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PubMed1957

The effects of anticholinesterases on the bronchioles and pulmonary blood vessels in isolated perfused lungs of the dog.

The effects of two potent inhibitors of cholinesterase, isopropylmethylphosphonofluoridate (sarin) and ethyl pyrophosphate (TEPP), were investigated on the bronchioles and pulmonary blood vessels in isolated dog lung preparations perfused with heparinized blood and ventilated artificially. These anticholinesterases caused gradual bronchoconstriction as indicated by a diminution in tidal air volume, a reduction in compliance and an increase in expiratory resistance. These effects were antagonized by atropine. An increase in pulmonary vascular resistance occurred which was enhanced by the addition of small quantities of acetylcholine to the perfusing blood. The pulmonary vascular effects of acetylcholine, sarin and TEPP were prevented and abolished by atropine. Evidence is presented which suggests that the site of action of these anticholinesterases is, at least in part, peripheral to the autonomic ganglia.

Acetylcholine↗

PubMed1958

The effect of some oximes in sarin poisoning.

The effects of monoisonitrosoacetone (MINA), diacetylmonoxime (DAM) and pyridine-2-aldoxime methiodide (P2AM) upon the cholinesterase of sarin poisoned rats have been studied. Monoisonitrosoacetone and diacetylmonoxime given before sarin protected blood and brain cholinesterase from inhibition. Monoisonitrosoacetone given after the appearance of signs of poisoning caused a rapid reactivation of brain cholinesterase. Diacetylmonoxime, at an equimolar dose, produced only a slight increase in enzyme activity, and pyridine-2-aldoxime methiodide, the best reactivator in vitro, reactivated blood but not brain cholinesterase. There is a relationship between protection and reactivation of brain cholinesterase and prevention and alleviation of signs of poisoning.

Animals↗

PubMed1958

Effect of inhibitors of choline acetylation on acetylcholine output and motility in response to anticholinesterases and to distension of the lumen of isolated guinea-pig ileum.

Some pharmacological effects of acyl-aryl compounds, which inhibit the enzymatic acetylation of choline, have been studied on the isolated guinea-pig ileum. Diphenylylbutylacetic acid (M.G. 1763) greatly reduced the output of acetylcholine from intestine. The intestinal contractions produced by anticholinesterase drugs were inhibited, while the response to acetylcholine itself was little affected. The contraction of longitudinal muscle elicited by raising intra-luminal pressure was also decreased, while the emptying phase of the peristaltic reflex was scarcely affected. There was a correlation between inhibitory activity and chemical structure.

Acetylation↗

PubMed1958

Potentiation of the response of frog rectus muscle to acetylcholine by isopropyl methyl phosphonofluoridate and its modification by pyridine-2-aldoxime methiodide.

Pyridine-2-aldoxime methiodide (P2AM) was used to study the relation between the recovery of cholinesterase activity of isolated frog rectus abdominis muscle and the change of isotonic response to acetylcholine after previous treatment with the anticholinesterase, isopropyl methyl phosphonofluoridate (sarin). Addition of P2AM to muscle which had been incubated with sarin produced an 88% decrease in potentiation to acetylcholine. This was accompanied by 71% and 35% recoveries of the cholinesterase activity of the intact and finely ground muscle respectively compared with controls from the contralateral muscle. Following pre-treatment with sarin, a two-hour rinsing with acetylcholine (3 mug./ml.) produced a 61% decrease in potentiation to acetylcholine accompanied by 24% and 4.5% recoveries of cholinesterase activity in intact and in ground muscle respectively. Since control experiments showed absence of uncombined sarin in the muscle after rinsing with acetylcholine solution, the results indicate a greater effectiveness of P2AM and acetylcholine in reactivating superficially situated cholinesterase of the frog rectus abdominis as compared with enzyme within the interior of the muscle.

Acetylcholine↗

PubMed1959

Oximes of alpha omega-diquaternary alkane salts as antidotes to organophosphate anticholinesterases.

