bluuebunny/crossref_metadata_2025 huggingface dataset:
A PROPOSED COMMON MECHANISM OF ACTION FOR GENERAL AND LOCAL ANAESTHETICS IN THE CENTRAL NERVOUS SYSTEM
Authors: FRANK G. B. , SANDERS H. D.
Published: July 2012

Procaine and several general anaesthetics block production of action potentials in frog skeletal muscle fibres by a single mechanism of action, which suggests that there might be a common basic mechanism of action on neurones in the central nervous system. Procaine or cinchocaine given alone to intact white mice produced “excitement” and convulsions but when given 60 min after phenobarbitone they caused central nervous depression. Large, convulsant doses of procaine or cinchocaine abolished the righting reflex in mice previously treated with small, subanaesthetic doses of phenobarbitone. In contrast, leptazol only antagonized the depression produced by phenobarbitone. When applied directly to neuronally isolated slabs of cat cerebral cortex, procaine or pentobarbitone reduced the sizes of the surface negative and surface positive responses to direct electrical stimulation of the cortex. Leptazol had the opposite effect. When given systemically, procaine only increased the electrical threshold for the surface positive response recorded from the isolated slab; ether either increased or did not change this threshold, and leptazol either decreased or did not change it. These results are consistent with the suggestion that general and local anaesthetics have a fundamentally similar action on neurones in the central nervous system.
THE RELEASE OF ACETYLCHOLINE BY SYMPATHETIC NERVE STIMULATION AT DIFFERENT FREQUENCIES
Authors: BURN J. H. , DROMEY J. J. , LARGE B. J.
Published: July 2012

Supramaximal stimulation of the periarterial nerves in the mesentery to the rabbit isolated ileum causes inhibition which is increased when hyoscine is added to the bath. This increase is, however, usually seen only when the stimulus frequency is low, and the addition of hyoscine usually makes no difference when the frequency is 10 shocks/sec or more. The observations suggest that, at low frequency, stimulation releases both acetylcholine and noradrenaline, but that at higher frequencies only noradrenaline is released. Similar observations have been made for the nictitating membrane of the cat. When the postganglionic fibres from the superior cervical ganglion were stimulated supramaximally, the contractions of the membrane increased in size as the frequency rose. In the presence of hyoscine the contractions were smaller, the greatest difference being for the lowest stimulus frequency, the difference diminishing as the frequency rose. These observations are consistent with the view that sympathetic cholinergic fibres in many situations release acetylcholine to act directly only at low frequencies, and that at higher frequencies the acetylcholine is almost entirely used to release noradrenaline.
UPTAKE OF 5‐HYDROXYTRYPTAMINE AND ADRENALINE IN THE LIVER
Authors: INNES I. R.
Published: July 2012

A dose of 5‐hydroxytryptamine caused a greater contraction of the cat nictitating membrane when injected into the jugular vein than when injected into the portal vein. The difference is attributed to uptake or destruction of 5‐hydroxytryptamine by the liver. The effects of portal and jugular injections became equal after administration of the monoamine oxidase inhibitors iproniazid or harmaline. Isoniazid, which does not inhibit monoamine oxidase, did not have this effect. Similarly, the effect of a portal injection of adrenaline was less than the effect of an equal jugular injection of adrenaline. Iproniazid and harmaline increased the effect of a portal injection, but not to equal the effect of a jugular injection. Isoniazid had no effect. Pyrogallol did not alter the ratio between the effects of portal and jugular injections of adrenaline, but increased the responses to both.
THE ACTION OF TRIETHYLCHOLINE ON THE PERISTALTIC REFLEX OF THE GUINEA‐PIG ILEUM
Authors: BOULLIN D. J.
Published: July 2012

The action of triethylcholine on the peristaltic reflex of the guinea‐pig isolated ileum has been studied. When perfused through the lumen in low concentrations triethylcholine first stimulated and then inhibited peristalsis. High concentrations gradually inhibited or abolished the reflex without prior stimulation. These inhibitory effects were reversed by choline, in the continued presence of triethylcholine. Similar responses followed application of triethylcholine to the serosal surface of the gut, except that high concentrations produced an immediate abolition of peristalsis which was not restored by choline. It is suggested that the effects of intraluminal triethylcholine are due either to enhancement of acetylcholine release or to reduction of acetylcholine synthesis, or to a combination of these factors, and that the results are evidence that acetylcholine is a humoral transmitter involved in the initiation of peristalsis.
FURTHER PHARMACOLOGY AND CHEMOTHERAPY OF CLOXACILLIN
Authors: ACRED P. , BROWN D. M.
Published: July 2012

In concentrations greatly in excess of therapeutic blood levels cloxacillin has a slight hypotensive action. As with other antibiotics, it sometimes causes diarrhoea in rabbits but, in doses up to 200 mg/kg, it does not have a teratogenic effect on the rabbit foetus. Cloxacillin is distributed throughout the body. High concentrations are found only in the liver and kidney, these reflecting the high concentrations in the bile and urine respectively. It differs from other penicillins investigated in that there appears to be little or no renal tubular secretion as demonstrated in experiments on the hen. Cloxacillin is excreted as the unchanged drug and as an active metabolite in the urine and bile. After oral administration it is metabolized in the caecum giving a penicillin which differs from the urinary metabolite and which has a greater antibiotic action against Sarcina lutea than the parent penicillin. The activity of the caecal metabolite against resistant and sensitive strains of Staphylococcus, however, remains similar to that of cloxacillin. Against infections due to resistant and sensitive Staphylococcus in animals cloxacillin is active by both the oral and subcutaneous routes and it is more effective orally than an equal subcutaneous dose of methicillin.
ACTION OF DEXAMPHETAMINE ON 5‐HYDROXYTRYPTAMINE RECEPTORS
Authors: INNES I. R.
Published: July 2012

