine weaning was significantly different between the two groups (P < 0.0001) with a probability of weaning 4.67 times higher in the steroid group than in the control group (95% CI: 2.30 - 9.49). CONCLUSIONS: Despite no observed benefits of the steroid administration on primary function recovery of transplanted grafts, administration of glucocorticoids should be a part of the resuscitation management of deceased donors with hemodynamic instability.


Assuntos
Morte Encefálica , Hemodinâmica/efeitos dos fármacos , Hidrocortisona/administração & dosagem , Nordefrin/administração & dosagem , Doadores de Tecidos , Obtenção de Tecidos e Órgãos/métodos , Vasopressinas/administração & dosagem , Idoso , Anti-Inflamatórios/administração & dosagem , Feminino , França , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Ressuscitação/métodos , Choque , Estatísticas não Paramétricas , Vasoconstritores/administração & dosagem
8.
Crit Care ; 18(6): 612, 2014 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-25672523

RESUMO

There is an increasing burden of responsibility for intensivists to optimize donation potential after the declaration of brain death in patients with catastrophic brain injury. Best practice for donor management, if present, has been formed on low quality and mainly observational studies or consensus. In particular, research into the use of corticosteroids has shown varied benefit. The specific and limited results of the CORTICOME study are less important than the systematic methodology and the development of rigour in the study of deceased organ donation. Donor management would benefit from continued systematic analysis of current literature, understanding of the physiologic basis for therapy, and further prospective controlled trials. Worldwide collaboration partnerships and funding are needed to optimize the management of deceased organ donation.


Assuntos
Morte Encefálica , Hemodinâmica/efeitos dos fármacos , Hidrocortisona/administração & dosagem , Nordefrin/administração & dosagem , Doadores de Tecidos , Obtenção de Tecidos e Órgãos/métodos , Vasopressinas/administração & dosagem , Feminino , Humanos , Masculino
9.
J Neurosci ; 33(11): 4867-74, 2013 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-23486957

RESUMO

The cervical sympathetic trunks (CSTs) contain axons of preganglionic neurons that innervate the superior cervical ganglia (SCGs). Because regeneration of CST fibers can be extensive and can reestablish certain specific patterns of SCG connections, restoration of end organ function would be expected. This expectation was examined with respect to the pineal gland, an organ innervated by the two SCGs. The activity of pineal serotonin N-acetyltransferase (NAT) exhibits a large circadian rhythm that is dependent on the sympathetic input of the gland, with high activity at night. Thirty-six hours after the CSTs were crushed bilaterally, nocturnal NAT was decreased by 99%. Three months later, enzyme activity had recovered only to 15% of control values, a recovery dependent on regeneration of CST fibers. Nevertheless, a small day/night rhythm was present in lesioned animals. Neither the density of the adrenergic innervation of the gland nor the ability of an adrenergic agonist to stimulate NAT activity was reduced in rats with regenerated CSTs. In addition, stimulation of the regenerated CST at a variety of frequencies was at least as effective in increasing NAT activity as seen with control nerves. These data suggest that the failure of pineal function to recover is not attributable to a quantitative deficit in the extent of reinnervation or synaptic efficacy. Rather, we suggest that there is some loss of specificity in the synaptic connections made in the SCG during reinnervation, resulting in a loss of the central neuronal information necessary for directing a normal NAT rhythm and thus normal pineal function.


Assuntos
Doenças do Sistema Nervoso Autônomo/patologia , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Axônios/patologia , Regeneração Nervosa/fisiologia , Glândula Pineal/fisiopatologia , Gânglio Cervical Superior/patologia , Animais , Arilalquilamina N-Acetiltransferase/metabolismo , Axônios/efeitos dos fármacos , Biofísica , Brocresina/farmacologia , Ritmo Circadiano/fisiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Estimulação Elétrica , Inibidores Enzimáticos/farmacologia , Regulação Enzimológica da Expressão Gênica/fisiologia , Isoproterenol/farmacologia , Masculino , Nordefrin/farmacologia , Glândula Pineal/metabolismo , Ratos , Ratos Sprague-Dawley , Gânglio Cervical Superior/efeitos dos fármacos , Simpatomiméticos/farmacologia , Fatores de Tempo , Tirosina 3-Mono-Oxigenase
10.
Biochim Biophys Acta ; 1824(4): 533-41, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22326747

