bluuebunny/crossref_metadata_2025 huggingface dataset:
PARTICIPATION OF AN UNUSUAL GANGLIONIC PATHWAY IN THE MEDIATION OF THE PRESSOR EFFECT OF PHYSOSTIGMINE IN THE RAT
Authors: GOKHALE S. D. , GULATI O. D. , JOSHI N. Y.
Published: July 2012

In spinal rats physostigmine failed to produce a pressor response even after treatment of the animals with hexamethonium, whereas noradrenaline, McN‐A‐343 (4‐(m‐chlorophenylcarbamoyloxy)‐2‐butynyltrimethylammonium chloride) and AHR602 (3‐acetoxy‐1‐benzyl‐1‐methylpyrrolidinium bromide) all produced large pressor effects. In rats anaesthetized with urethane, hexamethonium completely abolished the pressor effect of dimethylphenylpiperazinium but only partially blocked the pressor response to physostigmine; pressor effects of noradrenaline, McN‐A‐343 and AHR602 were potentiated. Combined treatment with hexamethonium and atropine and with hexamethonium and cocaine, however, completely abolished the pressor effect of physostigmine; simultaneously the pressor effects of McN‐A‐343 and AHR602 as well as of dimethylphenylpiperazinium were also blocked. P‐286 (N‐diethylaminoethyl‐N‐isopentyl‐N'N'‐di‐isopropylurea) produced an early and a late block of the pressor effect of physostigmine; the initial block was due to an adrenergic blocking action while the late block was probably due to a dual action of the drug in abolishing the effects of both the nicotinic and non‐nicotinic ganglion stimulants. Pressor responses to physostigmine, McN‐A‐343, AHR602 and dimethylphenylpiperazinium were abolished immediately after ganglion‐blocking doses of nicotine. It is suggested that an unusual ganglionic pathway participates in the mediation of the pressor response to physostigmine in the rat, especially when the established ganglionic pathways are blocked.
RELATIVE ACTIONS OF QUATERNARY METHYL DERIVATIVES OF TYRAMINE, DOPAMINE AND NORADRENALINE
Authors: CUTHBERT M. F.
Published: July 2012

Tyramine methiodide and dopamine methobromide have greater pressor effect (three‐ to five‐times) in the spinal cat than the parent amines. Noradrenaline methochloride has little pressor effect. Dopamine methobromide is about four times as potent as nicotine; tyramine methiodide is about equiactive to nicotine; and noradrenaline methochloride has only one‐tenth the potency of nicotine. Their pressor effects are usually abolished by hexamethonium but in some experiments the effect of noradrenaline methochloride persisted and was then abolished by tolazoline. Injected intravenously into the cat anaesthetized with chloralose, each of the three quaternary derivatives contracts the nictitating membrane; dopamine methobromide is again the most active, having more than six times the potency of nicotine. When the contractions of the nictitating membrane are induced by continuous stimulation of the preganglionic fibres of the cervical sympathetic nerve, intravenous injection of the quaternary derivatives of tyramine and dopamine has a biphasic effect; there is a block on which a contraction of the membrane appears to be superimposed. Noradrenaline methochloride produces only a further contraction of the membrane. On the isolated rectus abdominis muscle preparation of the frog, dopamine methobromide is the most active in contracting the muscle, being about twelve times as active as nicotine; noradrenaline methochloride is weakest, having only one‐hundredth the activity of nicotine. These effects are antagonized by hexamethonium. On the isolated phrenic nerve‐diaphragm preparation of the rat, the quaternary derivatives of tyramine and dopamine each have neuromuscular blocking properties, 0.7‐ and 3‐times respectively that of nicotine. Noradrenaline methochloride has no effect. In the sciatic nerve‐tibialis preparation of the cat, the quaternary derivatives of tyramine and dopamine are approximately equipotent in producing neuromuscular paralysis, having about three times the activity of nicotine and one‐fifth that of suxamethonium. These effects are not antagonized either by neostigmine or by edrophonium. Noradrenaline methochloride has no neuromuscular blocking effect. The nicotine‐like properties of these quaternized sympathomimetic amines are discussed. It is of interest that the presence of an hydroxyl group attached to the β‐carbon atom of the side‐chain greatly reduces nicotine‐like activity. By comparison, choline had about one forty‐fifth the pressor activity of ethyltrimethylammonium.
A COMPARISON OF THE GANGLION POTENTIALS AND BLOCK PRODUCED BY ACETYLCHOLINE AND TETRAMETHYLAMMONIUM
Authors: TAKESHIGE C. , VOLLE R. L.
Published: July 2012

Potentials recorded from the surface of the superior cervical ganglion of cats after an intra‐arterial injection of acetylcholine were characterized by a complex waveform which depended on the amount of drug administered. Small doses of acetylcholine evoked a potential consisting of low amplitude hyperpolarization followed by low amplitude depolarization. Somewhat larger doses of acetylcholine caused a triphasic potential containing an initial period of depolarization in addition to the periods of hyperpolarization and delayed depolarization. Still larger doses of acetylcholine produced usually a monophasic wave of depolarization. Small doses of atropine prolonged the initial period of depolarization and prevented the hyperpolarization and delayed depolarization. Hexamethonium reduced or abolished the initial depolarization and enhanced or unmasked the hyperpolarization. The block of transmission occurring during the falling phase of the initial depolarization or during the hyperpolarization was antagonized by atropine. Unlike acetylcholine, tetramethylammonium produced only a prolonged ganglion depolarization which was unaffected by atropine and blocked by hexamethonium. The block of transmission by tetramethylammonium was partially prevented by atropine. These findings support the proposals that three pharmacologically distinctive cholinoceptive sites are present in sympathetic ganglia and, further, that activation of a cholinoceptive site sensitive to atropine may be involved in the block of transmission produced by acetylcholine and related drugs.
THE EFFECTS OF ADRENALINE AND OTHER DRUGS AFFECTING CARBOHYDRATE METABOLISM ON CONTRACTIONS OF THE RAT DIAPHRAGM
Authors: BOWMAN W. C. , RAPER C.
Published: July 2012

