bluuebunny/crossref_metadata_2025 huggingface dataset:
Drug receptor sites in the rabbit saphenous nerve
Authors: WATSON P. J.
Published: July 2012

. The actions of acetylcholine, carbachol, methacholine, pilocarpine, nicotine, tetramethylammonium, 1,1‐dimethyl‐4‐phenylpiperazinium, histamine, 5‐hydroxytryptamine, angiotensin, bradykinin and potassium chloride were investigated on the sensory endings of the rabbit saphenous nerve.

. By means of specific antagonists the presence of separate receptor sites sensitive to acetylcholine, histamine, 5‐hydroxytryptamine and bradykinin were demonstrated.

. The cholinoceptive receptors were shown to be predominantly nicotinic, but there was evidence of the existence of at least a small population of muscarinic receptors.

. Catecholamines of both α and β types exhibited some stimulatory activity on administration. It is unlikely that this was due to either vasomotor effects or to any action involving the arrectores pilorum muscles.

. The α‐receptor stimulants modified the response to acetylcholine in a biphasic way. There was a brief enhancement of effect followed by a more prolonged depression. β‐receptor stimulation only produced a prolonged enhancement of acetylcholine‐evoked activity.

. The discharge generated by acetylcholine was augmented by anticholinesterases and blocked by ganglion blocking agents. None of these drugs in reasonable doses affected the response to stroking the fur. The results therefore support earlier evidence against a sensory cholinergic synaptic link.
A method for investigating the effects of drugs on the exploratory behaviour of mice
Authors: SHILLITO ELIZABETH E.
Published: July 2012

. Exploratory behaviour in mice was observed when they were put on a wooden board to which twelve tunnels were fixed. The number of different tunnels entered (indicating exploration) and the total entries into tunnels were recorded over 5 min on 2 successive days.

. Untreated mice entered more different tunnels in the first minute on the second day on the tunnel board, and this difference in behaviour was taken as an indication that exploration had occurred on the first day. When the behaviour of the treated mice on the second day was similar to that of inexperienced mice on the first day it was inferred that drug treatment had adversely affected exploration.

. Haloperidol 4 mg/kg, chlorpromazine 8 mg/kg and thioridazine 16 mg/kg adversely affected exploration at doses which almost immobilized the mice.

. Amphetamine at 8 mg/kg disrupted exploratory behaviour in the mice, although the mice were observed to move round the board very quickly.

. With tranylcypromine 2 mg and nialamide 100 mg, increased exploratory behaviour by comparison with controls was recorded in the mice when they were tested 24 h after drug treatment.

. Imipramine at 20 mg/kg reduced the total number of tunnels entered by the mice on the first day, but on the second day the mice behaved in a similar way to mice treated with monoamine oxidase inhibitors.
Ascorbic acid deficiency and pituitary adrenocortical activity in the guinea‐pig
Authors: HODGES J. R. , HOTSTON R. T.
Published: July 2012

. Guinea‐pigs kept on a diet deficient in ascorbic acid lost weight and became moribund in about 24 days.

. The adrenal ascorbic acid concentration fell rapidly during the first 2 weeks, and the plasma corticosteroid concentration and 17‐oxogenic steroid excretion rose sharply in the third week of ascorbic acid deficiency.

. Both histamine and corticotrophin increased the plasma corticosteroid concentration when injected during the second week but failed to change the pre‐existing high concentration of the steroid in the third week of ascorbic acid deficiency.

. The observations confirm that ascorbic acid is not involved in corticoidogenesis and that scurvy is a severe stress which increases adrenocortical activity to such an extent that the rate of synthesis of corticosteroids is incapable of matching the rate of their release.
The relationship between the level of cholinesterase in plasma and the action of suxamethonium in animals
Authors: HOBBIGER F. , PECK A. W.
Published: July 2012

. The neuromuscular blocking action of suxamethonium, given by intravenous injection, and the effect upon it of iso‐OMPA (tetraisopropyl pyrophosphoramide) in doses which produced marked selective inhibition of cholinesterase in blood were studied in anaesthetized rats and cats, and in mice.

. In cats experiments were also carried out in which suxamethonium was given by intravenous infusion until an effect which remained constant with time was achieved. From the degree of neuromuscular block (under equilibrium conditions) obtained with different infusion rates the infusion rate for 50% reduction in twitch tension of the indirectly stimulated soleus and gastrocnemius muscles (IR50) was calculated. The effect on it of raising the suxamethonium hydrolysing capacity of blood and of selectively reducing the level of cholinesterase in blood by various doses of iso‐OMPA was then investigated.

. At relevant stages of each experiment cholinesterase activity in blood was determined with butyrylcholine or benzoylcholine and where appropriate with suxamethonium as substrate.

. The results obtained show that in rats and cats the effectiveness of suxamethonium is unrelated to the level of cholinesterase activity in blood and that raising the suxamethonium hydrolysing capacity in the blood up to 22‐fold (in cats) only reduces the IR50 by a factor of 1.6.

. The enhancement of the effectiveness of suxamethonium in the three species (2‐ to 3‐fold in rats, 2‐ to 4‐fold in mice and 7‐ to 8‐fold in cats under the conditions used for comparison) which follows the administration of iso‐OMPA is attributable to inhibition of cholinesterase in the tissues.

. It is concluded that the results obtained clearly indicate that the species studied do not give information as regards suxamethonium and its metabolism which is applicable to man.
A simple method for measuring a picogram of acetylcholine using the clam (Mya arenaria) heart
Authors: COTTRELL G. A. , POWELL B. , STANTON M.
Published: July 2012

. A simple and reliable method is described for assaying 1 pg or less of acetylcholine (ACh) using a strip of clam (Mya arenaria) heart.

