bluuebunny/crossref_metadata_2025 huggingface dataset:
MUTUAL POTENTIATION OF AMPHETAMINE AND AMYLOBARBITONE MEASURED BY ACTIVITY IN RATS
Authors: RUSHTON RUTH , STEINBERG HANNAH
Published: July 2012

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.
THE EFFECTS OF BRETYLIUM AND GUANETHIDINE ON THE PRESSOR RESPONSES TO NORADRENALINE AND ANGIOTENSIN
Authors: LAURENCE D. R. , NAGLE R. E.
Published: July 2012

In normal human subjects the intravenous administration of bretylium and guanethidine rapidly increased the pressor response to intravenous infusions of noradrenaline, while the response to angiotensin was little or not affected. This result suggests that potentiation of noradrenaline by bretylium and guanethidine is not simply due to block of homeostatic reflexes, but is due to sensitization of arteriolar smooth muscle. But we, like others, have failed to demonstrate such an effect in man when measuring changes in blood flow during intra‐arterial infusions of noradrenaline.
AN ANTIHISTAMINE‐LIKE SUBSTANCE (OR SUBSTANCES) IN EXTRACTS PREPARED FROM HUMAN TISSUES
Authors: KOVACS B. A. , PELLETIER G. , ROSE B.
Published: July 2012

A method for the extraction of an antihistamine‐like substance (or substances) from human tissues is described. The method has demonstrated the presence of this active principle(s) in a large variety of human tissues, so far without exception. The substance(s) has a wide range of activity in antagonizing the in vitro effects of histamine, 5‐hydroxytryptamine and bradykinin and the Schultz‐Dale reaction on the guinea‐pig ileum and rat uterus preparations.
THE ACTION OF HISTAMINE ON THE ISOLATED HEART
Authors: BARTLET A. L.
Published: July 2012

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.
THE EFFECTS OF PRONETHALOL, DICHLOROISOPRENALINE AND DISOPYRAMIDE ON THE TOXICITY TO THE HEART OF OUABAIN AND ANAESTHETICS
Authors: SEKIYA A. , WILLIAMS E. M. VAUGHAN
Published: July 2012

An intermittent infusion of ouabain, 4 μg during 30 sec every 1.5 min, regularly caused ventricular fibrillation in guinea‐pigs. The β‐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.
THE EFFECT OF PROSTAGLANDIN E1 ON RESPONSES OF SMOOTH MUSCLE TO CATECHOL AMINES, ANGIOTENSIN AND VASOPRESSIN
Authors: HOLMES S. W. , HORTON E. W. , MAIN I. H. M.
Published: July 2012

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 longlasting.
A COMPARISON OF THE EFFECTS OF THE PLASMA KININS, BRADYKININ AND KALLIDIN, ON MYOCARDIAL BLOOD FLOW AND METABOLISM
Authors: PARRATT J. R.
Published: July 2012

Using a heated thermocouple technique it was shown that the plasma kinins, kallidin (lys‐bradykinin) and bradykinin, increased myocardial blood flow, when given either by single injection or by continuous slow infusion, in the rabbit, cat, dog, monkey and chimpanzee. In every experiment systemic arterial blood pressure and myocardial vascular resistance fell by an amount related to the log of the dose of the kinin administered. These effects were seen with quite small doses of bradykinin and kallidin and demonstrate that the myocardial vascular bed is very sensitive to these plasma kinins. In larger doses, bradykinin increased “corrected temperature”—the myocardial temperature change corrected for alterations in blood flow and with heat losses controlled. This response represents a stimulation of metabolic heat production which was not observed with kallidin.
ACTIONS OF MECAMYLAMINE, DIMECAMINE, PEMPIDINE AND THEIR TWO QUATERNARY METHO‐SALTS AT THE NEUROMUSCULAR JUNCTION
Authors: BLACKMAN J. G. , RAY C.
Published: July 2012

Mecamylamine, dimecamine and pempidine differed in neuromuscular‐blocking activity on the isolated phrenic nerve‐diaphragm preparation of the rat from the corresponding methiodides by a factor of less than two. It was concluded that the active component of each amine was the cation acting extracellularly. The finding that the neuromuscular‐blocking activity of mecamylamine at pH 6.7 was similar to the activity at pH 7.7 did not refute this conclusion. Mecamylamine, dimecamine methiodide, dimecamine and pempidine, at concentrations insufficient to cause block, could increase the twitch response of the rat diaphragm; the ability to do this increased in the above order. With pempidine (the most active compound) this effect, on the isolated sartorius muscle of the frog, was a direct action. During steady partial block by each of the compounds, the responses to brief tetanic stimulation, to neostigmine and to an increase in calcium concentration were similar to those observed during block by tubocurarine. From indirect evidence, pempidine methiodide appeared both to enhance the release of acetylcholine from motor‐nerve terminals and to cause postsynaptic block.
THE INFLUENCE OF PHENOXYBENZAMINE ON THE STORAGE OF NORADRENALINE IN RAT AND CAT TISSUES
Authors: FARRANT J. , HARVEY JUDITH ANN , PENNEFATHER JOCELYN N.
Published: July 2012

