The effect of vagal stimulation and eserine on isolated guinea-pig oesophagus.
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Animals↗
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Depolarization of the motor end-plate by decamethonium and acetylcholine.
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Acetylcholine↗
A study of the increased sensitivity of denervated and re-innervated muscle to depolarizing drugs.
1. The response of re-innervated muscles to depolarizing blocking drugs was studied.2. During the early stages of re-innervation the ;new' neuromuscular junctions are more sensitive to decamethonium and suxamethonium. The recovery from the block and the repolarization of the end-plate are markedly slowed.3. This increased sensitivity does not appear to be characteristic of all newly formed neuromuscular junctions. It was found that in new-born kittens the muscles are very insensitive to neuromuscular blocking drugs.4. It is concluded that the increased sensitivity of re-innervated muscles to depolarizing blocking drugs and the slow repolarization are due to a persistence of changes which developed during denervation.
Animals↗
The importance of peripheral changes in determining the sensitivity of striated muscle to depolarizing drugs.
1. The sensitivity of the flexor digitorum longus and soleus muscles to depolarizing drugs was tested after cross-union of their respective motor nerves.2. The alien innervation did not affect the sensitivity of either the flexor digitorum longus (FDL) or soleus muscles, which retained their normal characteristic responses to decamethonium and suxamethonium. The time course of muscle contractions was, however, altered by the cross-union operation.3. A considerable increase in sensitivity to depolarizing drugs was shown after de-afferentation and after tenotomy of the soleus muscles. Both these conditions are associated with muscle atrophy.4. It is suggested that hypersensitivity to depolarizing drugs can be expected in any situation where the muscle is undergoing atrophy.
Animals↗
Active transport of sodium and potassium in mammalian skeletal muscle and its modification by nerve and by cholinergic and adrenergic agents.
1. Active transport of Na(+) and K(+) by Na-rich extensor digitorum and soleus muscles of rat was found to be increased considerably when muscles were innervated during enrichment with Na(+) in K-free modified Krebs solution containing 160 mM-Na at 2 degrees C and recovery in a similar fluid with 10 mM-K and 137 mM-Na at 37 degrees C, bubbled with oxygen.2. Addition of acetylcholine (2.0 mug/ml.) to recovery fluid containing denervated extensors increased active transport, whereas addition of eserine (50 mug/ml.), decamethonium (0.1 mug/ml.) and to a lesser extent tubocurarine (0.26 mug/ml.) inhibited active transport. Blocking of nerve conduction in innervated extensor inhibited K(+) uptake more than Na(+) excretion.3. The membrane potential of Na-rich extensor muscles measured soon after re-immersion in recovery fluid was higher in denervated than in innervated muscles. In the latter it was close to the K-equilibrium potential (E(K)). It is suggested that denervation here makes the Na-pump electrogenic by decreasing K(+) uptake either by decreased permeability or by inactivating a K-pump. Evidence is presented that the latter is more likely.4. Addition of isoprenaline to Na-rich soleus muscles in recovery fluid increased active transport and reduced the membrane potential measured soon after re-immersion in recovery fluid. The Na-pump still remained electrogenic in the presence of isoprenaline. It was suggested that isoprenaline might also stimulate the Na-pump, perhaps through activation of lactic dehydrogenase.
Acetylcholine↗
The margin of safety of neuromuscular transmission.
