Showing papers in "British journal of pharmacology and chemotherapy in 1963"
TL;DR: Anti-inflammatory activity was readily observed in certain steroids, pyrazolidines, salicylates and sodium aurothiomalate, and the inhibition obtained by daily treatment with the steroid paramethasone disappeared when treatment was withdrawn.
Abstract: Arthritis induced in rats by mycobacterial adjuvant has been used for the study of compounds of known value in the treatment of rheumatoid arthritis in man. The development of the arthritic syndrome in treated and control rats was followed by measuring the changes in foot thickness of both hind-feet with a micrometer. This method allowed the effect of anti-inflammatory compounds to be expressed quantitatively. Anti-inflammatory activity was readily observed in certain steroids, pyrazolidines, salicylates and sodium aurothiomalate. Chloroquine and hydroxychloroquine were inactive. The inhibition obtained by daily treatment with the steroid paramethasone disappeared when treatment was withdrawn.
471 citations
TL;DR: Evidence is presented that the head-twitches are due to a central action of 5-hydroxytryptamine formed by decarboxylation of 5.hydroxyTryptophan, and the method may be valuable in the preliminary examination of compounds likely to have a centralaction.
Abstract: Injection of 5-hydroxytryptophan into mice produces a characteristic head-twitch. For a given period of observation this response may be assessed quantitatively either by observing the proportion of mice showing at least one head-twitch (a quantal response) or by counting the number of head-twitches for each mouse (a graded response). A method, based on the quantal response, of investigating the effect of centrally acting compounds on the head-twitch response is described. Evidence is presented that the head-twitches are due to a central action of 5-hydroxytryptamine formed by decarboxylation of 5-hydroxytryptophan. Head-twitches are potentiated by monoamine oxidase inhibitors and by phenytoin. Antagonists tested include an inhibitor of decarboxylase, antagonists of 5-hydroxytryptamine, some antihistamines, major tranquillizers and analgesic and sympathomimetic drugs. Drugs which neither potentiate nor inhibit the response include barbiturates and minor tranquillizers. The method may be valuable in the preliminary examination of compounds likely to have a central action.
337 citations
TL;DR: Measurement of the initial rates of noradrenaline uptake during perfusion with various concentrations of nonradioactive (+)- and (-)-noradrenalin showed that the uptake process exhibited stereochemical specificity, which suggested that diffusion did not play any significant role in the entry of nor adrenaline into the tissue.
Abstract: The uptake of noradrenaline by the isolated perfused rat heart was studied after perfusion with a medium containing various concentrations of (+/-)-[(3)H]-noradrenaline. Simultaneous measurement of the uptake of [(3)H]-noradrenaline and of the net increase in the noradrenaline content of the heart showed that [(3)H]-noradrenaline entering the heart both increased the tissue content and exchanged with endogenous noradrenaline. A large part (about 75%) of the endogenous noradrenaline pool, however, exchanged very slowly if at all with exogenous noradrenaline. The initial rates of noradrenaline uptake satisfied Michaelis-Menten kinetics with a Km for (+/-)-noradrenaline of 6.64x10(-7) M. Further analysis of the uptake process indicated that noradrenaline entered into at least two intracellular pools at different rates. Measurement of the initial rates of noradrenaline uptake during perfusion with various concentrations of nonradioactive (+)- and (-)-noradrenaline showed that the uptake process exhibited stereochemical specificity. The Km values for (+)- and (-)-noradrenaline were 13.9x10(-7) and 2.66x10(-7) M respectively. Cocaine acted as a potent competitive inhibitor of noradrenaline uptake. This finding suggested that diffusion did not play any significant role in the entry of noradrenaline into the tissue.
267 citations
TL;DR: A number of derivatives of tryptamine and phenethylamine, and certain other compounds, were tested on neurones in the cerebral cortex of cats by iontophoretic release from micro-pipettes; imidazolylacetic acid, dopamine, ephedrine and ergometrine were particularly effective.
Abstract: A number of derivatives of tryptamine and phenethylamine, and certain other compounds, were tested on neurones in the cerebral cortex of cats by iontophoretic release from micro-pipettes The characteristic action of many of these compounds was a depression of the neuronal discharge initiated by synaptic activity or by the application of L-glutamate; imidazolylacetic acid, dopamine, ephedrine and ergometrine were particularly effective Catechol amines, hydroxytryptamines and imidazolylacetic acid had a relatively quick and rapidly reversible action, not unlike that of γ-aminobutyric acid, whereas ephedrine and derivatives of lysergic acid diethylamide caused a slower and more prolonged depression of the amplitude of spikes, rather like atropine Several compounds, including 5-hydroxytryptamine, adrenaline and ergometrine, could also excite the same neurone when larger amounts were applied A few substances, such as dopa and methylergometrine, had a predominantly excitant action
265 citations
TL;DR: Both the new compounds affected intracellular potentials in the same way as quinidine, causing little change in the resting potential or duration of the action potential, but reducing the overshoot potential and slowing the rate of rise of theaction potential.
