bluuebunny/crossref_metadata_2025 huggingface dataset:
A SENSITIVE METHOD FOR THE ASSAY OF 5‐HYDROXYTRYPTAMINE
Authors: VANE J. R.
Published: July 2012

The movements of a strip of fundus from a rat stomach, suspended in a 5 ml. bath at 37°, are recorded by a spring‐loaded lever. The muscle is stretched for 15 to 30 sec. between contractions. 1 ng. 5‐Hydroxytryptamine (5‐HT), 10 ng. acetylcholine or 2 to 10 μg. of histamine all produce contractions, giving tracings about 4 cm. high. In the presence of hyoscine (10−7) low concentrations of 5‐HT can be assayed directly from mixtures of the three substances. Sympathomimetic amines interfere with the assay, but this can be overcome. The preparation is robust, potentially suitable for use with an automatic assay apparatus and 10 to 100 times more sensitive than the rat uterus.
HISTAMINE RELEASE AND PAIN PRODUCTION BY XANTHOSINE AND RELATED COMPOUNDS
Authors: MOULTON R. , SPECTOR W. G. , WILLOUGH D. A.
Published: July 2012

Xanthosine (5 to 50 μg.) caused pain on intradermal injection in all human subjects tested: in about half the subjects it also gave a flare. Inosinic acid, uric acid, allantoin, alloxan and theophylline caused pain, but not a flare by intradermal injection in man. Xanthine caused both pain and flare. A number of related compounds in similar doses caused neither pain nor flare. Inosine, inosinic acid, and guanosine, but not xanthosine, were powerful histamine liberators in animals. The lowering of the cat blood pressure, depression of the activity of the guinea‐pig ileum and stimulation of guinea‐pig uterus by adenosine were confirmed.
SUSCEPTIBILITY OF CERTAIN ENZYMES OF THE CENTRAL NERVOUS SYSTEM TO TETRODOTOXIN
Authors: KURIAKI K. , NAGANO H.
Published: July 2012

The neurotoxic poison from the roe of Fugu, a globe fish living in the waters of Japan, was investigated with reference to its effect on the main oxidation‐reduction systems, acetyl‐cholinesterase and choline‐acetylase in the brain of the guinea‐pig.

It was found that the poison inhibited the choline‐acetylase activity, even in a concentration of 4.4 × 10−7. Acetyl‐cholinesterase and cytochrome‐c‐oxidase activities were also inhibited in concentration of 1.3 × 10−5 and 0.8 × 10−5 respectively.
A METHOD OF ESTIMATING HISTAMINE IN PLASMA
Authors: ADAM H. M. , HARDWICK D. C. , SPENCER K. E. V.
Published: July 2012

The method is intended for the estimation of minute quantities of histamine in blood plasma. A neutralized trichloracetic acid extract of plasma is adsorbed at pH 8 on a column prepared by mixing a quantity of the cationic exchange resin Amberlite XE‐64 with powdered cellulose as a supporting medium. Histamine is adsorbed but N‐acetylnistamine is not: the amines can therefore be estimated independently. Elution of the histamine is by displacement with HCl. The eluate is converted into the solution for bioassay on the superfused guinea‐pig ileum.

In recovery experiments histamine was added in the range 25 to 100 ng. to solutions of known composition and to plasma (5 ml.) obtained from man and the cat. The mean recovery in this range for histamine added to plasma was 82.5% ±2 S.E. (17 estimations).

It was possible by this method to follow the concentration of histamine in the arterial plasma of the cat when histamine was infused intravenously at a rate of 330 ng./kg./min. There was no perceptible change in the arterial blood pressure during the infusion, but the plasma histamine rose from <0.3 ng./ml. to 3.4 ng./ml. (mean of 2 estimations).

The histamine equivalent of human plasma obtained from the antecubital vein was found to be less than 1 ng./ml.
PHARMACOLOGICAL PROPERTIES OF ESTERS OF 1‐ALKYL‐2‐HYDROXYALKYLPYRROLIDINE AND THEIR QUATERNARY DERIVATIVES
Authors: ACRED P. , ATKINS E. M. , BAINBRIDGE J. G. , BROWN D. M. , QUINTON R. M. , TURNER D.
Published: July 2012

A series of esters of 1‐alkyl‐2‐hydroxyalkylpyrrolidine and their quaternary derivatives have been shown to possess significant anti‐acetylcboline activity. The benzilic acid esters were the most active, followed by xanthene‐9‐carboxylic acid, fluorene‐9‐carboxylic acid and diphenylacetic acid esters in that order. The quaternary derivatives were more active than their corresponding tertiary compounds both in vivo and in vitro. The most active compound of the series tested in vivo was (1‐methylpyrrolid‐2‐yl)methyl benzilate methiodide and was as potent as atropine. There was a progressive decrease in anti‐acetylcholine activity and a proportional increase in local anaesthetic activity as the number of carbon atoms was increased from 1 to 3 in the pyrrolidyl side‐chain of the tertiary salts of the benzilic acid ester series. Likewise increasing the size of the group on the nitrogen atom led to a decrease in anti‐acetylcholine activity and an increase in local anaesthetic activity. Quaternization of the tertiary salts resulted in a loss of local anaesthetic activity. Most of the compounds tested possessed some antihistamine properties, while papaverine‐like activity was confined to the tertiary salts only. No significant neuromuscular blocking activity was evident.
THE OXIDATION OF CYSTAMINE AND HOMOCYSTAMINE BY MAMMALIAN ENZYMES
Authors: BERGERET BERNADETTE , BLASCHKO H.
Published: July 2012