. Clam heart preparations generally are extremely selective for ACh. The preparation described is at least 105 times less sensitive to the following: acetyl coenzyme A, adrenaline, choline, dopamine, γ‐aminobutyric acid, glutamic acid, histamine, 5‐hydroxytryptamine and noradrenaline.

. Because this preparation is one of the most sensitive known for detecting ACh, it should prove useful for assaying particularly low levels of this substance in biological extracts.
Effects of angiotensin and noradrenaline on discharge in fibres of the cervical sympathetic nerve in cats and dogs
Authors: MORRISON J. F. B. , PICKFORD MARY
Published: July 2012

The effects of angiotensin and noradrenaline on discharge frequency in single and few‐fibre preparations of the cervical sympathetic nerve of cats and dogs have been compared.

When equal changes in blood pressure were produced by intravenous infusion of these drugs, the changes found in sympathetic discharge were similar both in anaesthetized animals and in a decerebrate one.

Angiotensin and noradrenaline also have similar effects on discharge in sympathetic nerve fibres following complete denervation of the baroreceptor and chemoreceptor nerves.

It is concluded that when the blood pressure is raised to 200 mmHg by angiotensin, the drug has no central stimulant action on the sympathetic nervous system.
Pyrrolizidine alkaloids: actions on muscarinic receptors in the guinea‐pig ileum
Authors: POMEROY A. R. , RAPER C.
Published: July 2012

Eleven pyrrolizidine alkaloids have been tested on the isolated guinea‐pig ileum preparation.

Platyphylline, supinine, heleurine and cynaustraline were more potent in antagonizing responses to acetylcholine and carbachol than responses to histamine. Their anticholinergic activity appeared to involve a competitive mechanism.

Lasiocarpine, monocrotaline, spectabiline, sarracine, 7‐angelylheliotridine, heliotrine and senecionine had similar antagonistic potencies against responses to both acetylcholine and histamine.

The alkaloids had no appreciable activity as antagonists of acetylcholine in the isolated toad rectus abdominis preparation.

These results are discussed with respect to interactions of the alkaloids at receptor sites involved in anticholinergic activity at the muscarinic receptor.
Hypothermia produced in mice by histamine acting on the central nervous system
Authors: SHAW GRAHAM G.
Published: July 2012

In mice 1–10 μg histamine injected intraventricularly produces hypothermia.

This hypothermia was not antagonized by chlorcyclizine administered subcutaneously or intraventricularly, but chlorcyclizine injected intraventricularly was effective in antagonizing the hypothermia produced by a subcutaneous injection of histamine.

Pretreatment with atropine was without effect on the hypothermia produced by an intraventricular injection of 10 μg histamine.

Amphetamine and tranylcypromine not only effectively reduced the intensity of, or abolished, the hypothermia but also reversed the response to an intraventricular injection of 10 μg histamine so that hyperthermia was produced. Pargyline was without effect.

Tolazoline strongly potentiated the hypothermia produced by the intraventricular injection of 10 μg histamine, but phentolamine did not.

It is concluded that at least part of the hypothermia produced by a subcutaneous injection of histamine arises as a result of an action on the central nervous system.

The possible mechanisms by which histamine acting on the central nervous system produces hypothermia and the suggestion that histamine may have a physiological role in thermoregulation are discussed in the light of these findings.
Effect of electrical stimulation and high potassium concentrations on the efflux of [14C] glycine from slices of spinal cord
Authors: HOPKIN JUDY , NEAL M. J.
Published: July 2012

The effects of electrical stimulation and solutions containing a high concentration of potassium on the efflux of [14C] glycine from slices of rat spinal cord have been studied.

Slices of cord were incubated with [14C] glycine which rapidly accumulated in the tissue. The slices were then superfused in a small chamber and the radioactivity released from the tissue was measured. After superfusion for 60 min, 98% of the radioactivity remaining in the tissue was present as unchanged glycine.

The spontaneous efflux of [14C] glycine consisted of an initial rapid phase followed by a much slower release of [14C] glycine. After superfusion for 60 min, more than 65% of the radioactivity taken up during the incubation period was retained by the tissue.

When the slices were depolarized by electrical stimulation or by solutions containing a high concentration of potassium (40 mm), a striking increase in the efflux of [14C] glycine was produced. This effect was not reduced by the absence of calcium ions in the superfusion medium.

Electrical stimulation produced similar increases in the efflux of [3H] GABA and [14C] glutamate from slices of cord but had no significant effects on the efflux of [3H] alanine or [14C] urea.

The results are consistent with the suggestion that glycine may be an inhibitory synaptic transmitter substance in the mammalian spinal cord.
Modification of the vascular response to isoprenaline by cholinomimetic drugs
Authors: HAMILTON T. C.
Published: July 2012

Pilocarpine and other cholinomimetic drugs convert isoprenaline to a vasoconstrictor and pressor agent.

This effect of pilocarpine was abolished by atropine; it is thus an acetylcholine‐like response. It was not dependent on the integrity of the central nervous system or the adrenal glands and was not abolished by ganglionic blockade.

The constrictor action of isoprenaline after pilocarpine was abolished by propranolol; this action of isoprenaline is thus on the β‐adrenoceptor. Another β‐adrenoceptor stimulating agent, salbutamol, resembled isoprenaline in this situation, though papaverine and acetylcholine did not.

The constrictor action of isoprenaline after pilocarpine was abolished by phenoxybenzamine, guanethidine and cocaine; the effect did not appear after reserpine pretreatment.

