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2.
Fundam Clin Pharmacol ; 33(3): 314-326, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30365180

RESUMO

Childhood digestive disorders are a common occurrence and are sometimes unexplained. Maternal medication during the development of the foetus' digestive system may contribute to the increase in childhood digestive disorders, especially with drugs acting on the cholinergic system. This study investigated the association between prenatal exposure to drugs with atropinic properties and the use of digestive disorder medications in childhood (0-3 years). Children from POMME (PrescriptiOn Médicaments Mères Enfants), a French database of reimbursed drugs for pregnant women and their children, were included (N = 8 372). Each drug prescribed during antenatal life was assigned an atropinic score (0 = null, 1 = low, 3 = strong). The prenatal atropinic burden was calculated as the sum of atropinic scores of drugs prescribed. More than 30% (N = 2 652) of the children were prenatally exposed to atropinic drugs. They used significantly more digestive disorder medications than unexposed children (RRa = 1.11 [1.06; 1.16]). The strength of the association increased with the prenatal atropinic burden. Our results suggest long-term digestive effects after prenatal exposure to atropinic drugs.


Assuntos
Antagonistas Colinérgicos/efeitos adversos , Fármacos Gastrointestinais/administração & dosagem , Gastroenteropatias/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Adulto , Derivados da Atropina/administração & dosagem , Derivados da Atropina/efeitos adversos , Pré-Escolar , Antagonistas Colinérgicos/administração & dosagem , Estudos de Coortes , Bases de Dados Factuais , Feminino , França/epidemiologia , Gastroenteropatias/tratamento farmacológico , Gastroenteropatias/etiologia , Humanos , Lactente , Recém-Nascido , Masculino , Gravidez , Adulto Jovem
3.
J Am Chem Soc ; 140(30): 9392-9395, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30020777

RESUMO

Enantioselectivity increases with increasing carbonyl electrophilicity in 2-propanol-mediated reductive couplings of aldehydes with branched aryl-substituted allylic acetates to form products of carbonyl anti-(α-aryl)allylation. This unusual phenomenon is caused by aldehyde coordination to diastereomeric kinetic vs thermodynamic carbonyl binding sites that deliver enantiomeric products. Exploiting this effect, anti-diastereo- and enantioselective (α-aryl)allylations of fluoral hydrate and difluoroacetaldehyde ethyl hemiacetal were developed.


Assuntos
Acetaldeído/análogos & derivados , Acetais/síntese química , Compostos Alílicos/síntese química , Derivados da Atropina/síntese química , Irídio/química , 2-Propanol/química , Acetaldeído/química , Acetatos/química , Catálise , Cinética , Oxirredução , Estereoisomerismo , Termodinâmica
4.
J Am Chem Soc ; 140(24): 7433-7436, 2018 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-29870653

RESUMO

Hyoscyamine 6ß-hydroxylase (H6H) is an α-ketoglutarate dependent mononuclear nonheme iron enzyme that catalyzes C6-hydroxylation of hyoscyamine and oxidative cyclization of the resulting product to give the oxirane natural product scopolamine. Herein, the chemistry of H6H is investigated using hyoscyamine derivatives with modifications at the C6 or C7 position as well as substrate analogues possessing a 9-azabicyclo[3.3.1]nonane core. Results indicate that hydroxyl rebound is unlikely to take place during the cyclization reaction and that the hydroxylase versus oxidative cyclase activity of H6H is correlated with the presence of an exo-hydroxy group having syn-periplanar geometry with respect to the adjacent H atom to be abstracted.


Assuntos
Derivados da Atropina/química , Oxigenases de Função Mista/química , Catálise , Ciclização , Hidroxilação , Modelos Químicos , Conformação Molecular , Oxirredução
5.
Plant Cell Physiol ; 59(1): 107-118, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29095998