The ability of several drugs to restore directly elicited twitches of the rat diaphragm depressed by excess potassium chloride has been studied. The drugs found to be effective were sympathomimetic amines, insulin, glucagon, caffeine, theophylline, calcium chloride and hexosephosphates. The effects of the sympathomimetic amines and glucagon were blocked by β‐receptor blocking agents. Phloridzin blocked the effect of insulin and depressed that of glucagon. The increase in twitch tension still occurred under anaerobic conditions and was not abolished by the glycolytic inhibitor, iodoacetate. All of the effective drugs are known to affect carbohydrate metabolism and the suggestion by Ellis (1955) that the effect on contractions may be a result of increased intracellular hexosephosphate levels is discussed.
BRONCHOCONSTRICTOR ACTION AND ANTAGONISM OF A SLOW‐REACTING SUBSTANCE FROM ANAPHYLAXIS OF GUINEA‐PIG ISOLATED LUNG
Authors: BERRY P. A. , COLLIER H. O J.
Published: July 2012

Slow‐reacting substance produced in anaphylaxis (SRS‐A) increased resistance of the lungs to inflation in the guinea‐pig in vivo and caused isolated preparations of its tracheobronchial muscle to contract. SRS‐A also contracted human isolated bronchial muscle and some but not all preparations of rabbit trachea. Nonsteroid anti‐inflammatory drugs, which antagonize bronchoconstriction induced by kinins, but not that by histamine, acetylcholine, 5‐hydroxytryptamine, substance P, angiotensin or lung prostaglandin, also antagonized the bronchoconstrictor action of SRS‐A. This antagonism resembled that of kinins in being surmounted by higher doses of agonist, in the potencies of active drugs and in the types of drugs which were inactive. However, receptors in guinea‐pig tracheobronchial muscle for SRS‐A seem to be distinct from those for bradykinin, since preparations of this muscle could become unresponsive to either agent in vivo and in vitro, while remaining responsive to the other.
SOME ACTIONS OF CENTRALLY ACTIVE AND OTHER DRUGS ON THE TRANSMISSION OF SINGLE NERVE IMPULSES THROUGH THE ISOLATED SUPERIOR CERVICAL GANGLION PREPARATION OF THE RABBIT
Authors: ELLIOTT R. C. , QUILLIAM J. P.
Published: July 2012

The effect of some centrally‐active and other drugs on the transmission of single nerve impulses through the isolated superior cervical ganglion preparation of the rabbit has been studied by recording both preganglionic and postganglionic action potentials. Block of conduction in the axon could be distinguished from block of the synaptic mechanism. The drugs did not appear to exert any one characteristic form of blocking action. A continuous spectrum of drug action linked an agent such as meprobamate which acted predominantly on the synapse to benactyzine which acted mainly by blocking axonal conduction. The drugs have been divided into three groups. Group I: hexamethonium, meprobamate, paraldehyde, amylobarbitone, methylpentynol and azacyclonal; these acted relatively selectively at the ganglion. Group II: N714C (the cis‐isomer of chlorprothixene), prochlorperazine, methylpentynol carbamate, pipradrol, promethazine, perphenazine and procaine; the action of these drugs on the ganglion could be accounted for entirely in terms of their axonal depressant action. Group III: chlorprothixene, promazine, N720 (dihydrochlorprothixene), chlorpromazine, hydroxyzine and benactyzine; these drugs also blocked axonal conduction but in addition they appeared to exert a “facilitating” action at the ganglionic synapse. The actions of adrenaline, adrenochrome, iproniazid, ergotoxine, mescaline and lysergic acid diethylamide on transmission were also studied. The implications of the modifications of ganglionic transmission produced by these drugs is discussed.
DISTRIBUTION OF (2‐BROMOETHYL)ETHYL(NAPHTH‐1‐YLMETHYL‐[14C])AMINE HYDROBROMIDE IN THE RAT
Authors: GRAHAM J. D. P.
Published: July 2012

(2‐Bromoethyl)ethyl(naphth‐l‐ylmethyl)amine hydrobromide (SY28) is a halogenoal‐kylamine related to dibenamine. A dose of 10 mg/kg injected intravenously into rats antagonizes the pressor response to adrenaline for 36 hr. If this amount of SY28 labelled with 14C in the 1‐methyl position is administered, specific radioactivity is present in blood and tissues many days after the antagonism of adrenaline is relieved. The 14C is excreted in bile and in urine, but not in expired air. It is present in fat but not to a greater extent than it is in other tissues. It does not cross the placental barrier. There is no evidence that slow release from a lipid depot accounts for the long duration of action.
NEUROLOGICAL DISRUPTION PRODUCED IN HENS BY TWO ORGANOPHOSPHATE ESTERS
Authors: BARON R. L. , JOHNSON H.
Published: July 2012

A histological and enzymatic examination was made of the neurological disruption produced in hens by two organophosphate esters. Intraperitoneal administration of DEF (tributyl phosphorotrithiolate) and Merphos (tributyl phosphorotrithiojte) produced central and perpheral nervous system lesions accompanied by clinical signs of ataxia similar to those seen following administration of tri‐o‐cresyl phosphate. Histological examination (utilizing the Marchi stain) showed the occurence of spinal cord disruption before the onset of clinical ataxia. Oral administration of DEF and Merphos did not induce signs of peripheral weakness. However, severe lesions in the spinal cord and sciatic nerve were prominent. A discussion of the occurrence of central and peripheral nerve disruption either in the presence or absence of clinical ataxia is presented. Enzymatic examination of the effect of DEF on spinal cord and brain esterases at various intervals following administration showed a pattern of esterase inhibition similar to that found after tri‐o‐cresyl phosphate, dyflos and other organophosphates. Some prolonged inhibition is believed due to the extent of initial involvement rather than to selective prolonged inhibition.
THE USE OF ISOLATED ORGANS FOR DETECTING ACTIVE SUBSTANCES IN THE CIRCULATING BLOOD
Authors: VANE J. R.
Published: July 2012

