RESUMEN
1. The 2 Hz train-of-four ratio (TOF(ratio)) is used to monitor the degree of patient curarization. Using a rat phrenic nerve-hemidiaphragm preparation, we showed that antinicotinic agents, such as hexamethonium, d-tubocurarine and pancuronium, but not cisatracurium, decreased contractions produced by physiological nerve activity patterns (50 Hz) more efficiently than those caused by 2 Hz trains. Uncertainty about the usefulness of the TOF(ratio) to control safe recovery from curarization prompted us to investigate the muscarinic and adenosine neuromodulation of tetanic (50 Hz) fade induced by antinicotinic agents at concentrations that cause a 25% reduction in the TOF(ratio) (TOF(fade)). 2. Tetanic fade caused by d-tubocurarine (1.1 µmol/L), pancuronium (3 µmol/L) and hexamethonium (5.47 mmol/L) was attenuated by blocking presynaptic inhibitory muscarinic M(2) and adenosine A(1) receptors with methoctramine (1 µmol/L) and 1,3-dipropyl-8-cyclopentylxanthine (2.5 nmol/L), respectively. These compounds enhanced rather than decreased tetanic fade induced by cisatracurium (2.2 µmol/L), but they consistently attenuated cisatracurium-induced TOF(fade). The effect of the M(1) receptor antagonist pirenzepine (10 nmol/L) on fade produced by antinicotinic agents at 50 Hz was opposite to that observed with TOF stimulation. Blockade of adenosine A(2A) receptors with ZM 241385 (10 nmol/L) attenuated TOF(fade) caused by all antinicotinic drugs tested, with the exception of the 'pure' presynaptic nicotinic antagonist hexamethonium. ZM 241385 was the only compound tested in this series that facilitated recovery from tetanic fade produced by cisatracurium. 3. The data suggest that distinct antinicotinic relaxants interfere with fine-tuning neuromuscular adaptations to motor nerve stimulation patterns via activation of presynaptic muscarinic and adenosine receptors. These results support the use of A(2A) receptor antagonists together with atropine to facilitate recovery from antinicotinic neuromuscular blockade.
Asunto(s)
Antagonistas del Receptor de Adenosina A2/farmacología , Bloqueantes Neuromusculares/farmacología , Unión Neuromuscular/efectos de los fármacos , Antagonistas Nicotínicos/farmacología , Animales , Diafragma/efectos de los fármacos , Diafragma/fisiología , Sinergismo Farmacológico , Estimulación Eléctrica/métodos , Hexametonio/farmacología , Masculino , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Unión Neuromuscular/fisiología , Pancuronio/farmacología , Nervio Frénico/efectos de los fármacos , Nervio Frénico/fisiología , Ratas , Ratas Wistar , Receptor de Adenosina A2A/metabolismo , Receptor Muscarínico M1/metabolismo , Receptor Muscarínico M2/metabolismo , Periodo Refractario Electrofisiológico/efectos de los fármacos , Tubocurarina/farmacologíaRESUMEN
Toxins that block voltage-dependent K+ channels and those that modify Na+ channel gating exhibit positive inotropic effect on skeletal muscle. We compared the effect of the venom of Tityus cambridgei (Tc) and Tityus serrulatus (Ts) scorpions on mouse diaphragm force, in vitro. In indirect and direct (using D-tubocurarine 7.3 microM) stimulation, Tc, 10microg/mL, increased the contractile force, an effect prevented by tetrodotoxin (TTX) while Ts, 0.5 microg/mL, potentiated only indirectly stimulated diaphragm, thus indicating its activity is mainly mediated through acetylcholine release from nerve terminal. This effect is prevented by TTX and attenuated by the K+ channel opener cromakalim. In conclusion, our data show that while the positive inotropic effect of both venoms appears associated to the activity of Na+ and K+ channels, only Tc venom acts also directly on skeletal muscle. This finding call for further studies on Tc venom to identify the toxin responsible for its direct inotropic activity as it may have clinical applications.