RESUMO

Epinephrine is a naturally occurring adrenomedullary hormone that transduces environmental stressors into cardiovascular actions. As the only route in the catecholamine biosynthetic pathway, Phenylethanolamine N-methyltransferase (PNMT) catalyzes the synthesis of epinephrine. To elucidate the detailed mechanism of enzymatic catalysis of PNMT, combined quantum-mechanical/molecular-mechanical (QM/MM) calculations were performed. The calculation results reveal that this catalysis contains three elementary steps: the deprotonation of protonated norepinphrine, the methyl transferring step and deprotonation of the methylated norepinphrine. The methyl transferring step was proved to be the rate-determining step undergoing a SN2 mechanism with an energy barrier of 16.4kcal/mol. During the whole catalysis, two glutamic acids Glu185 and Glu219 were proved to be loaded with different effects according to the calculations results of the mutants. These calculation results can be used to explain the experimental observations and make a good complementarity for the previous QM study.


Assuntos
Simulação por Computador , Modelos Químicos , Feniletanolamina N-Metiltransferase/química , Biocatálise , Domínio Catalítico , Ácido Glutâmico/química , Humanos , Cinética , Metilação , Modelos Moleculares , Nordefrin/química , Oxirredução , Teoria Quântica , Termodinâmica
12.
Psychiatry Res ; 188(2): 197-202, 2011 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-21146875

RESUMO

Abnormalities in plasma monoamine metabolism reflect partly the illness of schizophrenia and sometimes the symptoms. Such studies have been repeatedly reported but have rarely taken both metabolites and parent amines or inter-amine activity ratios into account. In this study, the monoamines, their metabolites, turnovers and between-metabolite ratios in plasma were measured longitudinally in 32 schizophrenic patients treated with risperidone for 6 weeks, to examine possible biochemical alterations in schizophrenia, and to examine the association between treatment responses and psychopathology assessed according to the Positive and Negative Syndrome Scale (PANSS). The results showed lower level of plasma 3,4-dihydroxyphenylacetic acid (DOPAC) in relapsed versus first-episode schizophrenic patients, higher norepinephrine (NE) turnover rate (TR) in undifferentiated in comparison to paranoid schizophrenic patients and relatively higher metabolic activity of dopamine (DA) to serotonin (5-HT) in first-episode versus relapsed schizophrenic patients. Risperidone treatment induced a decrement of plasma DA levels and increments of plasma DOPAC and DA TR in the total group of schizophrenic patients. The turnover rate of 5-HT was was reduced in undifferentiated and relapsed subgroups of schizophrenic patients. The linkages between 5-HT TR, DA/NE relative activity and clinical symptomatology were also identified. These findings are consistent with an involvement of these systems in the pathogenesis of schizophrenia as well as in the responses to treatment, and the usefulness of certain biochemical indices as markers for subgrouping.


Assuntos
Antipsicóticos/uso terapêutico , Monoaminas Biogênicas/sangue , Risperidona/uso terapêutico , Esquizofrenia/sangue , Esquizofrenia/tratamento farmacológico , Ácido 3,4-Di-Hidroxifenilacético/sangue , Adulto , Análise de Variância , Monoaminas Biogênicas/metabolismo , Dopamina/sangue , Relação Dose-Resposta a Droga , Feminino , Humanos , Estudos Longitudinais , Masculino , Nordefrin/sangue , Escalas de Graduação Psiquiátrica , Serotonina/sangue , Estatística como Assunto , Estatísticas não Paramétricas , Fatores de Tempo , Adulto Jovem
13.
Anesth Prog ; 57(4): 139-44, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-21174567

