bluuebunny/crossref_metadata_2025 huggingface dataset:
THE SPECIFICITY OF SOME AGONISTS AND ANTAGONISTS FOR NICOTINE‐SENSITIVE RECEPTORS IN GANGLIA
Authors: BARLOW R.B. , BOWMAN FRANCES , ISON R.R. , McQUEEN D.S.
Published: July 2012

The guinea‐pig isolated ileum has been used to estimate the ability of substituted phenylalkylonium salts (related to nicotine) to stimulate or block receptors in ganglia. The effects of hexamethonium were used to indicate which were the most specific ganglion stimulants; these were tested on the blood‐pressure of pithed rats and for neuromuscular blocking activity on the rat diaphragm preparation.

m‐Hydroxyphenylpropyltrimethylammonium and 3,4‐dihydroxyphenethyltrimethyl‐ammonium (coryneine, ‘quaternary dopamine’) were the most active and specific ganglion stimulants but their usefulness in vivo may be limited by their neuromuscular blocking activity. The analogous tertiary compounds are being investigated.

The affinities of substances which were blocking agents at ganglionic receptors were measured on the isolated ileum with m‐hydroxyphenylpropyltrimethylammonium as agonist. The affinities of selected compounds for postganglionic receptors were measured in experiments on the ileum in the presence of hexamethonium and with carbachol as agonist. Some of the compounds were tested for neuromuscular blocking activity on the rat diaphragm.

Phenylbutyldiethylamine had ganglion‐blocking activity greater than pempidine and little postganglionic blocking or neuromuscular blocking activity. Its triethylammonium analogue had higher ganglion‐blocking activity but had appreciable neuromuscular blocking activity.

The aromatic ring system is not essential either for activity or affinity and the effects of substituents are not related to their effects on electron distribution. Stimulant activity is enhanced only by hydroxyl or amino groups in suitable positions; it is not improved by the presence of rigid features (double or triple bonds or a cyclopropane ring) in the side chain. Affinity is slightly increased by chloro or bromo groups in suitable positions but the unsubstituted compounds are among those with the highest affinity. Substituents have similar effects on affinity for postganglionic receptors, though for these receptors the compounds mostly have only about one‐tenth of their affinity for ganglionic receptors.
BICUCULLINE AND THE FROG SPINAL CORD
Authors: PIXNER D.B.
Published: July 2012

The effects of bicuculline on dorsal and ventral root activity and upon the depressant effect of γ‐aminobutyric acid (GABA) and glycine on ventral root responses have been studied on the isolated spinal cord of the frog.

In the absence of stimulation, the alkaloid induced a variety of activity of which the most notable was phasic simultaneous slow wave depolarization in the dorsal and ventral roots which could be reduced or suppressed by magnesium.

With low concentrations of bicuculline, the adjacent dorsal root response evoked by a single stimulus was depressed maximally before an increase in the ventral root response could be discerned.

The bicuculline‐induced dorsal root activity (in the absence of stimulation) was still apparent at times when the evoked dorsal root response was reduced.

Bicuculline did not differentiate between the depressant effects of GABA and glycine on the evoked ventral root responses.

The excitant effects of bicuculline reported here did not appear to be attributable to specific antagonism of the postsynaptic depressant action of GABA.
MECHANISM OF CATECHOLAMINE ANTAGONISM IN RAT HEART PRODUCED BY PILOCARPINE AND RELATED DRUGS
Authors: SADAVONGVIVAD C. , SANVARINDA P. , SATAYAVIVAD JUTAMAAD
Published: July 2012

High concentrations of pilocarpine and methacholine consistently lowered the potencies of a series of adrenoceptor agonists as shown by displacement of complete cumulative dose‐effect curves for their positive chronotropic action on rat isolated atria. The order of potency of the agonists was characteristic of β‐adrenoceptor activation and this was converted to the type which characterizes α‐adrenoceptor activation when pilocarpine was present.

Propranolol effectively blocked the adrenoceptor agonists in the presence of pilocarpine and phentolamine abolished the antagonistic actions of pilocarpine. Atropine, which by itself did not affect the action of the adrenoceptor agonists, abolished both the bradycardia and antagonism produced by pilocarpine.

It is concluded that pilocarpine antagonizes adrenoceptor agonists by muscarinic cholinoceptor activation without involving classical adrenoceptors.
STIMULATION OF RAT GASTRIC ADENYLATE CYCLASE BY HISTAMINE AND HISTAMINE ANALOGUES AND BLOCKADE BY BURIMAMIDE
Authors: McNEILL J.H. , VERMA S.C.
Published: July 2012

Histamine, 4‐methylhistamine, 3‐(β‐aminoethyl)‐1,2,4 triazole and betazole, in that order, stimulated adenylate cyclase prepared from rat gastric tissue in a dose‐dependent manner. Burimamide, an H2‐receptor blocking agent, in concentrations of 1–5 × 10−6 m antagonized this effect. The data lend some support to the hypothesis that elevated levels of cyclic adenosine 3′,5′‐monophosphate may be involved in histamine‐stimulated gastric secretions and that H2‐receptors are associated with adenylate cyclase.
PHARMACOLOGICAL OBSERVATIONS ON THE HYPOTENSIVE ACTION OF EXTRACTS OF TELEOST FISH UROPHYSES (UROTENSIN I) IN THE RAT
Authors: LEDERIS K. , MEDAKOVIĆ M.
Published: July 2012

Intravenous injections of urotensin I regularly caused a long‐lasting, dose‐related, lowering of blood pressure and an increase in heart rate in conscious rats, or a reduction in perfusion pressure in the isolated hind limb of the rat.

After subcutaneous administration, the hypotensive effect of urotensin I was greater in extent and in duration (> 24 hours).

Anaesthesia with ether, chloralose, pentobarbitone and thiobarbitone caused a decrease in blood pressure and only slightly diminished the hypotensive effect of urotensin.

Mecamylamine, hexamethonium, atropine, phenoxybenzamine, propranolol and diphenhydramine did not alter the effect of urotensin in conscious rats or in the isolated hind limb, although the effects of the respective agonists, i.e. nicotine, acetylcholine, noradrenaline, isoprenaline and histamine were inhibited.

