bluuebunny/crossref_metadata_2025 huggingface dataset:
ANAESTHETICS DEPRESS THE SENSITIVITY OF CORTICAL NEURONES TO l‐GLUTAMATE
Authors: RICHARDS C.D. , SMAJE J.C.
Published: July 2012

The effects of general anaesthetics on the responses of neurones to iontophoretically applied l‐glutamate have been examined in slices of the guinea‐pig olfactory cortex in vitro.

Concentrations of pentobarbitone, ether, methoxyflurane, trichloroethylene and alphaxalone that are known to depress synaptic transmission in the prepiriform cortex also depressed the sensitivity of prepiriform neurones to l‐glutamate.

Halothane, in concentrations that depress synaptic transmission (< 1%) did not alter the sensitivity of neurones to glutamate. Higher concentrations (> 1%) produced a dose‐related depression of the glutamate sensitivity of neurones.

All four volatile anaesthetics tested caused some cells to alter their glutamate‐evoked firing pattern to one in which the spike discharges were more closely grouped. Pentobarbitone and alphaxalone had no such effect.

If the sensitivity of the neurones to the endogenous excitatory transmitter is affected by anaesthetics in the same way as the glutamate‐sensitivity, these results suggest that halothane depresses synaptic transmission by decreasing the amount of transmitter released from the nerve terminals, whereas the other anaesthetics depress the sensitivity of the post‐synaptic membrane to the released transmitter.
GENERAL ANAESTHETICS AND THE ACETYLCHOLINE‐SENSITIVITY OF CORTICAL NEURONES
Authors: SMAJE J.C.
Published: July 2012

The effects of general anaesthetics on neuronal responses to iontophoretically‐applied acetylcholine have been examined in slices of guinea‐pig olfactory cortex maintained in vitro.

Acetylcholine excited 61% of the prepiriform neurones tested. The excitation was blocked by atropine, but not by dihydro‐β‐erythroidine or gallamine.

Alphaxalone reversibly depressed the acetylcholine‐sensitivity of prepiriform neurones. Pentobarbitone did not consistently depress the acetylcholine sensitivity of these cells.

Ether, methoxyflurane, trichloroethylene and halothane caused a dose‐related augmentation of acetylcholine‐induced firing.

These results show that general anaesthetics do not necessarily depress the sensitivity of nerve cells to all excitatory substances and that different anaesthetics may affect a particular excitatory process in various ways.
STRUCTURE‐ACTIVITY RELATIONS OF EXCITATORY AMINO ACIDS ON FROG AND RAT SPINAL NEURONES
Authors: BISCOE T.J. , EVANS R.H. , HEADLEY P.M. , MARTIN M.R. , WATKINS J.C.
Published: July 2012

A series of compounds structurally related to glutamic acid has been tested on frog and rat spinal neurones. The substances were added to procaine‐containing medium bathing the isolated hemisected spinal cord of the frog, and their potencies in depolarizing motoneurones were assessed by the magnitude of the potential produced in the ventral root. The electrophoretic technique was used to administer the substances around single interneurones of the rat spinal cord and the relative potencies of the compounds as excitants assessed by the magnitude of the currents required to produce similar rates of neuronal firing.

Parallel structure‐activity relations were observed in the two series of experiments, suggesting that the receptors for excitatory amino acids on frog and rat spinal neurones are similar.

Quisqualate, domoate and kainate were the strongest excitants in both animals, with potencies around two orders of magnitude higher than that of l‐glutamate.

2,4,5‐Trihydroxyphenylalanine (6‐OH‐DOPA) was a stronger excitant and l‐3,4‐dihydroxyphenylalanine (l‐DOPA) a weaker excitant than l‐glutamate on frog spinal motoneurones. The former compound was also a more potent convulsant than l‐glutamate on intraventricular injection into mouse brain. The lack of activity of 6‐OH‐DOPA on electrophoretic administration was attributed to oxidation.

Unlike the majority of amino acid excitants, several of the compounds shown in the present work to have moderate excitatory activity are not anionic at physiological pH. This indicates either that two negatively charged groups are not essential for interaction with a common excitatory receptor, or that more than one type of receptor is involved in the actions demonstrated.
SLEEP INDUCED BY DRUGS INJECTED INTO THE INFERIOR HORN OF THE LATERAL CEREBRAL VENTRICLE IN DOGS
Authors: HARANATH P.S.R.K. , VENKATAKRISHNA‐BHATT H.
Published: July 2012

1In unanaesthetized dogs, cholinomimetic drugs and their antagonists were injected into the inferior horn of the left lateral cerebral ventricle. Injection volumes of 5 μl were used to limit spread of the drugs beyond the inferior horn. The effects on EEG and behaviour were recorded and compared with the effects of the same doses given into the body of the right lateral ventricle a little behind the foramen of Monro.

2Injections of cholinomimetic drugs into the inferior horn (acetylcholine 1‐2 μg, physostigmine 1.0 μg, pilocarpine 100 μg and nicotine 10 μg) induced sleep during the following hour. The same doses injected into the body of the lateral ventricle did not produce sleep.

3Cholinolytic drugs (atropine 10‐20 μg, hyoscine 0.4‐1.6 μg, (±)‐tubocuraine 10‐20 ng and hexamethonium 40 μg) injected into the inferior horn also produced sleep, but the same doses injected into the body of the lateral ventricle were without effect. The EEG recorded after tubocurarine showed high voltage slow waves during sleep and desynchronized activation during rapid eye movement sleep.

4Noradrenaline (10 μg) injected into the inferior horn produced sleep whereas the same dose given into the body of lateral ventricle did not produce sleep. The results with 5‐hydroxytryptamine were equivocal.

