RESUMO
The main objective of the present study was to develop a sustained release multiple-unit beads of lamotrigine based on ionotropically cross-linked natural polysaccharides such as pectin (PTN) and okra mucilage (OM) and optimize the polymer-concentration, polymer ratio and cross-linker concentration by 23 full factorial design. Two different levels of three independent variables (total polymer concentration, polymer ratio and [CaCl2]) were considered for the experimental design. Drug-polymers compatibility was examined by FTIR, DSC, TGA and powder-XRD. The surface morphology of the bead before and after dissolution test was examined by SEM. Effects of the independent variables on bead-size, drug-encapsulation-efficiency (DEE), drug-release along with release similarity and difference factors were examined. The independent variables were then numerically optimized using Design-Expert software (Version 12) with the targets to meet USP-reference release profile after the analysis of variance of all the response parameters such as DEE, percent drug release at 2 h, 5 h, 12 h, Korsmeyer-Peppas rate constant, release similarity and difference factors. The optimized formulation showed excellent DEE of 89.2 ± 4.4% and a sustained release profile with release similarity factor of 94.9. Kinetic modeling of drug release data demonstrated a release mechanism combined of hydration, diffusion and erosion.
Assuntos
Abelmoschus/química , Portadores de Fármacos/química , Lamotrigina/administração & dosagem , Microesferas , Pectinas/química , Mucilagem Vegetal/química , Bloqueadores dos Canais de Sódio/administração & dosagem , Varredura Diferencial de Calorimetria , Preparações de Ação Retardada , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Tamanho da Partícula , Mucilagem Vegetal/isolamento & purificação , Espectroscopia de Infravermelho com Transformada de Fourier , Termogravimetria , Difração de Raios XRESUMO
Hyperbaric oxygen (HBO2) is acutely toxic to the central nervous system, culminating in EEG spikes and tonic-clonic convulsions. GABA enhancers and sodium channel antagonists improve seizure latencies in HBO2 when administered individually, while combining antiepileptic drugs from different functional classes can provide greater seizure latency. We examined the combined effectiveness of GABA enhancers (tiagabine and gabapentin) with sodium channel antagonists (carbamazepine and lamotrigine) in delaying HBO2-induced seizures. A series of experiments in C57BL/6 mice exposed to 100% oxygen at 5 atmospheres absolute (ATA) were performed. We predicted equally effective doses from individual drug-dose response curves, and the combinations of tiagabine + carbamazepine or lamotrigine were tested to determine the maximally effective combined doses to be used in subsequent experiments designed to identify the type of pharmacodynamic interaction for three fixed-ratio combinations (1:3, 1:1, and 3:1) using isobolographic analysis. For both combinations, the maximally effective combined doses increased seizure latency over controls > 5-fold and were determined to interact synergistically for fixed ratios 1:1 and 3:1, additive for 1:3. These results led us to explore whether the benefits of these drug combinations could be extended to the lungs, since a centrally mediated mechanism is believed to mediate hyperoxic-induced cardiogenic lung injury. Indeed, both combinations attenuated bronchoalveolar lavage protein content by ~ 50%. Combining tiagabine with carbamazepine or lamotrigine not only affords greater antiseizure protection in HBO2 but also allows for lower doses to be used, minimizing side effects, and attenuating acute lung injury.
Assuntos
Anticonvulsivantes/administração & dosagem , Oxigenoterapia Hiperbárica , Oxigênio/toxicidade , Convulsões/induzido quimicamente , Bloqueadores dos Canais de Sódio/administração & dosagem , Tiagabina/administração & dosagem , Animais , Carbamazepina/administração & dosagem , Gabapentina/administração & dosagem , Lamotrigina/administração & dosagem , Camundongos Endogâmicos C57BL , Convulsões/tratamento farmacológicoRESUMO
There is clinical and scientific interest in developing local anesthetics with prolonged durations of effect from single injections. The need for such is highlighted by the current opioid epidemic. Site 1 sodium channel blockers such as tetrodotoxin (TTX) are extremely potent, and can provide very long nerve blocks but the duration is limited by the associated systemic toxicity. Here we report a system where slow release of TTX conjugated to a biocompatible and biodegradable polymer, poly(triol dicarboxylic acid)-co-poly(ethylene glycol) (TDP), is achieved by hydrolysis of ester linkages. Nerve block by the released TTX is enhanced by administration in a carrier with chemical permeation enhancer (CPE) properties. TTX release can be adjusted by tuning the hydrophilicity of the TDP polymer backbone. In vivo, 1.0-80.0 µg of TTX released from these polymers produced a range of durations of nerve block, from several hours to 3 days, with minimal systemic or local toxicity.