RESUMO

Tropane alkaloids (TAs), especially hyoscyamine and scopolamine, are important precursors for anticholinergic and antispasmodic drugs. Hyoscyamine and scopolamine are currently obtained at commercial scale from hybrid crosses of Duboisia myoporoides × Duboisia leichhardtii plants. In this study, we present a global investigation of the localization and organization of TA biosynthesis in a Duboisia myoporoides R. Br. wild-type line. The tissue-specific spatial distribution of TAs within D. myoporoides is presented, including quantification of the TAs littorine, 6-hydroxy hyoscyamine, hyoscyamine, scopolamine and, additionally, hyoscyamine aldehyde as well as scopolamine glucoside. Scopolamine (14.77 ± 5.03 mg g-1), and to a lesser extent hyoscyamine (3.01 ± 1.54 mg g-1) as well as 6-hydroxy hyoscyamine (4.35 ± 1.18 mg g-1), are accumulated in leaves during plant development, with the highest concentration of total TAs detected in 6-month-old plants. Littorine, an early precursor in TA biosynthesis, was present only in the roots (0.46 ± 0.07 mg g-1). During development, the spatial distribution of all investigated alkaloids changed due to secondary growth in the roots. Transcripts of pmt, tr-I and cyp80f1 genes, involved in early stages of TA biosynthesis, were found to be most abundant in the roots. In contrast, the transcript encoding hyoscyamine 6ß-hydroxylase (h6h) was highest in the leaves of 3-month-old plants. This investigation presents the spatial distribution of biochemical components as well as gene expression profiles of genetic factors known to participate in TA biosynthesis in D. myoporoides. The results of this investigation may aid in future breeding or genetic enhancement strategies aimed at increasing the yields of TAs in these medicinally valuable plant species.


Assuntos
Alcaloides/biossíntese , Duboisia/metabolismo , Escopolamina/metabolismo , Tropanos/metabolismo , Derivados da Atropina/metabolismo , Vias Biossintéticas/genética , Duboisia/genética , Duboisia/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento , Regulação da Expressão Gênica de Plantas , Hiosciamina/biossíntese , Oxigenases de Função Mista/genética , Oxigenases de Função Mista/metabolismo , Folhas de Planta/genética , Folhas de Planta/crescimento & desenvolvimento , Folhas de Planta/metabolismo , Raízes de Plantas/genética , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/metabolismo , Plantas Medicinais/genética , Plantas Medicinais/crescimento & desenvolvimento , Plantas Medicinais/metabolismo , Alcaloides de Solanáceas/biossíntese
6.
Sci Rep ; 7(1): 8428, 2017 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-28814785

RESUMO

Spectral analysis of heart rate (HR) has been widely used to assess the autonomic cardiovascular control. A nonlinear approach, known as symbolic analysis, has been reported to be very useful to assess the autonomic control of cardiovascular system in humans, but very few studies reported on the differences between these two approaches on experimental models. Two distinct approaches were used to elicit autonomic changes in conscious Wistar rats: (1) pharmacological blockade of cardiac autonomic receptors with atenolol (ATE, N = 9) or methylatropine (ATR, N = 9) and (2) mild changes in arterial pressure (AP) induced by phenylephrine (PHE, N = 9) or sodium nitroprusside (NPS, N = 9). Series of cardiac interval (CI) and systolic AP (SAP) were assessed using spectral analysis and symbolic dynamics. Results show that, for spectral analysis, the power in high frequency band of CI and the power in low frequency band of SAP are the most reliable indices of vagal and sympathetic modulation, respectively. For symbolic analysis, results point 0V% and 1V% to be related to sympathetic and 2UV% to vagal modulation. Interestingly, the incidence of 1V patterns, hitherto with unknown meaning, was revealed the best index of sympathetic modulation in the rat and should be accounted for in the future studies.


Assuntos
Frequência Cardíaca/fisiologia , Análise Espectral/métodos , Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Animais , Atenolol/farmacologia , Derivados da Atropina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Eletrocardiografia , Análise de Fourier , Frequência Cardíaca/efeitos dos fármacos , Masculino , Nitroprussiato/farmacologia , Fenilefrina/farmacologia , Ratos Wistar
7.
Behav Neurosci ; 131(4): 312-24, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28714717

RESUMO

Acetylcholine contributes to accurate performance on some navigational tasks, but details of its contribution to the underlying brain signals are not fully understood. The medial septal area provides widespread cholinergic input to various brain regions, but selective damage to medial septal cholinergic neurons generally has little effect on landmark-based navigation, or the underlying neural representations of location and directional heading in visual environments. In contrast, the loss of medial septal cholinergic neurons disrupts navigation based on path integration, but no studies have tested whether these path integration deficits are associated with disrupted head direction (HD) cell activity. Therefore, we evaluated HD cell responses to visual cue rotations in a familiar arena, and during navigation between familiar and novel arenas, after muscarinic receptor blockade with systemic atropine. Atropine treatment reduced the peak firing rate of HD cells, but failed to significantly affect other HD cell firing properties. Atropine also failed to significantly disrupt the dominant landmark control of the HD signal, even though we used a procedure that challenged this landmark control. In contrast, atropine disrupted HD cell stability during navigation between familiar and novel arenas, where path integration normally maintains a consistent HD cell signal across arenas. These results suggest that acetylcholine contributes to path integration, in part, by facilitating the use of idiothetic cues to maintain a consistent representation of directional heading. (PsycINFO Database Record