5It is suggested that the site for induction of sleep lies in structures lining the inferior horn of the lateral cerebral ventricle and that the cholinomimetic drugs probably act by a depolarizing block and the acetlycholine antagonists by a competitive block.
NATURE OF HISTAMINE RECEPTORS CONCERNED IN CAPILLARY PERMEABILITY
Authors: BHARGAVA K.P. , NATH R. , PALIT G.
Published: July 2012

1Histamine and 2‐methyl‐histamine (H1‐receptor agonist) caused dose‐dependent increases in capillary permeability in albino mice, but 4‐methyl‐histamine (H2‐receptor agonist) caused no significant increase.

2Mepyramine (H1‐receptor antagonist) blocked the histamine‐induced increase in capillary permeability whereas burimamide (H2‐receptor antagonist) produced no significant blockade of the histamine‐response.

3Combined mepyramine and burimamide pretreatment did not give any significantly greater protection than mepyramine alone.

4The results indicate involvement of the H1‐receptors in histamine‐induced increase in capillary permeability.
KININ, KININOGEN AND KININASE LEVELS DURING ACUTE Babesia bovis (=B. argentina) INFECTION OF CATTLE
Authors: WRIGHT I.G.
Published: July 2012

Kinin levels began rising on day 3 after infection of cattle with Babesia bovis (=B. argentina) and attained a maximum value of 98% above preinfection levels by day 7.

Kininogen levels began falling on day 3 and reached minimum levels of 83% below preinfection levels on day 8.

Changes in both kinin and kininogen levels on day 3 coincided with the detection of low levels of parasites, and with a fall in packed cell volume.

Plasma kininase levels rose significantly 6 to 9 days after infection. Preparations of lysed and sonicated uninfected and infected red cells contained kininase activity, the respective red cell preparations being 23.9 and 11.4 times more active per mg protein than uninfected red cell preparations. The effect of pH, and the inhibitors disodium edetate, 1,10 phenanthroline and aprotinin on normal and infected plasma and on the various red cell preparations suggested that the rise in plasma kininase levels during infection was probably at least partly due to parasite products.

These results are discussed in relation to previous data showing that both kallikrein activation and the onset of hypotension also occur on or about day 3.
THE ACTION OF MELATONIN ON SINGLE AMPHIBIAN PIGMENT CELLS IN TISSUE CULTURE
Authors: MESSENGER E. ANGELA , WARNER ANNE E.
Published: July 2012

Neural crest material from neurula stage Xenopus embryos was tissue cultured as small aggregates of cells or a single cell suspension. Isolated pigment cells differentiated after 2 days in culture.

Melatonin (10−15 to 10−13 M) induced pigment granule condensation; it was 10,000 times more effective than any other compound tested.

Tests with appropriate agents showed the pigment cells to have β‐adrenoceptors and 5‐hydroxytryptamine receptors; these sites could be blocked without affecting the response to melatonin. Phentolamine blocked the effect of melatonin.

Removal of Na+ or Ca2+ from the bathing medium inhibited melatonin‐induced pigment granule condensation; 10 mM K+ induced pigment granule condensation. D600, Mn2+ and La3+, which inhibit Ca2+ entry, blocked the effect of melatonin.

Cyclic GMP induced pigment condensation and cyclic AMP pigment dispersion (10−2 to 10−4 M).

It is suggested that the action of melatonin is accompanied by depolarization and the entry of calcium ions.

Pigment cells in tissue culture could provide a useful bioassay method for melatonin.
THE RELEASE OF PROLACTIN BY MEDROXYPROGESTERONE ACETATE IN HUMAN SUBJECTS
Authors: CHAUDHURY R.R. , CHOMPOOTAWEEP S. , DUSITSIN N. , FRIESEN H. , TANKEYOON M.
Published: July 2012

Medroxyprogesterone acetate an injectable contraceptive when administered to four lactating women at a dose of 150 mg every three months significantly raised prolactin levels over those observed in four control women. Prolactin levels were higher at all times during 4–17 weeks in the drug‐treated women, irrespective of whether the samples were collected before or after suckling. It was also observed that while suckling clearly released prolactin in both groups the difference was greater in the women receiving the injection, indicating that the drug enhanced the release of prolactin in response to the suckling stimulus.
COMPARATIVE EVALUATION OF THE in vitro EFFECTS OF HYDRALAZINE AND HYDRALAZINE ACETONIDE ON ARTERIAL SMOOTH MUSCLE
Authors: BARRON K. , CARRIER O. , HAEGELE K.D. , McLEAN A.J. , McNAY J.L. , DU SOUICH P.
Published: July 2012

Dose‐response relationships to K+ were determined in isolated strips of rabit aorta.

K+ contractures were induced by 30 mM K+ in paired strips from individual animals. The effects of hydralazine and hydralazine acetone hydrazone (hydralazine acetonide) on these contractures were studied.

Hydralazine and hydralazine acetonide both produced dose‐dependent decreases of K+‐induced tone. Threshold concentrations for hydralazine were 11.89 ± 4.5 × 10−5 M (mean ± s.d.) and for hydralazine actonide 9.7 ± 4.6 × 10−5 M (0.5 < P < 0.4).

The magnitude of the effect of hydralazine acetonide was greater than that of hydralazine at all concentrations above threshold, as reflected in a significant difference (P < 0.05) in the slopes of dose‐response curves to the two treatments. The vasodilator effects of hydralazine and the acetonide were terminated by washout of the bath.

The differences in effect were not due to instability of hydralazine under in vitro conditions.