Assuntos
Anestésicos Locais/administração & dosagem , Portadores de Fármacos/química , Bloqueio Nervoso/métodos , Bloqueadores dos Canais de Sódio/administração & dosagem , Tetrodotoxina/administração & dosagem , Anestesia Local/métodos , Anestésicos Locais/farmacocinética , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/toxicidade , Plásticos Biodegradáveis/química , Plásticos Biodegradáveis/toxicidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/administração & dosagem , Portadores de Fármacos/toxicidade , Composição de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos , Liberação Controlada de Fármacos , Masculino , Camundongos , Permeabilidade , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/efeitos dos fármacos , Bloqueadores dos Canais de Sódio/farmacocinética , Tetrodotoxina/farmacocinética , Fatores de Tempo , Resultado do TratamentoRESUMO
Local anesthetics are used for performing various regional anesthesia techniques to provide intraoperative anesthesia and analgesia, as well as for the treatment of acute and chronic pain. Older medications such as lidocaine and bupivacaine as well as newer ones such as mepivacaine and ropivacaine are being used successfully for decades. Routes of administration include neuraxial, perineural, intravenous, various infiltrative approaches, topical, and transdermal. There are new innovations with the use of older local anesthetics in a novel manner, in addition to the development and use of new formulations. This chapter seeks to summarize the pharmacokinetics of local anesthetics and address the role of newer local anesthetics, as well as clinical implications, safety profiles, and the future of local anesthetic research. Finally, some clinical pearls are highlighted.
Assuntos
Anestesia Local/tendências , Anestésicos Locais/administração & dosagem , Anestesia Local/métodos , Anestésicos Locais/metabolismo , Bupivacaína/administração & dosagem , Bupivacaína/metabolismo , Vias de Administração de Medicamentos , Humanos , Lidocaína/administração & dosagem , Lidocaína/metabolismo , Mepivacaína/administração & dosagem , Mepivacaína/metabolismo , Procaína/administração & dosagem , Procaína/análogos & derivados , Procaína/metabolismo , Bloqueadores dos Canais de Sódio/administração & dosagem , Bloqueadores dos Canais de Sódio/metabolismoRESUMO
Efferent auditory feedback on cochlear hair cells is well studied regarding olivocochlear brainstem mechanisms. Less is known about how the descending corticofugal system may shape efferent feedback and modulate cochlear mechanics. Distortion-product otoacoustic emissions (DPOAEs) are a suitable tool to assess outer hair cell function, as they are by-products of the nonlinear cochlear amplification process. The present project investigates the effects of cortical activity on cubic and quadratic DPOAEs in mongolian gerbils, Meriones unguiculatus, through cortical deactivation using the sodium-channel blocker lidocaine. Contralateral cortical microinjections of lidocaine can lead to either an increase or decrease of median DPOAE levels of up to 10.95 dB. The effects are reversible and comparable at all tested frequencies (0.5-40 kHz). They are not restricted to the preferred frequency of the cortical site of injection. Recovery times are between 20 and 120 min depending on stimulation levels and emission type. When the injection is performed in the ipsilateral hemisphere, DPOAE level shifts are lower in amplitude compared to those after injection in the contralateral hemisphere. No significant changes in DPOAE levels are obtained after saline microinjections. Results indicate that deactivation of auditory cortex activity through lidocaine has a considerable impact on peripheral auditory responses in form of DPOAEs, probably through cortico-olivocochlear pathways.