Asunto(s)
Diafragma/efectos de los fármacos , Contracción Muscular/efectos de los fármacos , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio/efectos de los fármacos , Venenos de Escorpión/farmacología , Bloqueadores de los Canales de Sodio/farmacología , Canales de Sodio/efectos de los fármacos , Acetilcolina/metabolismo , Animales , Cromakalim/farmacología , Diafragma/inervación , Diafragma/metabolismo , Estimulación Eléctrica , Técnicas In Vitro , Activación del Canal Iónico/efectos de los fármacos , Masculino , Ratones , Fuerza Muscular/efectos de los fármacos , Fármacos Neuromusculares no Despolarizantes/farmacología , Nervio Frénico/efectos de los fármacos , Nervio Frénico/metabolismo , Canales de Potasio/metabolismo , Canales de Sodio/metabolismo , Tetrodotoxina/farmacología , Factores de Tiempo , Tubocurarina/farmacologíaRESUMEN
Objetivo: Estudiar la precurarización de la succinilcolina utilizando d-tubocurarina y rocuronio introduciendo los métodos restrictivo, conceptos de velocidad de acción y recuperación y una nueva semiología para evaluar las fasciculaciones. Material y método: Se administraron succinilcolina (1 mg x Kg-1) (n =21) sola o precedida por rocuronio o d-tubocurarina (60 ó 50 ug x Kg-1) (n =21 c/u), determinándose: la fase inicial de comienzo hasta 80 por ciento de bloqueo, tiempo de comienzo, máximo efecto, duración clínica, tiempo de reversión espontánea entre 10 por ciento y 25 por ciento y 25 por ciento a 50 por ciento. Se calculó la velocidad de acción (inicial, final y global) como la relación tiempo/bloqueo fraccionado y la velocidad de recuperación. El método restrictivo fue empleado para el estudio del tiempo de comienzo, utilizando un rango restringido de bloqueo. Las fasciculaciones fueron evaluadas por su intensidad en seis regiones anatómicas por cuatro observadores imparciales e independientes y las medias de sus valoraciones utilizadas para analizarlas. Resultados: Aparentemente ambos desfasciculantes prolongan la fase inicial, tiempo de comienzo y velocidad de la succinilcolina, pero el método restrictivo únicamente lo confirmó para el tiempo de comienzo y la velocidad global. La velocidad inicial fue más rápida que la final. El rocuronio redujo el efecto y la duración clínica e incrementó la velocidad de recuperación de la succinilcolina. Las fasciculaciones fueron más frecuentes e intensas en el tronco y miembro superior izquierdo, pero los precurarizantes las redujeron tanto en intensidad como localización Discusión: La precurarización no modifica la fase inicial de comienzo, surgiendo la posibilidad de practicar una intubación temprana. Debido al acortamiento que provoca la precurarización con rocuronio se hace evidente la necesidad precoz de nuevas dosis de relajantes.
Objective: To study the precurarization of succinylcholine with d-tubocurarine and rocuronium, using the restrictive method, speed of action and recovery principles and a particular evaluation for fasciculations Material & Methods: Patients received succinylcholine (1 mg x Kg-1) (n =21) either alone or preceded by d-tubocurarine or rocuronium (60 ó 50 micron g x Kg-1) (n =21 e/a), and the following clinical measurements were made: earlyphase of onset time (up to 80 percent blockade), onset time, maximal block, clinical duration and recovery time between 10 percent and 25 percent and 25 percent to 50 percent. Speed of action (initial, final and global)as the ratio between time and fractional blockade and speed of recovery, were calculated. Restrictive method was used for the study of the entire onset time on patients included in a limited range of final block. Intensity of fasciculations was evaluated by four independent observers blind to the drugs used in six anatomical regions and their mean values used for analysis. Results: Apparently, precurarizing drugs prolonged initial phase, onset time and reduced speed for succinylcholine, but only onset time and global speed were confirmed by restrictive method. After rocuronium, maximal effect as well as clinical duration of succinylcholine werereduced and speed of recovery increased. Fasciculations were more frequent and intense at the trunk and left upper arm, but precurarization reduced both intensity and localization prevalence. Discussion: As lack of changes on the initial phase of onset time for succinylcholine inducedby precurarization was noticed, an early tracheal intubation could be contemplated. Due to reduction on clinical duration after rocuronium,new doses of muscle relaxants are sooner necessary. The present method for evaluation of fasciculations shows how far they are spread and how effective precurarization was, given rise to doubts on previous results.