The oxidative deamination of cystamine and homocystamine by mammalian oxidases has been studied. The histaminase of pig kidney oxidizes homocystamine much more slowly than cystamine. The amine oxidase of mammalian liver (guinea‐pig, rabbit) oxidizes homocystamine more rapidly than cystamine. Both amines are oxidized by plasma (or serum) of ruminants (ox, sheep, goat) and of the horse. In the enzymatic oxidation of homocystamine both amino‐groups are removed; there is no evidence that a ring compound analogous to cystaldimine is accumulating.
THE CONCENTRATION OF ADRENALINE IN THE PLASMA OF RABBITS TREATED WITH RESERPINE
Authors: MUSCHOLL E. , VOGT MARTHE
Published: July 2012

Doses of 1 to 2.3 mg./kg. of reserpine given intravenously to rabbits raised the plasma adrenaline. The noradrenaline concentrations were too near the threshold of the method to decide whether any alterations followed the injection of reserpine. Control experiments, in which blood samples were taken from rabbits but no drug was given, showed only a very slight rise in adrenaline concentration after the first bleeding.
LOCAL EFFECTS AND MECHANISM OF ABSORPTION OF IRON PREPARATIONS ADMINISTERED INTRAMUSCULARLY
Authors: BERESFORD C. R. , GOLBERG L. , SMITH J. P.
Published: July 2012

An attempt has been made to correlate factors involved in the absorption of iron‐polysaccharide complexes administered intramuscularly. Different complexes varied greatly in degree of retention in muscle and in diffusibility in agar; these two characteristics were not closely related. The local changes in the muscle produced by the iron complexes consisted of an acute inflammatory reaction at the site of injection, with degenerative changes. Subsequent regeneration was rapid and complete. The major proportion of the absorption occurred during the initial 72 hr. and appeared to be mediated partly by the inflammatory reaction evoked, with enhancement of lymphatic transport of the iron complex. Rapid fixation by tissue macrophages impeded absorption and, with some complexes, this factor may make much of the injection inaccessible.
SOME PHARMACOLOGICAL ACTIONS OF CHOLINE 2:6‐XYLYL ETHER BROMIDE
Authors: WILLEY G. L.
Published: July 2012

The following pharmacological properties of choline 2:6‐xylyl ether bromide are described: (1) nicotine‐like stimulant action on the arterial blood pressure, on the nictitating membrane, and on the soleus and gastrocnemius muscles of cats; (2) muscarine‐like action on the arterial blood pressure of cats, and on the isolated guinea‐pig ileum; (3) antihistaminic and antimuscarinic actions on the isolated guinea‐pig ileum; (4) antisympathomimetic action on the arterial blood pressure of cats; and (5) neuromuscular blocking action on skeletal muscle of cats.
ASSAY OF THE CAPILLARY ACTION OF FLAVANOID COMPOUNDS IN MICE
Authors: LOCKETT MARY F. , JARMAN D. A.
Published: July 2012

A method is presented for the assay of biologically active flavanoids by measurement of the reduction which these compounds cause in the sensitivity of the skin capillaries of mice to histamine. The assay is economical of time, space, and apparatus. Limits of error may be calculated from internal evidence. Time/effect relationships are also given for the capillary actions of rutin and hisperidin and for some of their derivatives.
THE URINARY EXCRETION OF ADRENALINE AND NORADRENALINE BY RATS UNDER VARIOUS EXPERIMENTAL CONDITIONS
Authors: CRAWFORD T. B. B. , LAW W.
Published: July 2012

A study has been made of the excretion of adrenaline and noradrenaline in the urine of normal male rats and in the urine of these animals after the subcutaneous injection of saline, adrenaline, noradrenaline, morphine, insulin, iproniazid and thyroxine. The effects of thyroidectomy, adrenal demedullation and ether anaesthesia on the urinary output of adrenaline and noradrenaline have also been investigated. The findings are discussed against the background of the known effects of these treatments on the activity of the sympathetic nervous system.

The results demonstrate that urinary adrenaline and noradrenaline estimations in the rat can, under favourable conditions, serve as an indicator of an alteration of sympathetic activity following the administration of a drug or some other deviation from normal.
CONTINUOUS RECORDING OF ACID GASTRIC SECRETION IN THE RAT
Authors: GHOSH M. N. , SCHILD H. O.
Published: July 2012

A method is described for the continuous recording of acid gastric secretion in the rat. The stomach of the rat anaesthetized with urethane is perfused with a dilute sodium hydroxide solution by way of the oesophagus and the pH of the fluid emerging from a cannula in the pylorus is registered graphically. In passing through the stomach, the perfusate collects sufficient buffer to act as an approximately linear buffer system over the relevant range, so that the change in pH becomes a measure of acid secretion. The preparation is suitable for the bioassay of secretory stimulants. Ten or more drug doses can be administered in succession in one preparation, so that each animal serves as a self‐contained assay unit. Intravenous doses of histamine, methacholine, carbachol and acetylcholine produce a graded and reversible stimulation of acid secretion. The secretory effect of histamine is markedly and specifically potentiated by antihistaminases.
PERFUSION OF CEREBRAL VENTRICLES: EFFECTS OF DRUGS ON OUTFLOW FROM THE CISTERNA AND THE AQUEDUCT
Authors: BHATTACHARYA B. K. , FELDBERG W.
Published: July 2012

In cats under chloralose anaesthesia the cerebral ventricles were perfused with Locke solution at a rate of 0.1 ml./min. from an indwelling cannula in the lateral ventricle. The effluent was collected from a cannula either inserted into the cisterna magna or pushed into the aqueduct. When collection was from the cisterna the perfusion included relatively large areas of the sub‐arachnoidal spaces since in cats the foramina of Luschka form the only outlet from the fourth ventricle. Tubocurarine, histamine, and adrenaline injected intravenously caused great variations in outflow from the cisterna, but these changes did not occur when the collection was from the aqueduct. The changes in outflow from the cisterna were similar whether the injection produced a fall of arterial blood pressure as after tubocurarine and histamine, or a rise, as after adrenaline.
A COMPARISON OF SOME ATROPINE‐LIKE DRUGS IN MAN, WITH PARTICULAR REFERENCE TO THEIR END‐ORGAN SPECIFICITY
Authors: HERXHEIMER A.
Published: July 2012

Atropine, methanthelinium, propantheline, oxyphenonium, hyoscine, and hyoscine methyl‐bromide have been compared in man. After graded subcutaneous doses of these drugs simultaneous observations were made on the heart rate, salivary secretion, pupil size, near point of accommodation, micturition, and palmar sweating. This permitted a quantitative assessment of any differential effects of the drugs on the different end‐organs.

