Assuntos
Síndrome Miastênica de Lambert-Eaton/fisiopatologia , 4-Aminopiridina/análogos & derivados , 4-Aminopiridina/uso terapêutico , Adolescente , Adulto , Idoso , Amifampridina , Anticorpos Antinucleares/análise , Criança , Eletromiografia , Feminino , Acetatos de Germina/uso terapêutico , Guanidina , Guanidinas/uso terapêutico , Humanos , Síndrome Miastênica de Lambert-Eaton/terapia , Masculino , Pessoa de Meia-Idade , Músculos/patologia , Junção Neuromuscular/patologiaRESUMO
1. The open time of single Na+ channels in excised (outside-out) patches from cultured late-fetal rat ventricular myocytes was prolonged to several minutes by germitrine (0.5 mM) in order to analyse tetrodotoxin (TTX) blocking kinetics. 2. The germitrine modification appeared during depolarizing pulses that activated normal Na+ channels. Following repolarization to -100 mV, the modified Na+ channel remained activated for 136 +/- 186 s (mean +/- S.D., n = 54) with an open-channel current amplitude of -0.5 pA. The predominant open state with a mean open time of 0.13 s was interrupted by brief closing events lasting for milliseconds. Replacing extracellular Na+ by Cs+ decreased the current amplitude to -0.1 pA. 3. Extracellular superfusion with TTX (3 x 10(-7) M) of a single germitrine-activated Na+ channel induced full channel closures lasting seconds (blocked events) separated by channel reopenings (unblocked events) that were indistinguishable in terms of amplitude and gating kinetics from the germitrine-activated state in the absence of TTX. 4. Cumulative probability histograms of blocked and unblocked events (n greater than 140) collected during long-lasting germitrine modifications at 10(-7) and 3 x 10(-7) M-TTX are well described by single exponentials. The 3-fold increase in [TTX] decreased the time constant of the unblocked state, tau o, from 11.9 to 4.7 s, while the time constant of the blocked state, tau c, was not significantly altered from 8.6 to 9.7 s. A microscopic association rate constant of 7.7 x 10(5) M-1 s-1, dissociation rate constant of 0.11 s-1, and equilibrium dissociation constant of 1.4 x 10(-7) M (at -100 mV) were calculated (20 degrees C). 5. Increasing [TTX] to 10(-5) M decreased tau o to 86 ms. This argues against the existence of a slower conformational step interposed between the binding of TTX to an open channel and the resultant channel closure. 6. Setting the membrane potential to -50 or 0 mV subsequent to a germitrine modification at -100 mV did not significantly alter TTX (3 x 10(-7) M) blocking kinetics: tau o was 6.7 s at -50 mV and 5.2 s at 0 mV; tau c was 8.9 and 8.1 s, respectively. 7. These results suggest that blocked events correspond to the random times that a TTX molecule resides on the Na+ channel before it dissociates, and unblocked events correspond to the random waiting times of an unoccupied channel before it binds another toxin molecule.(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Cevanas/farmacologia , Coração Fetal/fisiologia , Acetatos de Germina/farmacologia , Canais de Sódio/efeitos dos fármacos , Tetrodotoxina/farmacologia , Potenciais de Ação , Animais , Células Cultivadas , Cinética , Potenciais da Membrana , Ratos , Ratos EndogâmicosAssuntos
Miastenia Gravis/tratamento farmacológico , Junção Neuromuscular/fisiologia , Transmissão Sináptica/efeitos dos fármacos , 4-Aminopiridina , Corticosteroides/uso terapêutico , Hormônio Adrenocorticotrópico/uso terapêutico , Cloreto de Ambenônio/uso terapêutico , Aminopiridinas/uso terapêutico , Cálcio/uso terapêutico , Inibidores da Colinesterase/uso terapêutico , AMP Cíclico/fisiologia , Edrofônio/uso terapêutico , Efedrina/uso terapêutico , Acetatos de Germina/uso terapêutico , Guanidina , Guanidinas/uso terapêutico , Humanos , Neostigmina/uso terapêutico , Fármacos Neuromusculares Despolarizantes , Potássio/uso terapêutico , Brometo de Piridostigmina/uso terapêutico , Sinapses/fisiologiaRESUMO
Dantrolene sodium, a muscle relaxant, does not have a clinically useful antagonist. The present study was undertaken to test the efficacies of germine monoacetate, 4-aminopyridine, neostigmine, and calcium chloride as possible agents for the reversal of the direct skeletal muscle depression produced by dantrolene sodium in the cat anesthetized with alpha-chloralose. Depression of the indirectly elicited twitch responses (0.1 Hz) of the tibialis anterior muscle by 25, 50, 75 and 84 per cent was produced by dantrolene, 0.16, 0.36, 0.88 and 1.13 mg/kg respectively; spontaneous recovery of twitch tension during the subsequent 30 min was negligible. After the 30-min observation period had elapsed, one of the reversal agents under study was given (iv) in divided doses at intervals of 10 min (five cats for each agent). Germine monoacetate (2 X 0.5 mg/kg) immediately reversed the dantrolene-induced twitch depression, with an over-shoot that persisted for an hour. 4-Aminopyridine (4 X 0.5 mg/kg) caused a steady but incomplete reversal to 17 per cent depression, 30 min after the last dose. Neostigmine (4 X 0.04 mg/kg) caused an immediate, but transient, reversal of the twitch depression, with overshoot. Calcium chloride (4 X 10 mg/kg) was without effect. It is concluded that germine monoacetate is the drug of choice for reversal of the muscle depression produced by dantrolene sodium in the cat.