1. The margin of safety for neuromuscular transmission in the tibialis and sartorius muscles of the cat has been determined by measuring the ratio by which end-plate depolarization produced by succinylcholine, decamethonium, octamethonium or iodocholine is antagonized, in the presence of neuromuscular block produced by tubocurarine, gallamine or DF-596. The estimate of the margin of safety was independent of the particular drugs chosen for the measurement.2. To produce threshold block to indirect stimulation once every 10 sec, a fractional occupancy by the antagonist of 0.76 +/- 0.05 (S.D.) was required; for nearly complete block, an occupancy of 0.917 +/- 0.16 (S.D.) was required. These figures correspond to factors of safety of 4.1 and 12 for the most sensitive and the most resistant groups of fibres respectively.3. The interaction between the agonists and the antagonists, when tested over a wide range of dosage, did not conform with the conditions of full competitive equilibrium. It was concluded that this arose, not because of some interfering non-competitive process, but because, during the relatively brief exposure to agonist, the equilibrium between the antagonist and the receptors is not significantly disturbed. An analysis of this condition of quasi-equilibrium is given. A correction downwards of the direct estimates of the margin of safety is required, but this proves to be small, about 8%, and may not be significant.4. The safety factor diminished when the motor nerve had been cut more than 5 hr; it is suggested that this represents an early sign of nerve degeneration.5. With dog sartorius muscle, results similar to those in the cat were obtained. But for deep block in the rabbit, the safety factor was only about 4.6. The existence of a substantial margin of safety influences considerably the interpretation of the time course of action of blocking drugs, and of comparisons between responses to nervous excitation and drug injection.
Animals↗
Effects of hyperventilation on the circulatory response of the rabbit to arterial hypoxia.
1. The circulatory effects of artificial hyperventilation with air and low oxygen mixtures were studied in rabbits anaesthetized with chloralose-urethane and given decamethonium iodide. The role of vagal afferents in the response to hypoxia was also assessed in spontaneously breathing unanaesthetized and anaesthetized animals.2. In the anaesthetized rabbit artificial hyperventilation inhibited all the changes in autonomic activity to the heart and peripheral circulation resulting from stimulation of the arterial chemoreceptors, and also reduced vagal efferent tone. In animals with section of the carotid sinus and aortic nerves the changes in autonomic activity observed during hypoxia and hyperventilation were much smaller than in normal animals and affected only cardiac autonomic activity.3. The effects of hyperventilation during hypoxia were mediated chiefly through vagal afferents rather than through the effects of hypocapnia. In the absence of changes in autonomic activity (e.g. during artificial hyperventilation with air) the circulatory effects were small and less clearly related to afferent vagal activity.4. In the spontaneously breathing anaesthetized and unanaesthetized rabbit vagal afferent activity resulting from the respiratory response to hypoxia inhibits sympatho-adrenal activity in the same way as during hypoxia with artificial hyperventilation.5. The importance of the vagal afferent input in the rabbit is discussed in relation to the qualitative differences in circulatory response with increasing severity of hypoxia, and in relation to the effects of anaesthesia.
Anesthesia, Intravenous↗
The secretion of pancreatic juice in response to stimulation of the vagus nerves in the pig.
1. The secretory response to stimulation of the vagus nerves has been examined in the pig and compared with that in the dog under similar experimental conditions.2. In the pig, stimulation of the vagus nerves caused a profuse flow of pancreatic juice with a high content of bicarbonate, in addition to a secretion of digestive enzymes; atropine suppressed the secretion of enzymes but failed to diminish the flow of bicarbonate-rich juice.3. Intra-arterial injections of acetylcholine closely imitated the effects of stimulation of the nerves, with the difference that both the flow of juice and the secretion of enzymes were abolished together by atropine.4. Stimulation of the nerves and injections of acetylcholine were effective after resection of the stomach and intestine: these stimuli can therefore act directly on the pancreas, independently of the release of gastro-intestinal hormones.5. In the dog, the pancreas differed from that of the pig in that stimulation of the vagus nerves and injections of acetylcholine acted predominantly on the secretion of enzymes and caused only a sparse flow of juice. Atropine annulled all these effects together.6. The results show that the vagus nerves can exert a much wider control of the secretion of pancreatic juice in the pig than in the dog. Possible mechanisms for this action are discussed.
Acetylcholine↗
The roles of striated and smooth muscle in the movement of the cat's nictitating membrane.