In the cat, phenoxybenzamine prevented the uptake of noradrenaline by the kidney but not by the uterus; dichloroisoprenaline prevented the uptake of noradrenaline by the uterus but not by the kidney. In the rat, a single dose of phenoxybenzamine prevented the uptake of noradrenaline by the heart, spleen and uterus and reduced the uptake by the duodenum. Prolonged treatment with phenoxybenzamine prevented the uptake by the heart and uterus but not by the spleen or duodenum. Both phenoxybenzamine and dichloroisoprenaline lowered the noradrenaline content of some tissues of the rat. Phenoxybenzamine did not antagonize the responses to noradrenaline of the nonpregnant cat uterus in situ, nor the responses of rat isolated ventricles, uterus or duodenum. It is concluded that the way in which these noradrenaline antagonists affect the storage sites for noradrenaline varies between organs. The effects of the drugs on the receptors for noradrenaline are not related to their effects on storage sites.
LEAKAGE OF TRANSMITTERS IN SALIVARY GLANDS
Authors: ASSARSON N. , EMMELIN N.
Published: July 2012

Salivary secretion evoked by sympathetic stimulation or by injection of guanethidine, adrenaline or synephrine is slightly reduced by parasympathetic antagonists in doses which abolish the secretory responses to stimulation of the parasympathetic nerve. Similarly, an adrenaline antagonist caused a small diminution of the salivary flow elicited by parasympathetic stimulation or by injection of methacholine chloride. Secretion caused by pilocarpine could be accelerated by physostigmine. We conclude that transmitter leaks in subliminal concentrations, as far as secretion is concerned, from the sympathetic and parasympathetic postganglionic nerve endings.
AN EFFECT OF PHENOBARBITONE ON GRISEOFULVIN METABOLISM IN THE RAT
Authors: BUSFIELD DOROTHY , CHILD K. J. , TOMICH E. G.
Published: July 2012

Prior administration of phenobarbitone to male and female rats dosed orally or intravenously with griseofulvin caused a fall in blood levels of the antibiotic. The effect of a single oral dose of phenobarbitone was significant after 12 hr and maximal between 12 and 48 hr, and it lasted for at least 96 hr; it was more pronounced when the barbiturate was administered repeatedly. Liver slices from animals dosed with phenobarbitone metabolized griseofulvin more rapidly than did those from undosed animals. The possible relevance of these findings to the clinical use of griseofulvin is discussed.
THE GANGLION BLOCKING ACTION OF PROCAINAMIDE
Authors: PATON W. D. M. , THOMPSON J. W.
Published: July 2012

In cats and rabbits procainamide (20 to 50 mg, intravenously) produced a fall of blood pressure of 20 to 50 mm Hg which reached a maximal effect within 1 min and lasted for about 5 min. Procainamide reduced the pressor responses to nicotine and to carotid arterial occlusion and reduced the depressor response to vagal stimulation, but did not antagonize the actions of adrenaline or noradrenaline on blood vessels. The contractions of the nictitating membrane to stimulation of the preganglionic cervical sympathetic nerve were partially or completely blocked by 20 to 50 mg of procainamide given intravenously. The ganglion blocking effect was more abrupt in onset and more slow to recover than that due to hexamethonium and had about 1/250th of the activity of the latter. Procainamide (1 mg) reduced the acetylcholine output of the perfused superior cervical ganglion to below 30% of the control value and blocked transmission completely. Small doses (10 μg) reduced the acetylcholine output but hardly affected ganglionic transmission. Procainamide, injected into the perfused superior cervical ganglion, blocked contractions elicited by stimulation of the preganglionic cervical sympathetic nerve for a longer period than those produced by acetylcholine injected into the perfusion circuit to the ganglion; the reverse was true for hexamethonium. Procainamide reduced the size of action potentials recorded from the superior cervical ganglion without altering the resting potential of the ganglion. The ganglion blocking activities of procainamide and hexamethonium often potentiated each other, especially when the preparation had been set up for several hours. On the guinea‐pig isolated ileum preparation, procainamide (0.5 × 10−4 g/ml.) antagonized responses due to acetylcholine, histamine and, most effectively, to nicotine. On the isolated heart, procainamide (1 mg) almost abolished the bradycardia produced by acetylcholine; 10 mg slowed and weakened the heart, while 100 mg stopped it. We conclude that procainamide, like procaine, blocks ganglionic transmission by (1) depressing the release of acetylcholine from preganglionic nerve endings; and (2) competing, with the acetylcholine which is released, for receptor sites on the ganglion cells. The amounts required to produce significant effects in vivo and in vitro are comparable. The methods available for detecting this type of ganglion blocking action are discussed.
TRANQUILLIZING AND HYPOTENSIVE ACTIVITIES OF TWELVE PHENOTHIAZINES
Authors: BHARGAVA K. P. , CHANDRA OM
Published: July 2012

Twelve phenothiazine derivatives have been compared in relation to their central sedative, tranquillizing and hypotensive activities. The ED50′s of the compounds to suppress the conditioned response, unconditioned response and forced locomotor activity were determined. Suppressions of the conditioned and unconditioned responses were taken as criteria for tranquillizing and central sedative activities respectively. The “tranquillizing ratio” (ED50 for unconditioned response/ED50 for conditioned response) was used as the criterion of tranquillizing activity in relation to sedative activity and for purposes of comparison this ratio was assigned a value of unity for chlorpromazine. Perphenazine was the most potent drug in suppressing the conditioned and unconditioned responses whereas fluopromazine had the maximal “tranquillizing index” activity. Six compounds had great, three moderate and three mild hypotensive activity when doses of 1 mg/kg were injected intravenously into dogs. The relationship of the chemical structure to the central sedative activity is discussed.
THIN‐LAYER CHROMATOGRAPHY AND BIOASSAY OF PROSTAGLANDINS IN EXTRACTS OF SEMEN AND TISSUES OF THE MALE REPRODUCTIVE TRACT
Authors: HORTON E. W. , THOMPSON C. J.
Published: July 2012