In conscious rats, pressor effects of adrenaline, noradrenaline, nicotine and angiotensin II, and depressor effects of acetylcholine and bradykinin, were decreased or inhibited, whereas the hypotensive effect of phenoxybenzamine was potentiated by previous administration of urotensin I. Carotid occlusion reflex was partially inhibited by lower doses of urotensin and abolished by higher doses in rats lightly anaesthetized with chloralose. Urotensin elicited postural hypotension in rats anaesthetized with pentobarbitone.

The increase in heart rate produced by urotensin was not affected by phenoxybenzamine, but was abolished by propranolol or ganglion blocking agents (mecamylamine or hexamethonium).

It is concluded that urotensin elicits hypotension in the rat by a direct dilatory action on the resistance vessels causing a simultaneous reflex tachycardia.
THE EFFECT OF PHASE‐SHIFT ON THE PASSIVE AVOIDANCE RESPONSE IN RATS AND THE MODIFYING ACTION OF CHLORDIAZEPOXIDE
Authors: DAVIES J.A. , NAVARATNAM V. , REDFERN P.H.
Published: July 2012

In rats trained to a 12 h light‐12 h dark cycle, advancing the phase by 6 h produced a resynchronization of the 24 h variation in passive avoidance response (PAR) which was completed after 10 days.

The attainment of the new steady state was preceded by a period of disruption which was greatest 5 days after phase‐shift.

The presence of chlordiazepoxide (62.5–500 μg/ml) in the drinking water during the days after phase‐shift produced a dose‐dependent lessening of the disruptive effect of phase‐shift, and a more rapid adaptation to the new light‐dark cycle.
EFFECT OF TEMPERATURE ON CHANGES, INDUCED BY OESTRUS, in α‐ AND β‐ADRENOCEPTOR ACTIVITIES OF THE RAT UTERUS
Authors: BUTTERWORTH K.R. , JARMAN D.A.
Published: July 2012

The α‐ and β‐adrenoceptor activities of the isolated rat uterus during the oestrous cycle were influenced greatly by temperature changes. During dioestrus, lowering the bath temperature to 25° C from 40° C increased two‐fold the inhibition produced by (–)‐adrenaline, (–)‐noradrenaline, (–)‐phenylephrine and (–)‐isoprenaline. During oestrus adrenaline, noradrenaline and phenylephrine produced biphasic responses of contraction followed by inhibition at 40° C and isoprenaline produced only inhibition. At 25° C the contractile α‐responses either were abolished (phenylephrine) or greatly reduced (adrenaline and noradrenaline), while the inhibitory β‐effects of all four amines were increased.
FACTORS AFFECTING THE CEREBROVASCULAR RESPONSE TO NORADRENALINE IN THE DOG
Authors: JAMES I.M. , MACDONELL LINDSAY
Published: July 2012

Noradrenaline infused into the internal carotid artery of the dog (0.01–1 μg kg−1 min−1) constricts the blood vessels of the cortex. This constriction is mediated by the action of noradrenaline on α‐adrenoceptors of the cerebral arteries.

Intravenous (1 μg kg−1 min−1) or intra common carotid arterial (0.01–1 μg kg−1 min−1) infusions of noradrenaline cause an increase in cortical blood flow that can be dissociated from changes in blood pressure.

The effect of intravenous noradrenaline on the cortical blood vessels and metabolism is blocked by high PaCO2 levels, or by the prior administration of (±)‐propranolol. (+)‐Propranolol is without such effect.

Following section of both vagi and both sinus nerves, intravenous noradrenaline fails to cause an increase in cortical blood flow.

In another series of animals the area of the carotid bifurcation was vascularly isolated and perfused with blood from a second dog. Chemoreceptor and baroreceptor activity was shown to be intact.

Administration of 5% CO2 to the donor dog caused an increase in cerebral blood flow in the recipient dog.

Administration of intravenous noradrenaline (1.0 μg kg−1 min−1) to the donor animal caused an increase in cerebral blood flow, cerebral O2 and glucose utilization of the recipient.

Administration of 5% CO2 and intravenous (—)‐noradrenaline (1.0 μg kg−1 min−1) caused a further increase in flow and metabolism.

This evidence suggests that the cerebrovasodilatation observed following intravenous noradrenaline is reflex and is triggered by chemoreceptor activity.

The evidence also suggests that the antagonism of the cortical dilatory effects of intravenous noradrenaline by raised PaCO2 in the intact animal must be at a site different from the peripheral chemoreceptors.
THE EFFECTS OF PROSTAGLANDINS ON GUINEA‐PIG ISOLATED INTESTINE AND THEIR POSSIBLE CONTRIBUTION TO MUSCLE ACTIVITY AND TONE
Authors: BENNETT A. , ELEY K.G. , STOCKLEY HELEN L.
Published: July 2012

Prostaglandins F1α and F2α caused contraction of the longitudinal muscle of both guinea‐pig isolated ileum and colon, apparently by acting directly on the muscle and on cholinergic nerves. They had little effect on ileal circular muscle.

Prostaglandins E1 and E2 caused contraction of the longitudinal muscle of guinea‐pig isolated colon, apparently by acting directly on the muscle and on excitatory nerves which are non‐cholinergic. Prostaglandin E1 seems more effective than E2 in stimulating these nerves.

It seems likely that prostaglandin release in vitro maintains the tone of the longitudinal muscle of guinea‐pig colon, whereas release of a prostaglandin E compound inhibits circular muscle tone.
LACK OF CARDIAC OR BRONCHODILATOR TACHYPHYLAXIS TO ISOPRENALINE IN THE DOG
Authors: MINATOYA H. , SPILKER B.A.
Published: July 2012

Tachyphylaxis to heart rate and bronchodilator effects of (±)‐isoprenaline was studied in anaesthetized open‐chest dogs by 5 procedures.

Heart rate responses to a series of intravenous injections of isoprenaline were essentially unchanged before and after a 15 min infusion of isoprenaline (at 3 doses).

Heart rate and bronchodilator responses in the same animal to an intravenous injection of isoprenaline were not significantly different before and after a 30 min infusion of isoprenaline (at 2 doses).