Small doses which depressed salivary secretion and palmar sweating did not necessarily accelerate the heart or slow micturition. Atropine and hyoscine, which are tertiary amines, had a greater effect than the other (quaternary) drugs on the iris and the ciliary muscle, compared with the effects on the other end‐organs studied. This difference may be related to the fact that quaternary compounds penetrate cellular membranes with difficulty.

The time course of the drug effects differed for different end‐organs. The changes in heart rate, salivary secretion, and sweating began and ended sooner than those affecting accommodation and the pupil. As the dose of a drug was increased, the peak effect on the heart rate and salivary secretion tended to occur sooner, but the peak effect on the iris and ciliary muscle always occurred later. It is suggested that the aqueous humour may be acting as a reservoir for the drugs. After methanthelinium, all the drug effects began sooner and reached their peak sooner than after the other drugs.
HAEMOGLOBINURIA CAUSED BY PROPYLENE GLYCOL IN SHEEP
Authors: POTTER B. J.
Published: July 2012

Haemoglobinuria occurred in sheep anaesthetized by an intravenous injection of pentobarbitone sodium containing propylene glycol: an equivalent dose failed to cause haemoglobinuria in rabbits. Intravenous injection of an aqueous solution of 20% propylene glycol caused haemoglobinaemia and haemoglobinuria in sheep. Neither distilled water nor 20% glycerol in water administered under identical conditions produced these effects.

Haemoglobinuria occurred on some occasions when an aqueous 20% solution of propylene glycol was administered to sheep after an injection of saline: it never occurred when a solution of 20% propylene glycol prepared with physiological saline was injected. It is suggested that saline may protect against the haemolytic action of propylene glycol in sheep and that propylene glycol should be avoided as a menstruum for pharmaceutical preparations to be used for injection into the blood stream of these animals.
THE CURATIVE POWER OF 4‐(2:6‐DIAMINOPYRIMIDIN‐4‐YLAMINO)PHENYLARSINE OXIDE (COMPOUND 12,065) IN INFECTIONS OF TRYPANOSOMA RHODESIENSE IN LABORATORY ANIMALS
Authors: BAKER J. R.
Published: July 2012

The toxicity to laboratory animals of 4‐(2: 6‐diaminopyrimidin‐4‐ylanimo)phenylarsine oxide (compound 12,065), and its ability to cure laboratory infections of Trypanosoma rhodesiense were investigated. The intramuscular LD50 to mice was 22 mg./kg.; rats were more susceptible. Monkeys tolerated two daily doses of 6 mg./kg., but not two daily doses of 10 mg./kg. The intramuscular CD50 to mice was about 6 mg./kg. with two strains of T. rhodesiense recently isolated from human patients, and 2 mg./kg. with a strain of T. rhodesiense which had been maintained by cyclical transmission through tsetse flies in the laboratory for about 17 months. These results are compared with those reported by Ainley and Davey (1958) for a strain of T. rhodesiense which had been maintained in the laboratory by cyclical transmission for about 12 years and then by syringe transmission for about 10 years. The syringe‐transmitted strain was at least 20 times more susceptible to the drug than the recently isolated strains. The potencies of compound 12,065 and melarsen oxide/BAL in curing T. rhodesiense infections in mice were compared: the CD50 for compound 12,065 was 6.5 mg./kg. and for melarsen oxide/BAL was 3.7 mg./kg. The ratios LD50/CD50 for the drugs were about 4 and 6 respectively.
THE DIFFERENCE IN THE METABOLISM OF INJECTED [14C]HISTAMINE IN MALE AND FEMALE RATS
Authors: WESTLING H.
Published: July 2012

[14C]Histamine was injected subcutaneously in rats. The urine was collected for 24 hr. and analysed for [14C]histamine and its various metabolites. It was found that male rats excreted less unchanged [14C]histamine than female ones, the difference between the sexes existing also when the animals were treated with aminoguanidine. The cause of the sexual difference appeared to be that the male rats had a larger capacity to methylate histamine.
THE EFFECT OF (+)‐LYSERGIC ACID DIETHYLAMIDE AND OTHER DRUGS ON THE CAROTID SINUS REFLEX
Authors: GINZEL K. H.
Published: July 2012

In cats, lysergic acid diethylamide (LSD) selectively blocked the reflex blood pressure rise following carotid chemoreceptor stimulation. It also reduced or abolished the chemoreceptor component of the pressor response to occlusion of the common carotid arteries. It did not inhibit the respiratory reflexes arising from the carotid chemoreceptors, unless spontaneous respiration was interfered with as a whole. The site of action was central, probably below the intercollicular level, regardless of whether the drug was administered by the intravenous route or into the lateral ventricle of the brain.

LSD did not block the baroreceptor depressor reflex elicited by stimulation of one carotid sinus nerve. LSD frequently caused the systemic pressure to fall, even after vagotomy and atropine, and this effect might account for the occasional reduction of the baroreceptor component of the carotid occlusion response. On the other hand, no relationship was found between the action of LSD on vasomotor tone and its blocking effect on the chemoreceptor pressor reflex.