Dexamphetamine contracted isolated preparations of rat stomach, dog retractor penis, rabbit aorta, rabbit uterus and all sections of guinea‐pig ileum. Adrenaline inhibited rat stomach and all but the terminal 10 cm of guinea‐pig ileum, but contracted dog retractor penis, rabbit aorta, rabbit uterus and the terminal portion of the guinea‐pig ileum. 5‐Hydroxytryptamine contracted all five preparations. Responses to dexamphetamine and 5‐hydroxytryptamine were not blocked in preparations protected by a high concentration of either drug during exposure to phenoxybenzamine in a dose which usually caused block. Responses to dexamphetamine and 5‐hydroxytryptamine were blocked in preparations protected by adrenaline. Responses to dexamphetamine in dog retractor penis, rabbit aorta and rabbit uterus were not reduced in preparations from animals treated with reserpine or after cocaine, indicating that the contraction is not mediated by released noradrenaline. It is concluded that dexamphetamine acts directly on 5‐hydroxytryptamine receptors in these smooth muscles and therefore cannot be regarded as a true sympathomimetic amine.
THE SUBCELLULAR LOCALIZATION OF DOPAMINE AND ACETYLCHOLINE IN THE DOG CAUDATE NUCLEUS
Authors: LAVERTY R. , MICHAELSON I. A. , SHARMAN D. F. , WHITTAKER V. P.
Published: July 2012

The distribution of dopamine (3,4‐dihydroxyphènylethylamine) between the subcellular fractions from homogenates of dog caudate nucleus was compared with the distributions of acetylcholine, 5‐hydroxytryptamine and lactate dehydrogenase activity. The distributions of noradrenaline and 5‐hydroxytryptamine between the subcellular fractions from homogenates of dog hypothalamus were also determined. Most of the dopamine, in contrast to acetylcholine, occurred in the soluble supernatant fraction; the remainder was associated with the fractions rich in pinched‐off nerve ending particles, but localization in any one fraction was not as sharp as that of acetylcholine. Evidence is presented that suggests that the dopamine occurs in a free or easily released form throughout cell cytoplasm.
THE UPTAKE OF NORADRENALINE BY THE ISOLATED PERFUSED RAT HEART
Authors: IVERSEN L. L.
Published: July 2012

The uptake of noradrenaline by the isolated perfused rat heart was studied after perfusion with a medium containing various concentrations of (+)‐[3H]‐noradrenaline. Simultaneous measurement of the uptake of [3H]‐noradrenaline and of the net increase in the noradrenaline content of the heart showed that [3H]‐noradrenaline entering the heart both increased the tissue content and exchanged with endogenous noradrenaline. A large part (about 75%) of the endogenous noradrenaline pool, however, exchanged very slowly if at all with exogenous noradrenaline. The initial rates of noradrenaline uptake satisfied Michaelis‐Menten kinetics with a Km for (±)‐noradrenaline of 6.64times10−7 μM. Further analysis of the uptake process indicated that noradrenaline entered into at least two intracellular pools at different rates. Measurement of the initial rates of noradrenaline uptake during perfusion with various concentrations of nonradioactive (+)‐ and (−)‐noradrenaline showed that the uptake process exhibited stereochemical specificity. The Km values for (+)‐ and (−)‐noradrenaline were 13.9times10−7 and 2.66times10−7 μM respectively. Cocaine acted as a potent competitive inhibitor of noradrenaline uptake. This finding suggested that diffusion did not play any significant role in the entry of noradrenaline into the tissue.
SOME PHARMACOLOGICAL PROPERTIES OF THE CIRCULAR AND LONGITUDINAL MUSCLE STRIPS FROM THE GUINEA‐PIG ISOLATED ILEUM
Authors: BROWNLEE G. , HARRY J.
Published: July 2012

A circular and a longitudinal muscle strip were prepared from adjacent parts of a guinea‐pig ileum and a direct pharmacological comparison made under identical conditions. The longitudinal preparation was sensitive to acetylcholine, methacholine, carbachol, 5‐hydroxytryptamine, histamine and nicotine, while the circular preparation was insensitive to 5‐hydroxytryptamine, histamine and nicotine, and responded to the choline esters only in high concentrations. Incubation of the preparations with the anticholinesterase, mipafox (NN‐diisopropylphosphodiamidic fluoride), sensitized both preparations to the action of acetylcholine; potentiation of the contraction of the longitudinal muscle was 16‐times; that of the circular one 4,000‐times. The longitudinal muscle was more sensitive than the circular muscle to acetylcholine whether both were treated with mipafox or not. Bradykinin and substance P both stimulated the longitudinal but not the circular muscle, an effect not modified after mipafox. Hyoscine antagonized the responses of the circular muscle strip, treated with mipafox, to acetylcholine and to histamine, but on the longitudinal muscle strip the response to histamine was not affected, the response to acetylcholine being competitively antagonized. Morphine, in the same concentrations on both circular and longitudinal muscle strips, antagonized the stimulant actions of nicotine and to a lesser extent of 5‐hydroxytryptamine, but the responses to histamine on the longitudinal muscle strip were not antagonized by morphine which was in contrast to its action on the circular muscle strip. These observations showed that the main differences in the responses of the circular and longitudinal muscle of the guinea‐pig ileum to drugs were in the intrinsic properties of the smooth muscle cells. In addition cholinesterase may protect the circular muscle cells. Finally the circular muscle strip preparation proved to be a useful tool to study the action of drugs on the nervous plexuses of the ileum of the guinea‐pig.
THE EFFECT OF SOME PHENOTHIAZINE TRANQUILLIZERS ON THE OESTROUS CYCLE OF ALBINO MICE
Authors: BHARGAVA K. P. , JAITLY K. D.
Published: July 2012