By acid ether extraction and thin‐layer chromatography, prostaglandins have been separated from biologically active compounds of other chemical groups. The technique does not, however, separate different prostaglandins from each other. The biological activity of the eluates was estimated on the rabbit isolated jejunum and the hamster isolated colon preparations in terms of prostaglandin E1; the concentrations (thus expressed) of prostaglandin in human semen ranged from 24 to 783 μg/ml. with a mean of 226 μg/ml. No prostaglandins (minimal detectable concentration, 0.5 μg/g) could be detected in the male reproductive organs of several species of laboratory animal.
A SENSITIVE METHOD FOR THE ASSAY OF CATECHOL AMINES
Authors: ARMITAGE A. K. , VANE J. R.
Published: July 2012

A strip of fundus from a rat's stomach was suspended in Krebs solution containing 5‐hydroxytryptamine. Movements of the muscle were recorded by means of a frontal writing lever giving a magnification of sixteen‐times. The strip relaxed when isoprenaline, adrenaline or noradrenaline was added to the organ‐bath in concentrations of 0.2 to 2 ng/ml. The preparation was most sensitive to isoprenaline and least sensitive to noradrenaline. The components of a mixture of two catechol amines could be assayed by superfusing the rat stomach and a chick rectum in the same stream of fluid.
THE DEMONSTRATION OF THE SITE OF ACTION OF THE ANTIMETABOLITE DRUG 6‐AZAURIDINE BY THE USE OF LEUCOCYTE CULTURES
Authors: BUTTOO A. S. , ELVES M. W. , ISRAËLS M. C. G. , ROATH O. S.
Published: July 2012

The ability of the lymphocyte cultured in vitro to transform and synthesize deoxyribonucleic has been utilized to locate the site of action of a new antimetabolite 6‐azauridine which acts by inhibiting nucleic acid synthesis. The exact site can be demonstrated by incorporating into the cultures nucleotides occurring distal and proximal to the presumed site of action of 6‐azauridine.
THE EFFECTS OF SOME CENTRALLY‐ACTING DRUGS ON GANGLIONIC TRANSMISSION IN THE CAT
Authors: BROWN D. A. , QUILLIAM J. P.
Published: July 2012

Transmission through the cat superior cervical ganglion was studied by recording the response of the nictitating membrane to both pre‐ and postganglionic cervical sympathetic nerve stimulation. The intra‐arterial injection of central depressant drugs to the ganglion through the lingual artery depressed transmission through the ganglion. The central depressant drugs tested were (in decreasing order of activity): amylobarbitone, pentobarbitone, carbromal, benactyzine, mephobarbitone, hydroxyzine, phenobarbitone, azacyclonol, methylpentynol carbamate, paraldehyde, phenytoin, mephenesin, chlorbutol, troxidone, methylpentynol and barbitone. All were weaker ganglion‐blocking agents than tetraethylammonium. The intra‐arterial injection of the central stimulant drugs leptazol, bemegride, amiphenazole and 5‐(1,3‐dimethylbut‐2‐enyl)‐5‐ethylbarbituric acid (McN 481) also depressed ganglionic transmission. Leptazol or bemegride did not antagonize the ganglion‐blocking action of amylobarbitone or troxidone. The intra‐arterial injection of pecazine and perphenazine, and the intravenous injection of barbitone, benactyzine, azacyclonol, hydroxyzine, mephenesin, methylpentynol and paraldehyde impaired the response of the nictitating membrane to both post‐ and preganglionic stimulation. The implications of these observations are discussed.
OBSERVATIONS ON THE MODE OF ACTION OF SOME CENTRAL DEPRESSANT DRUGS ON TRANSMISSION THROUGH THE CAT SUPERIOR CERVICAL GANGLION
Authors: BROWN D. A. , QUILLIAM J. P.
Published: July 2012

Methylpentynol, paraldehyde, amylobarbitone and procainamide blocked transmission through the cat superior cervical ganglion, and antagonized the ganglion‐stimulating actions of acetylcholine and carbachol injected intra‐arterially to the ganglion. Comparison with the effects of tetraethylammonium indicated that the impaired response to acetylcholine could not wholly account for the failure of transmission, which suggested that an impaired release of transmitter substance was a contributory factor. Methylpentynol, paraldehyde and procainamide also blocked the ganglion‐stimulating action of potassium chloride. In contrast, amylobarbitone and pentobarbitone did not block the stimulating action of potassium chloride, but antagonized specifically the actions of acetylcholine and carbachol. The anti‐acetylcholine activities of the two barbiturate drugs at this site accord with their relative ganglion‐blocking activities. It is concluded that the ganglion‐blocking action of methylpentynol, paraldehyde and procainamide arises from a nonspecific depression of both presynaptic and postsynaptic elements in the ganglion, but that barbiturate compounds act more specifically en the acetylcholine receptor.
A TERATOGENIC EFFECT OF A SULPHONAMIDE IN EXPERIMENTAL ANIMALS
Authors: PAGET G. E. , THORPE E.
Published: July 2012

