Search PubMed⌕ Search

Biomedical subjects

W D Paton

Publications and source records attributed to W D Paton.

At least 73 records · Page 4Linked to original sources
PubMed1971

The mechanism of acetylcholine release from parasympathetic nerves.

1. The output of acetylcholine from the plexus of the guinea-pig ileum longitudinal strip has been used to study the mechanism of acetylcholine release. From the effects of hexamethonium and tetrodotoxin, it was inferred that 60% of the normal resting output is due to propagated activity in the plexus, and 40% to spontaneous release. Tetrodotoxin virtually abolishes the increase in output in response to electrical stimulation.2. Resting acetylcholine output is increased when the bathing medium is changed in the following ways:(a) sodium replacement by sucrose, trometamol or lithium;(b) addition of ouabain or p-hydroxymercuribenzoate (PHMB), or withdrawal of potassium;(c) the combination of PHMB and partial sodium replacement;(d) addition of potassium; this increase in output becomes greater in the absence of sodium.3. The resting output is virtually abolished by calcium withdrawal, and is restored by barium substitution for calcium. It is also reduced by raising the magnesium concentration.4. The enhanced resting output in response to sodium withdrawal also occurs in the absence of calcium.5. Cooling to 5 degrees C greatly reduces both the resting output and the output in response to raised potassium concentration or to electrical stimulation.6. The increase in resting output due to potassium excess is slight up to 25 mM [K(+)](o), but increases thereafter with about the fourth power of the potassium concentration; it is resistant to tetrodotoxin.7. Synthesis of acetylcholine by the longitudinal strip is increased when output is enhanced by electrical stimulation, by potassium excess or by addition of barium, so that the acetylcholine content of the strip is maintained approximately normal. Synthesis is reduced, in relation to output, by potassium lack or by treatment with ouabain, and is virtually abolished by sodium withdrawal.8. The theory is discussed that acetylcholine release depends on inhibition of the activity of a (Na(+) + K(+) + Mg(2+))-activated ATPase at the axonal membrane.

Acetylcholine↗
PubMed1970

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↗
PubMed1969

The inhibitory action of noradrenaline and adrenaline on acetylcholine output by guinea-pig ileum longitudinal muscle strip.

1. Noradrenaline and adrenaline reduce the output of acetylcholine by the guinea-pig ileum longitudinal strip by up to 80%, both in resting conditions and after stimulation. The effect is graded with dose, and is detectable with noradrenaline 2 x 10(-7) g/ml. Adrenaline is approximately 4 times as active as noradrenaline, and its action after being washed out is more persistent.2. If resting output is high, both amines have a proportionately greater effect and their action, as dosage is increased, is to reduce resting output to a basal level, relatively constant from strip to strip, of about 10 ng/g/min.3. With stimulation, the effect of the amine is greater at low frequencies, when the output per volley is high, than at high frequencies. The effect is reduced by increasing the number of shocks delivered. There thus appears to be a basal output per volley, of the order of 1-2 ng/g/volley, which can be reached either by relatively rapid stimulation, by prolonged stimulation, or by treatment with these amines.4. If noradrenaline is applied during continued stimulation at 40/min, the depression of acetylcholine output during its presence is followed by an augmented output when the drug is withdrawn. The magnitude of this "overshoot" increases with the duration of noradrenaline exposure.5. Phenylephrine 4 mug/ml. and amphetamine 20 mug/ml. reduced the acetylcholine output, but isoprenaline 1 mug/ml., dopamine 1 mug/ml. and methoxamine 10 mug/ml. were ineffective.6. Phenoxybenzamine reduced the resting output and increased the stimulation output. Of the two other blocking agents examined, phentolamine had no effect on either resting or stimulation output and ergotamine transiently reduced stimulation output. The effect of phenoxybenzamine was not due to a reaction with either adrenoceptive or muscarinic receptors.7. Phenoxybenzamine, phentolamine and ergotamine abolished the effect of adrenaline and noradrenaline on both resting output and on output in response to stimulation.8. In strips obtained from animals treated with reserpine and guanethidine, a rise in resting acetylcholine output and in stimulation output at low frequencies was found. In these conditions, noradrenaline was still effective.9. Reducing the hydroxytryptamine content of the strips by treatment with p-chloro-(+/-)-phenylalanine did not significantly affect acetylcholine output.10. It is concluded that acetylcholine output by the nervous networks of the longitudinal strip is under the normal control of the sympathetic by a species of presynaptic inhibition mediated by alpha receptors. This implies that for a tissue under dual autonomic control, withdrawal of sympathetic control will lead to a parasympathetic response which is not only unopposed but also itself enhanced.