Some derivatives of LSD produced effects similar to those described for LSD, whether or not they possessed a psychotropic action in man, and independently of their efficiency as antagonists to 5‐hydroxytryptamine. Of a series of compounds chemically unrelated to LSD, chlorpromazine was found to block the chemoreceptor pressor rise after intracerebroventricular injection.
THE MODE OF ACTION OF QUINIDINE ON ISOLATED RABBIT ATRIA INTERPRETED FROM INTRACELLULAR POTENTIAL RECORDS
Authors: WILLIAMS E. M. VAUGHAN
Published: July 2012

An attempt has been made to show why quinidine, which has long been known not to lengthen the duration of the cardiac action potential, measured with external electrodes, and also not to lengthen, and sometimes to shorten, the absolute refractory period, nevertheless reduces the maximum frequency at which atria can respond to a stimulus. Simultaneous measurements have been made in electrically driven isolated rabbit atria of contractions, conduction velocity and intracellular potentials before and during exposure to a wide range of concentrations of quinidine sulphate. The resting potential remained undiminished, in contrast to the effect of quinidine on Purkinje fibres. In the therapeutic range of doses, up to 10 mg./l., the half‐time for repolarization was either shortened or unchanged, thus providing an explanation for the failure of quinidine to prolong the absolute refractory period. In contrast, even at low concentrations of quinidine, conduction velocity and the rate of rise of the action potential were greatly slowed, and the height of the overshoot was reduced. The terminal phase of the action potential was prolonged. It is known that the rate of rise of the action potential is a function of the level of repolarization at which an impulse takes off (the more negative the take‐off point, the faster the rate of rise). Normally, a stimulus introduced when repolarization has proceeded to 2/3 of the resting potential evokes a response with a rate of rise fast enough for propagation, so that the duration of the terminal 1/3 of the phase of repolarization has no influence upon the length of the effective refractory period. In the presence of quinidine, however, the rate of rise itself was directly reduced, thus repolarization had to proceed further before the critical take‐off point was reached at which the rate of rise was fast enough for propagation, and the duration of the terminal phase of repolarization thus became significant. It has been concluded that quinidine prolongs the effective refractory period by slowing the phase of depolarization, without any change necessarily occurring in the half‐time for repolarization, which determines the absolute refractory period. Acetylcholine accelerated the rate of rise of the action potential even in the presence of high concentrations of quinidine.
ISOLATED RABBIT ATRIA WITH SYMPATHETIC NERVE SUPPLY
Authors: HUKOVIC S.
Published: July 2012

The atria of the rabbit heart have been isolated together with their sympathetic nerves, so that the latter could be stimulated and the effect on the rate and amplitude of beating could be measured. Cocaine and phenoxybenzamine increased the response to stimulation. When the preparation was from rabbits previously given reserpine, stimulation of the sympathetic nerves caused inhibition. This inhibition was increased by eserine and abolished by atropine.
A HYPOTHESIS CONCERNING THE EFFECT OF COCAINE ON THE ACTION OF SYMPATHOMIMETIC AMINES
Authors: MACMILLAN W. H.
Published: July 2012

There is a store, perhaps in chromaffin tissue, of noradrenaline in tissues with a sympathetic innervation. The store is depleted by treatment with reserpine. Sympathomimetic amines like tyramine act only when this store is present and have no effect when the store is depleted. They also fail to act in the presence of cocaine. Catecholamines like noradrenaline have a much greater action than usual when the store is depleted, and they have a much greater action in the presence of cocaine. It is suggested that cocaine has the effect of blocking release from the store, so that the action of tyramine is abolished and the spontaneous release from the store which is responsible for the normal (low) sensitivity to noradrenaline is stopped. Noradrenaline is taken up into the store in the heart and the vessel wall from the blood, and the disappearance of noradrenaline from the blood is in part due to this uptake and not entirely to destruction. Cocaine may prevent this uptake of noradrenaline by the tissue stores. Experiments on rabbit atria, on the vessels of the rabbit ear and on the heart‐lung preparation are described which are consistent with this hypothesis.
THE CARDIO‐ACTIVE PRINCIPLE IN SPLEEN
Authors: COBBIN L. B. , THORP R. H.
Published: July 2012

A substance has been demonstrated in acetone extracts of freeze‐dried spleen which had cardiotonic properties on isolated papillary muscles from the cat and perfused hearts of the cat and guinea‐pig. This activity of the extract could not be explained by the presence of choline, acetylcholine, histamine, 5‐hydroxytryptamine, adrenaline or noradrenaline.
THE MECHANISM OF THE INHIBITION BY CARBONIC ACID OF THE SMOOTH MUSCLE CONTRACTION PRODUCED BY HISTAMINE AND OXYTOCIN
Authors: HALPERN B. N. , BINAGHI R. , MAYER M. , BUGNARD C.
Published: July 2012

Carbonic acid inhibited the stimulating action of histamine on guinea‐pig intestine and of oxytocin on the uterus of many animal species. This effect was relatively specific. Under the same conditions the actions of acetylcholine, KCl, adrenaline (on rabbit uterus), and ergot alkaloids were not inhibited. The electrical excitability of smooth muscle was similarly not affected. The inhibitory action of carbonic acid is directly proportional to its concentration in the medium in which the isolated organ is maintained. The study of the activity of histamine and oxytocin at different pH in a medium free of NaHCO3 and buffered with a mixture of sodium maleate and maleic acid suggested that the inhibitory action exerted by carbonic acid was specific and independent of the simultaneous modifications of the hydrogen ion concentration. The mechanism of these phenomena is discussed.
SOME QUANTITATIVE USES OF DRUG ANTAGONISTS
Authors: ARUNLAKSHANA O. , SCHILD H. O.
Published: July 2012