The effects of reserpine and of nine phenothiazine compounds on the oestrous cycle of albino mice were tested. With the exception of promethazine (which is not a tranquillizer) all the phenothiazine compounds and reserpine prolonged the oestrous cycle. The mechanism by which these tranquillizers interfere with the oestrous cycle is discussed.
THE SYMPATHETIC MECHANISM IN THE ISOLATED PULMONARY ARTERY OF THE RABBIT
Authors: BEVAN J. A. , SU C.
Published: July 2012

The nature of postganglionic sympathetic nervous transmission to vascular muscle in vitro was studied using the recurrent cardiac nerve‐pulmonary artery preparation of the rabbit. Experiments, similar to those which in other tissues have provided evidence to support a role for acetylcholine at the sympathetic postganglionic nerve‐effector cell junction, were carried out. The contractile response of the isolated artery to acetylcholine was blocked completely by atropine. High concentrations of acetylcholine and of hemicholinium had no effect on the contractile response to sympathetic nerve stimulation. Physostigmine, atropine and hemicholinium were without influence on the relationship between nerve stimulus frequency and response. Yohimbine, bretylium and reserpine blocked completely the response to nerve stimulation but did not affect that to applied acetylcholine. These results support the view that transmission in this preparation at the sympathetic postganglionic nerve‐effector cell junction is mediated by an adrenaline‐like transmitter and provide no evidence for the view that acetylcholne is involved at this site.
SOME PHARMACOLOGICAL EFFECTS OF A SERIES OF TRYPTAMINE DERIVATIVES
Authors: BRIMBLECOMBE R. W. , DOWNING D. F. , GREEN D. M. , HUNT R. R.
Published: July 2012

The methods of synthesis and some pharmacological properties of a number of N‐substituted tryptamines are described. Peripheral vasopressor activity decreased with increase in complexity of the substituent and was not related to toxicity or to behavioural activity. Activity in increasing the rectal temperature of rabbits appeared to parallel modifications in the open‐field behaviour of rats. Some compounds were investigated for their ability to block a conditioned avoidance‐response in rats and to affect operant conditioning in cats. Evidence is presented which suggests that the tryptamine derivatives are metabolized in vivo to more active forms.
STUDIES ON THE HYPERGLYCAEMIA INDUCED BY CHLORPROMAZINE IN RATS
Authors: BONACCORSI A. , GARATTINI S. , JORI A.
Published: July 2012

Chlorpromazine induces in rats a marked and long‐lasting hyperglycaemia which (a) is more marked at low than high room temperatures, (b) is inhibited by phentolamine but not by dibenamine, and (c) is prevented by adrenalectomy, by removal of the adrenal medullae and by treatment of the rats with reserpine. Other experimental results suggest that there is a correlation between the hyperglycaemia and the hypothermia induced by chlorpromazine and by its congeners. The hyperglycaemia seems to be the result of at least two factors: an activation of the adrenergic mechanisms and an impaired peripheral utilization of glucose.
ACTIONS OF SYMPATHOMIMETIC DRUGS ON THE SMOOTH MUSCLE AT THE JUNCTION OF THE BILE DUCT AND DUODENUM STUDIED IN SITU
Authors: BENZI G. , BERTÈ F. , CREMA A. , FRIGO G. M.
Published: July 2012

The actions of adrenaline, noradrenaline, phenylephrine and isoprenaline have been examined on flow through the terminal bile duct and on the tone of the duodenum in the vicinity of the terminal bile duct. These drugs were injected intravenously, or intra‐arterially into the blood supply of the junction of the bile duct and duodenum. The effects of the antagonistic drugs, dibenamine and dichloroisoprenaline, were also tested. Isoprenaline always relaxed the duodenum and increased the flow through the bile duct. Adrenaline, noradrenaline and phenylephrine relaxed the duodenum, but had variable effects on the flow through the bile duct. It is concluded that adrenaline acts directly on the smooth muscle of the bile duct to contract it, but the influence of the neighbouring duodenal muscle may nevertheless result in an increase in flow through the duct.
THE INFLUENCE OF CENTRALLY ACTING CHOLINOLYTIC DRUGS ON BRAIN ACETYLCHOLINE LEVELS
Authors: GIARMAN N. J. , PEPEU G.
Published: July 2012

A number of centrally acting cholinolytic drugs reduced levels of cerebral acetylcholine in the rat. Among its naturally occurring analogues, hyoscine had the greatest potency, producing a decrease of 31% at a dose of 0.63 mg/kg. Atropine methyl nitrate, which acts as a cholinolytic drug in the periphery, had no effect on brain acetylcholine levels. The fall in acetylcholine produced by hyoscine was greatest after 60 min and disappeared at about 120 min. The animals tended to show a partial tolerance to this effect of hyoscine when the drug was administered repeatedly. The reduction in acetylcholine after hyoscine was restricted to the cerebral hemispheres, and did not appear in subcortical regions of the brain. Hyoscine had no influence on the net synthesis of acetylcholine by acetone‐extracted powder of rat brain. In a series of four synthetic cholinolytic drugs, only the two with conspicuous psychotomimetic actions in man produced a decrease in brain acetylcholine comparable to that seen with hyoscine and related alkaloids.
QUANTITATIVE COMPARISON BETWEEN OXYTOCIN AND FOUR RELATED NEUROHYPOPHYSIAL PEPTIDES ON THE HUMAN UTERUS IN SITU
Authors: SAAMELI K.
Published: July 2012