These results suggest an action of cholinomimetic drugs at adrenergic nerve endings which permits the uptake of β‐adrenoceptor stimulating agents resulting in the release of neuronal transmitter.
5‐Hydroxytryptamine metabolism in sheep
Authors: BARTLET A. L.
Published: July 2012

5‐Hydroxytryptamine (5‐HT) (10 mg) administered intravenously to sheep was mostly excreted in the urine as 5‐HT‐O‐glucuronide (705 ± 162 μg, mean from six wethers ± s.e.m.) and 5‐hydroxyindolylacetic acid (5‐HIAA) (6,850 ± 1,538 μg). Oral administration of 5‐HT (100 mg) led to the excretion of 590 ± 212 μg 5‐HT‐O‐glucuronide (mean from five wethers ± s.e.m.) and 7,394 ± 2,093 μg 5‐HIAA in the urine.

After administration of dl‐5‐hydroxytryptophan (dl‐5‐HTP) (20 mg i.v. or 200 mg orally) sheep excreted about 5 mg 5‐HT in the urine together with 5‐HT‐O‐glucuronide and 5‐HIAA. The excretion of 5‐HT suggests that some DL‐5‐HTP perfused the liver and the lungs before being decarboxylated.

Twenty‐four hour specimens of control urine contained 335 ± 45 μg 5‐HT, 909 ± 90 μg 5‐HT‐O‐glucuronide and 3,352 ± 362 μg 5‐HIAA (seven sheep in each instance). Thus endogenous 5‐HT seemed to be conjugated with glucuronic acid to a greater extent than administered 5‐HT.

Although urinary 5‐HIAA was reduced after a single dose of isocarboxazid (20 mg/kg daily) the 5‐HT‐O‐glucuronide content of the specimens was not increased until two or three doses of the drug had been given.

Carbon tetrachloride (4 ml orally) reduced the urinary excretion of 5‐HT‐O‐glucuronide. Although the conjugation of 5‐HT with glucuronic acid was inhibited after administration of carbon tetrachloride the excretion of 5‐HT and 5‐HIAA was not increased. This observation suggests that carbon tetrachloride impaired the formation or clearance of endogenous 5‐HT in sheep.
Blockade of the reticulospinal inhibitory pathway by anaesthetic agents
Authors: FRANK G. B. , OHTA M.
Published: July 2012

Adult cats were decerebrated at the intercollicular level. The effect of the anaesthetic agents, pentobarbitone, paraldehyde, tribromethanol, chloralose and procaine on the reticulospinal inhibitory pathway, which produced inhibition of segmental reflex potentials, was analysed.

The doses which blocked this inhibitory pathway did not exceed the doses required to produce surgical level anaesthesia with any of the drugs.

After the reticular inhibition of the reflex potentials was abolished, the reflex potentials were augmented by reticular stimulation with a higher intensity. This was thought to be due to spread of current to the excitatory pathways which were not completely depressed by the anaesthetic agent.

The resistance of the reticular facilitation of the reflex potentials to inhibition by these drugs after abolition of inhibition corresponded in general to the degree of excitement in intact mice produced by the same drugs.

These findings seem to indicate that the preferential block of the reticulospinal inhibitory pathway may be an important neural mechanism for the excitement stage of anaesthesia.
Effects of isoprenaline and aminophylline on the chronotropic responses of the isolated guinea‐pig heart to vagal stimulation and acetylcholine
Authors: HADHAZY P.
Published: July 2012

In isolated perfused guinea‐pig hearts, isoprenaline (2 × 10−8 g/ml) reduced the negative chronotropic responses to vagal stimulation and to exogenous acetylcholine.

The β‐adrenoceptor antagonist LB46 (2 × 10−8 g/ml) abolished the effect of isoprenaline in reducing vagal bradycardia. LB46 itself did not alter the responses to vagal stimulation.

Increase in 86Rb efflux induced by acetylcholine was not affected by isoprenaline.

Aminophylline (2·3 × 10−4 g/ml) almost abolished the negative chronotropic effect of vagal stimulation.

The ‘antivagal’ effects of isoprenaline and aminophylline may be at a common site beyond the level of the cardiac β‐adrenoceptors, perhaps related to cyclic‐3′,5′‐AMP and/or sodium transport.
Temperature dependence of catecholamine depletion by reserpine in the heart of the toad (Bufo marinus)
Authors: CHANG P. , RAND M. J.
Published: July 2012

The catecholamines in toad ventricle were adrenaline (90%) and noradrenaline (10%); there was no dopamine.

Phenoxybenzamine and tyramine stimulated the isolated heart and reduced the catecholamine content.

Reserpine treatment of toads kept at 20° C did not affect the adrenaline but reduced the noradrenaline content of the ventricle.

At 37° C, reserpine caused depletion of both adrenaline and noradrenaline, and the stimulant actions of phenoxybenzamine and tyramine were lost.
Techniques for measuring histamine formation in mice
Authors: REILLY MARGARET A. , SCHAYER R. W.
Published: July 2012

Formation of 14C‐histamine from 14C‐l‐histidine was studied in mice using various inhibitors of histamine catabolism; these included aminoguanidine, pargyline and methylhistamine, inhibitors of diamine oxidase, monoamine oxidase, and the histamine‐methylating enzyme, respectively.

Four general approaches were used: inhibiting diamine oxidase and the histamine‐methylating enzyme and measuring 14C‐histamine in tissues or urine, or inhibiting diamine oxidase and monoamine oxidase and measuring 14C‐methylhistamine in tissues or urine. In some tests mice with normal concentrations of histidine decarboxylase were used; in others the enzyme was activated by pretreating mice with Freund's adjuvant.

Methylhistamine pretreatment increased 14C‐histamine in several tissues of mice but aminoguanidine had no significant effect; it was concluded that endogenously formed histamine is inactivated almost entirely by methylation.

There was no evidence of parallelism between the ability of tissues to form histamine and to inactivate endogenous histamine.