Various applications of pAx measurements are discussed based on the hypothesis that drugs and drug antagonists compete for receptors according to the mass law. Examples are given illustrating the use of pAx measurements to identify agonists which act on the same receptors and to compare the receptors of different tissues. Tests of competitive and noncompetitive antagonism are considered in relation to the antagonisms acetylcholine‐atropine, histamine‐atropine and acetylcholine‐cinchonidine. A new measure, pAh, is introduced to express the activity of unsurmountable antagonists.
DRUG RESISTANCE IN TRYPANOSOMES; EFFECTS OF METABOLIC INHIBITORS, pH AND OXIDATION‐REDUCTION POTENTIAL ON NORMAL AND RESISTANT TRYPANOSOMA RHODESIENSE
Authors: WILLIAMSON J.
Published: July 2012

A wide variety of metabolic inhibitors tested in vitro for trypanocidal activity on normal and drug‐resistant strains of Trypanosoma rhodesiense showed no relation between acquired drug resistance and changes in specific enzymatic function. Oxidation‐reduction potential is an important factor in trypanocidal action but is not obviously related to the development of resistance. The dependence on pH of the trypanocid action of ionizing drugs against both normal and resistant trypanosomes supports the postulate that the development of resistance involves physical changes in cell structures associated with the uptake of drug.
A COMPARISON BETWEEN THE EFFECTS OF EDROPHONIUM AND CHOLINE IN THE SKELETAL MUSCLES OF THE CAT
Authors: BLABER L. C. , BOWMAN W. C.
Published: July 2012

The effects of edrophonium and choline have been compared with those of the depolarizing substances acetylcholine, decamethonium, and suxamethonium, in both innervated and chronically denervated tibialis anterior muscles of cats under chloralose anaesthesia. Both edrophonium and choline were more potent antagonists to paralysis by tubocurarine than could be accounted for by their ability to stimulate the motor end‐plates directly; It appeared likely that direct depolarization of the end‐plate played no part in the anti‐curare action of edrophonium and only some part in the anti‐curare action of choline. A paralysis produced by the neuromuscular blocking agent, benzoquinonium, was more readily antagonized by a tetanus or by acetylcholine, suxamethonium, and decamethonium than a similar paralysis produced by tubocurarine. The tetraethyl ammonium ion was also slightly more effective against a paralysis by benzoquinonium. On the other hand, edrophonium was about 300 times and choline about five times less potent as an antagonist to benzoquinonium than to tubocurarine. Furthermore, the previous administration of benzoquinonium abolished the antagonistic action to tubocurarine of normally effective doses of edrophonium and reduced that of choline. These results were similar to those previously obtained with neostigmine, physostigmine and ethyl pyrophosphate and suggested that there was some similarity in the mechanism of action of all of these substances. Benzoquinonium, therefore, showed promise as a useful pharmacological tool for distinguishing compounds with this particular type of action. These anti‐curare compounds did not appear to act by Cholinesterase inhibition, nor by an increase in the sensitivity of the motor end‐plates. In common with other workers, we suggest that there is a pre‐synaptic mechanism of action.
THE CENTRAL ACTION OF LIGNOCAINE AND ITS EFFECT ON CARDIAC OUTPUT
Authors: KAO F. F. , JALAR ULLA H.
Published: July 2012

Fifty‐nine tests were performed on twenty‐four anaesthetized dogs in a study of the effects of lignocaine on circulatory and respiratory functions. In single‐dog experiments, it was shown that lignocaine (1 to 2 mg./kg. body weight) increased ventilation somewhat, but had no effect on O2 consumption. Cardiac output was increased due to a rise in both heart rate and stroke volume. There was an elevation of arterial blood pressure. The central blood volume was increased, but central venous pressure, total peripheral resistance and the ventilation‐perfusion ratio were decreased. The increase in cardiac output after lignocaine was abolished both in decerebrate and in vagotomized dogs. In cross‐circulation experiments with dogs, it was demonstrated that the primary site of action of lignocaine on cardiac output was central. The effect of lignocaine on cardiac output could be blocked by intravenous procaine.
PROTECTION AGAINST LETHAL ORGANOPHOSPHATE POISONING BY QUATERNARY PYRIDINE ALDOXIMES
Authors: HOBBIGER F. , SADLER P. W.
Published: July 2012

The effect of 18 pyridinium aldoximes on diethylphosphoryl‐acetocholinesterase in vitro and the protection against lethal poisoning by ethyl pyrophosphate (TEPP) in mice pretreated with 0.095 m.mole/kg. of these oximes was investigated. Monoximes and dioximes of polymethylenebispyridinium compounds were studied in greater detail since they were up to 22 times more potent than pyridine‐2‐aldoxime methiodide (2‐hydroxyiminomethyl‐N‐methylpyridinium iodide) in reactivating diethylphosphoryl‐acetocholinesterase in vitro and protected mice against lethal poisoning by up to 15 LD100 of ethyl pyrophosphate. These oximes were also up to 52 times more potent than pyridine‐2‐aldoxime methiodide in reactivating di‐isopropylphosphoryl‐acetocholinesterase in vitro and were effective in preventing lethal poisoning by dyflos (di‐isopropyl phosphorofluoridate). The antidotal action against diethyl phosphostigmine (Ro 3–0340) was even greater than that against ethyl pyrophosphate. Some of the most effective oximes had antidotal actions in poisoning by ethyl pyrophosphate, diethyl phosphostigmine and dyflos when given in 0.0095 m.mole/kg. and this effect was enhanced by 1 mg./kg. atropine sulphate.In vivo reactivation of diethylphosphoryl‐acetocholinesterases by 0.0095 or 0.095 m.mole/kg. of oximes of polymethylenebispyridinium compounds was demonstrated in blood but not in brain. Atropine‐like and neuromuscular blocking activities were studied on isolated organs and protection against lethal doses of neostigmine and related anticholinesterases were also investigated. Some of the oximes of polymethylenebispyridinium compounds have, relative to pyridine‐2‐aldoxime methiodide, a higher therapeutic ratio in mice and considerably greater water‐solubility. The possible advantages to be gained from their use in preference to pyridine‐2‐aldoxime methiodide are discussed.
CARDIOVASCULAR EFFECTS OF INTRAVENOUS INFUSIONS OF 5‐HYDROXYTRYPTAMINE IN MAN
Authors: LeMESSURIER D. H. , SCHWARTZ C. J. , WHELAN R. F.
Published: July 2012