Sixteen compounds of the general structure {HON: CH.C(5)H(4)N(+).[CH(2)](n).R(+)}2Br(-) have been synthesized in which the position of the oxime group in the pyridine ring, the second charged group R(+) and the number of methylene groups between the charged atoms have been varied. The rate at which these compounds reactivate cholinesterase inhibited by ethyl pyrophosphate has been studied and a number have been found which are more active than 2-hydroxyiminomethyl-N-methylpyridinium methanesulphonate. Since considerable variation in structure was found among those compounds which are better reactivators than the latter, the concept that 2-hydroxyiminomethyl-N-methylpyridinium salts are unique in their ability to fit the surface of the inhibited enzyme is no longer tenable. The reactivating power of these oximes correlated well with their ability, when given in conjunction with atropine, to save the lives of mice poisoned by ethyl pyrophosphate. The most effective compounds, NN'-trimethylenebis-(4-hydroxyiminomethylpyridinium bromide) and NN'-hexamethylenebis(2-hydroxyiminomethylpyridinium bromide), contained a further oxime group in R(+), but the second oxime group was not essential for high activity. These new oximes were also superior in saving the lives of mice poisoned with sarin (isopropyl methylphosphonofluoridate), but the improvement was not as dramatic as when the mice were poisoned with ethyl pyrophosphate. The toxicity of the compounds varied with both n and R(+) and was unrelated to the therapeutic potency.

Alkanes↗

PubMed1960

Reciprocal potentiating action of depolarizing drugs on the isolated frog rectus abdominis muscle.

Subthreshold concentrations of the depolarizing agents, acetylcholine and decamethonium, potentiated isotonic contractures of the isolated frog rectus abdominis muscle elicited by effective doses of either of these drugs or by choline in the absence of the anticholinesterases, sarin, or dyflos. Comparable potentiation of the contracture produced by decamethonium or choline could be obtained by alternate stimulation with acetylcholine in the absence of dyflos or sarin. Furthermore, dyflos alone did not effect potentiation in the absence of alternate stimulation with acetylcholine. Finally, the inhibitory action of tubocurarine, as measured by depression of the contracture elicited by decamethonium and acetylcholine, was not antagonized by sarin. It was concluded that the enhancement of the response to acetylcholine produced by dyflos and by sarin was brought about exclusively by their action as inhibitors of cholinesterase. The ability of dyflos and of sarin to potentiate contractures elicited by decamethonium or by choline may be attributed to a facilitation of the action of the depolarizing compounds by subthreshold concentrations of acetylcholine available in the presence of these anticholinesterases.

Acetylcholine↗

PubMed1960

The effects of intracisternal sarin and pyridine-2-aldoxime methyl methanesulphonate in anesthetized dogs.

Dogs poisoned by the anticholinesterase sarin could be saved by intravenous administration of atropine sulphate together with a suitable oxime. The central effects of intracisternal sarin were respiratory paralysis and vasomotor stimulation. The problem arose as to whether the oxime, being a quaternary nitrogen compound, could enter the brain from the blood, and could have a central action on the paralysed respiration. The methyl methanesulphonate of pyridine-2-aldoxime administered intracisternally, after sarin poisoning by the same route, was ineffective; atropine, given intravenously, was effective. The central and peripheral effects of sarin were thus reversed by the atropine-oxime therapy, the central effects by atropine, the peripheral by the oxime.

Animals↗

PubMed1962

Effects of organophosphorous compounds, oximes and atropine injected into the third ventricle of unanaesthetized dogs.