Quantitative assays of four synthetic peptides related to oxytocin were carried out on the post partum human uterus in vivo by means of external tocography. The following activities (U/mg, means and standard errors) were found: isoleucine8‐oxytocin 365 ± 70, asparagine4‐oxytocin 150 ± 40, desamino1‐oxytocin 1,030 ± 300, serine4‐isoleucine8‐oxytocin 335 ± 95. None of the conventional bioassay procedures proved to be fully reliable for predicting the oxytocic activity in man of peptides related to oxytocin. If the tocographically recorded effects of equipotent doses of the compounds are compared with those of oxytocin no qualitative differences can be observed.
THE SELECTIVITY OF DRUGS BLOCKING GANGLIONIC TRANSMISSION IN THE RAT
Authors: QUILLIAM J. P. , SHAND D. G.
Published: July 2012

By comparing the effects on ganglionic transmission and on the pre‐ and postganglionic nerves in the isolated superior cervical ganglion preparation of the rat, the selectivity of several drugs was assessed quantitatively. Hexamethonium, tetraethylammonium, nicotine and tubocurarine blocked transmission in concentrations which did not affect nervous conduction and were considered to be highly selective in action. Atropine, amylobarbitone and paraldehyde depressed nervous conduction appreciably in ganglion‐blocking doses, but not enough to account wholly for the block in transmission and they were therefore considered as being moderately selective. The ganglion blocking actions of mephenesin, procaine, methylpentynol, methylpentynol carbamate and benactyzine were nonspecific, showing general depression of neuronal activity. Ganglion block with bretylium was nonselective in its site of depression of the postganglionic neurone in concentrations which only partly depressed the preganglionic nerve.
A COMPARISON OF IMIPRAMINE, CHLORPROMAZINE AND RELATED DRUGS IN VARIOUS TESTS INVOLVING AUTONOMIC FUNCTIONS AND ANTAGONISM OF RESERPINE
Authors: HALLIWELL G. , QUINTON R. M. , WILLIAMS FRANCES E.
Published: July 2012

Seven structurally‐related compounds consisting of three antidepressant drugs (imipramine, desmethylimipramine and amitriptyline), three tranquillizing agents (promazine, chlorpromazine and chlorprothixene) and a hybrid, desmethylpromazine. have been examined in a series of tests involving autonomic functions and antagonism of reserpine. Activities of the compounds in antagonizing reserpine‐induced ptosis in rabbits and prolongation of alcohol hypnosis in mice give good correlation with their clinical actions, whilst their activities in augmenting excitation of rats by amphetamine and yohimbine toxicity in mice, and in reversing reserpine‐induced bradycardia in rats offer further evidence for drug‐induced sensitization to adrenergic or tryptaminic mechanisms, which is not however specific for antidepressant agents. No evidence has been obtained to indicate that a central parasympatholytic action is an important component of the antidepressant activity of imipramine and related drugs.
NONSPECIFIC DEPRESSANT ACTION OF γ‐AMINOBUTYRIC ACID ON SOMATIC REFLEXES
Authors: BHARGAVA K. P. , SRIVASTAVA R. K.
Published: July 2012

The effects of γ‐aminobutyric acid (GABA) on central integration of somatic reflexes in the cat have been studied by topical application, and by intrathecal or intracerebroventricular injection. Intrathecal injection of GABA inhibited the monosynaptic patellar reflex. The facilitation of the patellar reflex induced by strychnine, leptazol, tubocurarine and tetanus toxin was also inhibited. Polysynaptic facilitation of the patellar reflex induced in the spinal cat by electrical stimulation of the contralateral sciatic nerve was depressed by intrathecal GABA. Similarly, the supraspinal facilitation of the patellar reflex by electrical stimulation of the brain stem reticular formation was inhibited by application of GABA to the floor of the 4th ventricle. The polysynaptic inhibition of the patellar reflex at both levels was intensified by GABA. The flexor (tibialis anterior) reflex was depressed in the same manner as the extensor patellar reflex. The polysynaptic linguomandibular reflex was depressed by intracerebroventricular GABA. The depressant action of GABA at spinal and supraspinal levels of the neuraxis is discussed in relation to the role of GABA as an inhibitory transmitter in the central nervous system.
KININ‐FORMING AND DESTROYING ACTIVITIES OF SALIVA
Authors: AMUNDSEN E. , NUSTAD K.
Published: July 2012

Kininase activity is present in saliva obtained from the oral cavity but not in saliva obtained by cannulation of the parotid or submandibular ducts. This activity originates from squamous epithelial cells from the oral mucous membranes. Experiments with various inhibitors indicated that the kininase activity of squamous epithelial cells differs from that of plasma, and resembles that of erythrocytes. Kinin‐forming activity is present both in the glandular secretion and in the squamous epithelial cells.
POSSIBLE RELATIONSHIP BETWEEN TETRACYCLINE STABILITY AND EFFECT ON FOETAL SKELETON
Authors: TUBARO E.
Published: July 2012

A possible relationship between stability of a tetracycline and persistence in the foetal skeleton is discussed; it seems that the greater the stability of a tetracycline, the more it may interfere with bone‐forming processes. Therefore, assuming that limited instability does not impair antibiotic potency in vivo, the use of a low‐stability tetracycline seems to be a safer form of treatment in order to avoid undesired effects on the foetal skeleton.
MECHANISM OF THE PARALYSING ACTION OF PIPERAZINE ON ASCARIS MUSCLE
Authors: DEL CASTILLO J. , DE MELLO W. C. , MORALES T.
Published: July 2012