Assuntos
Córtex Auditivo/fisiologia , Cóclea/fisiologia , Células Ciliadas Auditivas/fisiologia , Audição , Emissões Otoacústicas Espontâneas , Estimulação Acústica , Animais , Audiometria de Tons Puros , Córtex Auditivo/efeitos dos fármacos , Vias Auditivas/fisiologia , Cóclea/efeitos dos fármacos , Feminino , Gerbillinae , Células Ciliadas Auditivas/efeitos dos fármacos , Audição/efeitos dos fármacos , Lidocaína/administração & dosagem , Masculino , Microinjeções , Núcleo Olivar/fisiologia , Emissões Otoacústicas Espontâneas/efeitos dos fármacos , Recuperação de Função Fisiológica , Bloqueadores dos Canais de Sódio/administração & dosagem , Espectrografia do Som , Fatores de TempoRESUMO
BACKGROUND: Wenxin Keli is a popular Chinese herb extract that approximately five million Asians are currently taking for the treatment of a variety of ventricular arrhythmias. However, its electrophysiological mechanisms remain poorly understood. METHODS AND RESULTS: The concentration-dependent electrophysiological effects of Wenxin Keli were evaluated in the isolated rabbit left ventricular myocytes and wedge preparation. Wenxin Keli selectively inhibited late sodium current (INa) with an IC50 of 3.8 ± 0.4 mg/mL, which was significantly lower than the IC50 of 10.6 ± 0.9 mg/mL (n = 6, P < 0.05) for the fast INa. Wenxin Keli produced a small but statistically significant QT prolongation at 0.3 mg/mL, but shortened the QT and Tp-e interval at concentrations ≥ 1 mg/mL. Wenxin Keli increased QRS duration by 10.1% from 34.8 ± 1.0 ms to 38.3 ± 1.1 ms (n = 6, P < 0.01) at 3 mg/mL at a basic cycle length of 2,000 ms. However, its effect on the QRS duration exhibited weak use-dependency, that is, QRS remained less changed at increased pacing rates than other classic sodium channel blockers, such as flecainide, quinidine, and lidocaine. On the other hand, Wenxin Keli at 1-3 mg/mL markedly reduced dofetilide-induced QT and Tp-e prolongation by attenuation of its reverse use-dependence and abolished dofetilide-induced early afterdepolarization (EAD) in four of four left ventricular wedge preparations. It also suppressed digoxin-induced delayed after depolarization (DAD) and ventricular tachycardias without changing the positive staircase pattern in contractility at 1-3 mg/mL in a separate experimental series (four of four). CONCLUSIONS: Wenxin Keli suppressed EADs, DADs, and triggered ventricular arrhythmias via selective inhibition of late INa.
Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Ativação do Canal Iônico/efeitos dos fármacos , Sódio/metabolismo , Taquicardia Ventricular/prevenção & controle , Taquicardia Ventricular/fisiopatologia , Fibrilação Ventricular/prevenção & controle , Fibrilação Ventricular/fisiopatologia , Animais , Feminino , Masculino , Coelhos , Bloqueadores dos Canais de Sódio/administração & dosagem , Resultado do TratamentoRESUMO
In songbirds, the basal ganglia outflow nucleus LMAN is a cortical analog that is required for several forms of song plasticity and learning. Moreover, in adults, inactivating LMAN can reverse the initial expression of learning driven via aversive reinforcement. In the present study, we investigated how LMAN contributes to both reinforcement-driven learning and a self-driven recovery process in adult Bengalese finches. We first drove changes in the fundamental frequency of targeted song syllables and compared the effects of inactivating LMAN with the effects of interfering with N-methyl-d-aspartate (NMDA) receptor-dependent transmission from LMAN to one of its principal targets, the song premotor nucleus RA. Inactivating LMAN and blocking NMDA receptors in RA caused indistinguishable reversions in the expression of learning, indicating that LMAN contributes to learning through NMDA receptor-mediated glutamatergic transmission to RA. We next assessed how LMAN's role evolves over time by maintaining learned changes to song while periodically inactivating LMAN. The expression of learning consolidated to become LMAN independent over multiple days, indicating that this form of consolidation is not completed over one night, as previously suggested, and instead may occur gradually during singing. Subsequent cessation of reinforcement was followed by a gradual self-driven recovery of original song structure, indicating that consolidation does not correspond with the lasting retention of changes to song. Finally, for self-driven recovery, as for reinforcement-driven learning, LMAN was required for the expression of initial, but not later, changes to song. Our results indicate that NMDA receptor-dependent transmission from LMAN to RA plays an essential role in the initial expression of two distinct forms of vocal learning and that this role gradually wanes over a multiday process of consolidation. The results support an emerging view that cortical-basal ganglia circuits can direct the initial expression of learning via top-down influences on primary motor circuitry.