It is concluded that hydralazine acetonide has intrinsic activity on vascular smooth muscle which differs significantly from that of the parent compound and that this may contribute to the hypotensive effects which follow administration of the parent compound.
A CONFORMATIONAL ANALYSIS FOR LEUCINE‐ENKEPHALIN USING ACTIVITY AND BINDING DATA OF SYNTHETIC ANALOGUES
Authors: BEDDELL C.R. , CLARK R.B. , LOWE L.A. , WILKINSON S. , CHANG K.‐J. , CUATRECASAS P. , MILLER R.
Published: July 2012

Leucine‐enkephalin and some analogues were assayed for activity in vitro on the mouse vas deferens and for binding to opiate receptors from rat brain.

The experimental data were analysed in terms of the stringency for glycine, a D‐amino acid or an L‐amino acid at each position in the peptide.

The observed configurational specificity was compared with the stringency that would be predicted to occur if enkephalin adopted certain hydrogen‐bonded conformations at the receptor.

A small subset of the conformations examined was found to be compatible with the experimental data.
BRL 13776: A NOVEL ANTIHYPERTENSIVE AGENT WITH INTERESTING MONOAMINE DEPLETING PROPERTIES
Authors: MELROSE JOANNE , PALFREYMAN M.G. , POYSER R.H. , WHITING R.L.
Published: July 2012

Oral doses of 10‐100 mg/kg of BRL 13776 lowered the blood pressure of both deoxycorticosterone acetate (DOCA)/NaCl‐treated hypertensive rats and untreated normotensive rats.

BRL 13776 (100 mg/kg, orally) also reduced the blood pressure of renal hypertensive cats (cellophane perinephritis model).

No tolerance developed to the blood‐pressure lowering action of BRL 13776 when an oral daily dose of 100 mg/kg was administered repeatedly for up to 15 days to hypertensive rats and cats.

The fall in blood pressure to BRL 13776 in rats was associated with a reduction of tissue catecholamines.

The catecholamine depletion occurred in all the peripheral tissues examined but in the brain was restricted to certain regions, these being the hind‐brain on single dosing and the hind‐brain, hypothalamus and mid‐brain on repeated dosing. Catecholamine levels in the cerebral hemispheres were not affected by either single or repeated doses of BRL 13776.

BRL 13776 caused some reduction of the 5‐hydroxytryptamine content of the heart but not of whole brain or any brain region.

Neither single doses (up to 900 mg/kg orally) nor repeated doses (100‐300 mg/kg orally) of BRL 13776 produced any significant behavioural effects in animals.

BRL 13776 is a new type of agent to display both antihypertensive and monoamine‐depleting properties. The reduction of noradrenaline in certain brain regions may be a cause of the antihypertensive response but depletion in the periphery could contribute in a major or minor way. The differential action on noradrenaline in the brain together with the lack of effect on 5‐hydroxytryptamine might also explain the apparent absence of behavioural effects.
CANNABIS, CATECHOLAMINES, RAPID EYE MOVEMENT SLEEP AND AGGRESSIVE BEHAVIOUR
Authors: CARLINI E.A. , LINDSEY C.J. , TUFIK S.
Published: July 2012

Previous work from our laboratory has shown that cannabis induces aggressive behaviour in rats that have been deprived of rapid eye movement (REM) sleep. It was suggested that this effect was related to brain catecholamines, with dopamine playing an agonist role and noradrenaline an inhibitory one. The present paper describes new experiments dealing with this subject.

Previous REM sleep‐deprivation enhanced both Δ9‐tetrahydrocannabinol (THC)‐induced hypothermia and nomifensine effects on aggressive behaviour.

A marihuana extract decreased brain dopamine turnover in REM sleep‐deprived rats, an effect not observed in non‐deprived rats. Noradrenaline metabolism was not altered.

Fighting behaviour was elicited in REM sleep‐deprived rats treated with 4 different dopamine‐β‐hydroxylase inhibitors.

Apomorphine, nomifensine and Δ9‐THC administered to non‐deprived rats pretreated with bis(4‐methyl‐1‐homopiperanzinyl‐thiocarbonyl) disulphide (Fla‐63), induced fighting behaviour.

Nomifensine and apomorphine induced fighting in non‐deprived rats pretreated with Δ9‐THC.

Clonidine inhibited the fighting elicited in REM sleep‐deprived rats by either Δ9‐THC or Fla‐63 pretreatment.

The data are discussed in terms of the influence of REM sleep‐deprivation (or the stress associated with deprivation) on the response to dopaminergic drugs and cannabis. Taken together they emphasize the participation of brain dopamine and noradrenaline systems in the aggressive behaviour studied.
CIRCULATORY EFFECTS OF PROSTAGLANDIN ENDOPEROXIDE ANALOGUES STUDIED IN THE DOG DURING LEFT VENTRICULAR BYPASS
Authors: ALTER I. , KOT P.A. , RAMWELL P.W. , ROSE J.C. , SHNIDER M.R.
Published: July 2012

Intravenous administration of both the 9α,11α‐(epoxymethano) and 11α,9α‐(epoxymethano) analogues of prostaglandin H2 (0.25 üg/kg) produced a prominent rise in pulmonary arterial pressure and a moderate increase in systemic arterial pressure.

Direct administration of the endoperoxide analogues (1.25 μg/kg) into the bypass reservoir produced a greater rise in systemic arterial pressure and less prominent rise in pulmonary arterial pressure.

An intravenous dose of prostaglandin F2α that was 20 times larger was needed to produce a comparable rise in pulmonary arterial pressure.

The pulmonary and systemic pressor responses produced by the endoperoxide analogues were due to a direct increase in the vascular resistance.
HYPOTHALAMIC ADRENALINE SYNTHESIS AFTER STIMULATION OF THE MEDIAL FOREBRAIN BUNDLE
Authors: TORDA CLARA
Published: July 2012

The problem of whether locally released noradrenaline can be methylated to adrenaline in the hypothalamus has been investigated.