Abstract: A quantitative comparison of the effects of quinidine, pronethalol and γ-di-isopropylamino-α-phenyl-α-pyrid-2-ylbutyramide (disopyramide) has been made on rabbit isolated atria. All three drugs raised the electrical threshold and reduced the contractions, the conduction velocity and the maximal frequency at which the atria would follow a stimulus. The descending order of potency was pronethalol, quinidine and disopyramide, but the range was small, pronethalol having about twice the activity of disopyramide. Both the new compounds affected intracellular potentials in the same way as quinidine, causing little change in the resting potential or duration of the action potential, but reducing the overshoot potential and slowing the rate of rise of the action potential. These results support the view that interference with depolarization is an essential feature of antifibrillatory activity.
153 citations
TL;DR: It is concluded that morphine is only a partial antagonist of 5-hydroxytryptamine receptors in nervous tissue and that phenoxybenzamine antagonizes more 5-Hydroxyt Kryptamine receptors than those in smooth muscle.
Abstract: The responses of the isolated guinea-pig ileum to coaxial stimulation of its nerves, to histamine, acetylcholine, bradykinin, nicotine, tetramethylammonium, 1,1-dimethyl-4-phenyl-piperazinium iodide and 5-hydroxytryptamine were studied, before and during anoxia, cooling, or exposure to hyoscine, phenoxybenzamine hydrochloride, morphine or hexamethonium. Dose ratios were used to determine the amount of block induced by these procedures. With the response to coaxial nerve stimulation as an indication of the excitability of the nervous tissue, it was found that anoxia or cooling abolished the response to single shocks. Under these conditions the response of the ileum to histamine, acetylcholine and bradykinin was hardly affected, indicating a direct action of these substances on the muscle fibres. The effects of nicotine, tetramethylammonium, dimethylphenylpiperazinium and 5-hydroxytryptamine were reduced to various degrees, and we have concluded that their main actions are indirect, through stimulation of cholinergic nerve fibres. When these indirect actions were prevented, increasing the dose revealed a direct action, a larger increase in dose being required for 5-hydroxytryptamine and dimethylphenylpiperazinium than for tetramethylammonium and nicotine. Exposure of the ileum to hyoscine and phenoxybenzamine showed that these direct actions of nicotine and tetramethylammonium were not only on acetylcholine receptors but also on receptors insensitive to hyoscine but sensitive to phenoxybenzamine. The main action of 5-hydroxytryptamine was on nervous elements, yet treatment of the ileum with phenoxybenzamine gave a higher dose ratio for 5-hydroxytryptamine than did treatment with morphine. The meaning of this result is discussed in relation to the general belief that receptors sensitive to morphine are in nervous tissue and receptors sensitive to phenoxybenzamine are in smooth muscle. We have concluded that morphine is only a partial antagonist of 5-hydroxytryptamine receptors in nervous tissue and that phenoxybenzamine antagonizes more 5-hydroxytryptamine receptors than those in smooth muscle.
142 citations
TL;DR: These experiments show that when the guinea-pig vas deferens is removed without the hypogastric nerve and stimulated transmurally by the method described, contractions are produced mainly by excitation of postganglionic adrenergic nerves.
Abstract: The isolated vas deferens of the guinea-pig contracted when stimulated transmurally with parallel wire electrodes. These contractions persisted in concentrations of hexamethonium, pentolinium, nicotine and mecamylamine which at the same time abolished the responses to hypogastric nerve stimulation. Procaine and lignocaine in local anaesthetic concentrations abolished the responses to transmural stimulation but potentiated the contractions produced by added noradrenaline. Guanethidine and bretylium in concentrations specific for adrenergic neurone blockade abolished the contractions due to transmural stimulation without impairing the responses of the muscle to added noradrenaline or acetylcholine. In contrast, high concentrations of the adrenergic-blocking agents phentolamine and dihydroergotamine were needed to block the contractions due to transmural stimulation; these concentrations also blocked the response to added noradrenaline but simultaneously reduced the responses to added acetylcholine or potassium chloride. Preparations from guinea-pigs previously treated with reserpine at first responded normally to transmural stimulation; thereafter the contractions diminished progressively but were never abolished. Hyoscine and atropine produced a small decrease in the response to transmural stimulation when present in concentrations up to 1×10-5 and a larger decrease only in concentrations of 1×10-4 or greater. Hemicholinium produced a small decrease of the contractions due to transmural stimulation in concentrations up to 1×10-4; concentrations of 5×10-4 present for 1 hr produced only a slightly greater reduction in response. These experiments show that when the guinea-pig vas deferens is removed without the hypogastric nerve and stimulated transmurally by the method described, contractions are produced mainly by excitation of postganglionic adrenergic nerves.
134 citations
TL;DR: Results showed that 5-hydroxytryptamine activates specific receptors sited at the intramural parasympathetic ganglion cells and mediated its response through the nervous plexus, similar to nicotine, choline phenyl ether and dimethylphenylpiperazinium.