1. When the movement of the nictitating membrane is recorded in the usual way, pulled out under load in cat, dog, or rabbit, end-plate-depolarizing drugs such as succinylcholine, decamethonium, nicotine, and 2268F, cause a retraction.2. This movement is due to activation of orbital striated muscle, as evidenced by the resistance of the movement to ganglion block or excision of the superior cervical ganglion and to administration of phentolamine or atropine, and by its great sensitivity to dimethyltubocurarine.3. End-plate-depolarizing drugs produce contractions of the superior and inferior oblique and of the recti muscles strong enough to account for the movements of the nictitating membrane, provided the known fascial connexions of the orbit allow transmission of a fraction of the extraocular muscle movement to the membrane.4. In post mortem specimens with the front of the orbit undisturbed, retraction of the central end of any of the ocular muscles produces movement of the nictitating membrane; the movement was greatest with the superior oblique and medial rectus. In vivo, detaching the superior oblique from its insertion into the globe sometimes abolished or reduced the response to end-plate-depolarizing drugs.5. With the membrane unloaded and retracted into the medial canthus, in the lightly anaesthetized or unanaesthetized dog or cat, these drugs cause a protrusion of the membrane, which can be sufficient to cover the cornea. This response also resists ganglion-block and is highly sensitive to dimethyltubocurarine.6. It is suggested that in the normal conscious animal the nictitating membrane is held retracted by a relatively small amount of sympathetic activity, and that its protrusion is an active mechanism under voluntary control mediated by the striated muscles of the orbit.7. The importance of these mechanisms in the interpretation of experiments in which the nictitating membrane is used are discussed.
Animals↗
Decamethonium in depolarized muscle and the effects of tubocurarine.
1. In rat diaphragms immersed in solution containing 5 mM potassium the maximum uptake of labelled decamethonium was found at the end-plate region. In muscles depolarized in solution containing potassium methyl sulphate the uptake was reduced but a peak concentration at the end-plate region was still demonstrated.2. The uptake of labelled decamethonium increased steadily with time and was interpreted in terms of the entry of decamethonium into the fibres. The permeability at 10-100 muM was similar to that of sodium.3. The uptake of decamethonium at the end-plate region was dependent on the concentration. At low values the uptake in depolarized muscle was uniform along the fibres. Increase in concentration produced a peak at the end-plate region. This was interpreted as a change in permeability such that half the maximum effect was present at a concentration of approximately 5 muM.4. At high concentrations the influx showed saturation and carrier-like kinetics with a half-saturation concentration of 400 muM.5. Tubocurarine inhibited the peak uptake in depolarized diaphragm. The results were consistent with competitive inhibition with an inhibitory constant of 0.07 muM.6. Acetylcholine in high concentration also inhibited the uptake of decamethonium in the end-plate region of depolarized muscle.
Acetylcholine↗
Intestinal transfer of choline in rat and hamster.
1. The transfer of choline was studied with sacs of everted intestine of rat and hamster.2. The choline transfer can be divided into two components, a diffusion process and a saturable process. The latter plays a relatively greater part at low concentrations of choline, which include the physiological concentration in the plasma. The saturable process is better seen in the hamster than in the rat.3. Intestinal transfer of choline is influenced by substances altering the availability of energy in the cell, and by some substances chemically or pharmacologically related to choline. These findings are consistent with some kind of specific mechanism for choline transfer.4. Part of the choline taken up by the cell appears as a metabolite not yet identified. The formation of the metabolite is a saturable process and is abolished by anaerobic conditions and by homogenization.5. The results are also discussed in relation to parameters of transfer.
Air↗
Ionic permeability changes induced by some cholinergic agonists on normal and denervated frog muscles.
1. The reversal potential of responses to iontophoretic application of acetylcholine, carbamylcholine and decamethonium has been measured at junctional and extrajunctional sensitive areas of the normal sartorius muscle of the frog.2. The values obtained with any one of the drugs at junctional spots were similar to those previously reported for the end-plate potential (about - 16 mV).3. On the other hand, at extrajunctional areas the reversal potential of responses to these agonists was found to have a mean value of - 42 mV. The muscle-tendon responses to acetylcholine reversed at - 51 mV.4. The response to decamethonium was used to determine the nature of the ionic permeability changes mediated by the extrajunctional receptors. The results obtained show that extrajunctional responses are due to an increase in conductance to Na(+) and K(+) but not to Cl(-).5. The reversal potential of acetylcholine responses in denervated frog sartorius was - 42 mV both at former junctional spots and at non-neural sensitized regions.6. These different values of the reversal potential can be due either to effects of receptor density on the ionic selectivity of the membrane or to regional variations in the extracellular ionic accumulation during the transmitter action.