During stimulation of the medial forebrain bundle (MFB) the hypothalamic adrenaline content increased somewhat, but the increase was not statistically significant (13%, mean of 10 experiments).

After inhibition of the activity of monoamine oxidase and catechol‐ O‐methyltransferase this increase was much larger (80%, mean of 9 experiments).

Adrenalectomy did not prevent the rise in hypothalamic adrenaline after stimulation of the MFB. These results suggest that noradrenaline released during activity of noradrenergic hypothalamic structures may be methylated to adrenaline in the hypothalamus.
SOME EFFECTS OF INTRAVENOUS PROSTAGLANDIN E1 AND ENDOTOXIN IN YOUNG CHICKENS
Authors: ARTUNKAL AKGÜL A. , MARLEY E. , STEPHENSON J. D.
Published: July 2012

The effects of intravenous prostaglandin E1 and endotoxin were studied in young chickens (11–17 days old).

At a thermoneutral ambient temperature (31°C), intravenous prostaglandin E1 produced behavioural and electrocortical sleep, increased oxygen consumption and, after an initial fall, elevated body temperature. Below thermoneutrality (16°C), the initial hypothermic effect was more marked and oxygen consumption was lowered.

The soporific actions of prostaglandin E1 were sufficient to counteract dexamphetamine‐induced behavioural and electrocortical arousal and vocalization.

Intravenous injection of the O‐somatic antigen of Shigella dysenteriae evoked, after a latent period, long lasting hyperthermia. This indicates that in young chicks the blood brain barrier is probably permeable to endotoxins.
CHARACTERIZATION OF THE ADRENOCEPTOR IN THE ISOLATED CREMASTER MUSCLE OF THE GUINEA‐PIG
Authors: GUPTA R.S. , KELKAR V.V.
Published: July 2012

Contractions of the isolated cremaster muscle of the guinea‐pig obtained in response to direct electrical stimulation were augmented by salbutamol, isoprenaline, adrenaline, noradrenaline and orciprenaline (in that order of potency), and by potassium chloride. Phenylephrine and xylometazoline had no effect.

The augmenting effect of isoprenaline on the twitch response was not altered by yohimbine or tolazoline, but was totally prevented by butoxamine, (‐) −1− (4‐nitrophenyl)‐2‐isopropylaminoethanol (INPEA), (±) ‐INPEA, sotalol, metalol and practolol; (+) ‐INPEA was much less effective. The augmenting effect of potassium was not altered by β‐adrenoceptor blockade.

The results are consistent with the view that the augmenting effect of the sympathomimetic agents is mediated through β2‐type of adrenoceptor in the skeletal muscle fibres.
HYPOTENSION PRODUCED BY INTRAVENOUS APOMORPHINE IN THE ANAESTHETIZED DOG IS NOT CENTRALLY MEDIATED
Authors: BOGAERT M.G. , BUYLAERT W.A. , WILLEMS J.L
Published: July 2012

Intravenous administration of apomorphine (1.25 to 20 μg/kg) in the anaesthetized dog produced a dose‐dependent decrease in blood pressure which was antagonized by haloperidol but not influenced by propranolol or atropine.

Intracarotid administration of apomorphine produced a systemic hypotension which was significantly smaller than that seen with intravenous injection.

Doses of apomorphine that caused a decrease in blood pressure on intravenous injection, had no effect on blood pressure or caused retching accompanied by an increase in blood pressure on intravertebral or intracisternal administration. The animals showed a marked hypotension on intra‐vertebral or intracisternal injection of clonidine.

From these results it is concluded that the hypotension seen with intravenous apomorphine cannot be explained by a central site of action.
MECHANICAL RESPONSES OF THE ISOLATED CERVIX AND UTERINE HORN OF PREGNANT RATS NEAR TERM TO DRUGS
Authors: HOLLINGSWORTH M. , ISHERWOOD CATHERINE N. M.
Published: July 2012

The responses of circularly cut strips of cervix and uterine horn from rats on days 20 and 22 of pregnancy to drugs were compared in vitro.

The cervix exhibited similar responses and sensitivities to acetylcholine, bradykinin, prostaglandin (PG) F2a (day 20) and isoprenaline (day 20) as did the uterine horn but was less sensitive or responded less consistently to isoprenaline (day 22), oxytocin and PGEj. PGE2 was more potent on the cervix (day 20).

Before term the relatively inextensible connective tissue of the cervix plus contractions of the smooth muscle would help to prevent foetal expulsion. At term the cervical smooth muscle is sufficiently unresponsive to allow cervical dilatation.
EFFECT OF CROTAMINE, A TOXIN OF SOUTH AMERICAN RATTLESNAKE VENOM, ON THE SODIUM CHANNEL OF MURINE SKELETAL MUSCLE
Authors: CHANG C. CHIUNG , TSENG K. HONG
Published: July 2012

Crotamine (0.5 μg/ml) augmented the single twitch response of the rat and mouse isolated diaphragm to direct stimulation and prolonged the time course of contraction. At higher doses (10 to 50 μg/ml), contracture was observed with spontaneous fibrillation.

The resting membrane potential of diaphragm was rapidly depolarized to about −50 mV within 5 minutes. No increase of depolarization occurred on prolongation of the incubation time or increase of crotamine concentration from 0.5 μg/ml to 50 μg/ml. The effect was not reversed by washing.

Tetrodotoxin, low Na+ (12 mm), Ca2+ (10 mm) and procaine (1 mm) prevented the crotamine‐depolarization. However, depolarization resumed when crotamine and the antagonists were removed.

Low Cl− (8.5 mm) and pretreatment with ouabain enhanced depolarization by crotamine.