The effects of piperazine on Ascaris muscle cells have been investigated with electrophysiological techniques. These cells have an average resting potential of about 30 mV interrupted by rhythmic spikes of myogenic origin (1 to 7 spikes/sec). With piperazine (10−3, w/v), the average resting potential increases above 40 mV and the pacemaker activity is suppressed. These changes are similar to those temporarily produced in the same cells by the electrical stimulation of inhibitory nerve fibres. Electrophoretic application of piperazine to different areas of the muscle cells shows that this drug hyperpolarizes their membrane only when applied to the region where both excitatory and inhibitory neuromuscular synapses are located. The degree of muscle hyperpolarization induced by piperazine depends upon the extracellular chloride concentration, decreasing when a fraction of the chloride ions is replaced by the larger, supposedly nonpenetrating, sulphate anions. Piperazine may, therefore, be regarded as a pharmacological analogue of a natural inhibitory transmitter.
ADVENTITIOUS FACTORS AFFECTING THE CONCENTRATION OF FREE FATTY ACIDS IN THE PLASMA OF RATS
Authors: BARRETT A. M.
Published: July 2012

The concentration of free fatty acids in the plasma of rats has been shown to be affected by the sex and body weight of the animals, their external environment, the availability of food and water, and the time of day and season of the year.
SOME PHARMACOLOGICAL PROPERTIES OF THIOPROPERAZINE AND THEIR MODIFICATION BY ANTI‐PARKINSONIAN DRUGS
Authors: LESLIE G. B. , MAXWELL D. R.
Published: July 2012

The pharmacological properties of a phenothiazine derivative thioproperazine have been compared with those of chlorpromazine, and the modifications by some anti‐Parkinsonian drugs of its actions on the central nervous system have been studied. Thioproperazine was less potent than chlorpromazine in lowering blood pressure and antagonizing adrenaline in the cat, in depressing respiratory rate in the rabbit, in producing hypothermia and analgesia and in reducing the minimum anaesthetic dose of hexobarbitone in mice, and in protecting rats from convulsions induced by tryptamine. It was roughly equipotent to chlorpromazine in reducing locomotor activity of mice. Thioproperazine was more potent than chlorpromazine in protecting grouped mice from the acute toxicity of dexamphetamine, in preventing the acute behavioural disturbances produced by dexamphetamine in the rat, in producing a state of experimental catatonia in the rat and in preventing the emetic action of apomorphine in the dog. Hyoscine, benztropine or promethazine greatly reduced the ability of thioproperazine to prevent behavioural changes due to dexamphetamine in the rat and also abolished symptoms of experimental catatonia produced by thioproperazine. In contrast, the antiapomorphine activity of thioproperazine in the dog was not reduced to any extent by hyoscine or benztropine.
OBSERVATIONS ON THE APPLICATION OF THE ROBBINS‐MONRO PROCESS TO SEQUENTIAL TOXICITY ASSAYS
Authors: HAWKINS D. F.
Published: July 2012

The Robbins‐Monro process is a sequential procedure which can be used in toxicity assays. The principal advantages are maximal economy of drug and animals and immediate availability of an estimate of the LD50 at any stage in the assay. The disadvantages are the need to wait for the outcome in each group of animals before testing the next group and the lack of an accurate method for determining confidence limits. Some practical details of the application of the method are given.
A SIMPLE METHOD FOR RECORDING THE ELECTROCARDIOGRAM AND HEART RATE FROM CONSCIOUS ANIMALS
Authors: FARMER J. B. , LEVY G. P.
Published: July 2012

The small bioelectrical signals of the heart detected at the body surface of animals are usually relayed to the initial amplifier stage of the electrocardiograph by the use of plate, needle or clip electrodes (Clark, Szabuniewicz & McCrady, 1966). In a series of experiments in which rapid and repeated measurements of the electrocardiogram (e.c.g.) and resting heart rate from conscious, unrestrained guinea‐pigs were required none of the standard methods proved suitable and a modification was therefore developed in which the animals stand on plate electrodes. This method has been used to obtain recordings from conscious mice, rats, cats and dogs, and some applications of the method are illustrated in the experiments described in this article.
Effect of prostaglandins E1 and E2 on intestinal motility in the guinea‐pig and rat
Authors: BENNETT A. , ELEY K. G. , SCHOLES G. B.
Published: July 2012

. Prostaglandins E1 and E2 affected intestinal activity both in vitro and in vivo.

. Serosal application of prostaglandin to guinea‐pig isolated ileum stimulated the longitudinal muscle but reduced peristaltic contractions of the circular muscle and the propulsion of fluid through the gut. Intraluminal application had little effect.

. Injection of prostaglandin into the bloodstream of anaesthetized rats stimulated the longitudinal muscle of the ileum and increased the intraluminal pressure. A similar response sometimes occurred in the guinea‐pig, but in general the effect was variable.

. Release of prostaglandin in the gut wall, but probably not into the blood or into the lumen of the gut, may play a part in controlling intestinal motility.
Effects of nicotine on electrocortical activity and acetylcholine release from the cat cerebral cortex
Authors: ARMITAGE A. K. , HALL G. H. , SELLERS C. M.
Published: July 2012

The effects of small amounts of nicotine on electrocortical activity and central acetylcholine (ACh) release have been studied on anaesthetized cats.

The most common effect of nicotine given intravenously in a dose of 2 μg/kg every 30 sec for 20 min was to cause desynchronization of the electrocorticogram, indicating cortical activation, and an increase in the release of cortical ACh.

A larger dose given less frequently (4 μg/kg every min for 20 min) caused, in some experiments, an increase and in others a decrease in cortical activity. Such changes were accompanied respectively by an increase or decrease in cortical ACh output.

The amounts of nicotine that affected the electrocorticogram and ACh release are probably similar to those absorbed by the cigarette smoker who inhales.

The effects of nicotine on the electrocorticogram were transient, but the effects on ACh were prolonged. This suggests that at least two pathways are involved in the nicotine response.
Some studies on cytisine and its methylated derivatives
Authors: BARLOW R. B. , McLEOD L. J.
Published: July 2012

In mice cytisine hydrochloride is less toxic intravenously than nicotine hydrogen tartrate, but more toxic by intraperitoneal or oral administration. Compared with cytisine, caulophylline hydrogen iodide is one‐fifth to one‐tenth as toxic and caulophylline methiodide is less than one‐thirtieth as toxic.