Sulphamoprine, when given in the diet at levels from 0.025% upwards to pregnant rats and mice, produced abnormalities of eruption of the incisor teeth and of the skull of the offspring. Rabbits are not susceptible to this teratogenic action.
A SENSITIVE METHOD FOR THE ASSAY OF ANGIOTENSIN
Authors: REGOLI D. , VANE J. R.
Published: July 2012

A method is described for the assay of angiotensin on the rat colon. Under the conditions of the assay, the preparation is sensitive to angiotensin and relatively insensitive to 5‐hydroxytryptamine, to histamine and to other substances which might be present in blood. Bradykinin and catechol amines do not interfere with the assay. Evidence is given for the specificity of the angiotensin receptors.
THE ACTION OF SYMPATHOMIMETIC AMINES ON THE OUTFLOW OF AQUEOUS HUMOUR FROM THE EYE
Authors: EAKINS K. E. , RYAN S. J.
Published: July 2012

The actions of adrenaline, noradrenaline and isoprenaline on the resistance to outflow of aqueous humour from the rabbit eye are described. In some experiments, correlations have been made with pupil diameter. Intravitreous injections of adrenaline, noradrenaline and large doses of isoprenaline decreased the resistance to outflow of fluid from the eye and dilated the pupil. Intravitreous injection of phentolamine was without effect on the intraocular pressure and resistance to outflow of aqueous humour, although such injections resulted in miosis. The actions of adrenaline, noradrenaline and large doses of isoprenaline on the outflow resistance were antagonized by phentolamine. Postganglionic sympathetic denervation did not affect the aqueous humour dynamics when the eyes where examined 2 weeks later, but all the denervated eyes exhibited miosis at this time. Much smaller doses of noradrenaline were required to lower the intraocular pressure and decrease the resistance to outflow of aqueous humour in the denervated eyes; in addition, the dose/response curve for the effect of noradrenaline on the outflow resistance was shifted to the left in these experiments. These results support the view that adrenaline α‐receptors are associated with the resistance to outflow of aqueous humour from the rabbit eye.
INHIBITION OF SYMPATHOMIMETIC EFFECTS ON THE HEART
Authors: BENFEY B. G. , VARMA D. R.
Published: July 2012

The adrenaline β‐receptor blocking drug, pronethalol, and the sympathomimetic amines, (–)‐ephedrine, (–)‐amphetamine, dexamphetamine, (–)‐Ω‐ephedrine and tyramine, inhibited the sympathomimetic effects of butyrylcholine and tyramine on the guinea‐pig isolated atrium. Being reversible and noncompetitive, this antagonism was unspecific and not due to blockade of adrenaline receptors, although pronethalol inhibited the effect of noradrenaline competitively.
THE EFFECTS OF DRUGS ON THE UPTAKE OF AMINES BY MAST CELLA
Authors: DAY MARGARET , STOCKBRIDGE ANNE
Published: July 2012

Neoplastic mast cells, taken from an ascitic tumour in mice and incubated in vitro, took up 14C‐labelled 5‐hydroxytryptamine and histamine from the medium. Uptake during the first hour gave an approximate measure of the initial rate. The amount of each amine taken up in this time was determined by bioassay and by radioactivity, the two methods giving similar results. The curves obtained by plotting initial rate of uptake against concentration in the medium suggested that the uptake of 5‐hydroxytryptamine was by an active process and also by diffusion, whereas uptake of histamine was by diffusion only. The cells also took up 14C‐labelled (±)‐noradrenaline and tryptamine, apparently by diffusion. The active uptake of 5‐hydroxytryptamine was inhibited by lowering the temperature to 25° C or by increasing the pH to 8.9, procedures which had little effect on histamine uptake. The effects of cocaine, imipramine, chlorpromazine, mepyramine, promethazine, phenoxybenzamine, lysergic acid diethylamide, bromolysergic acid diethylamide, methysergide, guanethidine, dichloroisoprenaline and pronethalol on the uptake of amines were examined. In general, any antagonist which inhibited uptake of 5‐hydroxytryptamine had little effect on uptake of histamine, and vice versa. Possible ways in which these antagonists produce their effects on amine uptake are discussed. A high concentration of 5‐hydroxytryptamine, of tryptamine or of noradrenaline inhibited uptake of histamine, but only tryptamine decreased uptake of 5‐hydroxytryptamine. These results, together with those from experiments with antagonists, suggest that there are specific binding sites for 5‐hydroxtryptamine in these cells.
PRODUCTION OF AN ANTI‐INFLAMMATORY SUBSTANCE AT A SITE OF INFLAMMATION
Authors: ROBINSON B. V. , ROBSON J. M.
Published: July 2012

The anti‐inflammatory effect of various substances was measured in rats implanted with cotton wool pellets. Injection or implantation of irritant materials decreased the deposition of granulation tissue on the pellets. As the amount of irritant material increased there was a corresponding decrease in the amount of tissue deposited on the pellets. There is evidence that this could not be explained by a limit to the amount of granulation tissue available within the body, and competition for it between the cotton pellets and the implanted substances. An alternative hypothesis that an antiinflammatory substance is produced at the site of irritation (the site of implantation of the irritant substance, such as polyester sponges) was investigated. The evidence obtained supports this hypothesis, Inflammatory exudate, squeezed from polyester sponges which had been implanted subcutaneously in the backs of adrenalectomized rats. The substance responsible for this effect is probably not a steroid, and is not normally present in the plasma of adrenalectomized animals. There is, however, some (although not conclusive) evidence that it is present in the plasma of animals in which sponges have been implanted. It does not appear to be produced by incubation in vitro of plasma with sponge. The significance of these observation is discussed.
FORMATION OF [14C]‐HISTAMINE IN VIVO IN NORMAL RATS AND IN RATS TREATED WITH LIOTHYRONINE
Authors: BJURO T. , WESTLING H. , WETTERQVIST H.
Published: July 2012