High K+ (25 to 50 mm) prevented the further depolarization by crotamine and the membrane potential was restored to normal on washout of crotamine with normal Tyrode solution.

Effective membrane resistance was decreased by about 50% by crotamine.

24Na‐influx of the rat diaphragm was increased by crotamine. 42K‐influx was slightly increased if tetrodotoxin was also present but was decreased in the absence of tetrodotoxin.

No effect on the miniature and evoked endplate potential of the rat diaphragm was observed. Skeletal muscles from frog and chick were not affected.

It is inferred that crotamine acts on a molecule regulating the Na+‐ permeability of the Na+ channel of murine muscles. It is proposed that extracellular K+ depresses the permeability of the Na+ channel by acting on the same regulator molecule.
COMPARISON OF THE ACTIONS OF OCTOPAMINE AND CATECHOLAMINES ON SINGLE NEURONES OF THE RAT CEREBRAL CORTEX
Authors: HICKS T.P. , McLENNAN H.
Published: July 2012

The technique of microelectrophoresis was used to compare the actions of octopamine, noradrenaline and dopamine on single cortical neurones of the rat.

Octopamine both excited and depressed neurones of the cortex. Frequently cells depressed by noradrenaline were excited by octopamine; occasionally the converse was true. The time courses of action of the two amines also differed. Dopamine‐elicited excitations were observed, but also were not correlated with octopamine‐elicited effects.

When octopamine and noradrenaline both caused depressant effects, octopamine frequently was of less apparent potency than noradrenaline. When these amines were excitatory, octopamine appeared at least as and sometimes more potent than noradrenaline.

Octopamine was only weakly effective on cortical neurones identified by antidromic stimulation of the pyramidal tract, or synaptically excited by stimulation of the ventrobasal thalamus.

α‐Flupenthixol and propranolol were without effect on octopamine‐elicited changes in firing rate at doses which were effective in blocking the actions of dopamine and noradrenaline respectively. Metoclopramide did not block the actions of any of the three agonists, but had strong effects of its own.

The results suggest that receptors sensitive to octopamine, and which appear to be pharmacologically distinct from those previously categorized as noradrenaline and dopamine receptors, may exist on central neurones of the rat.
A PHARMACOLOGICAL INVESTIGATION OF THE ELECTRICALLY EVOKED CONVULSIVE ACTIVITY INDUCED BY ADMINISTRATION OF CATECHOL IN THE ANAESTHETIZED RAT
Authors: ANGEL A. , DEWHURST D.G.
Published: July 2012

The response evoked by electrical stimulation at the wrist has been recorded from muscles of the forelimb of anaesthetized rats induced to convulse by administration of catechol.

This response can be divided into three temporally distinct components, the characteristics of which have been described.

The probability of occurrence of the two early components of the response has been measured before and after administration of various drugs. The results show that the first component is not affected by cholinoceptor or adrenoceptor blocking drugs or anticholinesterase agents. The probability of occurrence of the second component is significantly reduced by cholinoceptor blocking drugs and increased by physostigmine.

The implications of these results in explaining the convulsant actions of catechol are discussed.
FACTORS INFLUENCING THE RELEASE OF ACETYLCHOLINE FROM THE MYENTERIC PLEXUS OF THE ILEUM OF THE GUINEA‐PIG AND RABBIT
Authors: COWIE A. LOUISE , KOSTERLITZ H.W. , WATERFIELD ANGELA A.
Published: July 2012

The effects of electrical stimulation, changes in external ion concentrations and various drugs on acetylcholine release from the myenteric plexus were measured by bioassay in the presence of physostigmine and by recording the responses of the longitudinal muscle. In preparations from the guinea‐pig, the acetylcholine output per pulse increased with decreasing frequency of stimulation and reached its maximum at a frequency of 0.017 Hz (1/min) and thus ensured that the output per unit of time was constant at frequencies below 0.5 Hz. Spontaneous release was suppressed during stimulation at 0.017 Hz.

In the rabbit, the fractional acetylcholine release was lower than in the guinea‐pig. The output per pulse increased with decreasing frequency of stimulation but at a lesser rate, with the effect that the output per unit time decreased between 0.5 and 0.017 Hz.

In the guinea‐pig, reduction of the Ca2+ concentration, addition to the bath fluid of Mn2+, ganglion‐blocking drugs, morphine and catecholamines reduced output more at low than at high frequencies of stimulation. In the rabbit, acetylcholine output was less sensitive to changes in Ca2+ concentration and insensitive to Mn2+ and morphine.

In the guinea‐pig, morphine and catecholamines depressed both the contractile response and acetylcholine output whereas Mn2+ in concentrations up to 125 μm, bretylium and ganglion‐blocking drugs depressed only acetylcholine output.

In preparations from the guinea‐pig, drugs blocking noradrenergic neurones or α‐adrenoceptors, e.g. bretylium, phenoxybenzamine, thymoxamine and phentolamine, increased acetylcholine output during stimulation at high (1.5 to 10 Hz) but not at low frequencies.

The implications of these findings for the release of acetylcholine from different pools in the heterogeneous myenteric plexus are considered. The possible errors, introduced by the effects of physostigmine, on the size of the acetylcholine pools and on the transmission of impulses within the myenteric plexus are discussed.
COMPARISON OF THE RECEPTOR BINDING CHARACTERISTICS OF OPIATE AGONISTS INTERACTING WITH μ‐ OR K‐RECEPTORS
Authors: KOSTERLITZMM H.W. , LESLIE FRANCES M.
Published: July 2012

The receptor binding characteristics of various morphine‐like and ketazocine‐like opiate agonists were measured by inhibition of [3H]‐naloxone binding in homogenates of brain and of ileal myenteric plexus‐longitudinal muscle of the guinea‐pig. No differences were found for the two tissues.