RESUMO

The purpose of this prospective, randomized, double-blind crossover study was to compare the anesthetic efficacy of 2% mepivacaine with 1 : 20,000 levonordefrin versus 2% lidocaine with 1 : 100,000 epinephrine in maxillary central incisors and first molars. Sixty subjects randomly received, in a double-blind manner, maxillary central incisor and first molar infiltrations of 1.8 mL of 2% mepivacaine with 1 : 20,000 levonordefrin and 1.8 mL of 2% lidocaine with 1 : 100,000 epinephrine at 2 separate appointments spaced at least 1 week apart. The teeth were electric pulp tested in 2-minute cycles for a total of 60 minutes. Anesthetic success (obtaining 2 consecutive 80 readings with the electric pulp tester within 10 minutes) was not significantly different between 2% mepivacaine with 1 : 20,000 levonordefrin and 2% lidocaine with 1 : 100,000 epinephrine for the central incisor and first molar. However, neither anesthetic agent provided an hour of pulpal anesthesia.


Assuntos
Anestesia Dentária/métodos , Anestesia Local/métodos , Anestésicos Locais/administração & dosagem , Adulto , Estudos Cross-Over , Teste da Polpa Dentária , Método Duplo-Cego , Epinefrina/administração & dosagem , Feminino , Humanos , Lidocaína/administração & dosagem , Masculino , Maxila , Mepivacaína/administração & dosagem , Nordefrin/administração & dosagem , Estudos Prospectivos , Fatores de Tempo , Vasoconstritores/administração & dosagem , Adulto Jovem
14.
Dent Clin North Am ; 54(4): 687-96, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20831932

RESUMO

A clinically significant interaction between epinephrine or levonordefrin with nonselective beta-adrenergic blocking agents, although apparently rare in the dental setting, is potentially serious and can lead to significant hypertension with a concomitant reflex bradycardia. Based on the results of epinephrine infusion studies, the severity of the interaction seems dose related; small epinephrine doses cause less of a pressor response than larger doses. The interaction can be seen after intraoral submucosal injections but is generally of a smaller magnitude, at least with only 1 or 2 cartridges of lidocaine plus 1:100,000 epinephrine. However as demonstrated by 1 case report, some individuals are hypersensitive to this interaction. Inadvertent intravascular injections of local anesthetic plus vasoconstrictor and the use of high doses of vasoconstrictor are likely to result in a more pronounced response. Patients with significant cardiovascular disease may be especially vulnerable to the most serious sequelae resulting from the pressor reactions of the drug combination.


Assuntos
Antagonistas Adrenérgicos beta/efeitos adversos , Anestesia Dentária/efeitos adversos , Anestésicos Locais/efeitos adversos , Bradicardia/induzido quimicamente , Hipertensão/induzido quimicamente , Vasoconstritores/efeitos adversos , Antagonistas Adrenérgicos beta/farmacologia , Interações Medicamentosas , Epinefrina/efeitos adversos , Humanos , Metoprolol/efeitos adversos , Nordefrin/efeitos adversos , Propranolol/efeitos adversos
15.
J Neurochem ; 111(3): 696-702, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19694908

RESUMO

Recessively inherited loss-of-function mutations in the parkin, DJ-1, or PINK1 gene are linked to familial cases of early-onset Parkinson's diseases (PD), and heterozygous mutations are associated with increased incidence of late-onset PD. We previously reported that single knockout mice lacking Parkin, DJ-1, or PINK1 exhibited no nigral degeneration, even though evoked dopamine release from nigrostriatal terminals was reduced and striatal synaptic plasticity was impaired. In this study, we tested whether inactivation of all three recessive PD genes, each of which was required for nigral neuron survival in the aging human brain, resulted in nigral degeneration during the lifespan of mice. Surprisingly, we found that triple knockout mice lacking Parkin, DJ-1, and PINK1 have normal morphology and numbers of dopaminergic and noradrenergic neurons in the substantia nigra and locus coeruleus, respectively, at the ages of 3, 16, and 24 months. Interestingly, levels of striatal dopamine in triple knockout mice were normal at 16 months of age but increased at 24 months. These results demonstrate that inactivation of all three recessive PD genes is insufficient to cause significant nigral degeneration within the lifespan of mice, suggesting that these genes may be protective rather than essential for the survival of dopaminergic neurons during the aging process. These findings also support the notion that mammalian Parkin and PINK1 may function in the same genetic pathway as in Drosophila.