Abstract: Dose/response measurements were made on the guinea-pig isolated ileum with six agonists, acetylcholine, 5-hydroxytryptamine, nicotine, dimethylphenylpiperazinium, choline phenyl ether and histamine. The dose effects were repeated in the presence of each of twelve antagonists and one anticholinesterase. Acetylcholine and histamine were chosen because of their direct mode of action on smooth muscle, nicotine, dimethylphenylpiperazinium and choline phenyl ether were used as examples of drugs that act at the ganglionic acetylcholine receptor. 5-Hydroxytryptamine was the drug investigated. Hyoscine blocked the contractions caused by acetylcholine, 5-hydroxytryptamine and the ganglion-stimulants but left the responses to histamine unchanged. The anticholinesterase N,N'-diisopropylphosphorodiamidic fluoride (mipafox) potentiated all the agonists except histamine. The strength of potentiation decreased in the order 5-hydroxytryptamine, nicotine, dimethylphenylpiperazinium and choline phenyl ether, and acetylcholine. The local anaesthetic procaine inhibited to the same extent contractions elicited by 5-hydroxytryptamine, nicotine, dimethylphenylpiperazinium and choline phenyl ether. These results showed that 5-hydroxytryptamine, like nicotine, choline phenyl ether and dimethylphenylpiperazinium, mediated its response through the nervous plexus. Of those tested 5-hydroxytryptamine was the only specific antagonist to 5-hydroxytryptamine; lysergic acid derivatives produced spasm and prolonged changes in tone; phenoxybenzamine caused non-specific block. The diverse modes of action of a number of ganglion-blocking agents were selectively used. Thus hexamethonium, pentolinium, and nicotine in its competitive phase, blocked contractions due to nicotine, dimethylphenylpiperazinium and choline phenyl ether and left those due to 5-hydroxytryptamine, acetylcholine and histamine unchanged. The depolarizing ganglion-blocking agents, dimethylphenylpiperazinium and nicotine, inhibited the responses to all the indirectly acting drugs. Furthermore, mecamylamine, a drug with a less well-defined mode of action, partially inhibited contractions due to 5-hydroxytryptamine in a concentration that blocked those due to nicotine, dimethylphenylpiperazinium and choline phenyl ether. Pempidine, known to act like mecamylamine, did not antagonize 5-hydroxytryptamine. It is concluded that 5-hydroxytryptamine activates specific receptors sited at the intramural parasympathetic ganglion cells.
103 citations
TL;DR: On the rabbit fallopian tube in vivo prostaglandsins of the E series decreased both the tone and the peristalsis of the tube whereas prostaglandin F(1alpha) increased tubal tone.
Abstract: The biological activities of prostaglandins E(1), E(2), E(3) and F(1alpha) have been compared. Prostaglandins E(1), E(2), E(3) were qualitatively similar; E(1) and E(2) were about equiactive, but E(3) was less active on all preparations. Prostaglandin F(1alpha) was a less potent vasodilator than E(1) on the cat gastrocnemius muscle blood flow and skin blood flow and a less potent depressor drug on rabbit blood pressure. On the rabbit isolated jejunum F(1alpha) was twice as active as E(1) but on the guinea-pig isolated ileum E(1) was about forty times more active than F(1alpha). One qualitative difference between these prostaglandins was observed; on the rabbit fallopian tube in vivo prostaglandins of the E series decreased both the tone and the peristalsis of the tube whereas prostaglandin F(1alpha) increased tubal tone.
99 citations
TL;DR: In the rat and the chicken hypertension elicited by high doses of bombesin was often followed by secondary hypotension, andBombesin may be easily distinguished from all other known peptides active on vascular and extravascular smooth muscle by its effects on blood pressure.
Abstract: 1. The changes in blood pressure in response to parenteral administration of bombesin, the active tetradecapeptide of the skin of the European discoglossid frogs Bombina bombina and Bombina variegata variegata have been investigated in some experimental animals.
2. In most species, the polypeptide elicited hypertension which was usually gradual in onset and slow to disappear. Blood pressure increases rarely exceeded 40-50 mmHg. At the beginning of an experiment some dose-response relationship could often be observed, but later tachyphylaxis developed. During an intravenous infusion of bombesin the rise in blood pressure could sometimes be maintained at a steady level as long as the infusion was continued, but at other times, the rise of pressure slowly subsided with continued administration of the polypeptide. In the rat and the chicken hypertension elicited by high doses of bombesin was often followed by secondary hypotension.
3. Bombesin-induced hypertension was apparently not affected by pretreatment with either α- or β-adrenergic blocking agents. Similarly secondary hypotension was not abolished by atropine. Thus, the effect of bombesin on vascular smooth muscle seems to be predominantly a direct one.
4. Angiotensin was usually more potent than bombesin, and its effect on blood pressure was more rapid and of shorter duration. Tachyphylaxis to angiotensin was lacking or moderate.
5. In sharp contrast to the other species, the monkey responded to bombesin with frank hypotension, which was usually proportional to the dose. In the monkey the hypotensive effect of bombesin was equal to, or greater than that of eledoisin or physalaemin and bombesin-induced hypotension was of longer duration than that of the other polypeptides. Tachyphylaxis was moderate for low and adequately spaced doses of the polypeptide, but prompt and intense for high doses. Long-lasting hypotension was obtained by intravenous infusion of bombesin, but repeated infusions caused tachyphylaxis. Bombesin-induced hypotension was not affected by pretreatment with atropine.
6. Bombesin may be easily distinguished from all other known peptides active on vascular and extravascular smooth muscle by its effects on blood pressure. This does not apply to bombesin-like peptides, such as alytesin and ranatensin.
87 citations
TL;DR: It was concluded that the marked stimulant effects of the amphetamine-barbiturate mixtures on activity of rats could be regarded as due to true potentiation.