A method is described for the assay of circulating hormones after their injection or release into the circulation. The method is applicable to cats, dogs and rabbits, and consists of bathing or superfusing isolated smooth muscle preparations in a stream of heparinized arterial blood taken from and returned to the animal at a constant rate. The tone of the smooth muscle preparations was affected by small changes in the concentrations of various amines. Thus increases in blood concentrations of catechol amines can be assayed with the rat stomach strip and chick rectum preparations. The proportions of adrenaline and noradrenaline in a mixture can be determined. Circulating histamine can be assayed on the blood‐bathed guinea‐pig ileum and bradykinin on the rat duodenum preparations. The uses and limitations of the technique are discussed.
AN INVESTIGATION OF THE ADRENERGIC BLOCKING ACTION OF CHLORPROMAZINE
Authors: GOKHALE S. D. , GULATI O. D. , PARIKH H. M.
Published: July 2012

Antagonism by chlorpromazine of the responses of the rabbit aortic strip and the rat seminal vesicle to adrenaline and noradrenaline fulfils the conditions of competitive antagonism. Chlorpromazine was a remarkably potent antagonist (pA2 approximately 14) of adrenaline and noradrenaline. In the cat anaesthetized with chloralose small doses (1.8 to 4.5 mg/kg) of chlorpromazine greatly reduced or reversed the pressor effect of adrenaline but the pressor effect of noradrenaline was unaffected. A larger dose (9 mg/kg) of chlorpromazine slightly reduced the pressor effect of noradrenaline but caused a spectacular reversal of the pressor effect of adrenaline. This difference was not observed in rabbits and in cats treated with dichloroisoprenaline. Chlorpromazine potentiated the depressor effect of isoprenaline. On the basis of these findings it is concluded that in the cat chlorpromazine in small doses (1.8 to 4.5 mg/kg) has no real adrenergic blocking action and that the selective block of adrenaline pressor effects by these doses is due to a potentiation of adrenergic vasodilatation. Large doses (7.2 to 28.8 mg/kg) of chlorpromazine reduced the pressor effect of noradrenaline; reciprocal analysis showed that this inhibition is competitive.
SODIUM SULPHOMETHYL DERIVATIVES OF POLYMYXINS
Authors: BARNETT MARGARET , BUSHBY S. R. M. , WILKINSON S.
Published: July 2012

Variations in the treatment of polymyxin B and polymyxin E (colistin) with formaldehyde and sodium bisulphite produce sulphomethyl derivatives which differ quantitatively in acute toxicity and in antibacterial activities in vitro and in vivo. The acute intravenous LD50 values of some sixty samples of these derivatives range from six‐ to more than eighty‐fold those of the parent antibiotics; the in vitro antibacterial activities range from 2 to 12% and the in vivo activities from 20 to 50% of those of the parent antibiotics, with the most toxic derivatives showing the highest activities. When short and prolonged incubation methods are used, assays of the derivatives in solutions of different ages and of blood collected from man and dog after intramuscular injection, show that the antibacterial activities of these sulphomethyl derivatives depend on reversion to the unsubstituted form, and that the differences in the activities are due to variations in stability. These conclusions are supported by comparison of these sulphomethyl derivatives with stable acetyl derivatives. The lower in vivo activity is due, at least partly, to the high renal excretion of the substituted form. Electrophoresis shows that the derivatives are composite, the components corresponding to mono‐ to pentasulphomethyl polymyxin. Pain at the injection site is the most troublesome side‐effect of polymyxin therapy, and this is avoided with these derivatives. In rats injected with quantities some twenty‐times the usual human dose, the derivatives cause transitory decrease in urinary output and transitory proteinuria. After intramuscular injection of these derivatives into dogs, no antibiotic is detectable in the cerebrospinal fluid and concentrations present in the bile are not significantly different from those after injection of the parent antibiotic. When injected intracisternally into these animals, derivatives are less toxic than the parent compounds. These studies show that acute intravenous toxicity is a useful index of therapeutic efficiency and that derivatives with intravenous LD50 values of about 100 mg/kg are the most satisfactory ones. Because activity depends on reversion to the parent antibiotic, the use of these derivatives for topical application is contraindicated.
THE MECHANISM OF THE DEPRESSOR ACTION OF NORADRENALINE IN THE CAT
Authors: KARIM S. M. M.
Published: July 2012

In cats anaesthetized with pentobarbitone sodium or chloralose and injected with phenoxybenzamine or phentolamine, administration of (–)‐noradrenaline (5 to 20 μg) produced a fall of blood pressure which resembled in onset and duration that produced by adrenaline under similar conditions. The depressor action of noradrenaline was due mainly to dilatation of the splanchnic blood vessels. This could be abolished by administration of pronethalol, a drug known to block sympathetic β‐receptors.
AN ELECTROPHYSIOLOGICAL INVESTIGATION OF THE ACTIONS OF SOME AUTONOMIC BLOCKING DRUGS ON TRANSMISSION IN THE GUINEA‐PIG VAS DEFERENS
Authors: BURNSTOCK G. , HOLMAN MOLLIE E.
Published: July 2012