Asunto(s)
Humanos , Masculino , Adulto , Femenino , Fármacos Neuromusculares no Despolarizantes/administración & dosificación , Androstanoles/administración & dosificación , Fasciculación/prevención & control , Succinilcolina/efectos adversos , Tubocurarina/administración & dosificación , Fármacos Neuromusculares Despolarizantes/efectos adversos , Fármacos Neuromusculares no Despolarizantes/farmacología , Androstanoles/farmacología , Tiempo de Reacción , Tubocurarina/farmacologíaRESUMEN
Neuromuscular blocking agents suppress central respiratory activity through their inhibitory effects on preinspiratory neurons and the synaptic drive from preinspiratory neurons to inspiratory neurons. Central CO2-chemosensitive areas, which partly consist of CO2-excited neurons, in the rostral ventrolateral medulla are thought to provide tonic drive to the central respiratory network and involve cholinergic mechanisms, which led us to hypothesize that neuromuscular blocking agents can inhibit CO2-excited neurons and attenuate respiratory CO2 responsiveness. To test this hypothesis, we used isolated brainstem-spinal cord preparations from newborn rats. The increase of C4 burst frequency induced by a hypercapnic superfusate, i.e. respiratory CO2 responsiveness, was suppressed by the application of neuromuscular blocking agents, either d-tubocurarine (10, 100 microM) or vecuronium (100 microM). These agents (40 microM) also induced hyperpolarization and decreases in firing frequency of CO2-excited neurons in the rostral ventrolateral medulla. Our results demonstrate that neuromuscular blocking agents inhibit CO2-excited tonic firing neurons and attenuate respiratory CO2 responsiveness.
Asunto(s)
Células Quimiorreceptoras/efectos de los fármacos , Bulbo Raquídeo/efectos de los fármacos , Fármacos Neuromusculares no Despolarizantes/farmacología , Centro Respiratorio/efectos de los fármacos , Animales , Animales Recién Nacidos , Dióxido de Carbono/fisiología , Bulbo Raquídeo/citología , Neuronas/efectos de los fármacos , Ratas , Ratas Wistar , Respiración/efectos de los fármacos , Centro Respiratorio/fisiología , Tubocurarina/farmacología , Bromuro de Vecuronio/farmacologíaRESUMEN
Neuromuscular blocking agents suppress central respiratory activity through their inhibitory effects on preinspiratory neurons and the synaptic drive from preinspiratory neurons to inspiratory neurons. Central CO2-chemosensitive areas, which partly consist of CO2-excited neurons, in the rostral ventrolateral medulla are thought to provide tonic drive to the central respiratory network and involve cholinergic mechanisms, which led us to hypothesize that neuromuscular blocking agents can inhibit CO2-excited neurons and attenuate respiratory CO2 responsiveness. To test this hypothesis, we used isolated brainstem-spinal cord preparations from newborn rats. The increase of C4 burst frequency induced by a hypercapnic superfusate, i.e. respiratory CO2 responsiveness, was suppressed by the application of neuromuscular blocking agents, either d-tubocurarine (10, 100M) or vecuronium (100M). These agents (40M) also induced hyperpolarization and decreases in firing frequency of CO2-excited neurons in the rostral ventrolateral medulla. Our results demonstrate that neuromuscular blocking agents inhibit CO2-excited tonic firing neurons and attenuate respiratory CO2 responsiveness.
Asunto(s)
Animales , Recién Nacido , Ratas , Bloqueantes Neuromusculares/administración & dosificación , Bloqueantes Neuromusculares/farmacología , Respiración , Bromuro de Vecuronio/administración & dosificación , Bromuro de Vecuronio/farmacología , Tubocurarina/administración & dosificación , Tubocurarina/farmacologíaRESUMEN
The acute effect of Ambrosia paniculata was studied in several animal models of epilepsy. Intraperitoneal injections (0.01 mL/g body wt) of a decoction of the dry leaves significantly enhanced the latency to the first convulsion and survival time in mice injected with picrotoxin (7 mg/kg) or isoniazid (210 mg/kg). Epileptic spikes were induced by topical application of penicillin through a glass electrode filled with a penicillin-agar-saline mixture and recorded in sensorimotor and occipital cortices, in rats immobilized with d-tubocurarine. The plant decoction reduced significantly the spike amplitude in both sites. The mentioned effects were elicited at doses that also reduced general motor activity (Irwin test) and exploratory behavior. The decoctions were not effective against electroshock-induced convulsions in mice. The convulsions induced by isoniazid, picrotoxin, and penicillin differed from those induced by electroshock implicating selective disruption of GABAergic neurotransmission. The results suggest that A. paniculata, like several conventional antiepileptic drugs, might act by enhancing GABAergic neurotransmission, a hypothesis that requires further demonstration. These results explain and justify the traditional use of the plant in epilepsy.