Effects of Freund's adjuvant on tissue concentrations of 14C‐histamine were tested in mice with or without inhibitors of histamine catabolism. Results were essentially parallel in both cases but higher in the former.

The method of choice is measurement of 14C‐histamine in tissues of mice given aminoguanidine and methylhistamine, followed by 14C‐l‐histidine.

Other approaches listed above may be useful but require improvement, for example, a more specific assay for 14C‐methylhistamine and a stronger, longer‐lasting inhibitor of histamine‐methylation.
In vivo effects of cellulose sulphate on plasma kininogen, complement and inflammation
Authors: EISEN V. , LOVEDAY C.
Published: July 2012

The in vivo action of cellulose sulphate was studied in an attempt to clarify the role of complement and kinin formation in inflammation.

Inflammatory oedema was produced in the rat paw by heat (45·5° C), and on the ear by xylene. The oedema was assessed by comparing the ratio of fresh wet weight to dry weight of corresponding injured and non‐injured parts.

Following cellulose sulphate (6·5 mg/kg i.v.), plasma kininogen concentrations were promptly reduced by 90% or more. The reduction in complement titres was statistically significant and ranged from 17 to 65%. No toxic effects were observed. The oedema caused by heat or xylene was not reduced in these rats.

Cellulose sulphate (80 mg/kg i.p.) given over 3 days depleted plasma kininogen by about 90%, but reduced complement titres only slightly. These rats gained less weight and their condition was poor. Blood clotting was impaired and widespread haemorrhages were found. Heat and xylene produced significantly less oedema than in control rats. This diminished response is attributed to toxic side effects of cellulose sulphate, rather than depleted plasma kininogen and reduced plasma complement.

The results suggest that the inflammatory reactions to thermal and chemical injury can fully develop when plasma kininogen and complement are lowered.
Effect of eserine on the chick biventer cervicis preparation
Authors: BALDWIN D. W. , LESSER E.
Published: July 2012

The relationship between the capacity of the chick biventer preparation, both intact tissue and homogenate, to inactivate acetylcholine and the ability of eserine to increase the sensitivity of the tissue to acetylcholine have been investigated.

At concentrations of eserine of 2·69 × 10−9m and 2·69 × 10−8m the capacity of the whole tissue to inactivate acetylcholine is reduced by 5% and 15% respectively. These concentrations of eserine increase the sensitivity of the preparation to acetylcholine by factors of 2 and 4 respectively, without a change of slope in regression lines.

At concentrations of eserine of 2·69 × 10−7m and 2·69 × 10−6m the capacity of the whole tissue to inactivate acetylcholine is reduced by 40% and 80% respectively, and the sensitivity to acetylcholine increased by factors of 70 and 800 respectively, along with marked increases in the slopes of the regression lines.

An attempt has been made to quantify these differences by proposing a model in which cholinesterase in the tissue is regarded as a network, preventing the access of a large fraction of the acetylcholine to its site of action.

It is suggested that, whereas the increase in sensitivity to acetylcholine at eserine concentrations of 2·69 × 10−9m and 2·69 × 10−8m can be interpreted as an anticholinesterase effect (which is still present at higher concentrations), that seen at the higher concentrations may represent a direct action of eserine on the tissue.

It is further suggested that there are barriers to penetration in intact tissue to both substrate and inhibitor, which invalidate attempts to extrapolate results from homogenates.
Binding of N‐(2‐bromo ethyl)‐N‐ethyl‐N1‐naphthylmethylamine HBr (SY28) to the proteins of guinea‐pig vas deferens
Authors: GRAHAM J. D. P. , MOTTRAM D. R.
Published: July 2012

Vasa deferentia from guinea‐pigs were exposed to 14C‐SY28 HBr (5·32 × 10−6m) washed, lipid extracted, and broken up.

The tissue was digested with papain, hydrolyzed with 6 n HCl, and gel filtration performed.

Aliquots at each stage were used for paper chromatography and autoradiography.

Three labelled spots (in addition to unbound 2‐halogenoalkylamine) were located from acid hydrolysate and a fourth from gel filtrate.

Selected amino‐acids were complexed with 14C‐SY28 and the procedure repeated. The RF values were compared with those of the same amino‐acids with and without 6 n HCl.

Histidine, aspartic acid, arginine and serine gave a significant degree of binding of 14C‐SY28.

The theoretical implications are discussed.
Actions of acetylcholine and carbachol on the chick biventer cervicis muscle
Authors: MARSHALL I. G.
Published: July 2012

The possibility that carbachol may act on the chick biventer cervicis muscle by releasing acetylcholine was investigated.

Log dose‐response curves for acetylcholine and carbachol were constructed in the presence of triethylcholine, tubocurarine and physostigmine, in both innervated and denervated chick biventer cervicis muscles.

The log dose‐response curve for acetylcholine was shallower than that for carbachol and was moved to the left by triethylcholine, indicating potentiation. In the presence of physostigmine, the curve was as steep as that for carbachol, and like that for carbachol was moved to the right by triethylcholine, indicating antagonism. In the presence of tubocurarine, the log dose‐response curves for both acetylcholine and carbachol were moved to the right.

The log dose‐response curves for both acetylcholine and carbachol were moved to the left by chronic denervation, indicating increased sensitivity to these drugs. Both curves were moved similar distances to the right by excess magnesium ion concentration. No tachyphylaxis developed to repeated administration of carbachol in the presence of triethylcholine or tubocurarine, either in innervated or denervated muscles.