Intravenous infusions of 5‐hydroxytryptamine creatinine sulphate in doses of 1,2, and 3 mg./min. of the salt into 42 normal subjects caused a dilator response of the forearm vessels, consisting of an initial transient increase in flow usually followed by a smaller but sustained increase. A fall in forearm flow was not seen. Heart rate was invariably increased and the increase preceded other changes by 10 to 20 sec. suggesting a direct effect on the heart. The sustained increase in flow probably represents a balance between the direct constrictor action of the drug and a secondary dilator effect. The blood pressure response was variable and it appeared unlikely that it was responsible for more than a small part of the forearm flow changes. Two subjects appeared to be abnormally sensitive to the drug.
PHARMACOLOGICAL METHODS OF ESTIMATING INHIBITION OF DRUG OXIDATION IN THE MOUSE
Authors: LESSIN A. W.
Published: July 2012

Three pharmacological techniques for measuring inhibition of “non‐specific” oxidase activity in the mouse are described: (1) potentiation of pentobarbitone hypnosis, (2) potentiation of chlorpromazine hypothermia; and (3) reduction in the toxicity of octamethylpyrophosphorodiamide (schradan). Iproniazid, isoniazid, and β‐diethylaminoethyl 3,3‐diphenylpropylacetate (SKF 525A) gave comparable results in all three tests.
THE EFFECT OF LEVALLORPHAN TARTRATE AND OF ADIPHENINE HYDROCHLORIDE ON THE ANTIDIURETIC ACTION OF MORPHINE AND NICOTINE
Authors: SCHNIEDEN H.
Published: July 2012

Levallorphan antagonizes the antidiuretic effect of morphine. It is at least 25 times as potent as nalorphine in this respect. However, neither levallorphan nor adiphenine antagonized the antidiuretic action of nicotine.
BIOLOGICAL ACTIVITY OF SYNTHETIC POLYPEPTIDES WITH BRADYKININ‐LIKE PROPERTIES
Authors: KONZETT H. , STÜRMER E.
Published: July 2012

The biological activity of synthetic polypeptides containing the amino acids of natural pure trypsin‐bradykinin and snake‐venom‐bradykinin has been investigated. A series of tests for bradykinin‐like activity in stimulating plain muscle, depressing the blood pressure and increasing capillary permeability was used on various species. A nonapeptide with the following structure: H‐L‐Arg‐L‐Pro‐L‐Pro‐Gly‐L‐Phe‐L‐Ser‐L‐Pro‐L‐Phe‐L‐Arg‐OH elicited qualitatively and quantitatively the effects of the pure natural bradykinins. An octapeptide with the following structure: H‐L‐Arg‐L‐Pro‐Gly‐L‐Phe‐L‐Ser‐L‐Pro‐L‐Phe‐L‐Arg‐OH also exerted bradykinin‐like effects but was 50 to 100 times less active than the nonapeptide. Three other octapeptides and a heptapeptide were without any significant effect. Further work will demonstrate if the nonapeptide A is synthetic bradykinin or a peptide with bradykinin‐like activity.

Note added since submission of this paper: The data from this investigation were personally precommunicated to Elliott, Lewis, and Horton, who have since found that the structure of pure trypsin‐bradykinin is identical with the structure of the nonapeptide A. Therefore, this synthetic nonapeptide is in fact synthetic bradykinin.
TRANSMISSION FAILURE IN SYMPATHETIC NERVES PRODUCED BY HEMICHOLINIUM
Authors: CHANG V. , RAND M. J.
Published: July 2012

It has been shown by others that hemicholinium (α,α′‐dimethylethanolamino‐4,4′‐biacetophenone) inhibits the synthesis of acetylcholine, an effect which is reversed by choline. Hemicholinium produces a failure of response to nerve stimulation in the following sympathetically innervated preparations: guinea‐pig isolated vas deferens, rabbit isolated uterus, rabbit isolated colon, perfused rabbit ear, cat isolated atria and the piloerector muscles in the cat's tail. The blocking action of hemicholinium on the responses to postganglionic sympathetic stimulation resembles its blocking action against cholinergic nerve stimulation observed on rabbit isolated atria with vagus nerves, rabbit isolated vagina with pelvic nerves, and guinea‐pig isolated diaphragm with phrenic nerve. The failure of transmission produced by hemicholinium in sympathetic nerves and in cholinergic nerves can be reversed by choline. It is suggested that if there were a cholinergic junction at sympathetic nerve endings the mechanism of the blocking action of hemicholinium at these endings could be explained by inhibition of acetylcholine synthesis.
RECIPROCAL POTENTIATING ACTION OF DEPOLARIZING DRUGS ON THE ISOLATED FROG RECTUS ABDOMINIS MUSCLE
Authors: FLEISHER J. H. , CORRIGAN J. P. , HOWARD J. W.
Published: July 2012

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.
ASSAY OF LYSERGIC ACID DIETHYLAMIDE AND ITS PASSAGE FROM BLOOD INTO THE PERFUSED CEREBRAL VENTRICLES
Authors: DRASKOCI M.
Published: July 2012