Asunto(s)
Ambrosia/química , Epilepsia/tratamiento farmacológico , Preparaciones de Plantas/uso terapéutico , Análisis de Varianza , Animales , Anticonvulsivantes/uso terapéutico , Conducta Animal , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/fisiopatología , Diazepam/uso terapéutico , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Electroencefalografía/métodos , Electrochoque/efectos adversos , Epilepsia/inducido químicamente , Epilepsia/fisiopatología , Conducta Exploratoria/efectos de los fármacos , Isoniazida , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Penicilinas , Fitoterapia/métodos , Picrotoxina , Desempeño Psicomotor/efectos de los fármacos , Ratas , Tiempo de Reacción/efectos de los fármacos , Factores de Tiempo , TubocurarinaRESUMEN
Durante a sepse, grandes quantidades de óxido nítrico (NO) são sintetizadas pela enzima NO sintase tipo II. Em preparações neuromusculares, o NO produz ou acentua a fadiga de transmissão. 'Train-of-four'(TOF) são pulsos elétricos de 2 Hz aplicados ao nervo motor durante 2 segundos (4 contrações musculares) e o quociente entre as tensões musculares produzidas pela quarta (T4) e primeira (T1) contrações musculares (RTOF = T4/T1) é utilizado para avaliação do bloqueio da transmissão neuromuscular. A redução de RTOF é determinada por bloqueio dos receptores nicotínicos (Nn) facilitatórios e por estimulação dos receptores muscarínicos (M2) inibitórios do terminal nervoso motor. Estudos utilizando preparações neuromusculares de animais sépticos tratadas com bloqueadores neuromusculares em doses que reduzem os valores de RTOF sem promover alterações nas amplitudes das contrações musculares a 0,2 Hz não foram executados. Assim, utilizando preparações nervo ciático-músculo tibial anterior de ratos, verificamos que as menores doses de d-tubocurarina (d-TC), pancurônio (PANC) e galamina (GAL) capazes de produzir 30 por cento de redução em RTOF nos animais sham foram, respectivamente: 54,29 ± 2,86 mg/kg (n=7), 69,02 ± 6,13 mg/kg (n=5), 2,94 ± 0,33 mg/kg (n=4). A dose de d-TC foi menor em animais sépticos (34,53 ± 2,76 mg/kg, n=4), que em animais sham, porém os efeitos foram mais intensos e prolongados na sepse. d-TC (26,50 ± 0,68 mg/kg (n=5), promoveu 30 por cento de redução em RTOF nos animais sham submetidos à infusão de nitroprussiato de sódio (10 mg/kg/min). O tratamento com S-metilisotiouréia (SMT, 13 mg/kg) antagonizou a redução de RTOF em animais sépticos. As menores doses de PANC e GAL que reduziram RTOF em 30 por cento foram semelhantes em todos os grupos experimentais estudados e GAL promoveu efeitos similares em todas as condições experimentais. A redução de RTOF produzida por PANC foi menor que a induzida por d-TC e foi antagonizada pela administração de SMT....