Acetylcholine↗
The characteristics of 'end-plate noise' produced by different depolarizing drugs.
1. End-plate depolarization and associated ;membrane noise' due to decamethonium, acetylthiocholine and suberyldicholine have been examined and compared with the effects of acetylcholine and carbachol.2. The transient ionic channels resulting from the action of decamethonium and acetylthiocholine are of much shorter duration than those produced by acetylcholine. They are, therefore, similarly to carbachol channels, less effective in causing membrane depolarization.3. Suberyldicholine, on the other hand, produces ion channels whose duration exceeds that of acetylcholine.4. Lowering the temperature causes an increase in amplitude of the elementary potential change produced by decamethonium and acetylthiocholine.5. The relation between the characteristic features of drug-induced membrane noise and the underlying molecular reaction rates is discussed.
Acetylcholine↗
The study of (Methyl-3H)decamethonium dichloride incorporation into normal and dystrophic mouse muscle.
1. (Methyl-3H)decamethonium dichloride was injected intravenously into the tail vein of dystrophic and normal mice of the Bar Harbour strain 129 ReJ/dy in paralysing doses. 2. Scintillation counts were made of 1 mm sections of diaphragm and tibialis anterior which showed a normal distribution of tritiated decamethonium in the dystrophic animals. 3. Intraperitoneal injections of L-(gamma-3H)leucine were made into dystrophic and normal mice. Examination of diaphragm and tibialis anterior by scintillation counting showed the abnormal uptake typical of dystrophic involvement of murine muscle. 4. The normal distribution of (methyl-3H)decamethonium dichloride uptake by the dystrophic muscle does not support the concept of active denervation in this disease.
Animals↗
Sodium entry in rat diaphragm induced by depolarizing drugs.
1. An increased uptake of labelled sodium was found in the end-plate region of rat diaphragm following brief exposure to solution containing (24)Na plus carbachol (100 muM), with a wash in inactive saline. Tetrodotoxin (0.1 muM) was also present. Comparable results were obtained with decamethonium and suberyldicholine.2. With carbachol (100 muM) the influx of labelled sodium at the end-plate region was increased by a factor of at least three as compared with that at the end of the fibres.3. After entry the labelled sodium spread along the fibres with an apparent diffusion coefficient which was half that expected in the external solution.4. The dose-response curve for the effect of carbachol gave a half-maximal value of 72 muM.5. In muscles depolarized by potassium methyl sulphate the effect of carbachol on the entry of sodium was reduced although demonstrable.6. The entry of labelled sodium at the end-plate was maintained during prolonged exposure to carbachol (100 muM) or decamethonium (100 muM).7. The rate of entry of (24)Na obtained with carbachol, after corrections for the wash, was estimated as 1.5 x 10(3) ions channel(-1) sec(-1), measured over a period of 15 sec.8. Labelled decamethonium and labelled carbachol also accumulated at the end-plate region. After extrapolation to allow for the effects of the wash the entry of decamethonium when expressed as a clearance (pl. mg(-1) sec(-1)) was comparable to that of sodium, as expected if decamethonium and sodium enter through the same channels.
Animals↗
A comparison of current-voltage relations for full and partial agonists.