The depressant effect of Na+ on the inhibition of [3H]‐naloxone binding by opiate agonists varies widely, giving sodium shifts between 5 and 140. The relationship between Na+ concentration and inhibition of binding is non‐linear, the magnitude of the sodium shift varying directly with the slope of the regression of log IC50 on log [NaCl].

The sodium shift of ketazocine‐like agonists is lower than that of morphine‐like agonists but higher than that of opiates with dual agonist and antagonist action. A working hypothesis is proposed which suggests that the /c‐receptors for the ketazocine‐like drugs are less susceptible to the Na+ effect than the u‐receptors for the morphine‐like drugs.

For most of the morphine‐like but not the ketazocine‐like agonists, a good correlation has been found for the pharmacological activity in the myenteric plexus‐longitudinal muscle preparation and the inhibition of binding of [3H]‐naloxone at 12 mm Na+. An exception is fentanyl which has a much greater pharmacological potency than may be expected from its potency in inhibiting [3H]‐naloxone binding.
RELEASE OF [3H]‐N0RADRENALINE FROM THE MOTOR ADRENERGIC NERVES OF THE ANOCOCCYGEUS MUSCLE BY LYSERGIC ACID DIETHYLAMIDE, TYRAMINE OR NERVE STIMULATION
Authors: McGRATH J.C. , OLVERMAN H.J.
Published: July 2012

A method is described for labelling the neuronal noradrenaline (NA) stores of rat anococcygeus with [3H]‐NA and detecting subsequent release of 3H from the superfused tissue by nerve stimulation or drugs.

Lysergic acid diethylamide (LSD) or tyramine but not barium chloride or carbachol increased the efflux of 3H although each drug produced an equivalent contractile response. This confirms that LSD has an indirect sympathomimetic action.

LSD was found to produce a proportionately smaller reduction of the nerve‐induced efflux of 3H than of the accompanying contractile response.

The inhibition of nerve‐induced contractile responses by LSD was shown to be independent of the neuronal uptake of noradrenaline and any post‐junctional inhibition demonstrated to be non‐specific.
CORONARY ANAPHYLAXIS in vitro
Authors: CHAND N. , EYRE P.
Published: July 2012

The reactivity of isolated coronary arteries and cardiac veins of the calf to selected chemical mediators of anaphylaxis and to sensitizing antigen (horse plasma) was studied.

Both the coronary arteries and cardiac veins contracted to bradykinin, 5‐hydroxytryptamine (5‐HT), prostaglandin E2 (PGE2), PGF2α, histamine and carbachol.

Isoprenaline and PGE1 relaxed vessels which had been partially contracted by PGF2α, PGE2, histamine, 5‐HT, bradykinin, carbachol or antigen.

Horse plasma (antigen) contracted coronary vessels obtained from sensitized calves, but not from control calves. Subsequent antigen ‘challenge’ produced ‘desensitization’ (tachyphylaxis). After 1 or 2 h of rest, the anaphylactic response partially recovered although there was no change in tissue reactivity to the exogenous agonists.

Specific doses of atropine, mepyramine (H1‐blocker) and methysergide (5‐HT antagonist) did not modify the anaphylactic reaction in coronary arteries, suggesting a negligible role for these biogenic amines.

Compound PRD‐92‐EA (a new anti‐allergic agent) exhibited non‐specific receptor blocking activity towards histamine, 5‐HT and carbachol and inhibited the coronary anaphylactic reaction.
THE INFLUENCE OF CEREBRAL 5‐HYDROXYTRYPTAMINE ON CATALEPSY INDUCED BY BRAIN‐AMINE DEPLETING NEUROLEPTICS OR BY CHOLINOMIMETICS
Authors: FUENMAYOR LUIS D. , VOGT MARTHE
Published: July 2012

Catalepsy was produced in rats and mice by the subcutaneous injection of either tetrabenazine or the butyrophenone U‐32,802A (4′‐fluoro‐4‐{[4‐(p‐fluorophenyl)‐3‐cyclohexen‐1‐yl]amino} butyrophenone hydrochloride). Catalepsy was evaluated by the duration of total immobility on a vertical grid.

Pretreatment with p‐chlorophenylalanine (PCPA) reduced the intensity of catalepsy by 50% or more, whereas its time course remained the same.

5‐Hydroxytryptophan (5‐HTP), 10 mg/kg, enhanced the catalepsy induced by U‐32,802A or tetrabenazine, provided it was administered soon (45 min) after the neuroleptic; injections at 90 min had no effect. Otherwise untreated rats given this dose of 5‐HTP behaved normally on the grid.

The anticataleptic effect of PCPA was reversed by 5‐HTP.

Measurable changes in 5‐hydroxytryptamine (5‐HT) metabolism in the rat forebrain accompanied the modification of catalepsy by 5‐HTP and PCPA.

Methysergide (5 mg/kg) given 30 min before the neuroleptics to either mice or rats reduced the catalepsy, assessed 2.5 h after the methysergide. It also prevented the increase in neuroleptic‐induced catalepsy following 5‐HTP, 10 mg/kg.

Tryptophan, like 5‐HTP, increased the catalepsy seen in mice after U‐32,802A and tetrabenazine, and increased the production of 5‐hydroxyindol‐3‐ylacetic acid in the forebrain.

In the rat, intracerebroventricular injection of physostigmine produced catalepsy which was not modified by methysergide or PCPA but was abolished by atropine. Similarly, in the mouse, catalepsy induced by the subcutaneous injection of pilocarpine was abolished by atropine but not affected by either methysergide or 5‐HTP.

Atropine greatly reduced the catalepsy induced by U‐32,802A and tetrabenazine but lowered striatal homovanillic acid (HVA) only after U‐32,802A. d, l‐DOPA, 20 mg/kg, diminished the cataleptogenic effect of both neuroleptics and raised striatal HVA.