Membrane potentials have been recorded from the guinea‐pig isolated vas deferens with intracellular and sucrose‐gap electrodes during stimulation of the hypogastric nerve and of intramural nerve fibres. Atropine had no detectable effect on the excitatory junction potentials in response to nerve stimulation or on the spontaneous discharge of small potentials. High concentrations of adrenolytic drugs, acting on α‐receptors were needed to block the response to nerve stimulation and the spontaneous discharge. During the onset and recovery from yohimbine blockade, junction potentials in response to repetitive stimulation were not sustained. Bretylium initially reduced both the junction potentials and the spontaneous discharge. However, after 30 min exposure, the spontaneous discharge increased in frequency although the response to nerve stimulation was abolished. Block of the junction potentials by procaine was rapid in onset compared with that by bretylium and guanethidine, but the spontaneous discharge was not abolished. These results are discussed in relation to the mechanism of transmission from sympathetic nerve to smooth muscle.
ACTIONS OF HEMICHOLINIUM (HC‐3) ON NEUROMUSCULAR TRANSMISSION
Authors: EVANS E. R. , WILSON H.
Published: July 2012

Hemicholinium No. 3 (HC‐3; α,α'‐dimethylaminoethanol‐4, 4′‐biacetophenone) produced neuromuscular block of the tibialis anterior muscle‐sciatic nerve preparation of the anaesthetized cat which was of slow onset, of long duration and dependent on the nerve stimulus frequency. The failure of the compound to modify the response of the tibialis muscle to close‐arterial injections of acetylcholine suggested that the sensitivity of the motor endplate was not changed by it. The neuromuscular block produced by hemicholinium was antagonized by choline but only partly relieved by anticholinesterase drugs. The response to tetanic stimulation of the nerve during the neuromuscular block was well sustained and was followed by a slight posttetanic potentiation. The neuromuscular blocking action of hemicholinium could be relieved by temporary suspension of stimulation. These results suggest that the mode of action of hemicholinium at the neuromuscular junction is different from that of tubocurarine, and indicate that the action of hemicholinium is presynaptic, probably arising from a reduction in acetylcholine released by nerve stimulation.
PARALYTIC EFFECTS OF “PARALYTIC SHELLFISH POISON” ON FROG NERVE AND MUSCLE
Authors: EVANS M. H.
Published: July 2012

A purified extract of toxic lamellibranchs, Saxidomus giganteus (Deshayes), containing “paralytic shellfish poison,” has been tested for its effects on conduction and contraction in frog nerve and muscle. The poison was very toxic and concentrations within the range 0.025 to 0.1 μg/ml. paralysed isolated muscle preparations, with abolition of the muscle action potential. The poison did not readily penetrate the perineurium, but in desheathed sciatic nerves the conduction of nerve impulses was rapidly blocked by concentrations of 0.05 to 0.1 μg/ml. There was no evidence that the poison had any specific curarizing action at the neuromuscular junction, and the paralysis was not accompanied by any appreciable depolarization of the muscle membrane.
HISTAMINE PROTECTION PRODUCED BY PLANT TUMOUR EXTRACTS. THE ACTIVE PRINCIPLE OF TOMATO PLANTS INFECTED WITH GROWN‐GALL
Authors: CALAM D. H. , CALLOW R. K.
Published: July 2012

Guinea‐pigs were protected against the lethal effects of a histamine aerosol by intraperitoneal injection of stable extracts of normal tomato plants and of tomato plants infected with crown‐gall tumours. The protection was short‐lasting. No difference was observed between the activities of extracts of normal and of infected plants. The active principle of the extracts was isolated, and identified as the steroid alkaloid glycoside, tomatine.
EFFECTS OF CHLORPROMAZINE AND BROMOLYSERGIC ACID DIETHYLAMIDE ON GASTRIC SECRETION OF ACID INDUCED BY HISTAMINE IN RATS
Authors: AMURE B. O. , GINSBURG M.
Published: July 2012

In anaesthetized rats in which the lumen of the stomach was perfused with 0.001 to 0.00025 N‐sodium hydroxide solution and the pH of effluent fluid was recorded continuously, intravenous administration of chlorpromazine caused transient inhibition of acid secretion. After acid secretion had returned to the control level the responses to histamine were greater than those before chlorpromazine was given. Aminoguanidine, iproniazid and bromolysergic acid diethylamide also potentiated the effect of histamine on acid secretion but the initial inhibition was absent. Indirect evidence from experiments in which mixtures of aminoguanidine with chlorpromazine or bromolysergic acid diethylamide and of iproniazid with chlorpromazine or bromolysergic acid diethylamide were given, suggests that chlorpromazine and bromolysergic acid diethylamide enhance responses to histamine by inhibition of imidazole‐N‐methyl transferase.
THE EFFECT OF PHENOXYBENZAMINE AND OF TOLAZOLINE ON THE RESPONSE TO SYMPATHETIC STIMULATION
Authors: BURN J. H. , GIBBONS W. R.
Published: July 2012

The effect of phenoxybenzamine has been determined on the physiological response to sympathetic stimulation in two preparations, the rabbit isolated ileum and the guinea‐pig isolated vas deferens. In both preparations phenoxybenzamine increased the response to stimulation of low frequency, the response being inhibitory in the one and motor in the other. This increase was large. As the stimulus frequency was raised, phenoxybenzamine caused a progressively smaller increase in the response, and at high frequencies phenoxybenzamine decreased the response. These observations agree with those of earlier workers who showed that antiadrenaline substances have more than one property. They not only block the motor effects of adrenaline and noradrenaline, but at the same time they may increase the response to sympathetic stimulation. The observations which have been made are not consistent with the interpretation which has been placed by others on the effect of phenoxybenzamine on the amount of noradrenaline appearing in the splenic vein following sympathetic stimulation; this interpretation assumes that phenoxybenzamine will decrease the response to sympathetic stimulation at low frequency. The mode of action of phenoxybenzamine is discussed, and fresh evidence that it has an anticholinesterase action is given.
THE PART PLAYED BY CALCIUM IN DETERMINING THE RESPONSE TO STIMULATION OF SYMPATHETIC POSTGANGLIONIC FIBRES
Authors: BURN J. H. , GIBBONS W. R.
Published: July 2012