Abstract: Dose/response relations have been analysed for the actions of amphetamine-barbiturate mixtures on exploratory activity and ataxia in rats. Amphetamine sulphate and amylobarbitone sodium were studied separately and together (in a constant ratio of 1:20) in doses which ranged from those producing no effect to those which incapacitated the animals. Dexamphetamine and amylobarbitone were similarly studied in a ratio of 1:6.5; this corresponds to the ratio of a commercial preparation, Drinamyl. The results showed that mixtures could stimulate exploratory activity and their maximal effects were much greater than the effects produced by any dose of the separate drugs. The maximal effect with the first dose-ratio included conspicuous ataxia, but the maximal effect with the second ratio did not. Further experiments in which the dose of one drug was held constant and that of the other was varied showed that maximal effects on activity could be obtained with mixtures of dexamphetamine and amylobarbitone. Equivalent effects could be obtained both with relatively small and with relatively large amounts of the two drugs, in varying ratios; some constituent doses of the individual drugs were found to be optimal; whether the mixture effect was accompanied by ataxia depended largely on the constituent amount of barbiturate. For practical purposes mixtures producing maximal effects on activity with the smallest amounts of both drugs and not accompanied by ataxia might be most desirable, and these can be approximately read off from an isobol plotted from the results. It was concluded that the marked stimulant effects of the amphetamine-barbiturate mixtures on activity of rats could be regarded as due to true potentiation.
TL;DR: The results showed that a single brief exposure to an unfamiliar environment can markedly affect subsequent reactions to drugs, and interactions of this kind may have to be taken into account when it is desired to use animals repeatedly in tests of the action of drugs on behaviour.
Abstract: The activity of rats in an unfamiliar environment was studied in order to determine how far their reactions to an amphetamine-barbiturate mixture depended on whether or not they had been under the influence of this mixture while exposed to the same environment once before. The environment consisted of a Y-shaped runway, and the activity studied was the number of entries into the arms of the Y during a three-minute trial; the two trials took place three days apart. At the first trial the drug mixture practically doubled activity. At the second trial rats which had been under the influence of the drug mixture at the first trial were again made more active by the drug mixture, but the drug mixture did not increase the activity of rats which had received only saline at the first trial. These results showed that a single brief exposure to an unfamiliar environment can markedly affect subsequent reactions to drugs, and interactions of this kind may have to be taken into account when it is desired to use animals repeatedly in tests of the action of drugs on behaviour. The drug mixture also produced ataxia which was assessed quantitatively by measuring the variability of the “splay” of the rats' footprints; ataxia was unaffected by previous experience.
TL;DR: The results suggest that yohimbine releases noradrenaline from stores or nerves as a consequence of increased central sympathetic activity, and the lethal effects of a high dose of yOHimbine alone are not reduced by any of the treatments tested, and appear not to result from activation of sympathetic mechanisms.
Abstract: In mice, yohimbine appears to accentuate the normal "alarm" reactions (alerting, flight) to external stimuli. Imipramine increases this effect and at the same time converts a non-lethal dose of yohimbine into a lethal one. The effect of imipramine is greatly reduced by adrenalectomy or by treatment with reserpine, syrosingopine, ganglion-blocking drugs or adrenaline antagonists acting on sympathetic beta-receptors. Hypnotic, anti-convulsant or anaesthetic agents, tetrabenazine or antagonists of 5-hydroxytryptamine do not reduce the imipramine effect. A variety of drugs which, like imipramine, are known to interfere with the tissue binding of noradrenaline also increase the toxicity of yohimbine. Yohimbine significantly reduces brain noradrenaline content; adrenal catechol amines are slightly reduced. The results suggest that yohimbine releases noradrenaline from stores or nerves as a consequence of increased central sympathetic activity. Imipramine increases the actions and toxicity of yohimbine by increasing the effects of the released noradrenaline on beta-receptors. The lethal effects of a high dose of yohimbine alone are not reduced by any of the treatments tested, and appear not to result from activation of sympathetic mechanisms.
TL;DR: Reduction of the pressor responses to adrenaline in the rabbit following administration of prostaglandin E(1) has been confirmed, however, the effect is nonspecific since noradrenaline, angiotensin and vasopressin are also antagonized.
Abstract: Reduction of the pressor responses to adrenaline in the rabbit following administration of prostaglandin E1 has been confirmed. The effect is, however, nonspecific since noradrenaline, angiotensin and vasopressin are also antagonized. Analogous responses were observed in blood flow experiments on the cat hind limb but not on the rabbit isolated auricles or the rabbit isolated duodenum. Contractions of the cat nictitating membrane produced by sympathetic preganglionic stimulation or by adrenaline were not decreased following injection of prostaglandin E1 but the relaxation period was shorter. Contractions of the rabbit vas deferens induced in vivo by adrenaline were smaller after prostaglandin E1 and this effect tended to be long-lasting.
TL;DR: The adrenergic neurone block by BW 467C60 was inhibited by dopamine, cocaine and amphetamine in situations in which these amines inhibit the effects of bretylium and guanethidine.