Asunto(s)
Animales , Ratas , Óxido Nítrico , Óxido Nítrico/administración & dosificación , Óxido Nítrico/análisis , Óxido Nítrico/farmacología , Sepsis , Pancuronio/administración & dosificación , Pancuronio , TubocurarinaRESUMEN
Durante a sepse, grandes quantidades de óxido nítrico (NO) são sintetizadas pela enzima NO sintase tipo II. Em preparações neuromusculares, o NO produz ou acentua a fadiga de transmissão. 'Train-of-four'(TOF) são pulsos elétricos de 2 Hz aplicados ao nervo motor durante 2 segundos (4 contrações musculares) e o quociente entre as tensões musculares produzidas pela quarta (T4) e primeira (T1) contrações musculares (RTOF = T4/T1) é utilizado para avaliação do bloqueio da transmissão neuromuscular. A redução de RTOF é determinada por bloqueio dos receptores nicotínicos (Nn) facilitatórios e por estimulação dos receptores muscarínicos (M2) inibitórios do terminal nervoso motor. Estudos utilizando preparações neuromusculares de animais sépticos tratadas com bloqueadores neuromusculares em doses que reduzem os valores de RTOF sem promover alterações nas amplitudes das contrações musculares a 0,2 Hz não foram executados. Assim, utilizando preparações nervo ciático-músculo tibial anterior de ratos, verificamos que as menores doses de d-tubocurarina (d-TC), pancurônio (PANC) e galamina (GAL) capazes de produzir 30 por cento de redução em RTOF nos animais sham foram, respectivamente: 54,29 ± 2,86 mg/kg (n=7), 69,02 ± 6,13 mg/kg (n=5), 2,94 ± 0,33 mg/kg (n=4). A dose de d-TC foi menor em animais sépticos (34,53 ± 2,76 mg/kg, n=4), que em animais sham, porém os efeitos foram mais intensos e prolongados na sepse. d-TC (26,50 ± 0,68 mg/kg (n=5), promoveu 30 por cento de redução em RTOF nos animais sham submetidos à infusão de nitroprussiato de sódio (10 mg/kg/min). O tratamento com S-metilisotiouréia (SMT, 13 mg/kg) antagonizou a redução de RTOF em animais sépticos. As menores doses de PANC e GAL que reduziram RTOF em 30 por cento foram semelhantes em todos os grupos experimentais estudados e GAL promoveu efeitos similares em todas as condições experimentais. A redução de RTOF produzida por PANC foi menor que a induzida por d-TC e foi antagonizada pela administração de SMT....
Asunto(s)
Animales , Ratas , Óxido Nítrico , Óxido Nítrico/administración & dosificación , Óxido Nítrico/análisis , Óxido Nítrico/farmacología , Sepsis , Pancuronio/administración & dosificación , Pancuronio , TubocurarinaRESUMEN
Betahistine has been used to treat several vestibular disorders of both central and peripheral origin. The objective of this work was to study the action of betahistine in the vestibular endorgans. Experiments were done in wild larval axolotl (Ambystoma tigrinum). Multiunit extracellular recordings were obtained from the semicircular canal nerve using a suction electrode. Betahistine (10 microM to 10 mM; n = 32) inhibited the basal spike discharge of the vestibular afferent neurons with an IC50 of 600 microM. To define the site of action of betahistine, its interactions with the nitric oxide synthase inhibitor NG-nitro-L-arginine (3 microM) and with the cholinergic antagonists atropine (10 microM; n = 3) and d-tubocurarine (10 microM; n = 3) were studied. The action of betahistine when co-administered with these drugs was the same as that in control experiments, indicating that its effects did not include nitric oxide production or the activation of cholinergic receptors. In contrast, 0.01-1 mM betahistine reduced the excitatory action of kainic acid (10 microM; n = 6) and quiscualic acid (1 microM; n = 13). These results indicate that the action of betahistine on the spike discharge of afferent neurons seems to be due to a post-synaptic inhibitory action on the primary afferent neuron response to the hair cell neurotransmitter.
Asunto(s)
Betahistina/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Agonistas de los Receptores Histamínicos/farmacología , Inhibición Neural/efectos de los fármacos , Neuronas Aferentes/efectos de los fármacos , Vestíbulo del Laberinto/citología , Vestíbulo del Laberinto/efectos de los fármacos , Ambystoma , Animales , Atropina/farmacología , Betahistina/administración & dosificación , Relación Dosis-Respuesta a Droga , Agonistas de los Receptores Histamínicos/administración & dosificación , Antagonistas Muscarínicos/farmacología , Antagonistas Nicotínicos/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Nitroarginina/farmacología , Tubocurarina/farmacologíaRESUMEN
The electric organ discharge of Brachyhypopomus pinnicaudatus was studied by recording (1) the discharge field potentials in water at different conductivities and temperatures and (2) the spatiotemporal pattern of electromotive forces of the equivalent source. An early deflection, head positive (P wave), and a late deflection, head negative (N wave), are the major components of the discharge, however a striking double positive peak is generated at the abdominal level. Comparisons of this species with other pulse gymnotids provide evidence for common patterns of organization of the electrogenic system: (1) There is a head-to-tail activation wave along the fish; (2) the electromotive force increases exponentially from head to tail, but it is differentially attenuated by the passive tissues in male and females; (3) the abdominal region generates a complex species-specific waveform, whereas the tail discharge is similar across species. In B. pinnicaudatus the electric organ discharge waveform is sensitive to endocrine and environmental stimuli. The effect of seasonal sex differences on electrogenic and passive tissue, the changes in impedance matching between the fish's body and the environment, and the modulation of membrane properties by temperature, are able to modify the EOD waveform. Since these factors change during the breeding season, their appropriate combination might be crucial for reproduction.