The inhibition of the pendular movements in a loop of rabbit ileum caused by stimulating the periarterial nerves in the mesentery depends on the calcium concentration in the bathing fluid. The inhibition is small when the concentration is low, and increases as the concentration rises. In the lower ranges of calcium concentration there is rarely any change in the response to noradrenaline, so that the increase in inhibition is due to an increase in the amount of noradrenaline released. The effect of calcium is antagonized by magnesium. In the presence of hyoscine, nicotine inhibits the ileum, and this inhibition also depends on the concentration of calcium. Acetylcholine can sometimes be shown to cause inhibition, and again this inhibition depends on the concentration of calcium. These and other experiments show a close similarity between the release of catechol amines from the adrenal medulla by acetylcholine and the release of noradrenaline from the postganglionic fibre by stimulation or by nicotine. In both instances the calcium concentration plays a decisive part.
THE SYMPATHETIC POSTGANGLIONIC FIBRE AND THE BLOCK BY BRETYLIUM; THE BLOCK PREVENTED BY HEXAMETHONIUM AND IMITATED BY MECAMYLAMINE
Authors: BURN J. H. , GIBBONS W. R.
Published: July 2012

Acetylcholine, in the presence of atropine, has an action like that of sympathetic stimulation. When injected into the splenic artery it causes contraction of the spleen, but this action is blocked by hexamethonium; stimulation of the splenic nerves, however, is still effective. Thus hexamethonium distinguishes between sympathetic nerve stimulation and the action of acetylcholine. If bretylium is used instead of hexamethonium, there is no such distinction, for bretylium blocks the response to nerve stimulation as well as that to acetylcholine. It appeared that hexamethonium might block the action of acetylcholine by preventing its entry into the sympathetic fibre. Acetylcholine has some structural similarity to bretylium, since acetylcholine is a derivative of trimethylammonium and bretylium is a derivative of dimethylethyl‐ammonium. It has been found that hexamethonium, pentolinium and hemicholinium (HC‐3), which are all bis‐quaternary compounds, block the action of bretylium, presumably by preventing its entry into the fibre. Consistent with the view that ability to enter the fibre is important is the observation that mecamylamine and pempidine, which are ganglion‐blocking agents, but not either mono‐ or bis‐quaternary compounds, often abolish the response to stimulation of the sympathetic postganglionic fibre.
THE EFFECTS OF PHYSOSTIGMINE ON THE MECHANICAL AND ELECTRICAL RESPONSES OF THE CAT NICTITATING MEMBRANE
Authors: BOWMAN W. C. , CALLINGHAM B. A. , CUTHBERT A. W.
Published: July 2012

The effects of physostigmine on the electrical and mechanical responses of the nictitating membrane elicited by single nerve shocks have been studied in cats anaesthetized with a mixture of chloralose and pentobarbitone. The results were variable but the most consistent effect, observed with large doses of physostigmine, was a depression and prolongation of the contractions which was sometimes associated with augmentation of the characteristic rhythmic electrical activity of the smooth muscle. Although the amplitude of single responses was depressed, incomplete tetanic contractions were sometimes increased in tension because of the greater fusion which occurred as a result of prolongation of the units of contraction. Possible mechanisms underlying the effect of physostigmine are discussed.
THE MEASUREMENT OF ANALGESIC PROPERTIES OF INHALATION DRUGS GIVEN IN SUB‐ANAESTHETIC CONCENTRATIONS
Authors: NEAL M. J. , ROBSON J. M.
Published: July 2012

An electrical method of testing for analgesia in mice has been developed for use with inhalation anaesthetics given in sub‐anaesthetic concentrations. The anaesthetic drugs are administered in a gas chamber designed for the testing of analgesia without removal of the animals from the chamber.
THE ANALGESIC PROPERTIES OF SUB‐ANAESTHETIC DOSES OF ANAESTHETICS IN THE MOUSE
Authors: NEAL M. J. , ROBSON J. M.
Published: July 2012

Trichlorethylene in a sub‐anaesthetic concentration (0.5% v/v in oxygen) has an analgesic effect on mice, which develops slowly and reaches a maximum roughly equivalent to that produced by 5 mg/kg of methadone hydrochloride given by intraperitoneal injection. Ethyl chloride causes analgesia in sub‐anaesthetic concentrations (3%) but is much less potent than trichlorethylene. Halothane (0.75%) produces slight but definite analgesia. Cyclopropane and diethyl ether have no appreciable analgesic effect. Concentrations of nitrous oxide (up to 90%) in oxygen lack any observable analgesic action on the mouse. Trichlorethylene is considerably potentiated by nitrous oxide, its anaesthetic rather than its analgesic action being affected. Nitrous oxide (40%) potentiates the analgesic rather than the anaesthetic action of halothane (0.75%). However, increasing the concentration of nitrous oxide to 60% causes the anaesthetic action of halothane to predominate.
MODIFICATION OF THE EFFECTS OF GUANETHIDINE ON CARDIAC CATECHOL AMINES BY VARIOUS AGENTS
Authors: BHAGAT B.
Published: July 2012

A study has been made of the effect of injections of guanethidine in rats, in depleting catechol amines from the whole cardiac ventricles and from various subcellular fractions. Unlike reserpine, guanethidine first affected the concentration of the amines in the soluble fraction of the cell. Neither [2‐(2,6‐dimethylphenoxy)‐propyl]trimethylammonium chloride monohydrate (β‐methyl xylocholine) nor hemi‐cholinium affected the endogenous catechol amines or the uptake of injected noradrenaline, but each significantly reduced the action of guanethidine in depleting catechol amines. Administration of choline chloride after hemicholinium reversed its influence on guanethidine depletion. In cats, cocaine potentiated the pressor response to noradrenaline, but antagonized the response to tyramine and guanethidine, while bretylium and N‐o‐chlorobenzyl‐N'N“‐dimethylguanidine sulphate (BW392C60) potentiated the responses to noradrenaline, tyramine and guanethidine.
SOME PHARMACOLOGICAL PROPERTIES OF URIDINE NUCLEOTIDES
Authors: SMITH M. W.
Published: July 2012