Abstract: N-Benzyl-N'N”-dimethylguanidine sulphate (BW 467C60) and its ortho-chloro derivative (BW 392C60) had adrenergic neurone blocking and sympathomimetic effects resembling those of bretylium and guanethidine in cats, dogs and monkeys, but they were more potent in blocking adrenergic mechanisms in the cat. BW 467C60 was more active than its chloro derivative. Each compound inhibited release of noradrenaline during stimulation of the splenic nerve of cats, and increased smooth muscle responses to adrenaline and noradrenaline. Pressor responses to standard doses of tyramine were also increased except when large doses of BW 467C60 or BW 392C60 were given. The adrenergic neurone block by BW 467C60 was inhibited by dopamine, cocaine and amphetamine in situations in which these amines inhibit the effects of bretylium and guanethidine. In contrast to guanethidine, BW 467C60 and BW 392C60 did not lower the pressor amine content of the iris of cats 24 hr after administration of single doses of the compounds. BW 467C60 depressed the slope of curves relating the frequency of stimuli applied to the cervical sympathetic nerves and the resulting contraction of the nictitating membrane, but the effects of the lower rates of stimulation were preferentially inhibited. Large intravenous doses of BW 467C60 and BW 392C60 blocked autonomic cholinergic mechanisms and caused neuromuscular paralysis of voluntary muscle. These effects were brief, in contrast to the adrenergic neurone blockade. Both BW 467C60 and BW 392C60 were well absorbed from the alimentary tract. In contrast to guanethidine, BW 467C60 did not cause diarrhoea in guinea-pigs.
TL;DR: Indirect evidence has been presented to show that in the mid-brain and brain stem the change in acetylcholine level induced by gamma-butyrolactone is sharply localized in an area of the mesencephalon that contains the corpora quadrigemina.
Abstract: gamma-Butyrolactone, a depressant drug of the central nervous system, has been investigated for its ability to alter brain levels of 5-hydroxytryptamine, gamma-aminobutyric acid and acetylcholine in mice and rats; of these three compounds, only acetylcholine was changed in amount. Levels of acetylcholine in the cerebral cortex were increased by gamma-butyrolactone with a time-course which closely followed the depressed state of the animal. Indirect evidence has been presented to show that in the mid-brain and brain stem the change in acetylcholine level induced by gamma-butyrolactone is sharply localized in an area of the mesencephalon that contains the corpora quadrigemina.
TL;DR: A fluorimetric method for the estimation of 4-hydroxy-3-methoxyphenylacetic acid (homovanillic acid) has been developed and applied to normal brain tissue and the presence of homovanillsic acid in the caudate nucleus of normal animals of several species has been demonstrated.
Abstract: A fluorimetric method for the estimation of 4-hydroxy-3-methoxyphenylacetic acid (homovanillic acid) has been developed and applied to normal brain tissue. The presence of homovanillic acid in the caudate nucleus of normal animals of several species has been demonstrated.
TL;DR: The hypothesis is advanced that both dexamphetamine and guanethidine act on the store of noradrenaline at sympathetic nerve endings.
Abstract: After guanethidine had blocked the response of the cat nictitating membrane to sympathetic nerve stimulation, dexamphetamine restored the responses to all frequencies of stimulation. Dexamphetamine antagonized the sympathetic nerve block by guanethidine in the isolated sympathetically innervated rabbit ileum; the evidence suggests that the antagonism was competitive. Dexamphetamine antagonized the sympathetic nerve block by guanethidine in the isolated hypogastric nerve-vas deferens preparation of the guinea-pig. Doses of dexamphetamine, larger than those required to antagonize the blocking action of guanethidine, abolished the responses of the nictitating membrane, ileum and vas deferens to nerve stimulation. Dexamphetamine did not influence the depletion of noradrenaline by guanethidine in the heart and spleen of rabbits. The hypothesis is advanced that both dexamphetamine and guanethidine act on the store of noradrenaline at sympathetic nerve endings.
TL;DR: Large, convulsant doses of procaine or cinchocaine abolished the righting reflex in mice previously treated with small, subanaesthetic doses of phenobarbitone, consistent with the suggestion that general and local anaesthetics have a fundamentally similar action on neurones in the central nervous system.
Abstract: Procaine and several general anaesthetics block production of action potentials in frog skeletal muscle fibres by a single mechanism of action, which suggests that there might be a common basic mechanism of action on neurones in the central nervous system. Procaine or cinchocaine given alone to intact white mice produced "excitement" and convulsions but when given 60 min after phenobarbitone they caused central nervous depression. Large, convulsant doses of procaine or cinchocaine abolished the righting reflex in mice previously treated with small, subanaesthetic doses of phenobarbitone. In contrast, leptazol only antagonized the depression produced by phenobarbitone. When applied directly to neuronally isolated slabs of cat cerebral cortex, procaine or pentobarbitone reduced the sizes of the surface negative and surface positive responses to direct electrical stimulation of the cortex. Leptazol had the opposite effect. When given systemically, procaine only increased the electrical threshold for the surface positive response recorded from the isolated slab; ether either increased or did not change this threshold, and leptazol either decreased or did not change it. These results are consistent with the suggestion that general and local anaesthetics have a fundamentally similar action on neurones in the central nervous system.
TL;DR: It is postulated that 5-hydroxytryptamine, histamine and nicotine stimulate specific receptor sites within the intramural nerve plexuses of the guinea-pig isolated ileum.