Female rats treated with liothyronine or its solvent (control rats) were given an intravenous injection of [14C]‐l‐histidine. The amount of [14C]‐histamine in various tissues was measured at 10 min, 60 min and 22 hr after the injection. In control rats the glandular stomach contained large amounts of [14C]‐histamine at 10 and 60 min, with a sharp decline at 22 hr. The skin contained small amounts at 10 and 60 min, with a slight rise at 22 hr. In rats treated with liothyronine there was more [14C]‐histamine in the stomach at 10 and 60 min, but not at 22 hr after the injection of [14C]‐l‐histidine. The results support the following conclusions: (1) The glandular stomach in the intact rat forms more histamine than do other tissues; the gastric histamine is in a rapid state of turnover and is likely to contribute substantially to the urinary output of histamine. (2) After treatment with liothyronine the rat has an increased histamine formation in the stomach; this is probably the main cause of the raised urinary histamine excretion in such a rat.
COBALT COMPOUNDS AS ANTIDOTES FOR HYDROCYANIC ACID
Authors: EVANS C LOVATT
Published: July 2012

The antidotal potency of a cobalt salt (acetate), of dicobalt edetate, of hydroxocobalamin and of cobinamide against hydrocyanic acid was examined mainly on mice and rabbits. All the compounds were active antidotes for up to twice the LD50; under some conditions for larger doses. The most successful was cobalt acetate for rabbits (5 × LD50), which was effective at a molar cyanide/cobalt (CN/Co) ratio of 5, but had as a side‐effect intense purgation. Hydroxocobalamin was irregular in action, but on the whole was most effective for mice (4.5 × LD50 at a molar ratio of 1), and had no apparent side effects. Dicobalt edetate, at molar ratios of up to 2, was more effective for rabbits (3 × LD50) than for mice (2 × LD50), but had fewer side effects than cobalt acetate. The effect of thiosulphate was to augment the efficacy of dicobalt edetate and, in mice, that of hydroxocobalamin; but, apparently, in rabbits, to reduce that of hydroxocobalamin. Cobinamide, at a molar ratio of 1, was slightly more effective than hydroxocobalamin on rabbits and also less irregular in its action. Cobalt acetate by mouth was effective against orally administered hydrocyanic acid. The oxygen uptake of the body, reduced by cyanide, is rapidly reinstated when one of the cobalt antidotes has been successfully administered.
THE ADRENERGIC‐NEURONE BLOCKING ACTION OF SOME COUMARAN COMPOUNDS
Authors: FIELDEN R. , ROE A. M. , WILLEY G. L.
Published: July 2012

Ethyldimethyl(7‐methylcoumaran‐3‐yl)ammonium iodide (SK&F 90,109) and its guanidine analogue [N‐(7‐methylcoumaran‐3‐yl)guanidine nitrate] (SK&F 90,238) abolish the effects of adrenergic nerve stimulation in cats, as do xylocholine and bretylium. SK&F 90,109 has slight sympathomimetic actions; these are less marked than in SK&F 90,238. Large doses of SK&F 90,109 have an action, dependent on local noradrenaline stores, that delays the appearance of adrenergic‐neurone blockade in conscious cats. Responses to adrenaline are, in general, enhanced by each drug, but SK&F 90,238 transiently antagonizes tachycardia induced by adrenaline and isoprenaline. Both drugs inhibit the release of noradrenaline from the spleen during splenic nerve stimulation, but the release of catechol amines from the adrenal glands, in response to electrical or chemical stimulation, is unimpaired. In contrast to the prolonged adrenergic‐neurone blocking action, any inhibition of the effects of cholinergic nerve stimulation is transient. Large intravenous doses produce neuromuscular blockade. The compounds have a slight central depressant action. In contrast to reserpine and guanethidine the noradrenaline content of rat hearts is not appreciably lowered 24 hr after a single dose of either drug. Unlike xylocholine they are not local anaesthetics. Related compounds also block the effects of adrenergic‐nerve stimulation. The possible modes of action of these drugs are discussed.
THE RELATIONSHIP BETWEEN ANTICURARE ACTIVITY AND TIME COURSE OF THE ENDPLATE POTENTIAL; A STRUCTURE‐ACTIVITY APPROACH
Authors: KUPERMAN A. S. , OKAMOTO M.
Published: July 2012

A comparison of the effects of several quaternary ammonium ions has been made on the intracellularly recorded endplate potential of curarized frog muscle. The hydroxyanilinium ions usually caused an increase in endplate potential amplitude, a slowing of rate of rise and marked prolongation, but rarely caused spike generation. Contrariwise, tetraethylammonium and triethylphenylammonium consistently caused an increase in both amplitude and rate of rise of the endplate potential but no prolongation; these endplate potentials generated muscle spikes. The results suggest a relationship between rate of rise of the endplate potential and the probability of spike generation. Using the neurally evoked contractile response as a signal of transmitter action, the hydroxyanilinium ions were found to be relatively weak antagonists of tubocurarine at deep levels of curarization, indicating a ceiling effect. There was also a ceiling to the effect of hydroxyaniliniums on endplate potential amplitude. Thus, in the presence of high concentrations of tubocurarine, tetraethylammonium is a more potent anticurare agent than is triethyl(3‐hydroxyphenyl) ammonium.
AN IMPROVED MICROBATH
Authors: GADDUM J. H.
Published: July 2012