Heart rate responses were relatively constant to an isoprenaline injection given every 30 min during a 4 h infusion of isoprenaline (at 3 doses), but the magnitude of the response was smallest for the largest infusion dose (highest background heart rate) and greatest for the smallest infusion dose (lowest background heart rate).

Heart rate and bronchodilator responses in the same animal to isoprenaline were relatively constant during a 5 h infusion of isoprenaline (at 2 doses).

Bronchodilator responses to intratracheally administered isoprenaline aerosol were essentially unchanged during a 4–5 h period using various doses and procedures.

Tachyphylaxis to the heart rate or bronchodilator effects of isoprenaline was not observed. The present data give no support to the hypothesis that tachyphylaxis to isoprenaline aerosols is an important mechanism in asthma mortality.
THE OFFSET OF MORPHINE TOLERANCE IN RATS AND MICE
Authors: COX B.M. , GINSBURG M. , WILLIS JULIA , DAVIES J.K.
Published: July 2012

In rats and mice made tolerant to morphine by pretreatment with the drug, the shift to the right of the log dose/analgesic response line for morphine from its position in naive animals occurs without significant change in slope provided that sufficient time is allowed for elimination of pretreatment drug.

Responsiveness to the analgesic effects of morphine, given together with cycloheximide to prevent reinforcement of tolerance, was measured in rats (paw pressure method) and mice (hot plate method) at intervals during 1–23 days following cessation of a variety of regimens of tolerance‐inducing drug treatments.

A biphasic pattern of recovery of responsiveness was observed, which was independent of the regimen or the drug (morphine, methadone or diamorphine) used to induce tolerance. Estimates of the rates of the first, fast phase are imprecise but the rate of the second phase of offset, from 4th day after cessation of pretreatment had, in rats, a mean half‐time of 13.2 ± 0.53 days‐for all pretreatments combined, there being no significant differences between the various pretreatment regimens employed. In mice, similarly, a biphasic recovery of analgesic responsiveness was seen after morphine pretreatment, the mean half‐time of the slower phase being 17.4 days.

Precipitation of an acute withdrawal syndrome in rats by naloxone HC1 given 6 h after the final injection of a tolerance‐inducing treatment with morphine did not affect the subsequent rate of recovery from tolerance.

During the period following a tolerance‐inducing pretreatment with morphine in mice, the rate of attenuation of the naloxone‐evoked jumping response was faster than the rate of offset of tolerance.
INHIBITION OF IMMEDIATE HYPERSENSITIVITY REACTIONS IN LABORATORY ANIMALS BY A PHENANTHROLINE SALT (ICI 74,917)
Authors: EVANS D.P. , THOMSON D.S.
Published: July 2012

The activity of a new anti‐allergic compound, I.C.I. 74,917, has been studied in the rat, mouse and guinea‐pig.

Following intravenous administration, I.C.I. 74,917 inhibits in a dose‐dependent manner passive cutaneous anaphylaxis induced in rats and mice by heat‐labile homocytotropic antibody. In rats, its potency is approximately 300 times that of disodium cromoglycate.

To achieve maximal inhibition, it is necessary to administer I.C.I. 74,917 at the same time as antigenic challenge; dosing before or after challenge has much less effect.

Liberation of histamine, provoked by the antigenic challenge of mast cells passively sensitized in vitro by IgE‐like antibody, is reduced in the presence of I.C.I. 74,917.

Intravenous administration of the compound has no significant effect upon local blueing reactions provoked in the rat by intradermal injection of histamine, 5‐hydroxytryptamine or Compound 48/80. It has only a slight effect at high doses upon passive cutaneous anaphylaxis induced in the rat by heat‐stable homocytotropic or heterologous (guinea‐pig) antibodies.

Although not a bronchodilator in the guinea‐pig, I.C.I. 74,917 partially inhibits systemic anaphylaxis. A consistent reduction in the severity of antigen‐induced bronchospasm was demonstrated in the Konzett‐Rössler preparation at doses comparable to those inhibiting passive cutaneous anaphylaxis in the rat. However, there was only slight inhibition of passive cutaneous anaphylaxis in the guinea‐pig.

I.C.I. 74,917 itself induces bronchospasm when administered to anaesthetized guinea‐pigs or to a guinea‐pig isolated lung preparation. This effect is reversed by salbutamol, but is not prevented by the prior administration of mepyramine, atropine or methysergide.

These results indicate that in the rat, mouse and guinea‐pig, I.C.I. 74,917 is a potent inhibitor of certain types of immediate hypersensitivity reactions.
EFFECTS OF APOMORPHINE, ERGOCORNINE AND PIRIBEDIL ON AUDIOGENIC SEIZURES IN DBA/2 MICE
Authors: ANLEZARK G.M. , MELDRUM B.S.
Published: July 2012

Audiogenic seizures in DBA/2 mice have been studied after administration of drugs believed to act as dopamine agonists. Apomorphine at 0.4 mg/kg delays all phases of the response, the tonic phase is absent after 2.0 mg/kg; the clonic phase is abolished by 10 mg/kg. Ergocornine (0.5–8.0 mg/kg) produces effects on the latency and occurrence of seizure stages similar to those of apomorphine. Piribedil, ET 495 (4–100 mg/kg) is less potent; even after 100 mg/kg clonic and tonic phases occurred in 50% of the mice.
INHIBITORY EFFECTS OF CLONIDINE AND BS 100‐141 ON RESPONSES TO SYMPATHETIC NERVE STIMULATION IN CATS AND RABBITS
Authors: PACHA W. , SALZMANN R. , SCHOLTYSIK G.
Published: July 2012

In pithed cats, the spinal sympathetic outflow was stimulated preganglionically at segments C7 and T1 and heart rate responses and nictitating membrane tone were measured in parallel.

Clonidine and a related drug, BS 100‐141 (N‐amidino‐2‐(2,6‐dichlorophenyl)acetamide hydrochloride), caused a dose‐dependent inhibition of the stimulation‐induced tachycardia but did not inhibit responses of the nictitating membrane. The inhibition of heart rate was antagonized by the α‐adrenoceptor blocking drug, phentolamine.