Assuntos
Cérebro/fisiologia , Tentilhões/fisiologia , Aprendizagem/fisiologia , Vocalização Animal/fisiologia , Animais , Gânglios da Base/crescimento & desenvolvimento , Gânglios da Base/fisiologia , Mapeamento Encefálico , Cérebro/crescimento & desenvolvimento , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/farmacologia , Retroalimentação Sensorial , Tentilhões/crescimento & desenvolvimento , Agonistas de Receptores de GABA-A/administração & dosagem , Agonistas de Receptores de GABA-A/farmacologia , Ácido Glutâmico/fisiologia , Aprendizagem/efeitos dos fármacos , Masculino , Córtex Motor/crescimento & desenvolvimento , Córtex Motor/fisiologia , Vias Neurais/fisiologia , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-A/fisiologia , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/fisiologia , Reforço Psicológico , Bloqueadores dos Canais de Sódio/administração & dosagem , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/efeitos dos fármacos , Canais de Sódio/fisiologia , Fatores de Tempo , Vocalização Animal/efeitos dos fármacosRESUMO
BACKGROUND: This study assessed the cardiac electrophysiological and hemodynamic effects of an intravenous infusion of the combined ion channel blocker AZD1305. METHODS: After successful ablation of atrial flutter, patients were randomized to receive placebo (n = 12) or AZD1305 (n = 38) in 4 ascending dose groups. Electrophysiological and hemodynamic measurements were performed before and commencing 20 minutes after start of infusion. RESULTS: Left atrial effective refractory period increased dose and the primary outcome measure increased dose and plasma concentration dependently, with a mean increase of 55 milliseconds in dose group 3. There was a corresponding increase in right atrial effective refractory period of 84 milliseconds. The right ventricular effective refractory period and the paced QT interval also increased dose and concentration dependently, by 59 and 70 milliseconds, respectively, in dose group 3. There were indications of moderate increases of atrial, atrioventricular nodal, and ventricular conduction times. No consistent changes in intracardiac pressures were observed, but there was a small transient decrease in systolic blood pressure. Adverse events were consistent with the study population and procedure, and there were no signs of proarrhythmia despite marked delay in ventricular repolarization in some individuals. CONCLUSIONS: AZD1305 shows electrophysiological characteristics indicative of potential antiarrhythmic efficacy in atrial fibrillation.
Assuntos
Flutter Atrial/cirurgia , Compostos Azabicíclicos/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Carbamatos/farmacologia , Ablação por Cateter , Bloqueadores dos Canais de Sódio/farmacologia , Adulto , Idoso , Compostos Azabicíclicos/administração & dosagem , Compostos Azabicíclicos/efeitos adversos , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/efeitos adversos , Carbamatos/administração & dosagem , Carbamatos/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas , Feminino , Sistema de Condução Cardíaco/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Período Refratário Eletrofisiológico/efeitos dos fármacos , Bloqueadores dos Canais de Sódio/administração & dosagem , Bloqueadores dos Canais de Sódio/efeitos adversosRESUMO
OBJECTIVE: This study aimed to investigate the effect of amiloride on portal hypertension. Amiloride is known to inhibit Na(+)/H(+) exchangers on activated hepatic stellate cells. METHODS: Liver cirrhosis in rats was induced by bile duct ligation (BDL) or thioacetamide (TAA) administration. The effects of zymosan for Kupffer cell (KC) activation or a thromboxane (TX) analogue (U46619) were tested in isolated perfused livers of cirrhotic rats and in vivo. Downstream mechanisms were investigated using Rho kinase inhibitor (Y-27632) or amiloride. Acute and chronic effects of amiloride and canrenoate on portal pressure were compared in perfused livers and in vivo. TXB(2) efflux was measured by ELISA. The phosphorylation state of moesin (p-moesin) as an indicator of Rho kinase activity and expression of the thromboxane synthase were assessed by western blot analyses. The activity of hepatic stellate cells was analysed by western blot and staining for alpha-smooth muscle actin (alpha-SMA). RESULTS: In BDL rats, KC activation via zymosan increased portal pressure. This was attenuated by the Rho kinase inhibitor Y-27632. Increased thromboxane efflux following zymosan infusion remained unaltered by Y-27632. The infusion of amiloride attenuated zymosan- and U46619-induced increases in portal perfusion pressure. In vivo, direct administration of amiloride, but not of canrenoate, lowered portal pressure. In TAA and BDL rats, treatment with amiloride for 3 days reduced basal portal pressure and KC-induced increases in portal pressure whereas canrenoate had no effect. In livers of amiloride-treated animals, the phosphorylation state of moesin and the number of alpha-SMA positive cells were reduced. CONCLUSIONS: Amiloride lowers portal pressure in rat liver cirrhosis by inhibition of intrahepatic vasocontraction. Therefore, patients with cirrhosis and portal hypertension may benefit from amiloride therapy.