Abstract: The circular muscle strip is a new preparation for examining the action of drugs on the circular muscle of the guinea-pig isolated intestine. The preparation differed from the longitudinal muscle in that it was insensitive to drugs which act on autonomic effector tissues but, after inhibition of cholinesterase, it responded readily to choline esters, 5-hydroxytryptamine, histamine and nicotine. This behaviour necessitated the treatment of each strip with the anticholinesterase NN-diisopropylphosphodiamidic fluoride (mipafox) before each experiment. The contractions of the strip by 5-hydroxytryptamine, histamine and nicotine were abolished by procaine, botulinum toxin (Type A), morphine and hemicholinium, whilst the actions of acetylcholine and methacholine were unaffected. Contractions of the strip in response to each of the drugs were abolished by atropine and hyoscine. The action of nicotine was specifically antagonized by hexamethonium, that of 5-hydroxytryptamine by desensitization of the tissue to 5-hydroxytryptamine, and that of histamine either by desensitization of the tissue to histamine or by mepyramine. It is postulated that 5-hydroxytryptamine, histamine and nicotine stimulate specific receptor sites within the intramural nerve plexuses of the guinea-pig isolated ileum. Finally, botulinum toxin (Type A), morphine or hemicholinum, acting on the neuronal elements of the intramural plexuses, depressed the contractions of the circular muscle strip due to histamine or nicotine more readily than those due to 5-hydroxytryptamine.
TL;DR: Various extracts of brain were prepared with dilute and concentrated acid, acetone and n-butanol and when the extracts were applied to the guinea-pig isolated ileum, they produced a slow contraction which was not prevented by an antihistamine; in addition, the acid and acetone extracts inhibited the action of histamine.
Abstract: Various extracts of brain were prepared with dilute and concentrated acid, acetone and n-butanol. When the extracts were applied to the guinea-pig isolated ileum, they produced a slow contraction which was not prevented by an antihistamine; in addition, the acid and acetone extracts inhibited the action of histamine. Histamine in extracts of brain was separated from other pharmacologically active substances by chromatography on a carboxylic-acid resin and estimated biologically. The bulk of this histamine was found in small particulate material, whereas slow-reacting substance was found in particulate material of greater density. 5-Hydroxytryptamine was in both the small and large particles. There was no relationship between the distribution of these substances and that of succinic dehydrogenase activity. The measurement of histamine in brain both by biological assay on the guinea-pig ileum and by chemical assay using a fluorimetric procedure gave mean values of 53 and 246 ng/g of wet tissue, respectively. The high values obtained by the chemical assay are attributable in part to substances other than histamine which become fluorescent after reaction with o-phthalaldehyde in this procedure.
TL;DR: The influence of histamine and noradrenaline on coronary flow was variable but when the contractility of the heart increased there was a concomitant increase in coronary flow.
Abstract: A method is described for recording the coronary flow and the rate and the amplitude of contraction of an isolated heart maintained at constant temperature. Both histamine and noradrenaline increased the contractility of the guinea-pig heart. Pronethalol antagonized noradrenaline but not histamine. Mepyramine, 10-(2-pyrrolidin-1'-ylethyl)phenothiazine hydrochloride (pyrathiazine) and diphenhydramine reduced the contractility of the guinea-pig heart but did not antagonize the action of histamine. The influence of histamine and noradrenaline on coronary flow was variable but when the contractility of the heart increased there was a concomitant increase in coronary flow. Histamine decreased the contractility of the rat heart and the domestic fowl heart.
TL;DR: The results of experiments involving chronic denervation, addition of hexamethonium and histological examination tally with the assumption of a distribution of ganglionic cells along the nerve just outside the organ, with unexpected results in several ways.
Abstract: Experiments on the isolated vas deferens of guinea-pig and rat had unexpected results in several ways. The effect of stimulation of the hypogastric nerve was not abolished, but increased, by parasympathetic blocking agents or by sympathetic blocking agents such as dihydroergotamine and phenoxybenzamine. The sensitization is considered not due to anticholinesterase activity of the drugs. Prolonged contact with a stimulating agent evoked rhythmic contractions. Addition as well as removal of a drug from the bath caused a response. The results of experiments involving chronic denervation, addition of hexamethonium and histological examination tally with the assumption of a distribution of ganglionic cells along the nerve just outside the organ.
TL;DR: It is concluded that these adrenergic blocking agents cannot be used to distinguish conclusively between adrenergic and cholinergic nerves.
Abstract: The adrenergic blocking agents tolazoline, phentolamine, piperoxan, yohimbine, phenoxybenzamine, bretylium and guanethidine block the excitatory actions both of cholinergic nerves and of added acetylcholine on a variety of vertebrate smooth muscle preparations. These cholinergic blocking actions often occurred with concentrations lower than those required to block the response of the guinea-pig vas deferens to stimulation of the adrenergic hypogastric nerve. The anti-acetylcholine activities of these drugs have been studied in detail, using the guinea-pig rectum and the toad bladder as test organs. In preparations sensitive to eserine, the anticholinesterase actions of the drugs competed with their anti-acetylcholine actions, so that either potentiation or block of responses to acetylcholine and to cholinergic nerve stimulation occurred with different concentrations. The responses of the toad bladder to acetylcholine were not potentiated by eserine. This enabled the antagonism of acetylcholine by the anti-adrenergic drugs to be estimated without interference from their anticholinesterase activity. When blocking activity was assessed on guinea-pig rectum previously treated with dyflos, the results were qualitatively similar to those on the toad bladder. Phenoxybenzamine often completely blocks responses both to added acetylcholine and to cholinergic nerve stimulation in concentrations less than those required to block adrenergic nerves. Guanethidine and piperoxan also show strong cholinergic blocking activity. Bretylium, yohimbine, tolazoline and phentolamine were less potent. However, in concentrations required to block the effect on the vas deferens of hypogastric nerve stimulation, these drugs at least halved the effects of acetylcholine and often of cholinergic nerve stimulation. It is concluded that these adrenergic blocking agents cannot be used to distinguish conclusively between adrenergic and cholinergic nerves. For reliable analysis of autonomic innervation, the substances released upon nerve stimulation must be identified by specific biochemical techniques or bioassay.