Asunto(s)
Comunicación Animal , Pez Eléctrico/fisiología , Órgano Eléctrico/fisiología , Aire , Animales , Conductividad Eléctrica , Órgano Eléctrico/efectos de los fármacos , Campos Electromagnéticos , Electrofisiología , Ambiente , Femenino , Cabeza/fisiología , Masculino , Fármacos Neuromusculares no Despolarizantes/farmacología , Caracteres Sexuales , Conducta Sexual Animal/fisiología , Cola (estructura animal)/fisiología , Temperatura , Factores de Tiempo , Tubocurarina/farmacologíaRESUMEN
A acetilcolina liberada do terminal nervoso motor (TNM) pode modular sua pr6pria liberagdo (automodulação do TNM), interagindo com receptores nicotinicos (autoestimulação do TNM) ou muscarinicos (autoinibição do TNM) pré-juncionais. Por outro lado, tem-se demonstrado que a neuropatia induzida pelo estado diabético determine vários danos estruturais no interior do TNM, sem, contudo, interferir na velocidade e na integridade da transmissão neuromuscular. Estudos farmacológicos demonstram que animais diabéticos, quando comparados aos normais, são menos sensíveis a alguns bloqueadores neuromusculares (d-tubocurarina, galamina, pancurônio e decametônio). Esses resultados sugerem que alguma modificação no sistema de automodulação do TNM pode contrabalançar as deficiências neuronais induzidas pelo estado diabético. Dessa forma, o presente estudo foi conduzido com preparações nervo frênico-diafragma isolado de ratos (obtidas de animais normais e diabéticos) na tentativa de verificar se existiriam diferenças na fadiga neuromuscular induzida por drogas (d-tubocurarina, neostigmina, hexametônio). Nossos resultados mostraram que, embora não existissem diferenças na indução da fadiga neuromuscular induzida por d-tubocurarina, neostigmina ou hexametônio, o recobro da fadiga neuromuscular induzida por d-tubocurarina foi mais rápido em preparações neuromusculares obtidas de animais diabéticos. Essa diferença pode estar relacionada a alguma modificação induzida pelo estado diabético que determinou redugio da afinidade da d-tubocurarina para os receptores nicotínicos pré-juncionais
Asunto(s)
Animales , Ratas , Trietyoduro de Galamina , Hexametonio/uso terapéutico , Neostigmina , Pancuronio/uso terapéutico , TubocurarinaRESUMEN
The nicotinic acetylcholine receptor (AChR) presents two very well differentiated domains for ligand binding that account for different cholinergic properties. In the hydrophilic extracellular region of both alpha subunits there exist the binding sites for agonists such as the neurotransmitter acetylcholine (ACh) and for competitive antagonists such as d-tubocurarine. Agonists trigger the channel opening upon binding while competitive antagonists compete for the former ones and inhibit its pharmacological action. Identification of all residues involved in recognition and binding of agonist and competitive antagonists is a primary objective in order to understand which structural components are related to the physiological function of the AChR. The picture for the localisation of the agonist/competitive antagonist binding sites is now clearer in the light of newer and better experimental evidence. These sites are mainly located on both alpha subunits in a pocket approximately 30-35 A above the surface membrane. Since both alpha subunits are sequentially identical, the observed high and low affinity for agonists on the receptor is conditioned by the interaction of the alpha subunit with the delta or the gamma chain, respectively. This relationship is opposite for curare-related drugs. This molecular interaction takes place probably at the interface formed by the different subunits. The principal component for the agonist/competitive antagonist binding sites involves several aromatic residues, in addition to the cysteine pair at 192-193, in three loops-forming binding domains (loops A-C). Other residues such as the negatively changed aspartates and glutamates (loop D), Thr or Tyr (loop E), and Trp (loop F) from non-alpha subunits were also found to form the complementary component of the agonist/competitive antagonist binding sites. Neurotoxins such as alpha-, kappa-bungarotoxin and several alpha-conotoxins seem to partially overlap with the agonist/competitive antagonist binding sites at multiple point of contacts. The alpha subunits also carry the binding site for certain acetylcholinesterase inhibitors such as eserine