The results support the view that there is a facilitating or permissive action of 5‐HT‐containing neurones on neuroleptic‐induced catalepsy.
EFFECTS OF THE HISTAMINE H2‐RECEPTOR BLOCKING DRUGS BURIMAMIDE AND CIMETIDINE ON NORADRENERGIC TRANSMISSION IN THE ISOLATED AORTA OF THE RABBIT AND ATRIA OF THE GUINEA‐PIG
Authors: McCULLOCH M.W. , MEDGETT I.C. , RAND M.J.
Published: July 2012

In rabbit aortic strips, concentration‐response curves to noradrenaline (NA) were shifted to the right in a parallel and concentration‐dependent manner by the α‐adrenoceptor blocking drug, phentolamine and also by the histamine H2‐receptor blocking drugs, burimamide and cimetidine. Responses to 5‐hydroxytryptamine were not affected by these drugs.

Burimamide had the properties of a competitive antagonist of noradrenaline, possessing about one‐hundredth the potency of phentolamine. Cimetidine was weaker than burimamide and did not fulfil the requirements for competitive antagonism of noradrenaline.

In guinea‐pig isolated atria, in which noradrenergic transmitter stores were labelled with [3H]‐noradrenaline, phentolamine (3 μm), burimamide (30 μm) and cimetidine (30 μm), in decreasing order of effectiveness, each enhanced stimulation‐induced efflux of [3H]‐noradrenaline, indicating that their blocking effects on prejunctional α‐adrenoceptors in this tissue are in the same order of relative potency as on postjunctional α‐adrenoceptors in rabbit aortic strips.

In the concentrations used (30 μm), neither burimamide nor cimetidine interfered with the neuronal uptake of noradrenaline. Burimamide, and to a much lesser extent, cimetidine, increased the resting efflux of [3H]‐noradrenaline from guinea‐pig atria.

The effect of clonidine, a partial agonist on prejunctional α‐adrenoceptors in guinea‐pig atria, in increasing stimulation‐induced efflux of [3H]‐noradrenaline when stimulated with 150 pulses at 5 Hz was blocked by cimetidine (30 μm) and reversed by phentolamine (3 μm) and burimamide (30 μm).
THE EFFECTS OF SODIUM CROMOGLYCATE ON LUNG IRRITANT RECEPTORS AND LEFT VENTRICULAR CARDIAC RECEPTORS IN THE ANAESTHETIZED DOG
Authors: DIXON M. , JACKSON D.M. , RICHARDS I.M.
Published: July 2012

The time from the injection of sodium cromoglycate 10 to 50 μg/kg into a saphenous vein, the cervical carotid arteries, the left ventricle and the aortic arch, to the onset of reflex hypotension has been measured in anaesthetized dogs. The shortest latency was 16.9 s on injection of sodium cromoglycate into the left ventricle.

Instillation of 2% lignocaine into the pericardium of an anaesthetized dog blocked the reflex hypotensive response to sodium cromoglycate (10 to 50 μg/kg i.v.), and also prevented sodium cromoglycate (100 μg/kg) from reversing reflex bronchoconstriction induced by inhalation of an aerosol of histamine.

The effect of sodium cromoglycate (100 μg/kg i.v.) on resting discharge and histamine‐induced discharge (20 μ/kg i.v.) of five lung irritant receptors in five anaesthetized dogs has been studied. Sodium cromoglycate (100 μg/kg i.v.) did not affect the resting discharge of these receptors or their ability to respond to histamine.

Sodium cromoglycate (100 μg/kg i.v.) increased the rate of discharge of three receptors found in the endocardium of the left ventricle of the canine heart. A solution of sodium cromoglycate (0.1%) was applied topically to one receptor and its rate of discharge was increased.

It is suggested that in the dog, sodium cromoglycate produces reflex hypotension and reverses histamine‐induced reflex bronchoconstriction by activating receptors in the left ventricle of the heart.
CALCIUM REQUIREMENTS FOR ELECTRICALLY‐INDUCED RELEASE OF AN ENDOGENOUS OPIATE RECEPTOR LIGAND FROM THE GUINEA‐PIG ILEUM
Authors: OKA TETSUO , SAWA AIKO
Published: July 2012

Calcium requirements for electrically‐induced release of an endogenous opiate receptor ligand in the myenteric plexus‐longitudinal muscle strip of the guinea‐pig ileum were studied. The naloxone‐reversible depression of the electrically evoked contraction caused by stimulation at 10 Hz in normal Krebs solution was markedly reduced by decreasing the calcium concentration in the solution. The depression was greatly diminished by increasing the magnesium concentration in the solution. These results show that the electrically‐induced release of an opiate‐like material requires calcium ions.
PURINE ANTAGONISTS IN THE IDENTIFICATION OF ADENOSINE‐RECEPTORS IN GUINEA‐PIG TRACHEA AND THE ROLE OF PURINES IN NON‐ADRENERGIC INHIBITORY NEUROTRANSMISSION
Authors: COLEMAN R.A.
Published: July 2012

To test the possibility that adenosine receptors exist within the trachea of the guinea‐pig, an attempt has been made to identify a compound with adenosine antagonist activity in this tissue.

Quinidine, phentolamine, phenoxybenzamine, 2–2′‐pyridylisatogen tosylate (PIT) and caffeine were tested for antagonism of spasmolytic responses to adenosine, adenosine 5′‐triphosphate (ATP) and adenine on the guinea‐pig isolated trachea.

Quinidine (10 and 25 μg/ml), phentolamine (10 and 30 μg/ml) and phenoxybenzamine (10 μg/ml) had little or no effect on response to adenosine, ATP and adenine. PIT (21 μg/ml) potentiated responses to adenosine, ATP and adenine by an unexplained mechanism.