Assuntos
Acetilcolina/fisiologia , Cabeça/fisiologia , Navegação Espacial/fisiologia , Acetilcolina/química , Acetilcolina/metabolismo , Animais , Derivados da Atropina/farmacologia , Mapeamento Encefálico/métodos , Neurônios Colinérgicos/fisiologia , Sinais (Psicologia) , Feminino , Ratos , Ratos Long-Evans , Transdução de Sinais
8.
Brain Struct Funct ; 222(9): 4219-4237, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28656372

RESUMO

A remarkable example of maladaptive plasticity is the development of epilepsy after a brain insult or injury to a normal animal or human. A structure that is considered central to the development of this type of epilepsy is the dentate gyrus (DG), because it is normally a relatively inhibited structure and its quiescence is thought to reduce hippocampal seizure activity. This characteristic of the DG is also considered to be important for normal hippocampal-dependent cognitive functions. It has been suggested that the brain insults which cause epilepsy do so because they cause the DG to be more easily activated. One type of brain insult that is commonly used is induction of severe seizures (status epilepticus; SE) by systemic injection of a convulsant drug. Here we describe an alteration in the DG after this type of experimental SE that may contribute to chronic seizures that has not been described before: large folds or gyri that develop in the DG by 1 month after SE. Large gyri appeared to increase network excitability because epileptiform discharges recorded in hippocampal slices after SE were longer in duration when recorded inside gyri relative to locations outside gyri. Large gyri may also increase excitability because immature adult-born neurons accumulated at the base of gyri with time after SE, and previous studies have suggested that abnormalities in adult-born DG neurons promote seizures after SE. In summary, large gyri after SE are a common finding in adult rats, show increased excitability, and are associated with the development of an abnormal spatial distribution of adult-born neurons. Together these alterations may contribute to chronic seizures and associated cognitive comorbidities after SE.


Assuntos
Giro Denteado/fisiologia , Neurogênese/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Estado Epiléptico/patologia , Análise de Variância , Animais , Derivados da Atropina/farmacologia , Bicuculina/análogos & derivados , Bicuculina/farmacologia , Bromodesoxiuridina/metabolismo , Giro Denteado/efeitos dos fármacos , Agonistas de Aminoácidos Excitatórios/toxicidade , Feminino , Antagonistas de Receptores de GABA-A/farmacologia , Técnicas In Vitro , Ácido Caínico/toxicidade , Masculino , Agonistas Muscarínicos/toxicidade , Neurogênese/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Parassimpatolíticos/farmacologia , Fosfopiruvato Hidratase/metabolismo , Pilocarpina/toxicidade , Ratos , Ratos Sprague-Dawley , Estado Epiléptico/induzido quimicamente , Fatores de Tempo
9.
J Pharm Biomed Anal ; 143: 237-240, 2017 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-28618339

RESUMO

For the first time, an HPLC-MS/MS method for the determination pmol/l levels of troventol (TRV) and clenbuterol as an internal standard (IS) in human plasma was developed, validated and tested on biological samples. The method included solid phase extraction by Waters Oasis WCX cartridges and chromatographic separation on a YMC-Pack SIL (100mm×2.1mm, 5µm, 12nm) analytical column with acetonitrile-water-formic acid (50:50:0.1, v/v/v) as the mobile phase; the selected ion transitions were m/z 332.2→138.2 and m/z 277.0→203.1 for TRV and IS, respectively, in positive ionization mode. The calibration curve for TRV showed good linearity in the concentration range of 35-500pg/ml. The method was applied to real samples taken from healthy subjects after inhalation of an aerosol containing 640µg of TRV.


Assuntos
Espectrometria de Massas em Tandem , Derivados da Atropina , Calibragem , Cromatografia Líquida de Alta Pressão , Humanos , Reprodutibilidade dos Testes , Extração em Fase Sólida
10.
ACS Chem Neurosci ; 8(4): 712-717, 2017 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-28044440

RESUMO

Quaternary ammonium analogues of atropine that are unable to cross the blood-brain barrier are used to alleviate peripheral muscarinic toxicity in animal models of epilepsy produced by systemic administration of pilocarpine or diisopropylfluorophosphate (DFP). Currently, methylatropine is the most popular and potent of these quaternary derivatives; however, it is expensive and produced in limited quantity. Here, we propose the use of ethylatropine bromide as an alternative to methylatropine. The synthesis of ethylatropine bromide is simple, inexpensive and has low environmental impact. We demonstrate the efficacy of ethylatropine bromide to antagonize the carbachol induced rise in intracellular calcium in a calcium mobilization assay, and its ability to prevent pilocarpine-induced total fluid secretions in mice without blocking pilocarpine-induced seizures. The ease of synthesis, cost effectiveness, and efficacy makes ethylatropine bromide a desirable alternative to methylatropine as a peripherally restricted acetylcholine receptor antagonist.