and for the neurotransmitter 5-hydroxytryptamine which activate the receptor without interacting with the classical agonist binding sites. The link between specific subunits by means of the binding of ACh molecules might play a pivotal role in the relative shift among receptor subunits. This conformational change would allow for the opening of the intrinsic receptor cation channel transducting the external chemical signal elicited by the agonist into membrane depolarisation. The ion flux activity can be inhibited by non-competitive inhibitors (NCIs). For this kind of drugs, a population of low-affinity binding sites has been found at the lipid-protein interface of the AChR. In addition, several high-affinity binding sites have been found to be located at different rings on the M2 transmembrane domain, namely luminal binding sites. In this regard, the serine ring is the locus for exogenous NCIs such as chlorpromazine, triphenylmethylphosphonium, the local anaesthetic QX-222, phencyclidine, and trifluoromethyliodophenyldiazirine. Trifluoromethyliodophenyldiazirine also binds to the valine ring, which is the postulated site for cembranoids. Additionally, the local anaesthetic meproadifen binding site seems to be located at the outer or extracellular ring. Interestingly, the M2 domain is also the locus for endogenous NCIs such as the neuropeptide substance P and the neurotransmitter 5-hydroxytryptamine. In contrast with this fact, experimental evidence supports the hypothesis for the existence of other NCI high-affinity binding sites located not at the channel lumen but at non-luminal binding domains. (ABSTRACT TRUNCATED)
Asunto(s)
Receptores Nicotínicos/química , Receptores Nicotínicos/metabolismo , Acetilcolina/metabolismo , Animales , Sitios de Unión , Inhibidores de la Colinesterasa/farmacología , Humanos , Ligandos , Sustancias Macromoleculares , Modelos Moleculares , Músculos/metabolismo , Neuronas/metabolismo , Agonistas Nicotínicos/metabolismo , Antagonistas Nicotínicos/metabolismo , Antagonistas Nicotínicos/farmacología , Conformación Proteica , Tubocurarina/metabolismoRESUMEN
The methanol extract (mol. wt lower than 3,000 Da) of the sea squirt Phallusia nigra has stimulatory activity on guinea-pig ileum preparations. This effect was inhibited by cyproheptadine and mepyramine, but not be atropine. Mepyramine antagonized competitively the extract activity with a pA2 of 10.09 +/- 1.12, suggesting a direct activity on H1 histamine receptors. The extract was also assayed on guinea-pig right atria, however, only a mild increase in spontaneous contractions was observed compared to histamine, showing that the extract was a rather poor activator of cardiac H2 receptors. Histamine was not detected upon TLC analysis of the extract by comparison with an authentic standard.
Asunto(s)
Histamina/fisiología , Extractos de Tejidos/farmacología , Urocordados/química , Animales , Atropina/farmacología , Ciproheptadina/farmacología , Relación Dosis-Respuesta a Droga , Cobayas , Histamina/farmacología , Íleon/efectos de los fármacos , Íleon/metabolismo , Masculino , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Pirilamina/farmacología , Receptores Histamínicos H1/efectos de los fármacos , Receptores Histamínicos H1/metabolismo , Extractos de Tejidos/análisis , Extractos de Tejidos/química , Tubocurarina/farmacologíaAsunto(s)
Humanos , Sistema Cardiovascular/efectos de los fármacos , Bloqueantes Neuromusculares/efectos adversos , Bloqueantes Neuromusculares/farmacología , Alcuronio/efectos adversos , Alcuronio/farmacología , Atracurio/efectos adversos , Atracurio/farmacología , Bromuro de Vecuronio/efectos adversos , Bromuro de Vecuronio/farmacología , Hemodinámica , Relajación Muscular , Pancuronio/efectos adversos , Pancuronio/farmacología , Succinilcolina/efectos adversos , Succinilcolina/farmacología , Tubocurarina/efectos adversos , Tubocurarina/farmacologíaRESUMEN