It was concluded that the main action of triethylcholine in the chick biventer cervicis muscle is a tubocurarine‐like action, which, in the presence of acetylcholine, is masked by a weak anticholinesterase action. It was also concluded that the diminished response to carbachol in the presence of triethylcholine is due to the postjunctional blocking action of triethylcholine, and that carbachol owes none of its activity to an ability to release acetylcholine from the nerve terminals.
Actions of dexamphetamine and amphetamine‐like amines in chickens with brain transections
Authors: MARLEY E. , STEPHENSON J. D.
Published: July 2012

A method for preparing the encéphale isolé preparation in young fowls is described. Certain important differences were found between electrocortical activity of chicken and mammalian encéphale isolé preparations. Electrocortical effects of excitant sympathomimetic amines and their antagonism were readily quantified because of stable electrocortical activity of the chick encéphale isolé preparation.

Amphetamine‐like excitant amines ((+)‐ and (–)‐amphetamine, α‐methyltryptamine, tryptamine, β‐phenethylamine, cyclopentamine, β‐tetrahydronaphthylamine and tuaminoheptane) evoked electrocortical desynchronization in chick encéphale isolé preparations, confirming the central origin of these effects. Behavioural changes were also observed.

The electrocortical response to these amines was antagonized by methysergide, a selective tryptamine antagonist and by a catecholamine, α‐methyl‐noradrenaline. Behavioural changes were also antagonized.

Electrocortical desynchronization to dexamphetamine was prevented by an anterior transection of the brain which separated the telencephalon from the diencephalon. More posterior transections reduced the duration of the electrocortical response to dexamphetamine; intensity of response was either increased or decreased.
Protection against induction of supersensitivity to catecholamines by cocaine
Authors: INNES I. R. , KARR G. W.
Published: July 2012

Adrenaline, noradrenaline, isoprenaline, tyramine, phentolamine, pronethalol, histamine and acetylcholine were each tested for their ability to prevent cocaine from causing supersensitivity to catecholamines in cat spleen strips in vitro. A high concentration of one of these drugs was added to the bath 5 min before cocaine hydrochloride (10 μg/ml). The effect on subsequent responses to catecholamines was compared with the effect of cocaine in control strips in the absence of an interfering drug.

Phentolamine completely abolished the potentiating effect of cocaine. Large doses of adrenaline or noradrenaline reduced, but did not completely prevent, potentiation. Tyramine, isoprenaline, pronethalol, histamine and acetylcholine did not prevent potentiation.

The ability of these drugs to interfere with potentiation does not correlate well with their ability to interfere with uptake of noradrenaline. Interference with uptake by cocaine is therefore unlikely to account fully for potentiation.
Effects of methysergide on platelets incubated with reserpine
Authors: CUMINGS J. N. , HILTON BARBARA P.
Published: July 2012

Platelets were incubated with methysergide and related compounds (2‐bromo lysergic acid (BOL), ergotamine and methyl ergotamine) together with reserpine.

Methysergide inhibited the normal aggregation response of platelets to 5‐hydroxytryptamine (5HT) but did not affect the reduction in the 5HT content caused by reserpine, or the uptake of 5HT by the platelets.

BOL, ergotamine and methyl ergotamine behaved similarly. Methysergide had greater anti5HT potency than BOL, and methyl ergotamine had greater potency than ergotamine.

The use of platelets as a model for synaptic preparations is discussed.

The role of 5HT receptor sites on the platelet membrane and the significance of the results for migraine patients treated with methysergide are discussed.
Role of noradrenaline and 5‐hydroxytryptamine in tetrahydronaphthylamine‐induced temperature changes in the rat
Authors: BRUINVELS J. , KEMPER G. C. M.
Published: July 2012

Intraperitoneal administration of graded doses of tetrahydronaphthylamine (THN) to rats caused a dose dependent decrease in body temperature.

Intracisternal injection of graded doses of THN induced hypothermia, and implantation of crystalline THN rostral to the medial preoptic area and caudal to the striatum, caused hyperthermia.

Pretreatment of the rats with a MAO inhibitor changed the hypothermia into hyperthermia.

Intraperitoneal injection of 5‐hydroxytryptophan caused a hypothermia which could be reversed into hyperthermia when the rats were pretreated with a MAO inhibitor.

Pretreatment with parachlorophenylalanine enhanced the THN‐induced hypothermia.

Depletion of brain monoamines by Ro‐4–1284 in combination with an inhibition of the biosynthesis of noradrenaline (diethyldithiocarbamate) changed the THN‐induced hypothermia into hyperthermia.

It is concluded that THN affects body temperature in rats by two central mechanisms, viz. a decrease mediated by noradrenaline, probably in the hypothalamus, and an increase which might be mediated by 5‐hydroxytryptamine rostral to the medial preoptic area.
Interaction effects of ethanol and pyrazole in laboratory rodents
Authors: BLUM K. , GELLER I. , WALLACE J. E.
Published: July 2012

Interactions of pyrazole and ethanol were studied in three laboratory test procedures. They included sleeping time in mice, rotor rod balance in rats and lever pressing behaviour of rats.

Equimolar concentrations of pyrazole and 3‐methylpyrazole were compared for effects on enhancement of ethanol's activity on rotor rod holding time of rats.

Minimally effective doses of pyrazole, the LADH inhibitor, and 3‐methylpyrazole, a non‐inhibitor of LADH, when administered before ethanol, resulted in an increased behavioural depression. These interaction effects are probably not caused by inhibition of LADH but rather by an increase in the direct depressant action of either one or both of the compounds.
Drug‐induced changes in the release of [3H]‐noradrenaline from field stimulated rat iris
Authors: FARNEBO L.‐O. , HAMBERGER B.
Published: July 2012

Isolated rat irides were incubated with [3H]‐noradrenaline [3H‐NA] (10−7m), supervised with buffer and then stimulated by an electrical field. The effect of desipramine, clonidine, phentolamine, phenoxybenzamine, GD131, normetanephrine and 4‐tropolone‐acetamide on the stimulation‐induced overflow of [3H]‐NA was tested by adding the drug to the super‐fusing buffer. The effect of pretreatment with phentolamine or phenoxybenzamine on the stimulation‐induced overflow of [3H]‐NA was also studied.