Assuntos
Derivados da Atropina/farmacologia , Antagonistas Muscarínicos/farmacologia , Animais , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Agonistas Muscarínicos/toxicidade , Técnicas de Patch-Clamp , Pilocarpina/toxicidade
11.
Br J Clin Pharmacol ; 82(2): 478-86, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27085086

RESUMO

AIM: The aim of this study was to evaluate the potential effect of in utero exposure to drugs with atropinic properties on infant psychological development using atropinic burden (AB) scales. METHODS: Women from the EFEMERIS cohort, a French database including prescribed and dispensed reimbursed drugs during pregnancy and pregnancy outcomes, delivering between 2004 and 2010 were included (n = 43 740). Each drug was classified as having no (score = 0), few (score = 1) or strong (score = 3) atropinic properties. AB per woman was calculated by adding the atropinic scores of drugs prescribed during pregnancy. AB was categorized as exposure or no exposure. Secondary analyses were performed by dividing the exposure into four scores = [0], [1-8], [9-17] and [≥18]. Data for psychological development were extracted from children's medical certificates completed at 9 and 24 months. RESULTS: Thirty-four% (n = 14 925) of women received at least one atropinic drug during pregnancy. Women with AB ≥1 were older and received more drugs during pregnancy than unexposed women. At 24 months, more infants of mothers with AB ≥1 had difficulties to 'name a picture' (ORa , 1.18, 95% CI 1.03, 1.36) and to 'understand instructions' (ORa , 1.61, 95% CI 1.13, , 2.30]) compared with infants of unexposed women. Analyses of four groups of exposure and analyses excluding women receiving psychotropics led to similar results. CONCLUSIONS: The study showed significant association between in utero exposure to drugs with atropinic properties and fewer infant cognitive acquisitions at 24 months. Further exploring the potential effect of simultaneous use of drugs with atropinic effects among pregnant women will bring into consideration whether such prescriptions could be inappropriate for the child.


Assuntos
Derivados da Atropina/efeitos adversos , Resultado da Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Adulto , Fatores Etários , Derivados da Atropina/administração & dosagem , Desenvolvimento Infantil/efeitos dos fármacos , Pré-Escolar , Estudos de Coortes , Bases de Dados Factuais , Feminino , Seguimentos , França , Humanos , Lactente , Recém-Nascido , Masculino , Gravidez
12.
Basic Clin Pharmacol Toxicol ; 119(5): 453-457, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27098245

RESUMO

The cholinergic anti-inflammatory pathway (CAP) is a complex neuroimmune mechanism triggered by the central nervous system to regulate peripheral inflammatory responses. Understanding the role of CAP in the pathogenesis of rheumatoid arthritis (RA) could help develop new therapeutic strategies for this disease. Therefore, we investigated the participation of this neuroimmune pathway on the progression of experimental arthritis. Using antigen-induced arthritis (AIA) model, we investigated in mice the effects of vagotomy or the pharmacological treatments with hexamethonium (peripheral nicotinic receptor antagonist), methylatropine (peripheral muscarinic receptor antagonist) or neostigmine (peripheral acetylcholinesterase inhibitor) on AIA progression. Unilateral cervical vagotomy was performed 1 week before the immunization protocol with methylated bovine serum albumin (mBSA), while drug administration was conducted during the period of immunization. On day 21, 6 hr after the challenge with mBSA injection in the femur-tibial joint, the local neutrophil migration and articular mechanical hyperalgesia were assessed. Herein, we observed that vagotomy or blockade of peripheral nicotinic (but not muscarinic) receptors exacerbated the clinical parameters of this disease. Moreover, peripheral acetylcholinesterase inhibition by neostigmine treatment promoted a reduction of neutrophil recruitment in the knee joint and articular hyperalgesia. Our results demonstrated that peripheral activation of CAP modulates experimental arthritis, providing a pre-clinical evidence of a potential therapeutic strategy for RA.


Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Neurônios Colinérgicos/imunologia , Vias Eferentes/imunologia , Hiperalgesia/tratamento farmacológico , Neuroimunomodulação/efeitos dos fármacos , Infiltração de Neutrófilos/efeitos dos fármacos , Animais , Antígenos/efeitos adversos , Artrite Experimental/tratamento farmacológico , Artrite Experimental/etiologia , Artrite Reumatoide/tratamento farmacológico , Derivados da Atropina/farmacologia , Inibidores da Colinesterase/farmacologia , Hexametônio/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Antagonistas Muscarínicos/farmacologia , Neostigmina/farmacologia , Antagonistas Nicotínicos/farmacologia , Soroalbumina Bovina , Vagotomia
13.
Auton Neurosci ; 194: 26-31, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26769133

RESUMO

Cardiac autonomic tone can be assessed either by estimating separately vagal and sympathetic tones or by evaluating the net effect of their interaction, the so-called sympathovagal balance (SVB). To compare the most commonly used methods in rats, telemetric recordings of the electrocardiogram were performed in normotensive WKY rats, and in groups of spontaneously hypertensive (SHR) rats that were either untreated or chronically treated with the cholinesterase inhibitor, pyridostigmine, to enhance vagal tone. Cardiac autonomic blockers were administered alone and in combination, so that heart rate (HR) could be measured (1) under resting conditions, (2) with either autonomic branch blocked, and (3) with both branches blocked (which provided intrinsic HR, iHR). SVB was assessed as the ratio of resting HR to iHR. This calculation pointed to a sympathetic predominance in untreated SHRs and even more so in WKY rats, and to a marked vagal predominance in pyridostigmine-treated SHRs. By contrast, the ratio between low and high frequency components (LF/HF) of RR interval spectra did not significantly differ between the groups. Each autonomic tone was quantified as the HR change induced by its selective blocker or as the difference between iHR and HR after blockade of its counterpart. Both pharmacological methods indicated vagal enhancement in treated SHRs, but provided opposite results in terms of vagal vs. sympathetic predominance. These data seriously question the use of the LF/HF ratio as an index of SVB, and the possibility to reliably estimate vagal and sympathetic tones separately through current pharmacological approaches in conscious rats.


Assuntos
Sistema Nervoso Autônomo/fisiologia , Estado de Consciência , Animais , Atenolol/farmacologia , Atropina/farmacologia , Derivados da Atropina/farmacologia , Sistema Nervoso Autônomo/efeitos dos fármacos , Eletrocardiografia , Frequência Cardíaca/efeitos dos fármacos , Masculino , Antagonistas Muscarínicos/farmacologia , Parassimpatolíticos/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Simpatolíticos/farmacologia , Fatores de Tempo , Nervo Vago/efeitos dos fármacos , Nervo Vago/fisiologia
14.
Neuromolecular Med ; 17(3): 251-69, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25920465

RESUMO

Exposure to organophosphorous (OP) nerve agents such as soman inhibits the critical enzyme acetylcholinesterase (AChE) leading to excessive acetylcholine accumulation in synapses, resulting in cholinergic crisis, status epilepticus and brain damage in survivors. The hippocampus is profoundly damaged after soman exposure leading to long-term memory deficits. We have previously shown that treatment with three sequential doses of alpha-linolenic acid, an essential omega-3 polyunsaturated fatty acid, increases brain plasticity in naïve animals. However, the effects of this dosing schedule administered after a brain insult and the underlying molecular mechanisms in the hippocampus are unknown. We now show that injection of three sequential doses of alpha-linolenic acid after soman exposure increases the endogenous expression of mature BDNF, activates Akt and the mammalian target of rapamycin complex 1 (mTORC1), increases neurogenesis in the subgranular zone of the dentate gyrus, increases retention latency in the passive avoidance task and increases animal survival. In sharp contrast, while soman exposure also increases mature BDNF, this increase did not activate downstream signaling pathways or neurogenesis. Administration of the inhibitor of mTORC1, rapamycin, blocked the alpha-linolenic acid-induced neurogenesis and the enhanced retention latency but did not affect animal survival. Our results suggest that alpha-linolenic acid induces a long-lasting neurorestorative effect that involves activation of mTORC1 possibly via a BDNF-TrkB-mediated mechanism.


Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Soman/toxicidade , Ácido alfa-Linoleico/farmacologia , Animais , Antígenos Nucleares/biossíntese , Antígenos Nucleares/genética , Derivados da Atropina/uso terapêutico , Aprendizagem da Esquiva/fisiologia , Dano Encefálico Crônico/etiologia , Dano Encefálico Crônico/fisiopatologia , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Fator Neurotrófico Derivado do Encéfalo/genética , Replicação do DNA/efeitos dos fármacos , Diazepam/uso terapêutico , Eletrochoque , Comportamento Exploratório/efeitos dos fármacos , Hipocampo/fisiopatologia , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Proteínas Associadas aos Microtúbulos/biossíntese , Proteínas Associadas aos Microtúbulos/genética , Complexos Multiproteicos/antagonistas & inibidores , Complexos Multiproteicos/biossíntese , Complexos Multiproteicos/genética , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Neuropeptídeos/biossíntese , Neuropeptídeos/genética , Fármacos Neuroprotetores/antagonistas & inibidores , Fármacos Neuroprotetores/uso terapêutico , Neurotoxinas/metabolismo , Oximas/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/biossíntese , Proteínas Proto-Oncogênicas c-akt/genética , Compostos de Piridínio/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptor trkB/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Sirolimo/farmacologia , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/complicações , Estado Epiléptico/tratamento farmacológico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/biossíntese , Serina-Treonina Quinases TOR/genética , Ácido alfa-Linoleico/antagonistas & inibidores , Ácido alfa-Linoleico/uso terapêutico
15.
Braz J Med Biol Res ; 48(6): 523-7, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25831206