Assuntos
Degeneração Neural/genética , Neurônios/fisiologia , Proteínas Oncogênicas/deficiência , Proteínas Quinases/deficiência , Substância Negra/patologia , Ubiquitina-Proteína Ligases/deficiência , Fatores Etários , Animais , Contagem de Células/métodos , Dopamina/metabolismo , Eletroquímica/métodos , Locus Cerúleo/patologia , Camundongos , Camundongos Knockout , Nordefrin/metabolismo , Peroxirredoxinas , Proteína Desglicase DJ-1 , Tirosina 3-Mono-Oxigenase/metabolismo
16.
Aviakosm Ekolog Med ; 43(2): 27-9, 2009.
Artigo em Russo | MEDLINE | ID: mdl-19621799

RESUMO

The myoelectrode technique and microiontophoresis of physiologically active substances were applied to cats immobilized with neuromuscular relaxant to show that the classic neuromediators (acetylcholine, norepinephrine, GABA etc.) and regulatory peptides (enkephalins, TRHs, vasoactive intestinal peptide (VIP), somatostatin (SS) and others) can influence directly most neurons (58 to 100%) in the lateral vestibular nucleus (LVN). Enkephalins, VIP and SS retained largely their inhibitory effect on the neuron impulse activity in the presence of L-glutamate. Also, enkephalins, VIP and SS are able to stimulate or suppress the inhibitory effect of GABA and glycine. Consequently, the substances under study may act as LVN neuromediators and/or neuromodulators.


Assuntos
Acetilcolina/farmacologia , Nordefrin/farmacologia , Peptídeo Intestinal Vasoativo/farmacologia , Núcleo Vestibular Lateral/fisiologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Gatos , Iontoforese , Masculino , Microeletrodos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Núcleo Vestibular Lateral/efeitos dos fármacos , Simulação de Ausência de Peso
17.
Neuroscience ; 159(4): 1363-73, 2009 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-19409200

RESUMO

We have reported that hypoxia affects the hypothalamic-pituitary-adrenal (HPA) axis and behavior by driving the expression of central corticotropin-releasing hormone (CRH) and its receptors in adult mammals, and this effect is modulated by other factors. Here, we address whether or not intermittent hypoxia (IH) or restraint (R) or a combination of both (IH+R) during gestation would result in differential alteration of the HPA axis and behavior of the adult male offspring. Gravid rats were exposed to IH in a hypobaric chamber (10.8% O(2), altitude of 5 km), R, or both, daily for 4 h for 21 days. Control parameters were set at sea level (20.9% O(2)). All the stressors significantly and differentially increased CRH and corticotropin-releasing factor receptor type 1 (CRHR1) expression but decreased corticotropin-releasing factor receptor type 2 (CRHR2) in the paraventricular nucleus of the hypothalamus (PVN), enhanced CRHR1 mRNA and CRHR2 mRNA expression in the anterior pituitary, and increased plasma adrenocorticotropic hormone (ACTH) and corticosterone (CORT) levels and adrenal weight in adult male offspring aged 120 days. Furthermore, norepinephrine (NE) and dopamine (DA) levels significantly increased in the locus coeruleus (LC), while the percentage of entries into the open arms of the elevated-plus maze test (EPM) markedly declined. In all the above effects, the combination-induced effect was stronger than each stressor alone. Confocal imaging showed a rich colocalization of CRHR1 with CRH or urocortin I (Ucn I), and CRHR2 with CRH or urocortin III (Ucn III) in the PVN, and CRHR1 with CRH in the LC in EPM-tested groups. In conclusion, IH or R alone or both in combination during gestation sensitize the HPA axis and induce anxiety-like behavior of the adult male offspring, and the combined effects are significantly great than IH or R alone. The CRH-NE neural circuit between the PVN and LC through CRH receptor driving might partly be involved in the effects. The differential colocalization of CRH with CRHR1 might be the neural basis of these effects.