The surprising low oral toxicity of cytisine and nicotine may be ascribed to the method of administration; if the drug is placed directly in the stomach there is no possibility of absorption through buccal mucous membranes.

The peripheral effects of nicotine, cytisine and caulophylline are similar, though on some preparations those of nicotine last longer. In most tests cytisine is active in doses from a quarter to three‐quarters of those of nicotine, caulophylline in doses from 10 to 20 times those of cytisine. Caulophylline methiodide is virtually inactive.

Cytisine and caulophylline may differ from nicotine in their central effects.

Cytisine and caulophylline are active as the cations. The pKa of cytisine is 7.92 and that of caulophylline is 7.04; the difference accounts, in part, for the weaker activity of caulophylline. The caulophylline ion is generally one‐sixth to one‐third as active as the cytisine ion.

The introduction of the second methyl group to form the quaternary salt does not appear to cause a dramatic change in the conformation of the molecule. Caulophylline methiodide appears to be feebly active because it has feeble affinity.
Study on some selective β‐adrenoreceptor blocking effects of 1‐(4‐nitrophenyl)‐1‐hydroxy‐2‐methyl isopropylaminoethane (α‐methyl INPEA)
Authors: SOMANI PITAMBAR
Published: July 2012

. The effect of methyl substitution in the α‐carbon position of the ethanolamine side chain of INPEA was investigated on its β‐adrenoreceptor blocking activity in the isolated turtle heart and anaesthetized cats.

. In the turtle heart preparation, the pA2 value for erythro‐α‐methyl INPEA was 5·3, as compared with 6·9 for INPEA, while threo‐α‐methyl INPEA was extremely weak and its pA2 value could not be determined.

. In the intact cat experiments, α‐methyl INPEA produced a competitive blockade of the peripheral vasodilator effect of isoprenaline in doses ranging from 5 to 20 mg/kg. However, this agent had a minimal effect on the cardiac stimulant effect of the catecholamine.

. These results are consistent with the hypothesis that the β‐adrenoreceptors comprise a family of nonhomogeneous receptors and a selective blockade of only some, but not all, responses mediated through their activation can be achieved by specific molecular modification of the β‐adrenoreceptor blocking agents.
The pulmonary and systemic circulatory response to dopamine infusion
Authors: HARRISON D. C. , PIRAGES SUELLEN , ROBISON SHERILYN C. , WINTROUB B. U.
Published: July 2012

. The pulmonary and systemic circulatory responses to dopamine infused at 8, 15, 25 and 30 μg/kg per min were studied in eight mongrel dogs.

. Mean pulmonary artery pressure, mean left atrial pressure, mean aortic pressure, mean aortic flow and the electrocardiogram were monitored in open‐chest preparations. Pulmonary vascular resistance, systemic vascular resistance and stroke volume were calculated.

. Significant increases in mean pulmonary and aortic pressures were noted at dopamine infusions of 25 and 30 μg/kg per min. The left atrial pressure fell significantly at 15 μg/kg per min and rose significantly at 30 μg/kg per min. Mean aortic flow increased at all four doses, while heart rate showed no change. Pulmonary vascular resistance did not change significantly at any dose level, but systemic vascular resistance fell slightly at 8 and 15 μg/kg per min and rose significantly at 30 μg/kg per min. Stroke volume was significantly elevated at infusions of 25 and 30 μg/kg per min.

. The systemic circulatory response to dopamine is similar to that described by previous investigators.

. The increased pulmonary pressures without change in resistance suggest a dopamine‐induced increase in smooth muscle tension in the pulmonary vasculature.
Effects of cyclic 3′,5′‐AMP and other adenine nucleotides on the melanophores of the lizard (Anolis carolinensis)
Authors: HADLEY MAC E. , GOLDMAN JOEL M.
Published: July 2012

. Cyclic 3′,5′‐AMP has been reported to darken skins of the frog, Rana pipiens. This suggests that cyclic 3′,5′‐AMP may mediate the action of MSH on amphibian chromatophores. Since MSH also darkens skins of the lizard, Anolis carolinensis, we investigated the effects of cyclic 3′,5′‐AMP and other nucleotides on Anolis melanophores to determine whether cyclic 3′,5′‐AMP may be the intracellular mediator of hormone action on melanophores of another vertebrate class.

. Cyclic 3′,5′‐AMP, itself, causes a rapid melanin granule aggregation within melanophores of Anolis. This response is, however, somewhat nonspecific in that both 5′‐ATP and 5′‐ADP also lighten the skins by aggregating the melanin granules. Another nucleotide, 5′‐AMP, darkens the skins by dispersing melanin granules. Cyclic 2′,3′‐AMP does not darken or lighten Anolis skins.

. Dibutyryl cyclic 3′,5′‐AMP, which is considered to be better able to penetrate membranes and resist degradation by a specific phosphodiesterase, maximally darkens Anolis skins, as does MSH. This darkening by the potent dibutyryl cyclic 3′,5′‐AMP suggests that cyclic 3′,5′‐AMP may be the intracellular mediator of melanin granule dispersion within Anolis melanophores leading to skin darkening.

. Other evidence supporting the first‐messenger—second‐messenger hypothesis for melanophore regulation is discussed.

. The differences in responses of Anolis melanophores to adenine nucleotides may relate to the ability of these agents to penetrate melanophore membranes; thus, the nucleotides could exert their effects either intracellularly or extracellularly on the plasma membrane.
Anti‐inflammatory activity of the steroid alkaloid glycoside, tomatine
Authors: FILDERMAN R. B. , KOVACS B. A.
Published: July 2012

. Tomatine, isolated from extracts of crown gall‐infected tomato plants or obtained commercially, was tested for anti‐inflammatory activity using three different methods.