In isolated hearts of rabbits, noradrenaline release in response to adrenergic nerve stimulation was reduced by clonidine and BS 100‐141 and the effect was antagonized by phentolamine.

The results support the view that presynaptic α‐adrenoceptors are involved in the regulation of transmitter release from adrenergic nerves. Cardiac adrenergic nerves appear more sensitive to α‐adrenoceptor‐mediated inhibition of impulse transmission than the sympathetic nerves to the nictitating membrane.
EFFECT OF FENFLURAMINE ON 5‐HYDROXYTRYPTAMINE UPTAKE AND RELEASE BY RAT BLOOD PLATELETS
Authors: BUCZKO W. , DE GAETANO G. , GARATTINI S.
Published: July 2012

(+)‐Fenfluramine reduces the central stores of 5‐hydroxytryptamine (5‐HT) by a poorly understood mechanism.

Rat blood platelets have been used in this study as a simple model for serotoninergic nerve endings.

(+)‐Fenfluramine shows a dual effect: it inhibits the uptake of [14C]‐5‐HT by platelets and it releases newly absorbed [14C]‐5‐HT from platelets.

The inhibition of [14C]‐5‐HT uptake induced by (+)‐fenfluramine appears very rapidly, is concentration‐dependent and seems not to be competitive. (+)‐Fenfluramine is ten times less effective than chloroimipramine but ten times more effective than (+)‐amphetamine; (+)‐fenfluramine is more active than its (‐)‐isomer or its metabolite norfenfluramine ((+)‐ or (‐)‐form).

The release of [14C]‐5‐HT from platelets induced by (+)‐fenfluramine is concentration‐dependent but increases with increased incubation time. Both chloroimipramine and (+)‐amphetamine are in comparison very poor release inducers; (+)‐fenfluramine is more active than its (‐)‐isomer or its metabolites.

The effect on [14C]‐5‐HT uptake exerted by (+)‐fenfluramine and chloroimipramine in vitro could not be observed in vivo.

The observed effect of fenfluramine on the uptake and release of 5‐HT may explain the lowering action of fenfluramine on the brain 5‐HT level, an effect considered of importance for the anorectic effect of this drug.
ASSESSMENT IN THE GUINEA‐PIG ILEUM AND MOUSE VAS DEFERENS OF BENZOMORPHANS WHICH HAVE STRONG ANTINOCICEPTIVE ACTIVITY BUT DO NOT SUBSTITUTE FOR MORPHINE IN THE DEPENDENT MONKEY
Authors: HUTCHINSON M. , KOSTERLITZ H.W. , LESLIE FRANCES M. , WATERFIELD ANGELA A. , TERENIUS L.
Published: July 2012

Four benzomorphans which have potent antinociceptive activity in the hot‐plate and writhing tests in the mouse but do not suppress or precipitate withdrawal symptoms in the morphine‐dependent monkey, have been examined for their pharmacological actions in the guinea‐pig ileum and mouse vas deferens.

In the guinea‐pig ileum their agonist potencies are 1.5 to 400 times greater than that of normorphine or morphine whereas in the mouse vas deferens their potencies relative to morphine are 0.3 to 100. They exhibit no antagonist activity in either preparation. Benzomorphans which substitute for morphine in the morphine‐dependent monkey do not show such differences between their relative potencies in the guinea‐pig ileum and mouse vas deferens.

The relative potencies of the four benzomorphans to inhibit stereospecific [3H]‐dihydromorphine binding by membrane fragments from rat brain, are more closely related to their relative agonist potencies in the mouse vas deferens than to those found in the guinea‐pig ileum.

In order to antagonize the agonist actions of these benzomorphans, naloxone is required in concentrations which are 3 to 7 times higher than those needed for the antagonism of normorphine or morphine or of benzomorphans which suppress abstinence in morphine‐dependent monkeys.

It may be possible to use the three assays, namely, ratio of relative agonist potency in mouse vas deferens to that in guinea‐pig ileum, ratio of relative agonist potency to relative affinity to opiate receptors and the concentration of naloxone required for antagonism, for the prediction of the potential of new compounds to produce physical dependence.
γ‐AMINOBUTYRIC ACID RECEPTOR ON VASCULAR SMOOTH MUSCLE OF DOG CEREBRAL ARTERIES
Authors: FUJIWARA M. , MURAMATSU I. , SHIBATA S.
Published: July 2012

γ‐Aminobutyric acid (GABA) had a relaxant effect on dog cerebral arteries which was blocked only by picrotoxin, a known antagonist of GABA receptors. Other agents, adrenoceptor and ganglion blocking agents, atropine, reserpine, tetrodotoxin and ouabain, had no effect on the inhibitory action suggesting the existence of GABA receptors in the vascular smooth muscle of dog cerebral arteries.
EFFECTS OF DESIPRAMINE ON NEURONAL RESPONSES TO DOPAMINE, NORADRENALINE, 5‐HYDROXYTRYPTAMINE AND ACETYLCHOLINE IN THE CAUDATE NUCLEUS OF THE RAT
Authors: BEVAN P. , BRADSHAW C.M. , SZABADI E.
Published: July 2012

The sensitivity of single neurones to microelectrophoretically applied dopamine, noradrenaline (NA), 5‐hydroxytryptamine (5‐HT) and acetylcholine (ACh) was investigated in the caudate nucleus of the rat, anaesthetized with halothane. Both excitatory and depressant responses could be observed to each of the agonists. There was a high correlation between the direction of responses to dopamine and noradrenaline, whereas there was no significant correlation between the direction of responses to dopamine and ACh.

The effect of desipramine was studied on both excitatory and depressant responses to dopamine, NA and 5‐HT, and on excitatory responses to ACh. Both potentiation and antagonism of neuronal responses to monoamines and ACh could be observed after a brief application of desipramine.

Excitatory responses to glutamate were not affected by desipramine.

The observation that responses to dopamine and NA can be potentiated by desipramine in the caudate nucleus suggests that uptake blockade is not a prerequisite for potentiation.