On the isolated rat uterus, lysergic acid diethylamide had an oxytocic action in a concentration of 2 × 10−8; in smaller concentrations (10−9 to 10−10), which had no stimulating effect of their own, it potentiated acetylcholine‐induced contractions. This potentiating effect was made the basis for assaying minute amounts of lysergic acid diethylamide. The method was used to assay this substance in plasma of cats during its intravenous infusion at a rate of 10 μg./min./kg. During these infusions 0.4 to 2 ng./min. of lysergic acid diethylamide passed into the cerebral ventricles perfused with a salt solution of a composition resembling that of cerebrospinal fluid.
PHARMACOLOGICAL PROPERTIES OF THALIDOMIDE (α‐PHTHALIMIDO GLUTARIMIDE), A NEW SEDATIVE HYPNOTIC DRUG
Authors: SOMERS G. F.
Published: July 2012

Thalidomide (α‐phthalimidoglutarimide, “Distaval,” “Contergan”) is a new sedative hypnotic drug which produces no toxic effects when administered orally to animals in massive doses. This lack of toxicity may be due to a limited absorption. The drug has a quietening effect on the central nervous system, reducing the voluntary activity of laboratory animals and promoting sleep. Unlike the barbiturate drugs it does not cause an initial excitation in mice, incoordination or narcosis. It potentiates the actions of other central nervous system depressants, in particular the barbiturates. Its sedative effects are counteracted by central nervous system stimulants. It has no deleterious side effects and does not affect the heart, respiration or autonomic nervous system.
THE ACTION OF SYMPATHETIC BLOCKING AGENTS ON ISOLATED AND INNERVATED ATRIA AND VESSELS
Authors: HUKOVIĆ S.
Published: July 2012

A preparation is described of isolated rabbit atria with both vagus and sympathetic nerves. The action on it of bretylium and of choline 2,6‐xylyl ether bromide (TM10) was studied. A concentration of breylium sufficient to abolish the response to sympathetic stimulation also depressed the response to vagal stimulation. The effect was reversible, though more easily with choline xylyl ether. Both drugs abolished the accelerating action of acetylcholine in the presence of atropine, but they augmented the action of tyramine, and did not reduce that of amphetamine. In the vessels of the perfused rabbit ear they abolished the constrictor effect of nervous stimulation and of acetylcholine, but increased that of tyramine.
A STUDY OF ANTAGONISTS OF 5‐HYDROXYTRYPTAMINE AND CATECHOL AMINES ON THE RAT'S BLOOD PRESSURE
Authors: OUTSCHOORN A. S. , JACOB J.
Published: July 2012

The effects of 5‐hydroxytryptamine on the blood pressure of anaesthetized rats depended on the dose and the initial level of blood pressure. At medium blood pressure levels, 5‐hydroxytryptamine gave a depressor response and sometimes a pressor response which was more evident with large doses. The depressor effect was less apparent or even absent at low, and more pronounced at high, blood pressure levels, and the converse applied to the pressor components. Adenosine also gave a depressor and pressor response. Lysergic acid diethylamide, dihydroergotamine, 1‐(3,4‐dichlorophenyl)‐2‐isopropylaminoethanol (a dichloro analogue of isoprenaline), dibenamine and 1‐benzyl‐5‐methoxy‐2‐methyltryptamine antagonized 5‐hydroxytryptamine and catechol amines. Lysergic acid diethylamide and 1‐benzyl‐5‐methoxy‐2‐methyltryptamine were more effective against 5‐hydroxytryptamine, 1‐(3,4‐dichlorophenyl)‐2‐isopropylaminoethanol and dibenamine against catechol amines; dihydroergotamine was equally effective against both groups. These antagonists fell into two groups according to their action against the two types of effects (depressor and pressor) of 5‐hydroxytryptamine: lysergic acid diethylamide and 1‐(3,4‐dichlorophenyl)‐2‐isopropylaminoethanol acted preferentially against depressor effects; 1‐benzyl‐5‐methoxy‐2‐methyltryptamine and dibenamine preferentially against pressor; dihydroergotamine was not assignable to either group. Adenosine was affected similarly, but less than 5‐hydroxytryptamine.
EFFECTS OF RESERPINE, CHLORPROMAZINE AND SODIUM SALICYLATE ON THE ENZYMIC ACTIVITY OF RAT LIVER
Authors: KIRPEKAR S. M. , LEWIS J. J.
Published: July 2012

The effects of reserpine, chlorpromazine and sodium salicylate on oxidative phosphorylation, stimulation of glutamic acid oxidation and adenosinetriphosphatase activity have been compared in vitro with those of 2,4‐dinitrophenol using rat liver preparations. All three drugs inhibit oxidative phosphorylation, slightly stimulate glutamic acid oxidation and stimulate adenosine‐triphosphatase activity at high concentrations. Reserpine has no effect on adenosinetriphosphatase activity. It is suggested that the characteristic depressant effects of reserpine on isolated tissues in vitro may be due to interference with production of energy by oxidative phosphorylation.
EFFECTS OF ERGOMETRINE (ERGONOVINE) ON THE ISOLATED ATHEROSCLEROTIC HEART OF THE CHOLESTEROL‐FED RABBIT
Authors: KARP DOROTHY , RINZLER SEYMOUR H. , TRAVELL JANET
Published: July 2012

Ergometrine usually depresses the S‐T segment as in coronary insufficiency, when injected intravenously in rabbits with experimental coronary atherosclerosis and in patients with effort angina, but not in normal animals and man. To explain this difference, we carried out Langendorff perfusion studies in 32 normal and 29 atherosclerotic isolated rabbit hearts. Preliminary tests with ergometrine were done to ensure that advanced coronary atherosclerosis had developed in the rabbits fed a cholesterol diet; pathological examination of the heart after perfusion confirmed the result of the final test with ergometrine. Before drugs were perfused, the basal rate of coronary flow was greater, the heart rate was slower and the contractile amplitude was smaller in the atherosclerotic than in the normal hearts; nitroglycerin markedly increased flow in both normal and atherosclerotic groups. Ergometrine consistently caused a reduction in contractile amplitude with negligible changes in heart rate in both normal and atherosclerotic hearts. On coronary flow, however, the effects of ergometrine differed significantly in these groups; in doses of between 0.2 and 0.4 mg., the average decrease in flow was 8% in normal and 22% in atherosclerotic hearts. The effect was more variable in normal hearts and an increase in flow sometimes occurred. The difference in the response of normal and atherosclerotic hearts was particularly striking when ergometrine was given during recovery from a reduction of coronary flow which had been induced by vasopressin. Ergometrine then uniformly increased flow in the normal, but usually had the opposite effect in the atherosclerotic heart. In normal and atherosclerotic hearts, cardiac effects of vasopressin were similar. Tachyphylaxis to vasopressin, but not to ergometrine, was observed.
STRUCTURE‐ACTIVITY RELATIONSHIP OF TRYPTAMINE ANALOGUES ON THE HEART OF VENUS MERCENARIA
Authors: GREENBERG M. J.
Published: July 2012