Uridine di‐, tri‐ and monophosphates (UDP, UTP and UMP) contracted the goldfish intestine preparation in that order of decreasing potency. Adenosine triphosphate (ATP) sensitized the gut to UTP and UDP but not to UMP. The fluoro‐derivatives of UMP and UTP behaved like the unsubstituted nucleotides on the goldfish intestine but the main effect of 6‐azaUDP and large amounts of uracil and uridine was to cause a relaxation. Structure‐action relationships are discussed on the basis of these findings. UDPglucose and UDPacetylglucosamine each contracted the goldfish intestine but they were 500‐times less active than UDP. Other smooth muscle preparations (tortoise jejunum, rat uterus, guinea‐pig ileum and the fowl rectal caecum) contracted to UTP and UDP, but large amounts were needed. The cardiovascular effects in rats of UMP, UDP and UTP were complex and mediated mainly through an action on the peripheral blood vessels. In rats treated with phenoxy‐benzamine, UMP raised the blood pressure while UDP and UTP first lowered then raised the blood pressure. The fall in blood pressure was not abolished by pronethalol or atropine. The uridine phosphates affected the. rat isolated heart only under hypoxic conditions. UTP and UDP dilated the blood vessels of the rabbit ear and UTP was six‐times more effective than ATP. UTP and UDP were equiactive in increasing the force of beat of the frog isolated heart. UMP also had an effect if large amounts were given.
QUANTITATIVE STUDIES OF THE ANTAGONISM BY NALORPHINE OF SOME OF THE ACTIONS OF MORPHINE‐LIKE ANALGESIC DRUGS
Authors: COX B. M. , WEINSTOCK MARTA
Published: July 2012

A quantitative investigation has been made of the antagonism by nalorphine of the analgesia and lenticular opacity produced in mice by a number of compounds. ED50 values have been obtained for each drug in the absence and in the presence of increasing doses of nalorphine, and from these, appropriate dose‐ratios have been calculated. It has been possible to derive the equivalent of a pA2 value for each drug with nalorphine and, since these are almost identical, it may be concluded that all the drugs combine with similar receptors. Nalorphine antagonizes both actions by competing for the receptors. It was not possible to antagonize quantitatively the analgesic action of pethidine with nalorphine, although the lenticular effect could be abolished. The effect of nalorphine on the change in skin temperature in mice induced by some of the analgesic drugs was also investigated.
THE ACTION OF SODIUM 4‐HYDROXYBUTYRATE ON SPINAL REFLEXES
Authors: BASIL B. , BLAIR A. M. J. N. , HOLMES S. W.
Published: July 2012

The actions of sodium 4‐hydroxybutyrate, γ‐aminobutyric acid and meprobamate have been studied in unanaesthetized animals, in local anaesthetic tests, on isolated organ preparations, on convulsions induced by picrotoxin and strychnine, and on monosynaptic (patellar) and polysynaptic (plantar) reflexes of the spinal cord. Sodium 4‐hydroxybutyrate induced a sleep‐like state with three unusual features: the righting reflex was remarkably persistent, respiration was good throughout and recovery was abrupt. γ‐Aminobutyric acid was inactive and meprobamate caused flaccid paralysis with loss of the righting reflex. None of the agents affected the responses of the rat diaphragm either to direct stimulation of the muscle or to indirect stimulation through the phrenic nerve. Only meprobamate reduced the responses of the guinea‐pig isolated ileum preparation, showed local anaesthetic action and had an anticonvulsant action. All three compounds were capable, after intravenous or topical application, of blocking plantar reflexes in doses which did not affect the patellar reflex. The spinal animal responded in the same way, to the same dose of sodium 4‐hydroxybutyrate, as the decerebrate preparation. Topical application to the motor cortex had no effect on spinal reflexes. We conclude that sodium 4‐hydroxybutyrate acts preferentially on the internuncial neurones in the spinal cord but differs from meprobamate in its other actions. The similarity between the actions of sodium 4‐hydroxybutyrate and of γ‐aminobutyric acid provides further evidence in support of the hypothesis that sodium 4‐hydroxybutyrate is involved in the γ‐aminobutyric acid metabolic pathways.
COMPARISON OF THE EFFECTS OF BRETYLIUM, GUANETHIDINE AND BETHANIDINE ON SMOOTH MUSCLE RESPONSES TO DIFFERENT RATES OF SYMPATHETIC NERVE STIMULATION
Authors: GREEN A. F. , ROBSON R. D.
Published: July 2012

The relative effects of bretylium, guanethidine and bethanidine on smooth muscle responses to different rates of sympathetic nerve stimulation have been compared. The responses studied were vasoconstriction in the femoral vascular bed and contraction of the spleen in anaesthetized cats, vasoconstriction in perfused ears of rabbits and inhibition of pendular movements in rabbit isolated ileum preparations. Except in the isolated ileum, the action of bretylium on curves relating the frequency of nerve stimulation and the effect on response was different from that of guanethidine. Whereas bretylium caused relatively greater inhibition of responses to high stimulus frequencies and depressed the slopes of the curves, guanethidine preferentially suppressed responses to low stimulus frequencies and caused roughly parallel shifts of the curves. In each situation tested bethanidine was the most potent of the three blocking agents and in general its effect on frequency/response curves was intermediate between those of bretylium and guanethidine.
INFLUENCE OF METHYLDOPA ON CENTRAL EFFECTS OF RESERPINE
Authors: BENFEY B. G. , VARMA D. R.
Published: July 2012