TL;DR: It seems that the contractile response to physstigmine or neostigmine does not depend on their anticholinesterase activity, but on their ability to release acetylcholine from postganglionic parasympathetic nerve endings.
Abstract: Neostigmine (22 μg/ml) or physostigmine (33 μg/ml) contracted guinea-pig isolated tracheal chains The anticholinesterase diisopropylphosphodiamidic fluoride (mipafox) itself caused no contractile response even in concentrations of 100 μg/ml, yet neostigmine or physostigmine still caused contractions after treatment with mipafox The responses were abolished by hyoscine or atropine Local anaesthetics, cooling, ionic changes and hemicholinium, all known to inhibit the release of acetylcholine from nerve endings, abolished or much reduced the responses It seems that the contractile response to physostigmine or neostigmine does not depend on their anticholinesterase activity, but on their ability to release acetylcholine from postganglionic parasympathetic nerve endings
TL;DR: The main differences in the responses of the circular and longitudinal muscle of the guinea-pig ileum to drugs were in the intrinsic properties of the smooth muscle cells, and in addition cholinesterase may protect the circular muscle cells.
Abstract: A circular and a longitudinal muscle strip were prepared from adjacent parts of a guinea-pig ileum and a direct pharmacological comparison made under identical conditions. The longitudinal preparation was sensitive to acetylcholine, methacholine, carbachol, 5-hydroxytryptamine, histamine and nicotine, while the circular preparation was insensitive to 5-hydroxytryptamine, histamine and nicotine, and responded to the choline esters only in high concentrations. Incubation of the preparations with the anticholinesterase, mipafox (NN-diisopropylphosphodiamidic fluoride), sensitized both preparations to the action of acetylcholine; potentiation of the contraction of the longitudinal muscle was 16-times; that of the circular one 4,000-times. The longitudinal muscle was more sensitive than the circular muscle to acetylcholine whether both were treated with mipafox or not. Bradykinin and substance P both stimulated the longitudinal but not the circular muscle, an effect not modified after mipafox. Hyoscine antagonized the responses of the circular muscle strip, treated with mipafox, to acetylcholine and to histamine, but on the longitudinal muscle strip the response to histamine was not affected, the response to acetylcholine being competitively antagonized. Morphine, in the same concentrations on both circular and longitudinal muscle strips, antagonized the stimulant actions of nicotine and to a lesser extent of 5-hydroxytryptamine, but the responses to histamine on the longitudinal muscle strip were not antagonized by morphine which was in contrast to its action on the circular muscle strip. These observations showed that the main differences in the responses of the circular and longitudinal muscle of the guinea-pig ileum to drugs were in the intrinsic properties of the smooth muscle cells. In addition cholinesterase may protect the circular muscle cells. Finally the circular muscle strip preparation proved to be a useful tool to study the action of drugs on the nervous plexuses of the ileum of the guinea-pig.
TL;DR: It is concluded that nicotine, pempidine, hexamethonium, D-tubocurarine and hemicholinium probably block the response to stimulation of the hypogastric nerve by acting on peripheral ganglia in its pathway.
Abstract: The contractions of the guinea-pig isolated vas deferens elicited by electrical stimulation of the hypogastric nerve were completely blocked by the following drugs: guanethidine, bretylium, dimethylphenylpiperazinium hydrochloride, nicotine, pempidine, hexamethonium, hemicholinium, D-tubocurarine and procaine. However, when the vas deferens was stimulated through an electrode in its lumen, the contractions in response to frequent, short stimuli (50 shocks/sec, 1 msec duration) were blocked by guanethidine, bretylium and dimethylphenylpiperazinium, but were not affected by the remaining drugs, except that procaine and hemicholinium each caused some reduction in the responses. When the preparation was stimulated transmurally with shocks of 200 msec duration at 1 shock/sec, the contractions were unaffected by any of the above drugs, except hemicholinium which again caused a slow reduction of up to 50% of the original response. It is concluded that nicotine, pempidine, hexamethonium, D-tubocurarine and hemicholinium probably block the response to stimulation of the hypogastric nerve by acting on peripheral ganglia in its pathway. Hemicholinium appears to have an additional effect in depressing the responses of the smooth muscle of the vas deferens to direct electrical stimulation, and procaine may act both on the ganglia and at the nerve terminals.
TL;DR: An intermittent infusion of ouabain, 4 mug during 30 sec every 1.5 min, regularly caused ventricular fibrillation in guinea-pigs, and the beta-receptor blocking drug, pronethalol, increased the doses required to produce extrasystoles, completely prevented fibrilation, and significantly raised the lethal dose of oUabain.