RESUMO

The aim of this study was to investigate the effects of resistance exercise training on hemodynamics and cardiac autonomic control in ovariectomized spontaneously hypertensive rats. Female rats were divided into 4 groups: sedentary control (SC), sedentary hypertensive (SH), sedentary hypertensive ovariectomized (SHO), and resistance-trained hypertensive ovariectomized (RTHO). Resistance exercise training was performed on a vertical ladder (5 days/week, 8 weeks) at 40-60% maximal load. Direct arterial pressure was recorded. Vagal and sympathetic tones were measured by heart rate (HR) responses to methylatropine (3 mg/kg, iv) and propranolol (4 mg/kg, iv). Ovariectomy resulted in additional increases in blood pressure in hypertensive rats and was associated with decreased vagal tone. Resistance exercise trained rats had lower mean arterial pressure than untrained rats (RTHO: 159±2.2 vs SHO: 177±3.4 mmHg), as well as resting bradycardia (RTHO: 332±9.0 vs SHO: 356±5 bpm). Sympathetic tone was also lower in the trained group. Moreover, sympathetic tone was positively correlated with resting HR (r=0.7, P<0.05). The additional arterial pressure increase in hypertensive rats caused by ovarian hormone deprivation was attenuated by moderate-intensity dynamic resistance training. This benefit may be associated with resting bradycardia and reduced cardiac sympathetic tone after training, which suggests potential benefits of resistance exercise for the management of hypertension after ovarian hormone deprivation.


Assuntos
Sistema Nervoso Autônomo/fisiologia , Hemodinâmica/fisiologia , Hipertensão/fisiopatologia , Ovariectomia , Condicionamento Físico Animal/fisiologia , Treinamento de Resistência/métodos , Animais , Anti-Hipertensivos/farmacologia , Derivados da Atropina/farmacologia , Sistema Nervoso Autônomo/efeitos dos fármacos , Peso Corporal , Bradicardia/fisiopatologia , Bradicardia/prevenção & controle , Feminino , Hemodinâmica/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Menopausa/fisiologia , Parassimpatolíticos/farmacologia , Propranolol/farmacologia , Ratos Endogâmicos SHR , Ratos Wistar , Reprodutibilidade dos Testes , Fatores de Tempo
16.
Neuroscience ; 297: 262-71, 2015 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-25862588

RESUMO

We investigated the role of the autonomic nervous system to cardiovascular responses to obstructive apnea in awake, unrestrained rats, and measured expression of Fos induced by apnea in the brainstem. We implanted a tracheal balloon contained in a rigid tube to allow the induction of apnea without inducing pain in the trachea. During bouts of 15s of apnea, heart rate fell from 371±8 to 161±11bpm (mean±SEM, n=15, p<0.01) and arterial pressure increased from 115±2 to 131±4mmHg (p<0.01). Bradycardia was due to parasympathetic activity because it was blocked by the muscarinic antagonist, methylatropine. The pressor response was due to vasoconstriction caused by sympathetic activation because it was blocked by the α1 antagonist, prazosin. Apnea induced Fos expression in several brainstem areas involved in cardiorespiratory control such as the nucleus of the solitary tract (NTS), ventrolateral medulla (VLM), and pons. Ligation of the carotid body artery reduced apnea-induced bradycardia, blocked heart rate responses to i.v. injection of cyanide, reduced Fos expression in the caudal NTS, and increased Fos expression in the rostral VLM. In conclusion, apnea activates neurons in regions that process signals from baroreceptors, chemoreceptors, pulmonary receptors, and regions responsible for autonomic and respiratory activity both in the presence and absence of carotid chemoreceptors.