Methyldopa potentiated hypnosis due to hexobarbitone in mice, as did reserpine, chlorpromazine and 5‐hydroxytryptamine. Methyldopa antagonized the increase by reserpine of sleep due to hexobarbitone, but enhanced the potentiation by chlorpromazine and 5‐hydroxytryptamine of hypnosis due to hexobarbitone. The sedative effect of reserpine in mice and the emetic effect in pigeons were also antagonized by methyldopa. However, the effects of reserpine on convulsions due to leptazol and in causing ptosis were not antagonized by methyldopa. It is suggested that some effects of reserpine (potentiation of hexobarbitone‐sleeping time, sedation and emesis) are unrelated to changes in brain amine levels and that methyldopa, with its weak reserpine‐like actions, is an antagonist to reserpine.
POTENTIATION OF THE ACTION OF BRADYKININ ON SMOOTH MUSCLE BY CHYMOTRYPSIN, CHYMOTRYPSINOGEN AND TRYPSIN
Authors: EDERY H.
Published: July 2012

Chymotrypsin, chymotrypsinogen and trypsin sensitized the guinea‐pig isolated ileum and rat isolated uterus preparations to the action of bradykinin, whilst the responses to histamine, acetylcholine and 5‐hydroxytryptamine were unaffected. Chymotrypsin caused a quick contraction of the guinea‐pig ileum which was abolished by mepyramine and therefore probably mediated by histamine. Trypsin contracted the rat uterus as well as the guinea‐pig ileum; the latter contraction was slow, resistant to mepyramine and gave rise to tachyphylaxis. It is suggested that isolated smooth muscle preparations should be treated with chymotrypsin for use in the estimation of minute amounts of bradykinin.
The interaction between angiotensin and sympathetic vasoconstriction in the isolated artery of the rabbit ear
Authors: DAY M. D. , OWEN D. A. A.
Published: July 2012

. Infusions or injections of angiotensin into the isolated ear artery preparation of the rabbit produced only feeble vasoconstrictions and depressed the sensitivity of the preparation to sympathetic stimulation, tyramine and noradrenaline.

. The anti‐sympathetic effect of angiotensin was not prevented or reversed by noradrenaline or cocaine.

. The vasoconstrictor response to angiotensin was usually markedly increased during sympathetic stimulation or other procedures which liberate endogenous noradrenaline (for example, infusion of tyramine), but not when the perfusion pressure was raised by increasing the flow rate or by infusing noradrenaline.

. The vasoconstrictor action of tyramine was also potentiated by sympathetic stimulation.

. The potentiation by sympathetic stimulation of the responses to angiotensin was prevented by reserpine, guanethidine and phentolamine in concentrations which abolished sympathetic vasoconstriction.

. It is suggested that angiotensin facilitates the release of endogenous noradrenaline and owes part of its vasoconstrictor activity to this property.
The Schultz—Dale reaction of the depolarized guinea‐pig uterus
Authors: ARONSON A. S.
Published: July 2012

. The sensitized guinea‐pig uterus contracted on addition of antigen (egg‐albumin), even after it had been completely depolarized in an isotonic potassium sulphate solution.

. The contractile response of the depolarized preparation started at a later time after addition of the antigen, and had a smaller amplitude, than the Schultz—Dale contraction induced in the ordinary Ringer solution.

. A contracting substance was released from the depolarized uterus. The average histamine equivalent of this substance was 89% of the histamine concentration which reproduced the anaphylactic contraction and probably proportional to the mechanical response.

. The main component of the material released from the uterus in the ordinary Ringer was histamine. The material released from the depolarized uterus did not contain any demonstrable histamine activity.
The effect of central stimulant drugs on acetylcholine release from rat cerebral cortex
Authors: HEMSWORTH B. A. , NEAL M. J.
Published: July 2012

. The effects of central stimulant drugs injected intraperitoneally were examined on the release of acetylcholine (ACh) from the cerebral cortex of the anaesthetized rat. The effects of the drugs in increasing ACh release were approximately parallel to the increases produced in the electrical activity of the brain.

. Leptazol in a dose of 150 mg/kg increased the release of ACh by 2.9 times the resting release and in a dose of 300 mg/kg by 7.5 times; on the e.e.g. the injection produced a large increase in the electrical activity.

. Picrotoxin in a dose of 12 mg/kg increased the release of ACh by 7.5 times and on the e.e.g. caused a large increase in activity.

. Strychnine in doses of 8 mg/kg and 12 mg/kg increased the release of ACh by 2.0 and 2.4 times and produced a small increase in the activity of the e.e.g.

. Dexamphetamine in a dose of 100 mg/kg increased the release of ACh by 1.9 times and had no appreciable effect on the e.e.g.

. Nikethamide in a dose of 2 g/kg increased the release of ACh by 2.3 times and produced no appreciable change in the e.e.g.

. Caffeine in a dose of 100 mg/kg produced no significant effect on the release of ACh.
Further studies on the histidine‐histamine relationship in vivo: effects of endotoxin and of histidine decarboxylase inhibitors
Authors: REILLY MARGARET A. , SCHAYER R. W.
Published: July 2012

. Mice were injected with (14C)‐l‐histidine, killed at various intervals, and tissues assayed for (14C)‐histamine. In some cases free (14C)‐l‐histidine and total (14C) were also determined.

. Removal of stomach, the most active histamine‐forming tissue, failed to reduce the (14C)‐histamine content of any tested tissue; (14C)‐histamine concentrations in lung and muscle of gastrectomized mice were higher than in sham‐operated controls.

. In mice pretreated with endotoxin and subsequently injected with (14C)‐l‐histidine, the (14C)‐histamine content of liver, lung and muscle was markedly higher than in controls. The increased concentrations of (14C)‐histamine in endotoxin‐pretreated mice seemed to reflect a greater rate of formation; they could be attributed neither to changes in tissue concentration of (14C)‐l‐histidine, to increased uptake from other tissues, nor to impaired ability to inactivate histamine.