Assuntos
Ansiedade/etiologia , Hipóxia Fetal/complicações , Sistema Hipotálamo-Hipofisário/fisiopatologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Estresse Psicológico/complicações , Hormônio Adrenocorticotrópico/sangue , Animais , Ansiedade/fisiopatologia , Corticosterona/sangue , Dopamina/metabolismo , Feminino , Sistema Hipotálamo-Hipofisário/patologia , Masculino , Nordefrin/metabolismo , Sistema Hipófise-Suprarrenal/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/psicologia , RNA Mensageiro/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Restrição Física , Urocortinas/metabolismo
18.
Eur J Pharmacol ; 607(1-3): 60-7, 2009 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-19326476

RESUMO

Moxonidine (alpha2-adrenoceptor/imidazoline receptor agonist) injected into the lateral ventricle induces diuresis, natriuresis and renal vasodilation. Moxonidine-induced diuresis and natriuresis depend on central imidazoline receptors, while central alpha1-adrenoceptors are involved in renal vasodilation. However, the involvement of central alpha1-adrenoceptors on diuresis and natriuresis to central moxonidine was not investigated yet. In the present study, the effects of moxonidine, alpha-methylnoradrenaline (alpha2-adrenoceptor agonist) or phenylephrine (alpha1-adrenoceptor agonist) alone or combined with previous injections of prazosin (alpha1-adrenoceptor antagonist), yohimbine or RX 821002 (alpha2-adrenoceptor antagonists) intracerebroventricularly (i.c.v.) on urinary sodium, potassium and volume were investigated. Male Holtzman rats (n = 5-18/group) with stainless steel cannula implanted into the lateral ventricle and submitted to gastric water load (10% of body weight) were used. Injections of moxonidine (20 nmol) or alpha-methylnoradrenaline (80 nmol) i.c.v. induced natriuresis (196 +/- 25 and 171 +/- 30, respectively, vs. vehicle: 101 +/- 9 microEq/2 h) and diuresis (9.0 +/- 0.4 and 12.3 +/- 1.6, respectively, vs. vehicle: 5.2 +/- 0.5 ml/2 h). Pre-treatment with prazosin (320 nmol) i.c.v. abolished the natriuresis (23 +/- 4 and 76 +/- 11 microEq/2 h, respectively) and diuresis (5 +/- 1 and 7.6 +/- 0.8 ml/2 h, respectively) produced by i.c.v. moxonidine or alpha-methylnoradrenaline. RX 821002 (320 nmol) i.c.v. abolished the natriuretic effect of alpha-methylnoradrenaline, however, yohimbine (320 nmol) did not change renal responses to moxonidine. Phenylephrine (80 nmol) i.c.v. induced natriuresis and kaliuresis that were blocked by prazosin. Therefore, the present data suggest that moxonidine and alpha-methylnoradrenaline acting on central imidazoline receptors and alpha2-adrenoceptors, respectively, activate central alpha1-adrenergic mechanisms to increase renal excretion.


Assuntos
Agonistas alfa-Adrenérgicos/farmacologia , Imidazóis/farmacologia , Nordefrin/farmacologia , Receptores Adrenérgicos alfa 1/efeitos dos fármacos , Agonistas alfa-Adrenérgicos/administração & dosagem , Animais , Diurese/efeitos dos fármacos , Relação Dose-Resposta a Droga , Imidazóis/administração & dosagem , Receptores de Imidazolinas/efeitos dos fármacos , Receptores de Imidazolinas/metabolismo , Injeções Intraventriculares , Masculino , Natriurese/efeitos dos fármacos , Nordefrin/administração & dosagem , Fenilefrina/administração & dosagem , Fenilefrina/farmacologia , Potássio/urina , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/metabolismo , Sódio/urina
19.
Pediatr Pulmonol ; 44(1): 38-45, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19085921