It is suggested that the potentiation of neuronal responses to dopamine by desipramine may be responsible for the therapeutic efficacy of desipramine in Parkinson's disease.
POTENCY AND SELECTIVITY OF METHYL ANALOGUES OF PROSTAGLANDIN E2 ON RAT GASTROINTESTINAL FUNCTION
Authors: MAIN I.H.M. , WHITTLE B.J.R.
Published: July 2012

The potency and selectivity of action of prostaglandin E2 and its (15S)‐ or (15R)‐15 methyl and 16,16 dimethyl analogues on gastrointestinal function have been studied in the rat.

The (15S)‐15 methyl and 16,16 dimethyl analogues were 40 times as active as prostaglandin E2 in inhibiting pentagastrin‐stimulated acid secretion on intravenous administration to the anaesthetized rat, and 100 times as active on subcutaneous injection to the chronic fistula rat.

In antisecretory doses, the analogues, like prostaglandin E2, caused bile reflux and, in higher doses, profuse diarrhoea.

The (15S)‐15 methyl and 16,16 dimethyl analogues were at least 30 times as active as prostaglandin E2 in causing changes in intestinal intraluminal pressure in vivo, but were equipotent on isolated smooth muscle.

In equivalent antisecretory doses, the methyl analogues had little effect on systemic arterial blood pressure and resting mucosal blood flow compared with prostaglandin E2.

The (15R) methyl epimer administered parenterally had little effect on gastrointestinal function but brief acid incubation greatly increased its activity.
EXTRACTION FROM OX RETRACTOR PENIS OF AN INHIBITORY SUBSTANCE WHICH MIMICS ITS ATROPINE‐RESISTANT NEUROGENIC RELAXATION
Authors: AMBACHE N. , KILLICK S.W. , ZAR M. ABOO
Published: July 2012

The inhibitory post‐ganglionic transmission in the retractor penis of the ox resembles that of the dog and is not cholinergic or adrenergic. Acid extracts of this tissue have yielded an unidentified, labile, inhibitory substance which mimics the effect of its inhibitory nerves.
THE EFFECTS OF PROSTAGLANDINS E1, E2 AND F2αON VAGAL BRADYCARDIA IN THE ANAESTHETIZED MOUSE
Authors: FENIUK W. , LARGE B.J.
Published: July 2012

In anaesthetized mice prostaglandins E1 and E2 reduced the bradycardia caused by electrical stimulation of the sectioned peripheral vagus nerve; prostaglandin F2α produced only a slight inhibition of the vagal response.

None of the prostaglandins studied affected acetylcholine‐induced bradycardia.

Prostaglandins modify para sympathetic nerve activity in vivo presumably by a pre‐synaptic action.
AN ELECTROPHYSIOLOGICAL ANALYSIS OF THE EFFECTS OF RESERPINE ON ADRENERGIC NEUROMUSCULAR TRANSMISSION
Authors: BENNETT M.R. , MIDDLETON J.
Published: July 2012

An electrophysiological study has been made of the effects of depleting synaptic vesicles (i.e. small vesicles < 60 nm diameter) of their transmitter with reserpine on the quantity of transmitter released by nerve impulses, using the amplitude of the synaptic potential as a measure of transmitter release.

Pretreatment of adrenergic nerve terminals with reserpine sufficient to deplete the terminals of 70% of their noradrenaline (NA) did not change the total number of synaptic vesicles in the terminals, but did reduce the number with a large granular core as well as the quantity of NA released by a single nerve impulse by 80%.

Pretreatment of adrenergic nerve terminals with reserpine and iproniazid, to decrease vesicular NA but enhance cytoplasmic NA, had the same effect on synaptic vesicles and on the NA released by a single nerve impulse as did reserpine alone.

During a short train of impulses at high frequencies in reserpine pretreated terminals, the quantity of NA released by successive impulses increased until a steady‐state release was reached comparable to that in untreated preparations. This facilitated release could be quantitatively predicted in terms of the addition of the individual potentiations introduced by each impulse in the train.

These results are consistent with the idea that each quantum of transmitter is stored in a synaptic vesicle, and that these may be released by nerve impulses directly from the terminal by a process of exocytosis.
TIMID SINGLY‐HOUSED MICE: THEIR VALUE IN PREDICTION OF PSYCHOTROPIC ACTIVITY OF DRUGS
Authors: KRŠIAK M.
Published: July 2012

About 45% of singly‐housed male mice showed timidity (alert postures, running away, defensive postures) instead of aggression on interactions in pairs with group‐housed male mice, though their partners did not show any aggression. The isolation‐induced timidity was stable in repeated interactions. Timid mice also showed locomotion (walking across cage and rearing) and a small amount of sociable activity (sniffing, following partners and climbing over them).

Diazepam (5 mg/kg), chlordiazepoxide (20 mg/kg), chlorpromazine (7.5 mg/kg) and barbitone (60 mg/kg) given orally inhibited the isolation‐induced timidity without reducing other motor activities in the timid mice. Imipramine lessened timidity only in a dose (80 mg/kg) which also decreased other components of behaviour in the timid isolates. (+)‐Amphetamine and lysergic acid diethylamide (LSD) increased the timid response.

Comparison of the inhibition of timid activities with changes in other behaviour occurring at the same time seems a better measure of selective timidity‐reducing effects of drugs than the rota‐rod test.

Diazepam (5 mg/kg) increased sociable and locomotor activities. Barbitone (20 and 60 mg/kg) increased sociable activities; however, the higher dose also evoked some aggression in timid mice.

Behaviour of timid singly‐housed male mice seems to be a good measure for prediction of activity of drugs in relieving anxiety as well as for detection of aggression‐evoking and sociability‐increasing effects of drugs.
MEMBRANE POTENTIAL CHANGES INDUCED BY 5‐HYDROXYTRYPTAMINE IN THE RABBIT SUPERIOR CERVICAL GANGLION
Authors: WALLIS D.I. , WOODWARD B.
Published: July 2012

Changes in resting membrane potential induced by 5‐hydroxytryptamine (5‐HT) have been measured in the excised ganglion by the sucrose‐gap technique.