1. Local conductance changes produced by various bath-applied agonists at frog end-plate membrane were measured using focal recording of extracellular potential in voltage-clamped muscle fibres. The potential difference between a focal micropipette placed on the nerve terminal and another micro-pipette placed on or near inactive membrane was taken as proportional to the agonist-induced current through a small patch of an end-plate membrane. 2. The current-voltage (I--V) relation of active membrane was obtained directly by increasing the membrane potential in a ramp fashion. The change in membrane potential was slow enough for post-synaptic gating processes to reach equilibrium during the ramp. 3. During application of sufficiently low concentrations of full agonists (carbachol, (ACh) and partial agonists (choline and decamethonium) the I--V relation of end-plate membrane showed strong curvature in the range of -60 to -130 mV. The slope of I--V relations increased exponentially with membrane hyperpolarization, an e-fold change in conductance occurring for about 50 mV potential shift. 4. The curvature of the I--V relation of end-plate-membrane activated by the partial agonists choline and decamethonium became less as the agonist concentration was increased, and with high concentrations (choline 15 mM; decamethonium 250 micrometer) the I--V relation became almost straight. 5. When end-plate currents produced by high concentrations of partial agonists were matched by application of equi-active concentrations of carbachol, the carbachol-activated membrane still showed as much curvature in its I--V relation as when low concentrations of carbachol were used. 6. Choline and decamethonium concentrations for which the I--V relation was straight produced much greater depression of miniature end-plate currents than did carbachol concentrations which produced the same membrane current at the holding potential. 7. I--V relations for full agonists at high concentrations were obtained after alpha-bungarotoxin pre-treatment. During application of carbachol (400--500 micrometer) and ACh (30--40 micrometer; after complete inhibition of acetylcholinesterase activity) the I--V relation of end-plate membrane is much less curved than during application of low concentrations. 8. It is concluded that either the voltage sensitivity of agonist-induced end-plate conductance reflects voltage sensitivity of agonist binding, or the partial agonists used can exert a voltage-dependent 'local anaesthetic' action in addition to their agonist activity.
Acetylcholine↗
Recovery from decamethonium in rat muscle and denervated guinea-pig diaphragm.
1. In denervated guinea-pig diaphragm the depolarization produced by decamethonium (100 microM) was followed by an initial phase of recovery, and then by a slow restoration of membrane potential in the presence of the drug, with hyperpolarization. Membrane potentials were measured by repeated insertions. The slow phase of spontaneous recovery was not found in the absence of potassium or in the presence of ouabain (100 microM). 2. With 1 microM-decamethonium the net loss of potassium from denervated muscle was 17% by wet weight in 20 min as compared with controls, which represents a loss of over 30 mM in internal concentration. Similar results were obtained with 100 microM-decamethonium. Spontaneous recovery of potassium occurred in the succeeding 2 h in the presence of 1 microM and 100 microM-decamethonium. With 5 nM-decamethonium muscles exposed for 20 min had a potassium content which was not reduced as compared with controls. 3. In rat diaphragm decamethonium (100 microM) also produced depolarization and slow spontaneous recovery which was not seen in the absence of potassium or the presence of ouabain. With 3 mM-decamethonium spontaneous recovery of potential was complete in 5 min. 4. Change from 5 mM-potassium to potassium-free solution produced consistent hyperpolarization in denervated guinea-pig diaphragm. In rat diaphragm at 38 degrees C the results were variable, with some fibres showing hyperpolarization while others showed depolarization.
Action Potentials↗
Different types of blockade of crustacean acetylcholine-induced currents.
The voltage dependence, concentration dependence, and agonist dependence of blocking and unblocking produced by anticholinergic agents on the ionophoretically activated cholinergic currents of the lobster gastric mill 1 (g.m.1) muscle were examined. Although the ionophoretic technique provides only qualitative information as to blocking mechanisms it is useful in revealing slow components of the blocking action of some drugs. At least two qualitatively different types of voltage-dependent block of the crustacean cholinergic currents were observed. For pempidine, mecamylamine and decamethonium (also chlorisondamine: Lingle, 1983), a slowly developing voltage-dependent block was produced that led to the formation of a stable-blocked state. Recovery from this stable-blocked state is largely dependent on subsequent application of agonist. In contrast, recovery from the voltage-dependent block produced by QX-222, atropine, procaine and curare either proceeds independently of agonist application or occurs too rapidly to be observed by the present methods. Blockade by hexamethonium reveals anomalous voltage dependence, being enhanced over some voltages and relieved with additional hyperpolarization. Blockade by trimetaphan is largely independent of membrane potential except at higher concentrations.
Animals↗