RESUMO

INTRODUCTION: Adults with obstructive sleep apnea have increased sympathetic activity. It was hypothesized that in children with symptoms of obstructive sleep-disordered breathing (SDB), morning urine levels of catecholamines correlate with severity of nocturnal hypoxemia. METHODS: Children with snoring referred for polysomnography and controls without snoring were recruited. Morning urine norepinephrine, epinephrine, normetanephrine, and metanephrine levels were measured (ng/mg urine creatinine). RESULTS: Twelve children (age 5.2 +/- 2.3 years) with severe hypoxemia (oxygen saturation of hemoglobin-SpO2 nadir < or =86%), 20 subjects (age 6.1 +/- 2.1 years) with moderate hypoxemia (SpO2 nadir < or =90% and >86%), 22 children (age 6.6 +/- 1.5 years) with mild nocturnal hypoxemia (SpO2 nadir >90%), and 10 controls (age 7.1 +/- 2.8 years) were studied. Children with severe hypoxemia had significantly higher log-transformed norepinephrine levels (1.63 +/- 0.29) compared to those with moderate hypoxemia (1.43 +/- 0.22; P < 0.05) or compared to controls (1.39 +/- 0.31; P < 0.05). In subjects with SDB, log-transformed oxygen desaturation of hemoglobin index or SpO2 nadir predicted log-transformed norepinephrine levels after adjustment by age, gender and body mass index (r2 = 0.24; and r2 = 0.24, respectively; P < 0.01). CONCLUSIONS: Severity of nocturnal hypoxemia in children with intermittent upper airway obstruction during sleep correlates with morning urine levels of norepinephrine suggesting increased sympathetic tone.


Assuntos
Catecolaminas/urina , Hipóxia/urina , Nordefrin/urina , Apneia Obstrutiva do Sono/urina , Criança , Pré-Escolar , Feminino , Grécia , Humanos , Masculino , Fatores de Risco , Índice de Gravidade de Doença
20.
J Am Dent Assoc ; 139(8): 1080-93, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18682623

RESUMO

BACKGROUND: The authors conducted two multicenter, randomized, double-blinded, controlled Phase III clinical trials to study the efficacy and safety of phentolamine mesylate (PM) in shortening the duration and burden of soft-tissue anesthesia. The study involved 484 subjects who received one of four commercially available local anesthetic solutions containing vasoconstrictors for restorative or scaling procedures. METHODS: On completion of the dental procedure, subjects randomly received a PM or a sham injection (an injection in which a needle does not penetrate the soft tissue) in the same site as the local anesthetic injection. The investigators measured the duration of soft-tissue anesthesia by using standardized lip- and tongue-tapping procedures every five minutes for five hours. They also evaluated functional measures and subject-perceived altered function, sensation, appearance and safety. RESULTS: Median recovery times in the lower lip and tongue for subjects in the PM group were 70 minutes and 60 minutes, respectively. Median recovery times in the lower lip and tongue for subjects in the sham group were 155 minutes and 125 minutes, respectively. Upper lip median recovery times were 50 minutes for subjects in the PM group and 133 minutes for subjects in the sham group. These differences were significant (P < .0001). Recovery from actual functional deficits and subject-perceived altered function, sensation and appearance also showed significant differences between the PM and the sham groups. CONCLUSIONS: PM was efficacious and safe in reducing the duration of local anesthetic- induced soft-tissue numbness and its associated functional deficits. CLINICAL IMPLICATIONS: Clinicians can use PM to accelerate reversal of soft-tissue anesthesia and the associated functional deficits.


Assuntos
Antagonistas Adrenérgicos alfa/uso terapêutico , Anestesia Dentária , Anestésicos Locais/antagonistas & inibidores , Restauração Dentária Permanente , Raspagem Dentária , Fentolamina/uso terapêutico , Adolescente , Adulto , Idoso , Período de Recuperação da Anestesia , Carticaína/antagonistas & inibidores , Criança , Epinefrina/antagonistas & inibidores , Feminino , Humanos , Lidocaína/antagonistas & inibidores , Lábio/efeitos dos fármacos , Lábio/fisiologia , Masculino , Mepivacaína/antagonistas & inibidores , Pessoa de Meia-Idade , Nordefrin/antagonistas & inibidores , Prilocaína/antagonistas & inibidores , Segurança , Sensação/efeitos dos fármacos , Sensação/fisiologia , Fatores de Tempo , Língua/efeitos dos fármacos , Língua/fisiologia , Resultado do Tratamento , Vasoconstritores/antagonistas & inibidores
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