A method is described for the study of the actions of drugs and tissue extracts on small pieces of smooth muscle suspended in a bath with a capacity of 0.027 ml. The small size of the bath is an advantage when the total amount of active substance is small. The contractions are amplified 50‐ to 500‐times and recorded isotonically, or approximately isometrically, with a pen writer. This apparatus has the advantage over earlier models that it is more compact and convenient and that the temperature of the muscle can be controlled. It has been used for the estimation of small quantities of acetylcholine and other substances in tissue extracts.
THE ACTION OF MORPHINE‐LIKE DRUGS ON IMPULSE TRANSMISSION IN MAMMALIAN NERVE FIBRES
Authors: KOSTERLITZ H. W. , WALLIS D. I.
Published: July 2012

Experiments on nerves in situ and on isolated nerves provide no evidence that morphine interferes with impulse transmission in myelinated or nonmyelinated nerve fibres. The concentrations used in experiments on isolated nerves were 10‐ to 100‐times as high as those required to depress transmission a autonomic nerve‐effector cell junctions. Examination of the resting membrane potential, the action potential and the positive after‐potential, the conduction velocity, the time courses of the recovery of the size of the action potential and of the excitability after a conditioning stimulus, the ability of the axons to sustain repetitive activity and the posttetanic hyperpolarization gave no indication that morphine affects either the mechanisms involved in the initiation of the propagated impulse or those leading to restoration of the resting state after activity. Analgesic drugs, such as pethidine and methadone which have a local anaesthetic action, may cause a reversible decrease in the size of the compound action potential and in the conduction velocity of A‐B and C fibres.
ON THE ANTI‐INFLAMMATORY ACTIVITY OF SOME SUBSTITUTED PHENOLIC COMPOUNDS
Authors: LIGHTOWLER J. E. , RYLANCE H. J.
Published: July 2012

Some substituted dihydroxybenzenes have been examined for suppression of the yeast‐induced inflammatory reaction in the rat paw. This anti‐inflammatory activity is greatest in those compounds derived from resorcinol and in particular the halo‐genated 5‐methylresorcinols. The significance of the internuclear distance between the hydroxyl groups in the meta‐position to each other in resorcinol and the importance of the enhanced activity due to the halogen atom(s) is discussed. In this series the toxicity and activity could not be divorced.
THE PRESERVATION OF BRADYKININ BY PHENOTHIAZINES IN VITRO
Authors: KRIVOY W. , KROEGER D.
Published: July 2012

Chlorpromazine and phenoxybenzamine have been shown to potentiate the actions of bradykinin in vivo. To test whether this phenomenon could be due to inhibition of the enzymatic destruction of bradykinin, bradykinin was incubated with either tissue extracts or with carboxypeptidase B. Bradykinin was rapidly destroyed by acetone‐dried powders of brain and serum of various animals as well as by purified carboxypeptidase B. The rate of disappearance of bradykinin activity was decreased in the presence of phenothiazine derivatives, phenoxybenzamine and hydroxyzine, but not by compounds of a larger group including other psychotropic drugs, tranquillizers and ganglionic and adrenergic blocking agents. Spectrophotometric studies of the hydrolysis of hippuryl‐l‐arginine confirmed the presence of a carboxypeptidase B‐like activity in brain. The substances that acted as inhibitors of bradykinin destruction were also enzyme inhibitors as measured by this technique. Previous incubation of carboxypeptidase B with phenothiazines and zinc ions greatly reduced the enzymatic inhibition by the phenothiazines, which indicated a possible chelating action by these inhibitors on the metalo‐enzyme carboxypeptidase B.
STIMULANT ACTIONS OF VOLATILE ANAESTHETICS ON SMOOTH MUSCLE
Authors: RANG H. P.
Published: July 2012

A number of volatile anaesthetics, and some compounds synthesized in the search for new anaesthetics, have been tested on guinea‐pig intestinal smooth muscle in vitro. All the compounds produced a contractile response. This effect did not correlate well with convulsant activity in vivo among the compounds tested. Two kinds of stimulant effect were distinguishable: (1) Rapid, transient contractions, abolished by cocaine or lachesine; most of the anaesthetics in clinical use had this action. (2) Slow, sustained contractions, unaffected by cocaine or lachesine; this effect predominated among the fluorinated ring compounds. Hexamethonium and mepyramine did not affect the contractile response to any of the compounds. The first type of effect presumably represents excitation of postganglionic nerve cells, while the second type is a direct action on the muscle cell. The action of perfluoro‐benzene, which is of the latter kind, was studied further. Adrenaline and lack of calcium diminished the contraction in parallel with the contraction to histamine, which suggests that the cell membrane was the site of action; in contrast to the stimulant action of histamine or acetylcholine, the effect was highly temperature‐sensitive, being almost abolished by cooling to 32° C, and enhanced at 40° C. The depressant action of anaesthetics on smooth muscle is affected very little by temperature changes. These findings are discussed in relation to other observations which suggest a stimulant action of volatile anaesthetics on excitable tissues. Protein denaturation is tentatively suggested as a mechanism of action.
THE 5‐HYDROXYTRYPTAMINE CONTENT OF THE PLACENTA AND FOETUS DURING PREGNANCY IN MICE
Authors: ROBSON J. M. , SENIOR JUDITH B.
Published: July 2012