. Tomatine administered to intact rats intramuscularly in a dose range of 1–10 mg/kg or orally in doses of 15–30 mg/kg exerted a significant dose dependent inhibition of carrageenan induced paw oedema. The inhibitory effect of tomatine when given in a dose of 10 mg/kg intramuscularly to intact rats lasted more than 24 hr.

. In adrenalectomized rats significant dose‐related inhibition of paw oedema was obtained with tomatine and the inhibition at each dose level (0·5–10 mg/kg) was found to be greater than that found in intact animals.

. Tomatine administered subcutaneously to intact rats daily for 7 days in doses of 5 or 10 mg/kg exerted a significant, dose dependent inhibition of granulation tissue formation induced by the subcutaneous implantation of carrageenan impregnated cotton pellets.

. Tomatine administered to intact mice in a dose of 10 mg/kg subcutaneously 1 hr before the intraperitoneal injection of acidified saline and intravenous pontamine sky blue significantly decreased the leakage of the protein bound dye into the peritoneal cavity.

. Tomatidine, the aglycone of tomatine, was not effective at dose levels of 10–20 mg/kg in any of the three tests.
Pharmacological significance of biogenic amines in the lungs: histamine
Authors: AVIADO DOMINGO M. , SADAVONGVIVAD CHIRAVAT
Published: July 2012

. Eight animal species were investigated for the histamine content of the lung and can be divided into two groups: the low‐level group, ranging from 2 to 7 μg/g, consisting of the mouse, rat, guinea‐pig and rabbit; and the high‐level group, ranging from 12 to 35 μg/g, consisting of the cat, dog, goat and human. In two species of the high‐level group (cat and dog) the amount of histamine that elicited an increase in pulmonary resistance was one‐fifth to one‐tenth of the dose that elicited an increase in species of the low‐level group (rat and rabbit). There is an inverse relationship between the content of histamine and the dose of histamine that produces a 25% increase in pulmonary resistance.

. Anaphylaxis increases the histamine content of the lung of the rabbit but not of the lung of the guinea‐pig. In both species, anaphylaxis is accompanied by an elevation of the concentration of 5‐hydroxytryptamine in the lung, indicating the trapping of platelets in the lung.

. The development of severe parasitaemia in the mouse inoculated with Plasmodium berghei is accompanied by an elevation of the histamine content of the lung. This increase appears to be part of the response of the lung to parasitaemia.
Actions of sarin on fast‐twitch and slow‐twitch skeletal muscles of the cat and protective action by anticholinergic drugs
Authors: BRIMBLECOMBE R. W. , EVERETT SALLY D.
Published: July 2012

. The organophosphate cholinesterase inhibitor sarin has been studied for its effects on the contraction of fast‐twitch (flexor hallucis longus, FHL) and slow‐twitch (soleus) muscles in the cat.

. In both muscles lower doses (2·5 to 20 μg intra‐arterially) potentiated, and higher doses (20 μg and over) depressed, twitches produced by indirect stimulation. Muscle action potentials became repetitive. There was no simple relationship between degree of inhibition of blood cholinesterase and effect on muscle twitch.

. The effects of the drug on repetitively stimulated muscles were dependent on both dose and frequency of stimulation. Doses of 2·5 to 10 μg increased the degree of fusion of low frequency tetani (10 Hz for FHL, 5 Hz for soleus) but depressed and caused non‐maintenance of tetani at high frequencies (150 Hz and above for FHL, 60 Hz and above for soleus). Doses of 20 μg and above depressed and caused non‐maintenance of tetani at all frequencies.

. The anticholinergic drug N‐ethyl‐2‐pyrrolidylmethylcyclopentylphenyl glycollate (PMCG) injected intra‐arterially protected both muscles from the effects of sarin on twitch but less so from effects on tetani. When given after sarin the drug reversed twitch potentiation and repetitive firing. In contrast, atropine had little effect on the responses to sarin.

. The effects of (+)‐tubocurarine were compared with those of PMCG.

. The possible mode of action of PMCG is discussed.
Quantitative studies of the effect of antagonists on the acute toxicity of organophosphates in rats
Authors: NATOFF I. L. , REIFF B.
Published: July 2012

. The subcutaneous acute toxicities of the vinyl phosphate pesticides mono‐crotophos, dicrotophos, chlorfenvinphos, crotoxyphos, dichlorvos, mevinphos, and of the experimental compounds SD 4455 (cis‐2‐carboxy‐1‐methylvinyl dimethylphosphate) and SD 7779 (cis‐2‐(1‐phenylethoxy) carbonyl‐1‐methylvinyl diethylphosphate) have been determined in female rats.

. The effects on the log dose‐probit mortality curves to the vinylphosphates of the therapeutic subcutaneous administration of methylatropine, atropine, N‐methylpyridinium‐2‐aldoxime methanesulphonate and obidoxime have been studied.

. Elevation of the LD50 values by the therapeutic regimens was shown to be an unsatisfactory measure of therapeutic efficiency, while reduction of the effect of a maximally lethal dose (LD90) to less than that of a minimally lethal dose (LD10) provided a better quantitative measure of therapeutic efficiency.

. The combination of atropine sulphate (50 μmol base/kg) with obidoxime (250 μmol/kg) was found to be generally the most effective of the antidotal regimens.

The authors thank Mr. G. R. Ellender for his valuable technical assistance and Mr. D. L. Holmes, of the Statistics Unit of the Woodstock Agricultural Research Centre, for the statistical evaluations incorporated in this work.
The action of ranatensin, a new polypeptide from amphibian skin, on the blood pressure of experimental animals
Authors: GELLER R. G. , GOVIER W. C. , PISANO J. J. , TANIMURA T. , VAN CLINESCHMIDT B.
Published: July 2012

. The blood pressure response to ranatensin, an undecapeptide from the skin of the frog, Rana pipiens, has been studied in various experimental animals.