5‐HT produced a rapid depolarization, the threshold concentration for depolarization being around 10 μM. With concentrations of 100 μM or greater, repolarization began during the course of the supervision; this was followed by prolonged tachyphylaxis.

Tachyphylaxis was largely avoided by making injections into the superfusion stream. Standard injections of 0.2 μmol 5‐HT dissolved in 0.2 ml of Krebs solution were used routinely and could be given at 20–30 min intervals to evoke relatively constant responses.

The response to an injection consisted of a rapid depolarization, followed by a rapid repolarization and subsequent after‐hyperpolarization. The threshold quantity for depolarization was around 0.01 μmol, while the ED50 estimated from 6 dose‐response curves was 0.12 ± 0.02 μmol (mean ± s.e. mean).

Injections of 5‐HT (0.2 μmol), choline (10 μmol) and acetylcholine (9.9 μmol) produced depolarizations of similar magnitude.

Monoamine oxidase inhibitors failed to alter substantially the amplitude of depolarizations to 5‐HT.

5‐HT depolarizations were unaltered in amplitude when the impermeant anion benzenesulphonate was substituted for the chloride ion in Krebs solution, but were initially markedly reduced in amplitude in a sodium‐deficient medium; some recovery of the response subsequently occurred. The depolarization which persisted in sodium‐deficient solutions was much reduced or abolished when calcium ions were then removed from the superfusion medium. Removal of either calcium ions alone or potassium ions from the superfusion fluid did not reduce depolarization amplitude.

The after‐hyperpolarization was abolished in sodium‐deficient solutions, usually increased in potassium‐free solutions, reduced or abolished by ouabain or nicotine, but unaffected by calcium‐free solutions.

A depolarizing action of 5‐HT on presynaptic terminals in the ganglion appears probable.
ANTIOXOTREMORINE ACTION OF PROPRANOLOL
Authors: GANGULY D.K.
Published: July 2012

The influence of propranolol on the neuromuscular, tremor‐producing and muscarinic effects of oxotremorine was examined.

In the isolated rat phrenic nerve‐diaphragm preparation the neuromuscular blocking effect of oxotremorine was inhibited by propranolol in a dose‐dependent manner.

Propranolol intensified the paralytic effect of tubocurarine in the rat diaphragm and prevented antagonism of tubocurarine paralysis by tetraethylammonium.

Propranolol was devoid of any curare‐like effect in the isolated rectus abdominis muscle of the frog.

Vasodepressor responses to oxotremorine in rats and spasmogenic responses to oxotremorine in guinea‐pig ileum were not antagonized by propranolol.

A dose‐dependent antagonism of oxotremorine‐induced tremor in mice was observed after pretreatment with propranolol and it is suggested that this effect is due to an antagonism of a presynaptic effect of oxotremorine at skeletal neuromuscular junctions.
EFFECTS OF 5,7‐DIHYDROXYTRYPTAMINE ON AN IDENTIFIED 5‐HYDROXYTRYPTAMINE‐CONTAINING NEURONE IN THE CENTRAL NERVOUS SYSTEM OF THE SNAIL Helix pomatia
Authors: OSBORNE N.N. , PENTREATH V.W.
Published: July 2012

The effect of 5,7‐dihydroxytryptamine (5,7‐DHT) on an identified 5‐hydroxytryptamine (5‐HT)‐containing neurone in the CNS of the snail was studied by histochemical, biochemical and electrophysiological methods.

Low concentrations of 5,7‐DHT decreased the endogenous 5‐HT content of the neurone without affecting the amino acids, while relatively large amounts of the drug proportionately lowered 5‐HT and in addition slightly decreased the tryptophan and methionine content of the cell.

5,7‐DHT blocked the uptake of [3H]‐5‐HT into the neurone; the close analogue 5,6‐DHT was more potent.

As well as slightly influencing the accumulation of [3H]‐tryptophan by the neurone 5,7‐DHT inhibited the metabolism of this amino acid to form 5‐HT, probably by affecting the enzyme tryptophan‐hydroxylase.

5,7‐DHT produced a postsynaptic blockade of transmission from the neurone by blocking the 5‐HT receptors of the follower neurones. This effect appeared to be specific for 5‐HT receptors.

The data support the idea that 5,7‐DHT is neurotoxic for indoleamine‐containing neurones.
STIMULANT PROPERTIES OF BROMOCRIPTINE ON CENTRAL DOPAMINE RECEPTORS IN COMPARISON TO APOMORPHINE, (+)‐AMPHETAMINE AND l‐DOPA
Authors: JOHNSON A.M. , LOEW D.M. , VIGOURET J.M.
Published: July 2012

The activity of bromocriptine has been investigated in tests for the stimulation of central dopaminergic mechanisms. The results obtained have been compared with those of apomorphine, (+)‐amphetamine and l‐DOPA.

Bromocriptine (2.5 to 10 mg/kg) induced stereotyped sniffing and licking in rats. The stereotypy was more intense than that induced by L‐DOPA and less intense than that of apomorphine and (+)‐amphetamine over the dose ranges studied.

In rats lesioned unilaterally in the substantia nigra by local injection of 6‐hydroxydopamine, bromocriptine, like apomorphine and l‐DOPA, induced turning contralateral to the side of the lesion. The smallest dose of bromocriptine to induce turning was 0.5 mg/kg.

Reserpine‐induced catalepsy in mice was antagonized by bromocriptine, with an ED50 of 1.8 mg/kg. It was intermediate in potency to apomorphine and l‐DOPA.

Spontaneous locomotor activity in mice was stimulated by bromocriptine in a dose‐dependent manner from 2.5 to 10 mg/kg after an initial suppression of activity.

In all experiments, bromocriptine was characterized by a prolonged duration of activity after a delay in the onset of effect.

The stereotyped behaviour induced by bromocriptine was inhibited by prior administration of pimozide, reserpine or α‐methyl‐p‐tyrosine.

Bromocriptine‐induced turning behaviour was abolished by pretreatment with pimozide, and reduced after α‐methyl‐p‐tyrosine pretreatment.