Abstract: An intermittent infusion of ouabain, 4 mug during 30 sec every 1.5 min, regularly caused ventricular fibrillation in guinea-pigs. The beta-receptor blocking drug, pronethalol (5 mg/kg), increased the dose of ouabain required to produce extrasystoles, completely prevented fibrillation, and significantly raised the lethal dose of ouabain. Dichloroisoprenaline had similar effects, but a dose of 15 mg/kg was required. When fibrillation had already been produced by ouabain, pronethalol (3 to 4 mg) administered slowly restored a regular rhythm, but rapid injection sometimes produced cardiac arrest. As much as 20 to 25 mg/kg of pronethalol could be given to animals deeply anaesthetized with urethane or pentobarbitone, but with light chloroform or ether anaesthesia, 5 mg/kg of pronethalol caused a large fall in blood pressure and complete heart-block.
TL;DR: Tubocurarine and benzoquinonium reversed the initial "extinction" phase of the depressed tetani by abolishing the repetitive discharge in the nerve and in larger doses reversed the secondary depressant phase presumably by reducing the excessive end-plate depolarization.
Abstract: Repetitive discharges recorded from the ventral root and from the gastrocnemius muscle in response to single motor nerve shocks applied close to the muscle after injection of edrophonium, neostigmine or ambenonium were studied in cats anaesthetized with chloralose. Two closely spaced volleys with an interval of 1 to 5 msec between them produced more repetitive firing than did a single shock. With longer intervals, the repetitive firing was not potentiated by the second volley. All frequencies of tetanic stimulation depressed the repetitive firing and, for successive stimuli to produce a degree of repetitive firing equivalent to the first, it was necessary to stimulate at frequencies below 2 shocks/sec. With stimulation frequencies higher than 100 shocks/sec, repetitive firing did not occur unless the duration of the tetanus was shorter than about 30 msec when slight repetition followed the last stimulus of the train. With stimulation frequencies of 100 down to 20 shocks/sec, repetitive firing was produced only by the first volley of the tetanus. Subsequent nerve action potentials of the tetanus occurring during the repetitive firing in the nerve following the first volley were partially extinguished by collision with the back discharge. This effect contributed to the waning tetanus, which is characteristic of treatment with an anticholinesterase, but the main depression of tetanic contractions appeared to be a consequence of depolarization block through accumulating acetylcholine. Tubocurarine and benzoquinonium reversed the initial "extinction" phase of the depressed tetani by abolishing the repetitive discharge in the nerve and in larger doses reversed the secondary depressant phase presumably by reducing the excessive end-plate depolarization. The results are discussed in relation to the hypothesis that anticholinesterases may effect transmission by acting at three sites at the neuromuscular junction-on acetylcholinesterase, at the motor nerve ending and at the motor end-plate-and that reaction at any one site may be augmented by the production of reverberating activity across the junction.
TL;DR: It is concluded that the action of acetylcholine at the postganglionic parasympathetic receptors in the guinea-pig ileum depends upon the presence of the 4-carbonyl group (and presumably the onium group) for affinity and on the 3-ether oxygen atom and the trimethylammonium group for efficacy.
Abstract: Two sets of series of compounds, RN(+)Me(3), RN(+)Me(2)Et, RN(+)MeEt(2), RN(+)Et(3), and R'N(+)Me(3), R'N(+)Me(2)Et, R'N(+)MeEt(2), R'N(+)Et(3), have been prepared, in which R is a 2-(diphenylacetoxy)ethyl, 2-(benziloyloxy)ethyl, 2-(2,2-diphenylethoxy)ethyl, 3-(diphenylmethoxy)propyl or 3,3-diphenylbutyrylmethyl group, and R' is a 2-acetoxyethyl, 2-ethoxyethyl, 3-methoxypropyl or butyrylmethyl group: compounds of the first set therefore differ from those of the second set in that they contain a diphenylmethyl group (or a benziloyl group) in place of a methyl group. The former compounds are antagonists of acetylcholine whereas most of the latter act like acetylcholine. The affinity constants of the former compounds for the acetylcholine receptors of the guinea-pig ileum have been determined and the equipotent molar ratios relative to acetylcholine have been measured for the latter compounds. The variation of the affinity constant with the constitution of the onium group in the antagonists (the diphenylmethyl compounds) was sufficiently consistent from one series to another for it to seem likely that corresponding changes in affinity with the constitution of the onium group would occur in the agonists. From the relative activity of the agonists and with this knowledge of relative affinity it was possible to assess the effects of their structure on efficacy. Substitution of one methyl in the onium group by an ethyl group in these compounds increased affinity but decreased efficacy. The replacement of a second methyl by a second ethyl group had little effect on affinity but decreased efficacy still further. The replacement of the ester link in acetylcholine by a 4-ether oxygen atom (as in the diphenylmethoxypropyl and methoxypropyl compounds) did not appreciably reduce affinity but markedly reduced efficacy, whereas the replacement of the ester link by a 3-ether oxygen atom (as in the diphenylethoxyethyl and ethoxyethyl compounds) markedly reduced affinity but did not reduce efficacy. The diphenylbutyrylmethyl compounds had low affinity and the butyrylmethyl compounds had low efficacy. We conclude that the action of acetylcholine at the postganglionic parasympathetic receptors in the guinea-pig ileum depends upon the presence of the 4-carbonyl group (and presumably the onium group) for affinity and on the 3-ether oxygen atom and the trimethylammonium group for efficacy.