Assuntos
Amilorida/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Hipertensão Portal/tratamento farmacológico , Cirrose Hepática Experimental/complicações , Amilorida/administração & dosagem , Animais , Anti-Hipertensivos/administração & dosagem , Ácido Canrenoico/administração & dosagem , Ácido Canrenoico/uso terapêutico , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Hipertensão Portal/etiologia , Hipertensão Portal/fisiopatologia , Células de Kupffer/fisiologia , Cirrose Hepática Experimental/fisiopatologia , Masculino , Pressão na Veia Porta/efeitos dos fármacos , Pressão na Veia Porta/fisiologia , Ratos , Ratos Sprague-Dawley , Bloqueadores dos Canais de Sódio/administração & dosagem , Bloqueadores dos Canais de Sódio/uso terapêutico , Tromboxano A2/fisiologia , Quinases Associadas a rho/fisiologiaRESUMO
Osthol, a Chinese herbal compound, has been shown to possess vasorelaxant and neuroprotective properties. Not much is known about the effects of osthol on ionic channels, activities of which are implicated in vasorelaxation and neuroprotection. In this work we report that osthol could inhibit voltage-gated Na (+) currents with state-dependence in mouse neuroblastoma N2A cells (IC (50) = 12.3 microM and 31.5 microM at holding potentials of - 70 mV and - 100 mV, respectively). Current blockade was equally effective in both extracellular and intracellular application of osthol. Osthol (18 microM) did not significantly affect the kinetics and voltage-dependence of Na (+) channel activation, but left-shifted the steady-state inactivation curve (V (1/2) = - 60.5 mV and - 78.7 mV in the absence and presence of osthol, respectively). Osthol also mildly but significantly retarded channel recovery from inactivation (recovery time constant = 19.9 ms and 35.6 ms in the absence and presence of osthol, respectively). In addition, osthol blocked Na (+) currents in a frequency-dependent fashion: blockades of 17 %, 34 % and 49 % when currents were triggered at 0.33 Hz, 1 Hz and 3.33 Hz, respectively. Taken together, our results therefore suggest that osthol blocked voltage-gated Na (+) channels intracellularly with state- and frequency-dependence.
Assuntos
Cumarínicos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Magnoliopsida/química , Fármacos Neuroprotetores/farmacologia , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Cumarínicos/administração & dosagem , Medicamentos de Ervas Chinesas/química , Ativação do Canal Iônico/efeitos dos fármacos , Camundongos , Neoplasias , Neuroblastoma , Fármacos Neuroprotetores/administração & dosagem , Fitoterapia , Bloqueadores dos Canais de Sódio/administração & dosagemRESUMO
Ranolazine modulates the cardiac voltage-gated sodium channel (NaV 1.5) and is approved by the FDA in the treatment of ischemic heart disease. Ranolazine also targets neuronal (NaV 1.7, 1.8) isoforms that are implicated in neuropathic pain. Therefore, we determined the analgesic efficacy of ranolazine in a preclinical animal model of neuropathic pain. Both intraperitoneal and oral administration of ranolazine dose-dependently inhibited the mechanical and cold allodynia associated with spared nerve injury, without producing ataxia or other behavioral side effects. These data warrant clinical investigation of the potential use of ranolazine in the treatment of neuropathic pain.