The results obtained support the conclusion that bromocriptine acts by stimulating dopamine receptors in the central nervous system and that intact catecholamine synthesis and granular amine storage mechanisms are necessary for it to bring about its effects.
THE UPTAKE AND SUBCELLULAR DISTRIBUTION OF RADIO‐LABELLED METABOLITES OF DIGITOXIN IN THE GUINEA‐PIG ISOLATED PERFUSED HEART
Authors: DUTTA S. , MARKS B.H. , STEPHEN P.M.
Published: July 2012

Comparisons were made of the uptake and inotropic effects of concentrations of 0.1 μm of digitoxin and its cleavage products digitoxigenin‐bis‐digitoxoside, digitoxigenin‐mono‐digitoxoside and digitoxigenin in the isolated perfused hearts of guinea‐pigs.

Digitoxin produced the greatest inotropic responses in this series, while the sequence of cleavage products produced progressively smaller responses.

The uptake of digitoxin was significantly higher than that of the three metabolites, and the uptake of metabolites became progressively less with cleavage. The highest binding in each case was found in the microsomal fraction.

The uptake of all four digitaloids was reduced when the potassium in the perfusion medium was increased.
PERIPHERAL EFFECTS OF FENFLURAMINE
Authors: MITCHELL G.E.D. , MOTTRAM D.R.
Published: July 2012

The peripheral cardiovascular effects of the centrally acting anorexigenic agent, fenfluramine hydrochloride, have been investigated in the rat.

After intravenous administration of fenfluramine, an immediate hypotensive response, followed by a reflex rise in blood pressure was recorded. This was followed by a prolonged fall in blood pressure which frequently failed to return to pre‐drug levels.

The antagonists, propranolol and atropine, failed to inhibit this hypotensive effect of fenfluramine.

The effects of 5 mg/kg fenfluramine for 1 h on the blood pressure responses to the sympathomimetic amines, tyramine, methoxamine and metaraminol were studied.

The responses to the indirectly acting tyramine were reduced by 50% following fenfluramine, while those to the directly acting methoxamine remained unaffected by the drug. Responses to metaraminol, an amine with both direct and indirect actions, were also unaffected to a significant degree by fenfluramine.

Studies on rat isolated vas deferens again showed that responses to tyramine are greatly reduced following fenfluramine.

In addition fenfluramine itself produced spontaneous contractions of the vas deferens. These contractions were blocked by the α‐adrenoceptor blocking agents phentolamine and thymoxamine.

It is suggested that fenfluramine exerts an effect at the adrenergic nerve terminal, either by displacing noradrenaline stores or by inhibition of the amine uptake process.
COMPOUNDS DESIGNED TO FIT A SITE OF KNOWN STRUCTURE IN HUMAN HAEMOGLOBIN
Authors: BEDDELL C.R. , GOODFORD P.J. , NORRINGTON F.E. , WILKINSON S. , WOOTTON R.
Published: July 2012

The three‐dimensional coordinates of the atoms in human haemoglobin are known, and there is a specific site in the deoxygenated form of the protein at which 2,3‐diphosphoglycerate (DPG) interacts.

Molecular models of this site have been constructed and used to design compounds which should bind to the deoxy conformation and stabilize it. These compounds should thereby promote oxygen liberation, as does DPG.

The compounds so designed were found to promote oxygen liberation. Their relative potencies, as assessed by sigmoidal dose‐response curves, are in the predicted sequence.
INDOMETHACIN‐INDUCED ALTERATIONS IN CORTICOSTEROID AND PROSTAGLANDIN RELEASE BY ISOLATED ADRENOCORTICAL CELLS OF THE CAT
Authors: LAYCHOCK SUZANNE G. , RUBIN R.P.
Published: July 2012

The effects of purported prostaglandin synthesis inhibitors on steroid and prostaglandin (E and F) release from trypsin‐dispersed cat adrenocortical cells were investigated.

Low indomethacin concentrations potentiated adrenocorticotrophin (ACTH)‐evoked prostaglandin and steroid release, whereas higher concentrations depressed both responses to ACTH. The steroidogenic response to exogenous prostaglandin E2 was not markedly altered over a wide range of indomethacin concentrations.

Indomethacin enhanced basal steroid release but did not enhance basal prostaglandin E or F release.

5, 8, 11, 14‐Eicosatetraynoic acid (ETA) elicited a concentration‐dependent inhibition of ACTH‐induced steroid release, but had little effect on prostaglandin E2‐induced steroid release. A high concentration of ETA inhibited prostaglandin E and F release.

These data are discussed in relation to the concept that prostaglandins provide a critical link in ACTH‐induced corticosteroidogenesis.
DEPRESSION BY MORPHINE OF EXCITATORY JUNCTION POTENTIALS IN THE VAS DEFERENS OF THE MOUSE
Authors: HENDERSON G. , NORTH R.A.
Published: July 2012

Intracellular recordings were made from smooth muscle cells of the mouse vas deferens. Excitatory junction potentials (e.j.ps) were evoked by stimulation of the intramural nerves.

Normorphine (50 nm‐5 μm) depressed the amplitude of the e.j.p. The ED50 was 430 nm. The latency of the e.j.p. and the resting membrane potential of the smooth muscle cells were unaffected by normorphine.

The depression of the e.j.p. by narcotic analgesic drugs was stereospecific.

Naloxone (100 nm) completely reversed the depression of the e.j.p. produced by normorphine (1 μm). Naloxone (100 nm) alone did not alter the amplitude of the e.j.p.

Normorphine (1 μm) did not prevent the depolarization of the smooth muscle cells produced by exogenous noradrenaline (10 μm).

It is concluded that narcotic analgesic drugs act directly upon the transmitter release sites to reduce the amount of noradrenaline liberated by each nerve impulse.
THE CONTRIBUTION OF EXTRANEURONAL UPTAKE TO THE TRACHEA‐BLOOD VESSEL SELECTIVITY OF β‐ADRENOCEPTOR STIMULANTS in vitro IN GUINEA‐PIGS
Authors: O'DONNELL STELLA R. , WANSTALL JANET C.
Published: July 2012

The potencies relative to isoprenaline of isoetharine, tertiary butyl noradrenaline, salbutamol, orciprenaline, Me 506, rimiterol, fenoterol, carbuterol and terbutaline on isolated preparations of guinea‐pig trachea and blood vessels (perfused hind limb) were determined. All the compounds were selective for trachea and selectivity values, i.e. relative potency on trachea divided by relative potency on hind limb, ranged from 2.3 to 21.4.