The effects of four organophosphorous compounds, three oximes and atropine sulphate, injected through an indwelling cannula into the third ventricle of unanaesthetized dogs were examined. The effects of 200 mug of dyflos were involuntary micturition, defaecation, akinesia of hind limbs and pronounced disturbances of awareness; those of 100 mug of ethyl pyrophosphate were tremor, restlessness and signs of fear; 500 mug to 5 mg of dyflos and 250 mug to 500 mug of ethyl pyrophosphate caused vomiting, salivation, twitches of facial muscles and recurrent epileptiform seizures. The injection of 40 to 80 mg of dimefox and of 50 mg of schradan elicited involuntary micturition, vomiting, salivation and defaecation. These effects occur probably after these substances have passed into the blood stream and have been converted in the liver to potent anticholinesterases. This view is supported by the finding of reduced blood cholinesterase activity. At a dose level of 12.5 mg, 1,1'-trimethylenebis(4-hydroxyiminomethylpyridinium bromide) produced strong convulsions. At this dose level pralidoxime iodide and diacetyl monoxime produced no observable effects. Atropine sulphate in a dose of 1 mg caused disturbances in consciousness and behaviour followed by convulsions. Intraventricular atropine and to a minor extent intraventricular oximes were able to antagonize the effects of intraventricular ethyl pyrophosphate. Pralidoxime iodide exerted a strong antagonistic effect also on intravenous injection.

Animals↗

PubMed1962

Actions of some anticholinesterases on the smooth muscle of the chick amnion.

The actions of both reversible and irreversible anticholinesterase drugs on the nerve-free smooth muscle of the chick amnion are described. The tertiary compound physostigmine and the irreversible inhibitor diisopropylfluorophosphonate were found to be active in causing contractions, whereas the quaternary compound neostigmine and the irreversible inhibitor Mipafox were only slightly active in this respect. Manometric studies showed that all four compounds were highly active, however, in inhibiting the cholinesterase found in the chick amnion. The effects produced by these compounds in the organ bath are thought to be due to the accumulation of endogenously produced acetylcholine within the tissue. Evidence for an intracellular action of endogenously produced acetylcholine in the smooth muscle of the chick amnion is discussed.

Acetylcholine↗

PubMed1962

Mechanism of the antagonism by pralidoxime and 1,1-trimethylenebis(4-hydroxyiminomethylpyridinium) of the action of echothiphate on the intestine.

Pralidoxime chloride (pyridine-2-aldoxime methochloride; Protopam Chloride) and 1,1'-trimethylenebis(4-hydroxyiminomethylpyridinium bromide) (TMB-4) antagonize the spasm of the isolated or intact small intestine of the rabbit caused by the anticholinesterase, echothiophate iodide (S-2-dimethylaminoethyl OO-diethyl phosphorothiolate methiodide; Phospholine Iodide). In vitro, both oximes also antagonize the spasm caused by acetylcholine. The quantitative relationships have been studied in comparison with the activity of atropine against echothiophate and acetylcholine. Echothiophate-treated intestine which is subjected to a concentration of oxime sufficient to cause 100% restoration of function (but not cholinesterase reactivation) will go back into spasm on washing out both drugs. Strips treated with a high concentration of oxime, sufficient to cause 100% reactivation of cholinesterase, exhibit normal control tone and motility after washing. It is concluded that pralidoxime and 1,1'-trimethylenebis(4-hydroxyiminomethylpyridinium bromide) have an anticholinergic action as well as the ability to reactivate cholinesterase and that this action plays a significant part in the initial recovery of function under the conditions of these experiments.

Animals↗

PubMed1962

An eserine-like action of chloral hydrate.

The intra-arterial injection of chloral hydrate potentiated the transmission of nerve impulses through the cat superior cervical ganglion, antagonized the ganglionblocking action of hexamethonium, and greatly enhanced the ganglion-stimulant action of acetylcholine. Effects on the ganglion-stimulant actions of carbachol, nicotine, tetramethylammonium and potassium chloride were slight or absent. Chloral hydrate itself usually had no direct stimulant action. The neuromuscular-blocking action of tubocurarine on the isolated rat diaphragm preparation was completely and rapidly reversed by chloral hydrate. This reversal was prevented by previoustreatment of the muscle with neostigmine. Chloral hydrate potentiated the actions of acetylcholine and nicotine on the isolated rabbit duodenum, and, in concentrations exceeding 1 mg/ml., produced a spasm which was abolished by hyoscine but not by mepyramine. It was concluded that these eserine-like effects were manifestations of an anticholinesterase action of chloral hydrate. Neither chloralose nor trichlorethanol showed evidence of this property.

Acetylcholine↗

PubMed1953