Acetylcholine↗
PubMed1968

The origin of acetylcholine released from guinea-pig intestine and longitudinal muscle strips.

1. Strips of longitudinal muscle can be obtained from guinea-pig ileum either retaining or free from Auerbach's plexus.2. The denervated strip is unresponsive to electrical stimulation by brief shocks, whether given singly or in trains; it also fails to respond to nicotine or dimethylphenylpiperazinium iodide (DMPP), and eserine causes no spasm.3. Denervated strips neither contain detectable acetylcholine (< 0.4 ng/mg), nor release it spontaneously (< 5 pg/mg/min) or in response to stimulation (< 31 pg/mg/min). The acetylcholine metabolism of the innervated strip is therefore that of the adherent Auerbach's plexus. Innervated strips had a mean acetylcholine content of 28 ng/mg, a mean resting output of 94 pg/mg/min and an output in response to stimulation at 10 c/s of 700-1200 pg/mg/min.4. By comparing the responses of innervated and denervated strips it was concluded that arecoline, methylfurmethide, alpha,beta-ethylal-gamma-tri-methylammonium propanediol iodide (2268 F), muscarine, histamine, tremorine, oxytocin, and substance P, like acetylcholine, act primarily on the smooth muscle directly; and that angiotensin, barium, potassium, m-bromophenyl choline ether and 5-hydroxytryptamine have a progressively increasing proportionate effect on the nerve plexus. Nicotine and DMPP were inactive in the absence of the plexus.5. The longitudinal muscle with its accompanying plexus contains about one quarter of the acetylcholine of the whole ileum, and is responsible for about one fifth of the output to electrical stimulation.6. The volley output of acetylcholine by the innervated strip declines sharply as rate of stimulation increases. Output of acetylcholine was reduced by morphine and by cocaine, particularly when resting or when stimulated at low rates.7. Acetylcholine output by whole ileum from guinea-pig declines in the absence of glucose, but is insulin-independent. Output by strips of ileum from rats made diabetic with alloxan was similar to that from normal rats.8. The similarity in properties of acetylcholine output from innervated strips, where it must come from nervous tissue, to that from whole ileum, and the insulin-independence of output from whole ileum suggest that the whole of the acetylcholine output of intestine is nervous in origin.9. Comparison of the acetylcholine metabolism of the innervated strip with that of the superior cervical ganglion suggests that the typical features of the former (high resting output, high volley output at low rates, low minute output at high rates of stimulation, and sensitivity to morphine) may be linked with the absence of specialized neuro-effector junctions and represent a relatively primitive transmission process.

Acetylcholine↗
PubMed1967

Animals at very high pressures of helium and neon.

At pressures up to 125 atmospheres, helium failed to anesthetize mice; at slightly higher pressures (135 to 145 atmospheres) it proved lethal. With Italian newts (Triturus italicus), whose sensitivity to anesthesia by nitrogen is similar to that of mice, responsiveness was lost at pressures between 165 and 245 atmospheres, whether the pressure was achieved with helium or neon, or hydrostatically. It was concluded that the anesthetic pressures of helium and neon, for mice and newts, are higher than the tolerable mechanical pressures.

Anesthetics↗
PubMed1967

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↗