5‐Hydroxytryptamine (5HT) levels were measured in blood and tissues from pregnant mice. Blood levels remained constant during pregnancy and were the same as those in nonpregnant female mice. Placental levels of 5HT increased throughout pregnancy as did the foetal levels. The maternal blood volume of the placenta also increased with advancing gestation. 5HT levels were measured after treatment of the mother with 5HT, and the critical placental level of 5HT observed at about the time of death of the foetus was determined. The levels of 5HT in the placenta and foetus after treatment of the mother with several monoamine oxidase inhibitors were measured, and found to show no significant increase above the normal levels in these tissues. Treatment with cyproheptadine, a 5HT antagonist, did not delay parturition.
EFFECTS OF AMPHETAMINE ON THE RESPONSES OF THE GUINEA‐PIG ISOLATEP VAS DEFERENS PREPARATION TO HYPOGASTRIC, NERVE STIMULATION
Authors: EDGE N. D.
Published: July 2012

In concentrations from 1 to 100 μg/ml., amphetamine potentiated responses of the isolated vas deferens preparation of the guinea‐pig stimulated via the hypogastric nerve at rates of from 5 to 40 shocks/sec. Potentiation was more pronounced with low than with high stimulus frequencies. A concentration of 500 μg/ml. of amphetamine had a blocking action which was more pronounced at high than at low stimulus frequencies. This effect contrasted with the ganglionic blocking action of hexamethonium which had a greater effect at low than at high stimulus frequencies.
EFFECTS OF CENTRAL DEPRESSANT DRUGS UPON ACETYLCHOLINE RELEASE
Authors: MATTHEWS E. K. , QUILLIAM J. P.
Published: July 2012

Several central depressant and other drugs have been examined for their effects upon acetylcholine release from the stimulated, perfused cat superior cervical ganglion and rat isolated phrenic nerve‐diaphragm preparations. The acetylcholine released was assayed biologically. Amylobarbitone sodium, chloral hydrate, trichloroethanol, methylpentynol, methylpentynol carbamate, paraldehyde, procaine hydrochloride and troxidone reduced the presynaptic release of acetylcholine from the ganglion. They also exhibited a postsynaptic blocking action, this component of depressant activity being particularly prominent with paraldehyde and troxidone. Closely analogous findings were obtained at the neuromuscular junction with methylpentynol and its carbamate, paraldehyde, procaine hydrochloride, trichloroethanol and troxidone. At both sites the drug‐induced depression, both of transmission and of acetylcholine output, was reversible. Whereas hexamethonium regularly blocked ganglionic transmission with no effect upon acetylcholine release, tetraethylammonium not only completely blocked ganglionic transmission but concomitantly augmented acetylcholine output. These results are discussed in relation to the electrophysiological and metabolic events associated with neuro‐effector transmission.
The effects of drugs inhibiting catecholamine uptake on tyramine and noradrenaline‐induced contractions of the isolated rat vas deferens
Authors: BARNETT A. , SYMCHOWICZ S. , TABER R. I.
Published: July 2012

. Cocaine did not antagonize the tyramine‐induced contractile response of the isolated rat vas deferens at the same concentrations which markedly potentiated the contractile response to noradrenaline.

. Imipramine and amitriptyline non‐competitively antagonized the contractile response to tyramine but did not potentiate noradrenaline. Desmethylimipramine produced both potentiation of noradrenaline and antagonism of tyramine.

. Dexchlorpheniramine non‐competitively antagonized the contractile response to tyramine. It also produced an atypical potentiation of noradrenaline in which lower concentrations of noradrenaline were potentiated to a greater extent than higher ones.

. Imipramine inhibited the in vitro uptake of noradrenaline‐3H in rat vas deferens as did cocaine, desmethylimipramine and dexchlorpheniramine. These results suggest that the α‐adrenergic blocking property of imipramine masks the potentiation of noradrenaline by uptake inhibition.

. Evidence is also presented which suggests that α‐adrenergic blockade of released noradrenaline may be the major mechanism for tyramine inhibition by imipramine‐like drugs. This may explain why cocaine, which has no real alpha blocking action, is ineffective against tyramine.
In vitro studies on the mechanism of kinin formation by trypanosomes
Authors: BOREHAM P. F. L.
Published: July 2012

. An investigation into the mechanism of kinin release in trypanosomiasis has been made in vitro.

. Trypanosomes contain a low level of kininase but no kinin‐forming enzyme nor substrate for salivary kallikrein.

. The kininase activity in the plasma of infected rats does not differ from that of normal animals, and trypanosomes do not affect the breakdown of synthetic bradykinin by enzymes in the blood.

. In trypanosomiasis the kininogenase precursor in plasma is activated. The hypothesis is put forward that the antigen‐antibody complex may be involved in this.
Sensitization of smooth muscle to plasma kinins: effects of enzymes and peptides on various preparations
Authors: EDERY H. , GRUNFELD Y.
Published: July 2012

The influence of various materials, principally hydrolases and peptides, on the sensitivity to stimulating substances has been studied in a wide range of isolated and in vivo smooth muscle preparations.