The effect of desipramine, clonidine, phentolamine, phenoxybenzamine and GD131 on uptake of [3H]‐NA in isolated irides was determined.

Desipramine moderately increased the stimulation‐induced overflow at concentrations which almost completely inhibited neuronal uptake. It was calculated that in the isolated rat iris 30–40% of the released [3H]‐NA is inactivated by reuptake into the nerve terminal. This figure may represent the true reuptake percentage in this preparation. Desipramine‐induced inhibition of [3H]‐NA release from the nerve terminal, possibly via a negative feed‐back mechanism, may also contribute to this low figure.

Phentolamine and phenoxybenzamine, in concentrations or doses which did not inhibit neuronal uptake of [3H]‐NA, consistently increased the stimulation‐induced overflow. This increase was further augmented when neuronal uptake was inhibited.

The α‐adrenoceptor stimulating drug clonidine decreased the stimulation‐induced overflow.

GD131, normetanephrine and 4‐tropolone‐acetamide did not greatly affect the stimulation‐induced overflow of [3H‐NA].

It is concluded that the increased [3H]‐NA overflow obtained after α‐adrenoceptor blockade is due to an increased [3H]‐NA release from the nerve terminals.
Neuromuscular blocking activity of a new series of quaternary N‐substituted choline esters
Authors: GINSBURG SARA , KITZ R. J. , SAVARESE J. J.
Published: July 2012

The neuromuscular blocking activity of a new group of mono‐ and diquaternary N‐substituted choline esters of several carboxylic acids has been evaluated in various whole animal preparations in the mouse, rat and cat.

A basic non‐depolarizing mechanism was present in all but one compound—a depolarizing agent, which was studied for comparison. There was evidence of facilitatory activity and nicotinic stimulation in the monoquaternary compounds. These effects were diminished in the diquaternary compounds.

The presence of a bulky aromatic ring system on the nitrogen atom appeared to increase both neuromuscular blocking potency and facilitatory activity in the experimental animal. A similar relationship had previously been demonstrated in vitro in another study.

The duration of action, although short in most compounds, did not correlate well with previously determined in vitro hydrolysis rates, possibly because of species differences.

The general pharmacology of each compound appeared to depend considerably upon the structure of the choline moiety.
Interaction of albumin and fusidic acid: Appendix on interaction of albumin and fusidic acid
Authors: GÜTTLER F. , TYBRING L. , ENGBERG‐PEDERSEN H.
Published: July 2012

By combining the agar plate diffusion technique for determination of antibiotic activity and zone microelectrophoresis in agar gel, the activity of fusidic acid in individual serum proteins of blood and pus obtained from patients given sodium fusidate revealed albumin to be responsible for the protein binding of this antibiotic.

Based on the assumption that only free fusidic acid is microbiologically active, the relationship between the concentration of albumin and the ratio of free to total fusidic acid was determined at four concentrations of free fusidic acid, using as test organisms four differently sensitive variants of a Staphylococcus aureus strain. At each concentration an increasing amount of albumin (0–40 mg/ml culture medium) decreased the activity of fusidic acid as determined in serial dilutions (IC50).

The law of mass action expressed as Langmuir's adsorption isotherm was valid if a correction for the influence of albumin on the sensitivity of the strain of Staph. aureus was introduced. For other test organisms no correction is necessary. The constant in Langmuir's adsorption isotherm was K = 78400 ± 8200 l./mol and n = 3·15 (95% confidence limits: 2·09–5·52).

The mean blood concentration was 20·8 μg/ml and the mean pus concentration 17·2 μg/ml in nineteen sets of blood and pus samples. The ratio of pus to blood corresponds to the ratio of published values for the protein concentrations in serum and in inflammatory oedema.

It is concluded that for albumin bound drugs the ‘storage depot’ of the organism also includes the fluid of the tissue spaces including the inflammatory oedema. As recent studies have revealed an extravascular albumin pool similar in size to the plasma pool, this ‘storage depot’ should not be neglected.
Noradrenaline uptake by non‐innervated smooth muscle
Authors: BURNSTOCK G. , McLEAN J. R. , WRIGHT MARY
Published: July 2012

Uptake of noradrenaline (NA) into the non‐innervated smooth muscle cells of the human umbilical artery and the chick amnion has been studied with the fluorescence histochemical technique for localizing monoamines. Comparison has been made with uptake into sympathetically innervated smooth muscle of the rabbit ear artery.

Accumulation of NA within non‐innervated smooth muscle cells is observed histochemically after exposure to much lower concentrations of NA (10−7 g/ml) than in sympathetically innervated smooth muscle cells, where accumulation occurs with NA (10−5 g/ml).

In contrast to innervated smooth muscle, uptake of NA (10−4 g/ml) by non‐innervated smooth muscle is characterized by lack of inhibition by phenoxybenzamine, normetanephrine and cold, although some inhibition is apparent at lower NA concentrations. Retention of NA during prolonged washing in NA‐free Krebs demonstrates that it is strongly bound within the non‐innervated smooth muscle cells, particularly in the nucleus.