Responses to isoprenaline (the reference compound), tertiary butyl noradrenaline and isoetharine were potentiated on trachea by 50 μm phenoxybenzamine (PHB) and by other inhibitors of extraneuronal uptake (ENU). Under these conditions the selectivity values of all the compounds was close to unity.

Selectivity values were also close to unity if they were calculated from data obtained without ENU inhibition, provided that only those compounds not potentiated by PHB on trachea were used.

It is proposed that the trachea‐blood vessel selectivity shown by β‐adrenoceptor stimulants can be caused by the influence of ENU upon them, rather than by their ability to distinguish between two β2‐adrenoceptors.

The suggestion that differences exist between β2‐adrenoceptors in respiratory and vascular smooth muscle is not supported by the in vitro experiments described.
THE INTERACTION BETWEEN ANTHELMINTIC DRUGS AND HISTAMINE IN Ascaris suum
Authors: PHILLIPS JEAN L. , STURMAN GILLIAN , WEST G.B.
Published: July 2012

Piperazine reduced the histamine content of Ascaris suum, yet it greatly increased the uptake of histamine from the surrounding medium, the neuromuscular structures of the nematode preferentially increasing in amount.

Bephenium reduced the histamine content of Ascaris and the uptake of histamine from the surrounding medium. However, the relative amount in the neuromuscular structures increased.

The flaccid paralysing action of piperazine may thus involve increased histamine absorption whereas the spastic paralysing action of bephenium may be independent of histamine.
INFLUENCE OF DOPAMINE AND NORADRENALINE ON ISOLATED CEREBRAL ARTERIES OF THE DOG
Authors: TODA N.
Published: July 2012

Effects of dopamine and noradrenaline were compared in helically‐cut strips of canine cerebral arteries.

Dopamine caused a greater maximal contraction than noradrenaline, although the ED50 for noradrenaline was appreciably less. The contraction induced by these amines was reversed to a relaxation by treatment with phenoxybenzamine.

Relaxation induced by dopamine in phenoxybenzamine‐treated and prostaglandin‐contracted cerebral arteries was not influenced by 1 μm propranolol, while relaxation induced by noradrenaline at low concentrations (2 μm and 10 μm) was significantly attenuated. Neither aminophylline nor atropine affected the relaxant effect of dopamine.

A mechanism other than β‐adrenergic, cholinergic or adenosine‐related appears to be involved in the relaxation elicited by dopamine in cerebral arterial strips.
A COMPARISON BETWEEN THE HYPOTHERMIA INDUCED BY INTRAVENTRICULAR INJECTIONS OF THYROTROPIN RELEASING HORMONE, NORADRENALINE OR CALCIUM IONS IN UNANAESTHETIZED CATS
Authors: METCALF G. , MYERS R.D.
Published: July 2012

The hypothermia produced by intraventricular injections of thyrotropin releasing hormone (TRH) in unanaesthetized cats has been investigated.

TRH is more potent than either noradrenaline or calcium ions. It is estimated that the equi‐potent molar ratio for TRH: noradrenaline: calcium is 1:900:27,000.

TRH injections also produce profuse salivation, tachypnoea, cutaneous vasodilatation and frequently defaecation and vomiting. It is considered that the increased respiration is a major cause of the hypothermia.

Prior administration of phentolamine antagonized noradrenaline‐induced hypothermia but did not affect hypothermia produced by TRH or calcium ions. Pretreatment with α‐methyltyrosine did not affect the hypothermia induced by TRH, calcium ions or noradrenaline.

The calcium antagonists verapamil and xylocaine did not antagonize hypothermia induced by an injection of calcium ions.

The constituent amino acids of TRH did not produce hypothermia either individually or collectively. Thyroxine sodium produced a rise in temperature that was slow in onset, consistent with its known metabolic effects. TSH produced a small hypothermia unrelated to dose.
LONG‐TERM EFFECTS OF N‐2‐CHLOROETHYL‐N‐ETHYL‐2‐BROMOBENZYLAMINE HYDROCHLORIDE ON NORADRENERGIC NEURONES IN THE RAT BRAIN AND HEART
Authors: ROSS S.B.
Published: July 2012

N‐2‐Chloroethyl‐N‐ethyl‐2‐bromobenzylamine hydrochloride (DSP 4) 50 mg/kg intraperitoneally, produced a long‐term decrease in the capacity of brain homogenates to accumulate noradrenaline with significant effect 8 months after the injection. It had no effect on the noradrenaline uptake in homogenates from the striatum (dopamine neurones) and on the uptake of 5‐hydroxytryptamine (5‐HT) in various brain regions.

In vitro DSP 4 inhibited the noradrenaline uptake in a cortical homogenate with an IC50 value of 2 μm but was more than ten times less active on the dopamine uptake in a striatal homogenate and the 5‐HT uptake in a cortical homogenate.

DSP 4 (50 mg/kg i.p.) inhibited the uptake of noradrenaline in the rat heart atrium in vitro but this action was terminated within 2 weeks.

DSP 4 (50 mg/kg i.p.) caused a decrease in the dopamine‐β‐hydroxylase (DBH) activity in the rat brain and heart. The onset of this effect was slow; in heart a lag period of 2–4 days was noted. In brain the DBH‐activity in cerebral cortex was much more decreased than that in hypothalamus which was only slightly affected. A significant effect was still found 8 months after the injection. The noradrenaline concentration in the brain was greatly decreased for at least two weeks, whereas noradrenaline in heart was only temporarily reduced.

The long‐term effects of DSP 4 on the noradrenaline accumulation, the DBH activity and noradrenaline concentration in the rat brain were antagonized by desipramine (10 mg/kg i.p.).

It is suggested that DSP 4 primarily attacks the membranal noradrenaline uptake sites forming a covalent bond and that the nerve terminals, as a result of this binding, degenerate.