Assuntos
Aminopiridinas/farmacologia , Cloreto de Cálcio/farmacologia , Cevanas/farmacologia , Dantroleno/antagonistas & inibidores , Acetatos de Germina/farmacologia , Contração Muscular/efeitos dos fármacos , Neostigmina/farmacologia , 4-Aminopiridina , Animais , Gatos , Eletromiografia , Feminino , MasculinoAssuntos
Bloqueadores Neuromusculares/antagonistas & inibidores , Animais , Inibidores da Colinesterase/farmacologia , Colinesterases/fisiologia , Interações Medicamentosas , Acetatos de Germina/farmacologia , Humanos , Placa Motora/metabolismo , Bloqueadores Neuromusculares/administração & dosagem , Bloqueadores Neuromusculares/efeitos adversos , Fármacos Neuromusculares não Despolarizantes/farmacologia , Neurotransmissores/metabolismo , Succinilcolina/farmacologiaRESUMO
Germine (GER), germine-3-monoacetate (GMA) and germine-3,16-diacetate (GDA) when treated with 9:1 mixture of concentrated sulfuric acid and glacial acetic acid yield a deep purple color with characteristic ultraviolet absorption spectra. Combination of the color reaction with TLC makes possible the quantitative determination of these compounds in buffered solutions of pH 7.4 with a > 90% yield and satisfactory accuracy. It was observed that GDA incubated in such solutions is slowly transformed into GMA. The transformation of GDA to GMA was significantly faster with higher than with lower concentrations of GDA. There was no detectable breakdown of GMA under the same experimental conditions.
Assuntos
Cevanas , Acetatos de Germina , Animais , Dióxido de Carbono , Cevanas/análise , Fenômenos Químicos , Química , Cromatografia em Camada Delgada , Acetatos de Germina/análise , Concentração de Íons de Hidrogênio , Músculos/metabolismo , Oxigênio , Ratos , Fatores de TempoAssuntos
Fitoterapia , Plantas Medicinais , Nervo Isquiático/efeitos dos fármacos , Alcaloides de Veratrum/farmacologia , Animais , Cevanas/farmacologia , Acetatos de Germina/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Bloqueio Nervoso , Protoveratrinas/farmacologia , Rana esculenta , Relação Estrutura-Atividade , Veratridina/farmacologia , Veratrina/farmacologiaRESUMO
The action potential of guinea pig papillary muscle exposed to the ceveratrum alkaloid germitrine (2 mugM) is followed by a long-lasting after-depolarization (maximal amplitude, 8 mV; half-time of decay, 32 seconds; total duration, approximately 75 seconds). This after-depolarization interrupts the terminal phase of repolarization. During repetitive stimulation (0.1-1.0 Hz; 80 nM germitrine) the after-depolarizations that follow consecutive action potentials are summed, causing persistent depolarization of up to 10 mV. The after-depolarization is reversibly abolished by tetrodotoxin (TTX). Test contractions evoked at various times during or after the germitrine-induced after-depolarization reveal a phase during which the ability of the muscle to develop force is transiently increased. This positive inotropic influence reaches its maximum 1 minute after the conditioning stimulus and thereafter decays with a half-time 4.8 times longer than the half-time of decay of the after depolarization. It is reversibly abolished by TTX and augmented by dihydro-ouabain (DHO). We conclude: Germitrine induces an after-depolarization by prolonging dramatically the Na permeability component which is mediated by the fast Na channels and normally restricted to the first few milliseconds of the action potential. The germitrine-induced selective and persistent increase of sarcolemmal sodium permeability (PNA) causes a positive inotropic effect, probably because intracellularly accumulating Na ions exchange for extracellular Ca ions.
Assuntos
Cevanas/farmacologia , Acetatos de Germina/farmacologia , Contração Miocárdica/efeitos dos fármacos , Músculos Papilares/ultraestrutura , Sarcolema/metabolismo , Sódio/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Estimulação Elétrica , Acetatos de Germina/antagonistas & inibidores , Cobaias , Técnicas In Vitro , Potenciais da Membrana/efeitos dos fármacos , Músculos Papilares/metabolismo , Estimulação Química , Tetrodotoxina/farmacologia , Fatores de TempoRESUMO
The effect of protoveratrine A and germine-3-acetate (GMA) on the release mechanism of acetylcholine from the nerve terminals of the Auerbach plexus in the longitudinal muscle layer of the guinea-pig ileum was studied. Protoveratrine A, GMA and germine potentiated neuroeffector transmission in Auerbach's plexus in the longitudinal muscle preparation provided the neurons were stimulated at low frequencies (less than 10 Hz). Protoveratrine A and GMA enhanced the release of acetylcholine from the nerve terminals during the resting period and at low frequency of stimulation (less than 10 Hz). At continous stimulation with high frequency they were ineffective (greater than 10 Hz). When trains of 20 stimuli, with a pulse interval of 0.1 s (10 Hz) were repeatedly applied with intervals of 0.1 to 20 s between trains, the effect of GMA to increase ACh release depended on the length of the train interval; the longer the resting period between trains the higher was the output of ACh. This fact indicates that the release of ACh increased primarily during the resting periods following single stimuli or trains. The effect of GMA on ACh release proved to be highly temperature-dependent: in the presence of GMA Q10 increasing from 3.25 to 4.92. A high Ca concentration, removal of Mg or lowering of the Na concentration abolished the effect of GMA to enhance ACh release.