A number of tryptamine analogues and other exciter agents have been tested on the heart of Venus mercenaria. The method of estimation of potency, especially for irreversibly acting compounds, is discussed. Specificity of action with respect to the site of action of 5‐hydroxytryptamine is defined experimentally. The specific activity of tyramine and phenethylamine and the non‐specific excitatory action of indole and skatole indicate that the indole ring is neither necessary nor sufficient for 5‐hydroxytryptamine‐like activity. Tryptamine analogues differ in mode of action as well as potency. Congeners without a 5‐hydroxyl group tend to act more slowly and irreversibly as well as less strongly than 5‐hydroxytryptamine. Methyl substitution also increases the time of action and difficulty of reversal. However, the potency of such compounds may be increased or decreased depending upon the position of substitution and the presence of the 5‐hydroxyl group. The relations between structure and potency and mode of action are discussed. Suggestions are made concerning the effective conformation of the 5‐hydroxytryptamine molecule and the nature of its receptor.
THE ISOLATED CHICK BIVENTER CERVICIS NERVE‐MUSCLE PREPARATION
Authors: GINSBORG B. L. , WARRINER JOAN
Published: July 2012

The isolated biventer cervicis nerve‐muscle preparation can be used to distinguish between neuromuscular blocking agents which cause depolarization and those which do not. Both reduce the contractions caused by nerve stimulation, but depolarizing drugs also cause a contracture of the muscle.
THE RELEASE OF ACETYLCHOLINE FROM MAMMALIAN MOTOR NERVE ENDINGS
Authors: STRAUGHAN D. W.
Published: July 2012

The release of acetylcholine from rat and guinea‐pig isolated diaphragm preparations stimulated through the phrenic nerve was optimal at 37° in Krebs solution with 5 × 10−6neostigmine methylsulphate. The amount of acetylcholine released by a 20 min. tetanus was reduced by cooling. At frequencies of stimulation above 6/sec. the release was less than that predicted. This “failure” was unaffected by the addition of 1 × 10−6choline. The acetylcholine release declined with continued stimulation at 25/sec. In the absence of nerve stimulation, there was a small continuous resting release of acetylcholine which seemed to originate in the muscle fibres. These results are discussed in the light of current electrophysiological knowledge of the quantal release of acetylcholine.
EXPERIMENTS ON THE PHARMACOLOGY OF HYDROXYDIONE SODIUM SUCCINATE
Authors: LERMAN L. H. , PATON W. D. M.
Published: July 2012

The actions of hydroxydione sodium succinate (“Viadril”) have been studied in chloralose or decerebrate cats, or cats otherwise untreated. It is virtually devoid of action at the neuromuscular, ganglionic, or peripheral adrenergic synapse. After rapid intravenous injection, hydroxydione produced a transient hypotension with little bradycardia and stimulated the respiration. These effects were over in 1 to 2 min. and were reduced if injection was slow or the hydroxydione diluted. Vagotomy did not alter the depressor response, but reduced the respiratory stimulation. In the untreated or the decerebrate animal, as much as five times the anaesthetic dose of hydroxydione was required to depress the respiration or blood pressure. Chloralose potentiated these depressant actions 5 to 10 fold. Both the circulatory and the respiratory depression appeared to be mediated centrally. Decerebrate rigidity was readily lessened by hydroxydione, but the pinna reflex and conjunctival reflex were relatively resistant to its action, and the knee jerk outstandingly so.
CARDIOVASCULAR ACTIONS OF PHENOXYBENZAMINE
Authors: BENFEY B. G.
Published: July 2012

Phenoxybenzamine increased the force of contraction and rate of the heart and lowered the blood pressure of dogs in pentobarbitone anaesthesia. This was preceded by depression of cardiac contractile force and a rise in blood pressure when phenoxybenzamine was injected following ganglion‐blocking drugs or atropine. The positive inotropic and chronotropic and the hypertensive effects of phenoxybenzamine were prevented by pretreatment with reserpine or guanethidine.
THE EFFECT OF ADRENALINE, NORADRENALINE AND ISOPRENALINE ON THE GUINEA‐PIG UTERUS
Authors: HERMANSEN K.
Published: July 2012

The actions of adrenaline, noradrenaline and isoprenaline were compared on the isolated guinea‐pig uterus. In uteri from immature animals (200 to 350 g) adrenaline caused relaxation which changed to a biphasic effect and finally to a contraction in the course of an experiment (6 to 8 hr). Noradrenaline always caused contraction and isoprenaline relaxation. In uteri from oestrogen‐treated animals adrenaline and noradrenaline caused contraction and isoprenaline caused relaxation. Isoprenaline potentiated the contraction produced by adrenaline and reversed the adrenaline relaxation to a contraction. The change of the pharmacological action of adrenaline was not related to the Na+ and K+ content of the uterus, which remained constant throughout an experiment involving repeated application of the amines. Nor could it be related to a change in the glycogenolytic effect of adrenaline estimated by determinations of total glycogen of the muscle which, however, may not reflect a momentary change in rate of breakdown.