Assuntos
Apneia/patologia , Apneia/fisiopatologia , Tronco Encefálico/fisiopatologia , Vigília , Análise de Variância , Animais , Derivados da Atropina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Tronco Encefálico/efeitos dos fármacos , Corpo Carotídeo/citologia , Células Quimiorreceptoras/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Masculino , Proteínas Oncogênicas v-fos/metabolismo , Parassimpatolíticos/farmacologia , Prazosina/farmacologia , Ratos , Ratos Wistar , Tirosina 3-Mono-Oxigenase/metabolismo
17.
Hypertension ; 65(6): 1238-44, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25870195

RESUMO

Cardiac hypertrophy, which is commonly caused by hypertension, is a major risk factor for heart failure and sudden death. Endogenous ghrelin has been shown to exert a beneficial effect on cardiac dysfunction and postinfarction remodeling via modulation of the autonomic nervous system. However, ghrelin's ability to attenuate cardiac hypertrophy and its potential mechanism of action are unknown. In this study, cardiac hypertrophy was induced by transverse aortic constriction in ghrelin knockout mice and their wild-type littermates. After 12 weeks, the ghrelin knockout mice showed significantly increased cardiac hypertrophy compared with wild-type mice, as evidenced by their significantly greater heart weight/tibial length ratios (9.2±1.9 versus 7.9±0.8 mg/mm), left ventricular anterior wall thickness (1.3±0.2 versus 1.0±0.2 mm), and posterior wall thickness (1.1±0.3 versus 0.9±0.1 mm). Furthermore, compared with wild-type mice, ghrelin knockout mice showed suppression of the cholinergic anti-inflammatory pathway, as indicated by reduced parasympathetic nerve activity and higher plasma interleukin-1ß and interleukin-6 levels. The administration of either nicotine or ghrelin activated the cholinergic anti-inflammatory pathway and attenuated cardiac hypertrophy in ghrelin knockout mice. In conclusion, our results show that endogenous ghrelin plays a crucial role in the progression of pressure overload-induced cardiac hypertrophy via a mechanism that involves the activation of the cholinergic anti-inflammatory pathway.


Assuntos
Cardiomegalia/metabolismo , Colinérgicos , Grelina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Pressão Ventricular/fisiologia , Análise de Variância , Animais , Derivados da Atropina/farmacologia , Cardiomegalia/fisiopatologia , Modelos Animais de Doenças , Grelina/metabolismo , Camundongos , Camundongos Knockout , Nicotina/farmacologia , Distribuição Aleatória , Valores de Referência , Transdução de Sinais/fisiologia
18.
Am J Physiol Regul Integr Comp Physiol ; 308(8): R714-23, 2015 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-25673780

RESUMO

The crosstalk between the immune and the autonomic nervous system may impact the cardiovascular function. Toll-like receptors are components of the innate immune system and play developmental and physiological roles. Toll-like receptor 9 (TLR9) is involved in the pathogenesis of cardiovascular diseases, such as hypertension and heart failure. Since such diseases are commonly accompanied by autonomic imbalance and lower baroreflex sensitivity, we hypothesized that TLR9 modulates cardiac autonomic and baroreflex control of arterial pressure (AP). Toll-like receptor 9 knockout (TLR9 KO) and wild-type (WT) mice were implanted with catheters into carotid artery and jugular vein and allowed to recover for 3 days. After basal recording of AP, mice received methyl-atropine or propranolol. AP and pulse interval (PI) variability were evaluated in the time and frequency domain (spectral analysis), as well as by multiscale entropy. Spontaneous baroreflex was studied by sequence technique. Behavioral and cardiovascular responses to fear-conditioning stress were also evaluated. AP was similar between groups, but TLR9 KO mice exhibited lower basal heart rate (HR). AP variability was not different, but PI variability was increased in TLR9 KO mice. The total entropy was higher in TLR9 KO mice. Moreover, baroreflex function was found higher in TLR9 KO mice. Atropine-induced tachycardia was increased in TLR9 KO mice, whereas the propranolol-induced bradycardia was similar to WT mice. TLR9 KO mice exhibit increased behavioral and decreased tachycardia responses to fear-conditioning stress. In conclusion, our findings suggest that TLR9 may negatively modulate cardiac vagal tone and baroreflex in mice.