Assuntos
Acetanilidas/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Neuralgia/tratamento farmacológico , Piperazinas/administração & dosagem , Acetanilidas/farmacologia , Acetanilidas/uso terapêutico , Animais , Ataxia/induzido quimicamente , Temperatura Baixa , Avaliação Pré-Clínica de Medicamentos , Injeções Intraperitoneais , Injeções Subcutâneas , Masculino , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/fisiopatologia , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Estimulação Física , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Distribuição Aleatória , Ranolazina , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Bloqueadores dos Canais de Sódio/administração & dosagem , Bloqueadores dos Canais de Sódio/farmacologia , Bloqueadores dos Canais de Sódio/uso terapêuticoRESUMO
Dietary sodium restriction coupled with axotomy of the rat chorda tympani nerve (CTX) results in selectively attenuated taste responses to sodium salts in the contralateral, intact chorda tympani nerve. Converging evidence indicates that sodium deficiency also diminishes the activated macrophage response to injury on both the sectioned and contralateral, intact sides of the tongue. Because a sodium-restricted diet causes a robust increase in circulating aldosterone, we tested the hypothesis that changes in neurophysiological and immune responses contralateral to the CTX could be mimicked by aldosterone administration instead of the low-sodium diet. Taste responses in rats with CTX and supplemental aldosterone for 4-6 days were similar to rats with CTX and dietary sodium restriction. Responses to sodium salts were as much as 50% lower compared with sham-operated and vehicle-supplemented rats. The group-related functional differences were eliminated with lingual application of amiloride, suggesting that a major transduction pathway affected was through epithelial sodium channels. Consistent with the functional results, few macrophages were observed on either side of the tongue in rats with CTX and aldosterone. In contrast, macrophages were elevated on both sides of the tongue in rats with CTX and the vehicle. These results show that sodium deficiency or administration of aldosterone suppresses the immune response to neural injury, resulting in attenuation of peripheral gustatory function. They also show a potential key link among downstream consequences of sodium imbalance, taste function, and immune activity.
Assuntos
Aldosterona/metabolismo , Comportamento Animal , Nervo da Corda do Tímpano/metabolismo , Macrófagos/metabolismo , Cloreto de Sódio na Dieta/metabolismo , Percepção Gustatória , Paladar , Língua/inervação , Administração Oral , Aldosterona/administração & dosagem , Amilorida/administração & dosagem , Animais , Axotomia , Comportamento Animal/efeitos dos fármacos , Nervo da Corda do Tímpano/efeitos dos fármacos , Nervo da Corda do Tímpano/cirurgia , Dieta Hipossódica , Relação Dose-Resposta a Droga , Potenciais Evocados , Feminino , Furosemida/administração & dosagem , Bombas de Infusão Implantáveis , Injeções Intraperitoneais , Ativação de Macrófagos , Macrófagos/efeitos dos fármacos , Modelos Animais , Ratos , Ratos Sprague-Dawley , Bloqueadores dos Canais de Sódio/administração & dosagem , Cloreto de Sódio na Dieta/administração & dosagem , Inibidores de Simportadores de Cloreto de Sódio e Potássio/administração & dosagem , Percepção Gustatória/efeitos dos fármacos , Fatores de Tempo , Língua/imunologiaRESUMO
The nucleus accumbens (Acb) is a part of the striatum which integrates information from cortical and limbic brain structures, and mediates behaviors which reinforce reward. Previous work has suggested that neuronal synchrony mediated by gap junctions in Acb-related areas is involved in brain pleasure and reward. In order to gain insight into functional aspects of the neural information processing at the level of the striatum, we explored the possible role of Acb gap junctional communication and chemical synapses on reward self-stimulation in rats using positive reinforcement. Rats were trained to press a lever that caused an electrical current to be delivered into the hypothalamus, which is recognized to cause pleasure/reward. Intracerebral infusion into the Acb of the gap junctional blocker carbenoxolone (CBX) decreased the lever-pressing activity. Considering that the net effect of blocking gap junctions is a reduced synchronized output of the cellular activities, which at some level represents a decrease in excitability, two other inhibitors of neuronal excitability, carbamazepine (CBZ) and tetrodotoxin (TTX), were infused into the Acb and their effects on lever-pressing assessed. All manipulations that diminished excitability in the Acb resulted in reduced lever-pressing activity. CBX and TTX were also infused into motor cortex mediating forelimb lever-pressing with no effect. However, a manipulation that has the net effect of increasing excitation, the infusion of the opiate antagonist naloxone, also decreased significantly brain self-stimulation. We conclude that reward behaviors depend to a great extent on both excitability and gap junction-mediated mechanisms in Acb neuronal networks. Thus, the Acb provides a site for the study of pleasure/reward, addiction and conscious experience.