After inhibition of catechol‐O‐methyl transferase, the accumulation of NA in innervated smooth muscle closely resembles that in non‐innervated smooth muscle.
Pharmacology of 4‐hydroxypropranolol, a metabolite of propranolol
Authors: FITZGERALD J. D. , O'DONNELL STELLA R
Published: July 2012

4‐Hydroxypropranolol, a metabolite produced after oral administration of propranolol, has been shown to be a β‐adrenoceptor blocking drug. It is of similar potency to propranolol in antagonizing the effects of isoprenaline on heart rate and blood pressure in cats and against isoprenaline protection of guinea‐pigs from bronchospasm. It is not cardioselective.

In rats depleted of catecholamine 4‐hydroxypropranolol produced an increase in heart rate, suggesting that it has intrinsic sympathomimetic activity.

In anaesthetized dogs 4‐hydroxypropranolol produced a decrease in heart rate and dP/dt and an increase in A‐V conduction time at doses within the range 0·09–1·25 mg/kg. These effects are a result of β‐adrenoceptor blockade. In dogs depleted of catecholamines these same doses produced an increase in heart rate and dP/dt and a decrease in A‐V conduction time. These responses were antagonized by propranolol, and were due to the intrinsic sympathomimetic activity of the compound. At higher doses (5·25 and 13·25 mg/kg) a further dose dependent decrease in heart rate and dP/dt and an increase in A‐V conduction time occurred. This trend was also seen in animals depleted of catecholamines. These changes represent membrane stabilizing activity of 4‐hydroxypropranolol.

4‐Hydroxypropranolol is a potent β‐adrenoceptor blocking drug with both intrinsic sympathomimetic activity and membrane stabilizing activity.
Sleep produced by clonidine (2‐(2,6‐dichlorophenylamino)‐2‐imidazoline hydrochloride)
Authors: HOLMAN R. B. , SHILLITO ELIZABETH E. , VOGT MARTHE
Published: July 2012

The dose of clonidine (given intravenously) required to elicit sleep in the young chick is 1/25th to 1/50th of an equiactive dose of noradrenaline. The approximate ed50 is 001 μmol/kg. Phentolamine (10–15 mg/kg, but not 5 mg/kg) antagonizes the action of both clonidine and noradrenaline.

Intensive treatment with p‐chlorophenylalanine (700 mg/kg for 3–4 days) does not prevent the hypnotic effect of clonidine in the chick, although brain 5‐HT is reduced to 15% of normal. Neither is natural sleep modified.

Sleep after clonidine is not affected by methysergide (0·1–1 μmol/kg, i.m.), but prevented by LSD (0·1–0·3 μmol/kg). The effect of LSD is interpreted as a physiological antagonism.

Clonidine (50 mg/kg) injected intravenously into adult rats causes sleep which is not abolished by phentolamine (5 mg/kg) or by p‐chlorophenylalanine in doses which interfere with natural sleep.

When, per kg body weight, the same dose of clonidine is injected into the lateral cerebral ventricle of rats, sleep ensues in more than half the animals, and persistent eating in about a third; only one of seventeen rats showed no change in behaviour. Eating and sleeping remained unaltered after p‐chlorophenylalanine. The actual dose of clonidine injected into the lateral ventricle was 0·037 μmol, amounting to about 0·15 μmol/kg or 15 times the dose required intravenously in the chick. Noradrenaline 0·15 μmol per (intraventricular) injection caused eating but no sleep, whereas higher doses produced ataxia and paresis.

The work suggests that clonidine does not elicit sleep by an action requiring the integrity of the 5‐HT‐containing neurones arising in the raphé nuclei, and that its action is not on tryptamine receptors. In the chick, sleep appears to be produced by a central sympathomimetic effect; it is possible, but not certain, that this also holds for the rat.

The intravenous hypnotic dose of clonidine for the cat is about the same as that for the rat, but injection is not accompanied by signs of peripheral sympathetic stimulation.
Comparison of the antinociceptive activities of physostigmine, oxotremorine and morphine in the mouse
Authors: PLEUVRY BARBARA J. , TOBIAS M. A.
Published: July 2012

Morphine, oxotremorine and physostigmine showed antinociceptive activity in mice using the hot plate reaction time test.

The action of morphine, but not that of oxotremorine, was antagonized by naloxone and by nalorphine, whereas the effect of physostigmine was unaffected by naloxone and increased by nalorphine.

The antinociceptive effects of morphine and of physostigmine were increased by procedures reported to increase the ratio of 5‐hydroxytryptamine to dopamine in the brain. It was decreased by procedures reported to cause a fall in brain 5‐hydroxytryptamine or a rise in dopamine relative to 5‐hydroxytryptamine.

The antinociceptive effect of oxotremorine was potentiated by procedures reported to decrease brain noradrenaline and was unaffected by procedures altering brain 5‐hydroxytryptamine.

The results suggest differences in the mode of action of morphine and physostigmine on the one hand and of oxotremorine on the other.
Interaction in the cerebral metabolism of the biogenic amines: Effect of intravenous infusion of l‐tryptophan on the metabolism of dopamine and 5‐hydroxyindoles in brain and cerebrospinal fluid
Authors: MOIR A. T. B.
Published: July 2012

In dogs, an intravenous injection of l‐tryptophan followed by intravenous infusion of l‐tryptophan, although unable to maintain stable concentrations of tryptophan in the plasma or cerebrospinal fluid, produced stable, raised concentrations of 5‐hydroxyindol‐3‐ylacetic acid (5‐HIAA) in the cerebrospinal fluid (c.s.f.). This indicated that it was possible to raise the concentrations of the 5‐hydroxyindoles in brain and to maintain the cerebral metabolism in a new steady state.

The regional distribution of the total molal concentration of the 5‐hydroxyindoles in brain after the administration of tryptophan was similar to the distribution found in control animals, thus suggesting the normal rate limiting step of metabolism, the activity of the enzyme tryptophan 5‐hydroxylase, was still the controlling factor.