Transmitter release evoked by nerve stimulation is highly dependent on Ca2+ entry through voltage-activated plasma membrane channels. Calcium influx may be modified in some neuromuscular diseases like Lambert-Eaton syndrome and amyotrophic lateral sclerosis. We studied the pharmacologic sensitivity of the transmitter release process to different calcium channel blockers in normal human muscles and found that funnel web toxin and omega-Agatoxin-IVA, both P-type calcium channel blockers, blocked nerve-elicited muscle action potentials and inhibited evoked synaptic transmission. The transmitter release was not affected either by nitrendipine, an L-type channel blocker, or omega-Conotoxin-GVIA, an N-type channel blocker. The pharmacologic profile of neuromuscular transmission observed in normal human muscles indicates that P-like channels mediate transmitter release at the motor nerve terminals.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio/fisiología , Unión Neuromuscular/fisiología , Neurotransmisores/metabolismo , Potenciales de Acción/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Membrana Celular/fisiología , Humanos , Músculos Intercostales , Unión Neuromuscular/efectos de los fármacos , Nitrendipino/farmacología , Péptidos/farmacología , Poliaminas/farmacología , Valores de Referencia , Músculos Respiratorios , Venenos de Araña/farmacología , Transmisión Sináptica/efectos de los fármacos , Tubocurarina/farmacología , omega-Agatoxina IVA , omega-Conotoxina GVIAAsunto(s)
Fármacos Neuromusculares no Despolarizantes/farmacología , Fármacos Neuromusculares no Despolarizantes/química , Fármacos Neuromusculares no Despolarizantes/farmacocinética , Fármacos Neuromusculares no Despolarizantes/efectos adversos , Interacciones Farmacológicas , Anestésicos Locales , Anestésicos por Inhalación , Antibacterianos , Tubocurarina , Alcuronio , Pancuronio , Bromuro de Vecuronio , Atracurio , PipecuronioAsunto(s)
Interacciones Farmacológicas , Fármacos Neuromusculares no Despolarizantes/efectos adversos , Fármacos Neuromusculares no Despolarizantes/química , Fármacos Neuromusculares no Despolarizantes/farmacocinética , Fármacos Neuromusculares no Despolarizantes/farmacología , Alcuronio , Anestésicos por Inhalación , Anestésicos Locales , Antibacterianos , Atracurio , Pancuronio , Pipecuronio , Tubocurarina , Bromuro de VecuronioRESUMEN
Bothropstoxin, a 13,700 mol. wt myotoxic phospholipase homologue isolated from the venom of Bothrops jararacussu and devoid of PLA2, proteolytic or hemolytic activities, inhibited muscle twitch tension, evoked either directly or indirectly through stimulation of the motor nerve in the mouse phrenic-diaphragm preparations. The compound action potential of the muscle was also abolished with a similar time course. In addition, the toxin (0.7 mM) evoked membrane depolarization which was inhibited in the presence of 10 mM Ca2+. In chick biventer cervicis muscle, the toxin (2 mM) induced a contracture that reached its maximum amplitude in 44.8 +/- 15.6 min (n = 6) and was not blocked by either d-tubocurarine or tetrodotoxin. The time to maximum amplitude was reduced to 5.5 +/- 1.0 min (n = 4) in nominally Ca(2+)-free Krebs solution and was completely abolished in Ca(2+)-free Krebs solution containing 1 mM EGTA.
Asunto(s)
Venenos de Crotálidos/farmacología , Músculos/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Animales , Calcio/farmacología , Pollos , Estimulación Eléctrica , Técnicas In Vitro , Masculino , Ratones , Contracción Muscular/efectos de los fármacos , Nervio Frénico/efectos de los fármacos , Músculos Respiratorios/efectos de los fármacos , Músculos Respiratorios/inervación , Tetrodotoxina/farmacología , Tubocurarina/farmacologíaRESUMEN
Rapid decrement of response to repeated stimuli is a characteristic of hippocampal neurons. To assess the possible role in this process of cholinergic afferents from the medial septal nucleus, a series of cholinergic antagonists were administered intraventricularly to chloral hydrate-anesthetized rats. Auditory stimuli were delivered in pairs to the rats, and the evoked response was recorded from an electrode in the CA3 layer of the hippocampus. The most prominent component of the auditory evoked potential recorded in this region (N40) showed over 60% decrement in the amplitude of the response to the second stimulus when the two stimuli were delivered 0.5 s apart. Only neuromuscular-type nicotinic antagonists, alpha-bungarotoxin and (+)-tubocurarine, disrupted this decrement of response to repeated auditory stimuli. The muscarinic antagonist, scopolamine, and the ganglionic-type nicotinic antagonists, kappa-bungarotoxin and mecamylamine, were without effect. The results suggest that a subset of nicotinic receptors mediate the gating of response to auditory stimuli in the hippocampus.