Chymotrypsin raised the susceptibility of the guinea‐pig isolated ileum to peptides related to bradykinin and also sensitized isolated ileum and fundus of rat and albino gerbil to bradykinin. No sensitization to the kinin occurred in the following preparations: rat, gerbil and rabbit duodenum; rat colon and urinary bladder; dog tracheal chain; and rabbit jejunum. Chymotrypsin and peptides structurally related to the active centre of the enzyme did not affect the permeability increasing property of bradykinin in guinea‐pig skin microcirculation vessels. In contrast, intravenously administered chymotrypsin markedly augmented the bronchoconstrictor action of the kinin.

Ficin and pronase increased the sensitivity of guinea‐pig ileum to bradykinin. Pronase also sensitized the gerbil ileum and this effect was abolished by previous treatment with di‐isopropylfluorophosphonate (dyflos). Pronase destroyed bradykinin after incubation.

Reduced glutathione potentiated the response to bradykinin of guinea‐pig ileum but did not affect its sensitivity. The potentiation also occurred in a chymotrypsin‐treated preparation.

It is assumed that specific sensitization elicited by proteinases might derive from an effect on the protein envelope of smooth muscle membrane.
Post‐tetanic and drug‐induced repetitive firing in the soleus muscle of the cat
Authors: BOWMAN W. C. , GOLDBERG A. A. J. , RAPER C.
Published: July 2012

The effects of a high frequency indirect tetanus on the responses to subsequent infrequently applied nerve shocks have been compared in the tibialis anterior and soleus muscles of cats and rabbits.

Post‐tetanic augmentation of twitches in the cat soleus muscle was shown to be partly due to repetitive firing and partly due to increased synchronization of the muscle fibre response. Post‐tetanic repetitive firing was not evident in the responses of the other three muscles studied.

Post‐tetanic repetitive responses in the cat soleus muscle and nerve did not originate in the nerve trunk and were not produced by direct muscle stimulation; they were abolished by doses of tubocurarine smaller than those necessary to reduce the twitch tension below the pre‐tetanic level. These findings support the conclusion of others that the repetitive firing originates at the neuromuscular junction.

The repetitive firing could not be explained by an increase in the sensitivity of the motor endplates to acetylcholine, suggesting that an increase in and/or a prolongation of the output of transmitter from the motor nerve contributes to it.

The cat soleus muscle was shown to be more sensitive to neostigmine than were the other three muscles studied, and acetylcholinesterase determinations showed that this muscle possesses less enzyme activity.

It is concluded that an increase in transmitter output, coupled with a weaker cholinesterase activity, probably accounts for the post‐tetanic repetitive activity in the cat soleus muscle.

Post‐tetanic repetitive firing was absent in cat soleus muscles which had been cross‐innervated with the nerve formerly innervating a fast‐contracting muscle.
The accumulation of guanethidine by human blood platelets
Authors: BOULLIN D. J. , O'BRIEN R. A.
Published: July 2012

When human blood platelets were incubated aerobically in plasma containing 2 × 10−7 to 10−3M radioactive guanethidine for 10 min to 6 hr, the drug was accumulated against a concentration gradient until concentration ratios (platelet/plasma) of up to 80: 1 were obtained.

The decline in rate of uptake after 3 hr appeared to result from a decrease in platelet viability, because accumulation was reduced by prolonged incubation before addition of guanethidine.

Uptake was energy‐dependent because it was inhibited by cold and ouabain.

Sodium ions were essential for guanethidine uptake and retention of 5‐hydroxytryptamine (5‐HT).

Accumulation was inhibited by 5‐HT, desipramine, cocaine, dexamphetamine, bretylium, tyramine and noradrenaline; bethanidine, p‐chlorophenylalanine and (–)‐α‐methyldopa were inactive.

Guanethidine was tightly bound to platelets, only 10% being lost from labelled cells during 60 min incubation in drug‐free plasma; but efflux was increased by addition of amphetamine.

The binding sites for guanethidine seemed to be different from those for 5‐HT since guanethidine accumulation was independent of 5‐HT levels, and neither guanethidine uptake or release were affected by reserpine.

Guanethidine was not metabolized by platelets or plasma in vitro.

We consider that, if our results regarding uptake, binding and release of guanethidine are confirmed in vivo, and also found to apply to other pharmacologically active agents, then the eventual loss of a platelet‐bound substance may increase pharmacological action by raising plasma levels.
Decrease in ionic permeability of the cell membrane in guinea‐pig atrial tissue by treatment with antifibrillatory agents and hexobarbitone, determined by means of 86Rb
Authors: ZWIETEN P. A. van
Published: July 2012

The influence of antifibrillatory agents on the release of previously accumulated 86Rb+ ions was studied in guinea‐pig isolated left auricles, incubated in a K+‐free Tyrode solution that contained an equivalent concentration (2.7 mm) of Rb+. The auricles were stimulated electrically at a frequency of 100/min and showed entirely “normal” mechanical behaviour in the incubation medium.

Quinidine, tetracaine, hexobarbitone‐Na and propranolol caused a dose‐dependent negative inotropic effect. The frequency of beating (100/min) was usually not affected by these drugs.

The reduction in contractile force was accompanied by a dose‐dependent inhibition of 86Rb release. The concentration‐response curves for both the mechanical effect and the influence on 86Rb release almost coincided for quinidine, although these curves diverged for the other drugs studied.

It is suggested that all the four different antifibrillatory drugs cause a general reduction of the membrane permeability to inorganic ions. The mechanism of this membrane stabilization remains unknown.