Tryptophan administration caused a greater proportionate increase in the concentration of 5‐HIAA than in that of 5‐hydroxytryptamine (5‐HT) in all regions of brain, perhaps indicating that the ‘storage’ capacity for 5‐HT becomes filled under these conditions.

Administration of tryptophan caused a large rise in the concentration of homovanillic acid in c.s.f. demonstrating that there was an interaction between the cerebral metabolism of tryptophan and dopamine.
Interaction in the cerebral metabolism of the biogenic amines: Effect of intravenous infusion of l‐tryptophan on tryptophan and tyrosine in brain and body fluids
Authors: MOIR A. T. B.
Published: July 2012

The distribution of the amino‐acids tryptophan and tyrosine has been determined in plasma ultrafiltrate, whole plasma, erythrocytes, cerebrospinal fluid (c.s.f.) and various regions of the brain in dogs.

The effect of tryptophan administration on the distribution of both these amino‐acids showed that the alterations produced in tryptophan concentration did not appear to change the concentrations of tyrosine from their normal pattern.

The implications of these results with regard to amino‐acid transport systems in man and dog are discussed.
Effect of p‐nitromethylamphetamine on biogenic amines and their amino‐acid precursors in rat brain
Authors: LEONARD B. E. , SHALLICE SUSAN A.
Published: July 2012

Low doses of p‐nitromethylamphetamine caused small increases in the concentrations of brain noradrenaline and dopamine in the rat; a dose of 60 mg/kg however, caused a decrease in the concentrations of both amines. p‐Nitromethylamphetamine caused behavioural hyperexcitability only at doses which approximated to half the ld50 (68 mg/kg).

p‐Nitromethylamphetamine potentiated the action of 4,α‐dimethyl‐m‐tyramine in depleting brain noradrenaline. This suggests that it may affect brain noradrenaline concentrations by utilizing a reserpine resistant uptake mechanism.

p‐Nitromethylamphetamine decreased the concentration of brain 5‐hydroxytryptamine.

Changes in the blood and brain concentrations of tyrosine and γ‐amino‐n‐butyric acid concentration in the brain could not be correlated with the changes in brain amines. However, a rise in the concentration of brain tryptophan appeared to be correlated with the fall in brain 5‐hydroxytryptamine.
Interaction between prostaglandins and gonadotrophins in the rabbit ovary
Authors: BEDWANI J. R. , HORTON E. W.
Published: July 2012

It has been suggested that prostaglandins function as feedback modulators of hormonal actions which are mediated by adenosine 3′,5′‐monophosphate (cyclic AMP). This hypothesis has been tested on the rabbit ovary, whose steroidogenic response to luteinizing hormone (LH) is mediated by the cyclic nucleotide.

Prostaglandin E1 (1–100 μg/ml) reduced the production of progesterone by rabbit ovaries incubated in the presence of a submaximal concentration of LH, but had no effect on the formation of this steroid when exogenous cyclic AMP was used as the stimulating agent. The prostaglandin was without effect on the formation of 20α‐hydroxypregn‐4‐en‐3‐one in the presence of either LH or cyclic AMP.

Prostaglandin E2 (1 μg/ml) was without effect on ovarian steroidogenesis in the presence of LH.

There was no evidence that exogenous prostaglandin E1 was inactivated during incubation with rabbit ovaries in the presence of LH.

Prostaglandin E‐like compounds were detected in homogenates of incubated rabbit ovaries. However, concentrations of LH sufficient to stimulate steroidogenesis did not stimulate the synthesis of these compounds by the ovary in vitro, nor their release from the ovary in vivo.

It is concluded that the prostaglandin‐like compounds detected in the ovary are unlikely to play a role in the regulation of steroidogenesis. The results of this investigation do not support the hypothesis that prostaglandins function as general modulators of hormonal actions which are mediated by cyclic AMP.
Monoamine oxidase in sympathetic nerves: a transmitter specific enzyme type
Authors: GORIDIS C. , NEFF N. H.
Published: July 2012

When rat brain or superior cervical ganglion monoamine oxidase was incubated with increasing concentrations of clorgyline, using tyramine as substrate, the inhibition of the enzyme could be represented by a pair of sigmoidal curves joined by a horizontal region where inhibition was constant. Tyramine appeared to be metabolized by two enzymes, one of which was highly sensitive to clorgyline, designated A, whereas the other enzyme, designated B, was less sensitive to clorgyline.

The ratio of A/B activity for brain was 6/4 while in the ganglion it was 9/1.

When the experiments were repeated using noradrenaline as the substrate, the inhibition of the enzyme followed a simple sigmoidal curve where deamination was inhibited by low concentrations of clorgyline as observed with enzyme A.

We conclude that tyramine is deaminated by both A and B enzymes whereas noradrenaline is deaminated only by enzyme A, the enzyme which is most active in the ganglion. Our observations are consistent with the hypothesis that a specific intraneuronal monoamine oxidase plays an important role in the catabolism of noradrenaline in sympathetic nerves.
Preparation and assay of urogastrone, an inhibitor of gastric acid secretion
Authors: LAWRENCE A. J. , SCHILD H. O. , SMITH G. M.
Published: July 2012

Urogastrone, an acid gastric secretion inhibitor extracted from human urine, was assayed in the anaesthetized rat by circulating through its stomach a succinic‐propionic buffer and recording electrometrically the secretion of acid in response to carbachol, and inhibition of carbachol secretion by urogastrone.

Quantitative assay procedures are described requiring the administration of only one or two doses of urogastrone to each rat.

An extraction procedure for urogastrone is described based on the use of zeocarb, a cationic polystyrene resin.

The most purified samples contained 40–80 times the amount/milligram which was just detectable by the assay method.