. Results of studies on in vivo effectiveness of several histidine decarboxylase inhibitors are reported.

. The following conclusions are supported by the evidence presented: (a) in stressed mice, those tissues which show activation of histidine decarboxylase also show increased ability to form histamine in vivo; (b) tissue histamine is largely formed locally; (c) histidine decarboxylase inhibitors are highly effective in blocking histamine formation in mast cells and in stomach, but do not normally reach the locus of an inducible form of histidine decarboxylase; (d) the inducible form of histidine decarboxylase in liver may be located in phagocytic microvascular endothelial cells; (e) in conditions favouring near‐maximal activation of histidine decarboxylase, the histamine‐methylating enzyme of liver and diamine oxidase of intestine showed no inducible characteristics; (f) blood histamine concentrations do not accurately reflect changes in tissue histamine formation.
The binding of 3H‐digitoxigenin by guinea‐pig atrial tissue
Authors: KUSCHINSKY K. , LÜLLMANN H. , van ZWIETEN P. A.
Published: July 2012

. The uptake and release of 3H‐digitoxigenin by electrically driven, guinea‐pig isolated atria (frequency 180/min) has been determined for two different medium concentrations of the genin. Both concentrations—1 × 10−7 and 5 × 10−7 g/ml.—caused a pronounced increase in contractile force.

. The uptake of 3H‐digitoxigenin reached equilibrium after approximately 2 hr of incubation. At equilibrium, the tissue/medium radioactivity ratio reached a value of about 8 for both concentrations studied. After initial saturation of the atria with 3H‐digitoxigenin, approximately 60% of the accumulated genin was released on wash‐out in genin‐free Tyrode solution for 2 hr.

. After presaturation of the atria with equimolar concentrations of either digitoxigenin or digitoxin (both non‐radioactive) the uptake of 3H‐digitoxigenin occurred more slowly. After 2 hr of incubation approximately 60–70% of the tissue bound digitoxigenin or digitoxin had exchanged against 3H‐digitoxigenin from the medium. Presaturation of the atria with ouabain in equimolar concentration did not significantly affect the uptake of 3H‐digitoxigenin.

. The release process of 3H‐digitoxigenin was not affected by the same concentration of non‐radioactive digitoxigenin as used for the accumulation of the genin.

. The kinetic properties of 3H‐digitoxigenin, determined by means of isotope techniques, are very similar to those of 3H‐digitoxin. The discrepancy between kinetic and pharmacological behaviour is, however, much larger for digitoxigenin than for digitoxin. Obviously, the presence or absence of the sugar moieties considerably influences the behaviour of the molecule towards the specific receptors, without particularly affecting the binding to unspecific, cellular structures.
Interaction between desipramine, tyramine, and amphetamine at adrenergic neurones
Authors: BRODIE B. B. , COSTA E. , GROPPETTI A. , MATSUMOTO C.
Published: July 2012

. Small doses of tyramine (10 μg/kg intravenously) are taken up by rat heart, which can concentrate the amine 7.3‐fold over the plasma level.

. Desipramine (DMI) blocks the uptake of small doses of tyramine by rat heart, but in doses of 20 mg/kg intraperitoneally, it does not affect the cardiac concentrations of tyramine following 20 mg/kg intramuscularly of the drug. The same dose of DMI prevents the depletion of noradrenaline (NA) elicited by intramuscular injection of tyramine 20 mg/kg.

. DMI prevents the depletion of heart NA elicited by (+)‐amphetamine 5 mg/kg given intraperitoneally to demedullated rats and enhances the heart concentration of amphetamine.

. Liposoluble amphetamine enters sympathetic nerves by simple diffusion. It is suggested that DMI prevents the release of heart NA caused by this indirect sympathomimetic through an action within the adrenergic neurone.
The pharmacological properties of fibrinogen degradation products
Authors: BULUK KAROL , MAŁOFIEJEW MICHAŁ
Published: July 2012

A method of obtaining partially purified products of plasmin degradation of fibrinogen (F.D.P.) is described. The F.D.P. passes through dialysing tubes and does not lose its activity during heating for 15 min at a temperature of 56° C.

In experiments on isolated organs, F.D.P. in small doses potentiates the contractile action of bradykinin, kallidin, angiotensin, histamine, 5‐hydroxytryptamine, acetylcholine, adrenaline and noradrenaline. In high concentrations, F.D.P. induces an increase in initial tonus of the smooth muscles and simultaneously lowers the sensitivity of the smooth muscles to the action of the pharmacologically active substances mentioned.

A similarity in the effect of different concentrations of KC1 and different concentrations of F.D.P. on the contractile reaction of the guinea‐pig intestine to constant doses of histamine and bradykinin and on the initial tonus of the smooth muscles is observed.

A hypothesis is presented that F.D.P. in small doses potentiates the contractile action of amines and polypeptides on the smooth muscles and in larger doses increases the initial tonus of these muscles by changing the concentration of the cell electrolytes.
Influence of rat plasma and of various cations on the anti‐eledoisin activity of morin
Authors: GASCON A. L.
Published: July 2012

The musculotropic activity of eledoisin on the isolated guinea‐pig ileum is antagonized by morin, a flavonoid derivative.

The anti‐eledoisin activity of morin is abolished by fresh rat plasma and by deproteinized rat plasma, but not by deionized plasma.

Cupric acetate can restore the inhibitory property of the deionized plasma and can also inactivate morin.

This effect of rat plasma and of cupric acetate is inhibited by (–)‐penicillamine and by N‐acetyl‐(±)‐penicillamine.

It is concluded that, when in contact with rat plasma, morin is probably inactivated as a consequence of the formation of a complex with the plasma copper.