Assuntos
Junções Comunicantes/fisiologia , Núcleo Accumbens/fisiologia , Recompensa , Transdução de Sinais/fisiologia , Animais , Carbamazepina/administração & dosagem , Carbenoxolona/administração & dosagem , Fármacos do Sistema Nervoso Central/administração & dosagem , Estimulação Elétrica , Junções Comunicantes/efeitos dos fármacos , Hipotálamo/fisiologia , Masculino , Atividade Motora/efeitos dos fármacos , Córtex Motor/efeitos dos fármacos , Naloxona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Wistar , Reforço Psicológico , Transdução de Sinais/efeitos dos fármacos , Bloqueadores dos Canais de Sódio/administração & dosagem , Tetrodotoxina/administração & dosagemRESUMO
Several epidemiologic and clinical studies show that following myocardial infarction, dietary supplements of omega-3 polyunsaturated fatty acids (omega3FA) reduce sudden death. Animal data show that omega3FA have antiarrhythmic properties, but their mechanisms of action require further elucidation. The effects of omega3FA supplementation were studied in female rabbits to analyze whether their antiarrhythmic effects are due to a reduction of triangulation, reverse use-dependence, instability, and dispersion (TRIaD) of the cardiac action potential (TRIaD as a measure of proarrhythmic effects). In Langendorff-perfused hearts challenged by a selective rapidly activating delayed rectifier potassium current inhibitor that has been shown to exhibit proarrhythmic effects (dofetilide; 1 to 100 nM), omega3FA pretreatment (30 days; n=6) prolonged the plateau phase of the monophasic action potential; did not slow the terminal fast repolarization; reduced the dofetilide-induced prolongation of the action potential duration; reduced dofetilide-induced triangulation; and reduced dofetilide-induced reverse use-dependence, instability of repolarization, and dispersion. Dofetilide reduced excitability in omega3FA-pretreated hearts but not in control hearts. Whereas torsades de pointes (TdP) were observed in five out of six in control hearts, none were observed in omega3FA-pretreated hearts. Docosahexaenoic acid (DHA) inhibited the sodium current with ultrafast kinetics. Dietary omega3FA supplementation markedly reduced dofetilide-induced TRIaD and abolished dofetilide-induced TdP. Ultrafast sodium channel block by DHA may account for the antiarrhythmic protection of the dietary supplements of omega3FA against dofetilide-induced proarrhythmia observed in this animal model.
Assuntos
Antiarrítmicos/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Sistema de Condução Cardíaco/efeitos dos fármacos , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/efeitos dos fármacos , Torsades de Pointes/prevenção & controle , Potenciais de Ação , Animais , Antiarrítmicos/administração & dosagem , Dieta , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/administração & dosagem , Feminino , Sistema de Condução Cardíaco/metabolismo , Sistema de Condução Cardíaco/fisiopatologia , Cinética , Perfusão , Fenetilaminas , Coelhos , Bloqueadores dos Canais de Sódio/administração & dosagem , Canais de Sódio/metabolismo , Sulfonamidas , Torsades de Pointes/induzido quimicamente , Torsades de Pointes/metabolismo , Torsades de Pointes/fisiopatologiaRESUMO
The rat continues to be an important tool to assess cardiac electrophysiologic (EP) effects of test agents and to study the distribution/role of ion channels in cardiovascular diseases. However, no data have been described that accurately measure discrete cardiac EP parameters in rats in vivo. Therefore, we developed a method to assess cardiac EP in rats and then profiled several ion channel agents. Briefly, rats were instrumented with endocardially placed electrodes to assess cardiac refractoriness and conduction. Administration of class I agents resulted in a dose-dependent slowing of ventricular conduction. The potassium channel blocker 4-aminopyridine caused significant increases in atrial and ventricular refractoriness. An IKr blocker had little or no effect on atrial and ventricular refractoriness but significantly increased AV nodal refractoriness. Additionally, an IKs blocker had little effect on rat cardiac EP. The L-type blocker diltiazem caused a dose-dependent delay in AV node conduction and an increase in AV node refractoriness. Overall, this study provides normative data that describe the roles of Na, Ca, and K channels in rat cardiac electrophysiology, in vivo. Furthermore, the model provides a method to assess changes in cardiac electrophysiology in the setting of disease by using well-established rat models of induced or genetic cardiovascular disease.