. Ranatensin raised blood pressure in the dog and rabbit. The response was not altered by atropine, phentolamine, propranolol or hexamethonium, suggesting a direct peripheral vasoconstrictor action. In both animals ranatensin was about one‐tenth as potent as angiotensin. Tachyphylaxis to ranatensin did occur, but there was no cross‐tachyphylaxis with angiotensin, bradykinin, or noradrenaline.

. The peptide lowered blood pressure in the monkey, being as potent as eledoisin. The response was not altered by atropine, phentolamine, propranolol, tripelennamine, tetraethylammonium, bretylium, or methysergide. This again suggests a direct peripheral action on vascular smooth muscle. There was no tachyphylaxis to the depressor action, nor was there cross‐tachyphylaxis with angiotensin, eledoisin, bradykinin, or noradrenaline.

. Ranatensin did not alter the blood pressure in cats and had a variable action in the guinea‐pig with a rapid onset of tachyphylaxis.

. Ranatensin has a variable effect on the blood pressure in the rat that is related to the basal level of blood pressure. When the blood pressure is high, the response to the peptide is hypotension. Ranatensin raises blood pressure in the rat when the basal blood pressure is low. The pressor response to ranatensin appears to be due, in part, to the release of noradrenaline from peripheral sympathetic nerve endings.

. The composite action of ranatensin on blood pressure of various experimental animals is unlike that of any other peptide. Its hypertensive action in the dog or rabbit, together with a potent hypotensive action in the monkey, readily distinguishes it from all other vasoactive peptides.
The effect of parachlorophenylalanine on the behaviour of cats
Authors: HOYLAND VALERIE J. , SHILLITO ELIZABETH E. , VOGT MARTHE
Published: July 2012

. Male and female kittens and adult cats were given p‐chlorophenylalanine orally.

. After treatment, some of the male cats showed mounting behaviour and the kittens and non‐oestrous females showed an increase in treading and rubbing which was similar to one aspect of pro‐oestrus behaviour.

. The treated animals also appeared to suffer from skin irritation and showed increased restlessness which accompanied sleep deprivation.

. Injection of 5‐hydroxytryptophan stopped abnormal sexual activity and restored normal sleep for about 5 hours.

. It is concluded that 5‐hydroxytryptamine‐containing neurones inhibit sexual behaviour in cats and that this role can be seen in male and, to some extent, also in female animals.
Actions of bretylium tosylate at the neuromuscular junction
Authors: FERRY G B. , NORRIS BERYL
Published: July 2012

The actions of bretylium tosylate on neuromuscular transmission in the rat phrenic nerve diaphragm preparation have been investigated by electrophysiological methods. Additional experiments have been made on the effect of the drug on the frog rectus preparation and on the acetylcholinesterase of erythrocytes.

After bretylium, there was a reduction in the amplitudes of miniature endplate potentials (mepps), endplate potentials (epps) and acetylcholine potentials recorded in the diaphragm, and also in the contractures of the rectus in response to acetylcholine (ACh) and to carbachol.

After bretylium, there was a prolongation of the time courses of epps and ACh potentials. Under certain circumstances there was enhancement of the amplitudes of epps and ACh potentials and of the contractile responses to ACh but not to carbachol.

Bretylium reduced the velocity of hydrolysis of ACh by erythrocyte ghosts. This inhibition was competitive and the Ki of bretylium was 0·053 mm.

Bretylium did not cause a reduction in the mean quantal content of the epp in junctions blocked with Mg++.

It is concluded that bretylium exerts both facilitatory and inhibitory influences on neuromuscular transmission, which, exerted simultaneously, may give the false appearance that the drug has little action at this synapse.
Plasma concentration, uptake by liver, and biliary excretion of tritiated cardiac glycosides in the isolated perfused guinea‐pig liver
Authors: KOLENDA K.‐D. , LÜLLMANN H. , PETERS T. , SEILER K.‐U.
Published: July 2012

Investigations were carried out on isolated perfused guinea‐pig livers. Different doses of tritiated ouabain, digoxin, and digitoxin were added to the perfusion medium and the subsequent plasma elimination, hepatic uptake, and biliary excretion quantitatively measured. After the perfusion, extracts of liver, bile and plasma were subjected to thin layer chromatography in order to detect the radioactively labelled glycosides and their metabolites.

The ouabain concentration in the plasma approached the equilibrium stage within 45 minutes. At this time 40% of the administered dose had been taken up by the liver, and no further elimination occurred. The elimination curve for ouabain followed a simple exponential function. After 1 h the tissue medium (T/M) ratio was approximately 3. In bile hardly any radioactivity could be detected. Ouabain was therefore not excreted by the liver.

Up to 80% of the digitoxin was eliminated from the plasma within 4 hours. The elimination of radioactive material for the dose range studied could be described by a hyperbolic function. The T/M ratio in the liver varied with time. At the beginning it was as high as 10 and after 4 h reduced to approximately 3. After 45–60 min the concentration of radioactive material in the bile was 500 times as high as that in the plasma. Almost 70% of the administered radioactivity was excreted with the bile within 4 hours. At the end of the perfusion almost all the identifiable substances in plasma and bile were polar metabolites, as shown by thin layer radiochromatography.

Digoxin behaved similarly to digitoxin.

The findings led to the following hypothesis: uptake of cardiac glycosides into the liver cells occurs by a passive diffusion process and is related to their lipid solubility. On the other hand excretion in the bile occurs in general if polar metabolites are formed in the liver cells.