Assuntos
Pressão Arterial , Barorreflexo , Bradicardia/metabolismo , Sistema Cardiovascular/inervação , Imunidade Inata , Taquicardia/metabolismo , Receptor Toll-Like 9/metabolismo , Nervo Vago/metabolismo , Animais , Derivados da Atropina , Comportamento Animal , Bradicardia/induzido quimicamente , Bradicardia/genética , Bradicardia/imunologia , Bradicardia/fisiopatologia , Sistema Cardiovascular/imunologia , Condicionamento Psicológico , Modelos Animais de Doenças , Medo , Frequência Cardíaca , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Propranolol , Transdução de Sinais , Taquicardia/induzido quimicamente , Taquicardia/genética , Taquicardia/imunologia , Taquicardia/fisiopatologia , Fatores de Tempo , Receptor Toll-Like 9/deficiência , Receptor Toll-Like 9/genética , Nervo Vago/imunologia , Nervo Vago/fisiopatologia
19.
Am J Physiol Heart Circ Physiol ; 308(2): H101-7, 2015 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-25416192

RESUMO

We investigated the effects of acute pyridostigmine (PYR) treatment, an acetylcholinesterase inhibitor, on arterial pressure (AP), heart rate (HR), cardiac sympathovagal balance, and the incidence of arrhythmias during the first 4 h after myocardial infarction (MI) in anesthetized rats. Male Wistar rats were implanted with catheters into the femoral artery and vein for AP recordings and drug administration. Rats received the autonomic receptor blockers methyl-atropine (1 mg/kg iv) and propranolol (2 mg/kg iv) at intervals of 15 min, 1 h after saline (n=16) or PYR (0.25 mg/kg iv, n=18), to indirectly assess sympathovagal balance. Acute treatment with PYR increased cardiac vagal (86±7 vs. 44±5 beats/min) and decreased sympathetic tone (-31±8 vs. -69±7 beats/min). Different animals were implanted with ECG electrodes and catheters. A large MI was induced via left coronary artery ligation after basal recordings. Rats received PYR (n=14) or saline (n=14) 10-15 min after MI, and the recordings lasted up to 4 h. In part of the animals, hearts were removed for connexin43 quantification after all procedures. MI elicited a fall in AP (-45±5 mmHg), a progressive rise in HR (26±14 beats/min), and an increase in corrected QT interval (33±13 ms). PYR elicited a prompt bradycardia (-50±14 beats/min) that returned to basal levels over time, and it prevented the lengthening of the corrected QT interval. Treatment with PYR increased by ∼20% the occurrence of rats free of arrhythmias after MI. MI markedly decreased connexin43 in left ventricles, and PYR treatment partially prevented this decrease.


Assuntos
Arritmias Cardíacas/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Conexina 43/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Brometo de Piridostigmina/uso terapêutico , Animais , Arritmias Cardíacas/prevenção & controle , Derivados da Atropina/farmacologia , Pressão Sanguínea , Inibidores da Colinesterase/farmacologia , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Propranolol/farmacologia , Brometo de Piridostigmina/farmacologia , Ratos , Ratos Wistar , Nervo Vago/efeitos dos fármacos , Nervo Vago/fisiologia
20.
J Med Chem ; 57(15): 6739-50, 2014 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-25051097

RESUMO

Bivalent ligands of G protein-coupled receptors have been shown to simultaneously either bind to two adjacent receptors or to bridge different parts of one receptor protein. Recently, we found that bivalent agonists of muscarinic receptors can simultaneously occupy both the orthosteric transmitter binding site and the allosteric vestibule of the receptor protein. Such dualsteric agonists display a certain extent of subtype selectivity, generate pathway-specific signaling, and in addition may allow for designed partial agonism. Here, we want to extend the concept to bivalent antagonism. Using the phthal- and naphthalimide moieties, which bind to the allosteric, extracellular site, and atropine or scopolamine as orthosteric building blocks, both connected by a hexamethonium linker, we were able to prove a bitopic binding mode of antagonist hybrids for the first time. This is demonstrated by structure-activity relationships, site-directed mutagenesis, molecular docking studies, and molecular dynamics simulations. Findings revealed that a difference in spatial orientation of the orthosteric tropane moiety translates into a divergent M2/M5 subtype selectivity of the corresponding bitopic hybrids.


Assuntos
Derivados da Atropina/química , Antagonistas Muscarínicos/química , Naftalimidas/química , Ftalimidas/química , Derivados da Escopolamina/química , Regulação Alostérica , Animais , Derivados da Atropina/síntese química , Derivados da Atropina/farmacologia , Sítios de Ligação , Células CHO , Cricetulus , Agonismo Inverso de Drogas , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Agonistas Muscarínicos/síntese química , Agonistas Muscarínicos/química , Agonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/síntese química , Antagonistas Muscarínicos/farmacologia , Mutação , Naftalimidas/síntese química , Naftalimidas/farmacologia , Ftalimidas/síntese química , Ftalimidas/farmacologia , Ensaio Radioligante , Receptor Muscarínico M2/agonistas , Receptor Muscarínico M2/antagonistas & inibidores , Receptor Muscarínico M2/genética , Derivados da Escopolamina/síntese química , Derivados da Escopolamina/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade
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