Assuntos
Ética Médica/história , Holocausto/história , Direitos Humanos/história , Consentimento Livre e Esclarecido/história , Drogas em Investigação , Alemanha , História do Século XX , Humanos , Militares , Parassimpatomiméticos , Síndrome do Golfo Pérsico , Brometo de Piridostigmina , Estados Unidos , United States Food and Drug AdministrationAssuntos
Acetilcolina/metabolismo , Anestésicos Locais/farmacologia , Canais Iônicos/efeitos dos fármacos , Piperidinas/farmacologia , Receptores Colinérgicos/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Anuros , Eletrofisiologia , Técnicas In Vitro , Cinética , Ligantes , Potenciais da Membrana/efeitos dos fármacos , Rana pipiens , Fatores de TempoRESUMO
The effects of single and repetitive injections of neostigmine on neuromuscular physiology were examined in rat extensor digitorum longus muscles. The characteristic facilitation of neuromuscular transmission associated with acute anticholinesterase treatment was accompanied by significant pre- and postsynaptic alterations in neuromuscular transmission. Three days of neostigmine treatment caused a decrease in indirectly and directly elicited muscle contraction. Miniature end-plate potential amplitude and frequency, end-plate potential amplitude, junctional acetylcholine sensitivity and quantal content of nerve-evoked end-plate potentials were also decreased by this treatment. By 22 to 25 days of continued treatment, the decreased rate of transmitter release had returned almost to normal, whereas the alterations of the postsynaptic membrane persisted for as long as 106 days. Alterations were also found in the muscle action potential and in certain passive electrical properties of the extrajunctional muscle membrane. In addition, many of the physiological changes were correlated directly with the morphological changes observed in rats treated similarly. We conclude that neostigmine treatment in rats in therapeutic doses has deleterious effects on neuromuscular physiology and neuromuscular ultrastructure. Although the pattern of these changes is not identical with that seen in rabbit and human myasthenia gravis, the neostigmine treatment used in patients with myasthenia gravis may contribute in part to the neuromuscular alterations observed in this disease.
Assuntos
Contração Muscular/efeitos dos fármacos , Neostigmina/farmacologia , Junção Neuromuscular/efeitos dos fármacos , Acetilcolina/farmacologia , Animais , Interações Medicamentosas , Feminino , Técnicas In Vitro , Potenciais da Membrana/efeitos dos fármacos , Membranas/efeitos dos fármacos , Placa Motora/efeitos dos fármacos , Músculos/efeitos dos fármacos , Músculos/ultraestrutura , Ratos , Transmissão Sináptica/efeitos dos fármacos , Fatores de TempoRESUMO
Brief and chronic exposure of rats to neostigmine methylsulfate produced marked morphological alterations of the fine structure at the end-plate region of the extensor digitorum longus muscles. These changes were dose and time dependent and were restricted primarily to the subjunctional myofibrillar apparatus and membrane-bound organelles. In addition, significant presynaptic alterations were observed including synaptic vesicle depletion and the appearance of numerous coated vesicles and membrane cisternae, which indicated continuing nerve terminal hyperactivity. With chronic treatment, degeneration and partial recovery of the nerve axon also were observed. The morphological changes of the end-plate region induced by neostigmine did not occur in most fibers after brief denervation and were eliminated entirely by chronic nerve section. Thus, the postsynaptic degenerative changes caused by neostigmine treatment observed in nondenervated animals appear to result primarily from greatly increased synaptic activity and not primarily from a direct neostigmine reaction with the pre- or postsynaptic membranes. Since the myopathic changes observed in this study were produced by neostigmine, a drug which is commonly employed in the routine treatment of human patients with myasthenia gravis, continued use of neostigmine for long-term therapy in noncrisis situations may not be accepted as being free from risk.
Assuntos
Neostigmina/farmacologia , Junção Neuromuscular/efeitos dos fármacos , Animais , Axônios/efeitos dos fármacos , Axônios/ultraestrutura , Relação Dose-Resposta a Droga , Feminino , Placa Motora/efeitos dos fármacos , Placa Motora/ultraestrutura , Denervação Muscular , Junção Neuromuscular/ultraestrutura , Ratos , Fatores de TempoAssuntos
Colchicina/farmacologia , Músculos/efeitos dos fármacos , Receptores Colinérgicos/efeitos dos fármacos , Acetilcolina/farmacologia , Animais , Transporte Axonal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Potenciais da Membrana/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Junção Neuromuscular/efeitos dos fármacos , Ratos , Nervo Isquiático/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacosRESUMO
Partial denervation of rat extensor digitorum longus and soleus muscles resulted in the appearance of denervated and innervated surface muscle fibers lying adjacent to one another. The denervated muscle fibers showed the typical signs of denervation while the innervated muscle fibers were similar to those of control muscles. We conclude that denervated fibers do not induce substantial physiological changes in adjacent innervated muscle fibers.