Caffeine (25 μg/ml) partially relaxed the trachea and inhibited spasmolytic responses to both adenosine and ATP, but not to adenine, isoprenaline, aminophylline or prostaglandin E2 (PGE2).

A number of compounds related to caffeine (xanthine, hypoxanthine, theophylline and theobromine) were tested for adenosine antagonist activity. Xanthine (300 μg/ml) and hypoxanthine (300 μg/ml) did not relax the trachea or antagonize spasmolytic responses to adenosine. Both theophylline (10 μg/ml) and theobromine (30 μg/ml) partially relaxed the trachea; theophylline, but not theobromine, antagonized spasmolytic responses to adenosine.

pA2 values for caffeine and theophylline as antagonists of adenosine were 4.3 and 4.7 respectively. However, the slopes of the Schild plot regressions were significantly less than 1.0 for both compounds.

Four compounds, adenine, AH 8883, M30966 and ICI 63197, which like caffeine and theophylline, have phosphodiesterase inhibitory activity were tested for adenosine antagonist activity in the trachea. Adenine and AH 8883 had no effect and M30966 and ICI 63197 caused significant potentiation.

The effects of caffeine and theophylline were also investigated on the non‐adrenergic inhibitory response to nerve stimulation (NAIR). Both caffeine (100 μg/ml, n = 4) and theophylline (30 μg/ml, n = 4) enhanced the NAIR (20 Hz) while virtually abolishing matched responses to exogenous adenosine.

The results support the existence of adenosine receptors in the guinea‐pig trachea.
HYDRALAZINE: EFFECT ON THE OUTFLOW OF NORADRENALINE AND MECHANICAL RESPONSES EVOKED BY SYMPATHETIC NERVE STIMULATION OF THE RAT TAIL ARTERY
Authors: CHEVILLARD C. , MATHIEU M.N. , SAIAG B. , WORCEL M.
Published: July 2012

The effects of hydralazine on the vasoconstrictor responses to field stimulation of sympathetic nerves were studied in the isolated proximal segments of the rat tail artery. Vasoconstrictor responses to transmural stimulation were depressed by superfusion of hydralazine (0.3, 3 and 30μm) in a concentration‐dependent manner. The inhibition appeared slowly and was not easily reversed by washing.

Hydralazine (30 nm, 0.3 and 3 μm) reduced the stimulation‐induced overflow of tritium from proximal and distal segments of the tail artery labelled with [3H]‐noradrenaline in a concentration‐dependent manner. This phenomenon appeared rapidly and was easily reversed by washing.

Theophylline (0.5 mm) did not affect the inhibitory effect of hydralazine on the stimulation‐induced tritium efflux from the distal segment of the rat tail artery.

The present results indicate that hydralazine has, in addition to its action on vascular smooth muscle, a very marked effect on sympathetic nerve terminals. The mechanism of this presynaptic inhibition appears to be different from the postsynaptic effect, in view of the much shorter delay, the shape of the dose‐effect curve, and the lack of interaction with theophylline.
SITES OF ACTION OF MOJAVE TOXIN ISOLATED FROM THE VENOM OF THE MOJAVE RATTLESNAKE
Authors: GOPALAKRISHNAKONE P. , HAWGOOD B.J. , HOLBROOKE S.E. , MARSH N.A. , DE SA S. SANTANA , TU A.T.
Published: July 2012

Mojave toxin isolated from the venom of the Mojave rattlesnake (Crotalus scutulatus scutulatus) produced an irreversible blockade of the contractile response of the mouse hemidiaphragm to stimulation of the phrenic nerve in vitro, at concentrations of 0.16 to 20 μg/ml; the response to direct stimulation was not affected over a testing period of several hours.

Mojave toxin (1 to 4 μg/g) was injected into the tail vein of mice and the intoxicated hemidiaphragm preparation was removed either for testing the contractile response or for intracellular recording.

In fully intoxicated hemidiaphragms the contractile response to indirect stimulation was either small and transient or absent, whilst the response to direct stimulation was well maintained.

Intracellular recording showed that resting membrane potentials of the muscle fibres were within the normal range. Endplates were difficult to locate but miniature endplate potentials (m.e.p.ps) were recorded at sites at which neurally evoked responses either could not be detected or did not exceed 2 mV which corresponds to transmitter release of a few quanta only.

The mean frequency of m.e.p.ps at fully intoxicated endplates was not significantly different from controls but potassium depolarization produced only a small increase in m.e.p.p. frequency relative to the control response. A 50 Hz tetanus had no effect on m.e.p.p. frequency.

When a sub‐lethal dose (3 μg) of Mojave toxin was injected into one hindlimb of mice and the tissues examined at 72 h, there was histological evidence of myonecrosis.

The isolated perfused heart of the rat was exposed to recycled Mojave toxin (50 and 100 μg/ml) but showed no change in rate or force of ventricular contraction.

Post‐mortem examination of intoxicated mice showed a frequent incidence of localized areas of interstitial and intra‐alveolar haemorrhage in the lungs. Other organs including skin and muscle were not affected.

Mojave toxin showed antigenic similarities to crotoxin, the lethal neurotoxin in the venom of the South American rattlesnake, as determined by the ability of antiserum raised against crotoxin to neutralize Mojave toxin.

With systemic Mojave intoxication of rapid onset, the cause of death was respiratory paralysis. However, the toxin acts at multiple sites at differing rates of action. With a slower rate of intoxication, impaired respiration may act synergistically with cardiovascular changes to produce circulatory failure. The desirability of using an antivenin with a high titre against Mojave toxin is indicated.
THE EFFECTS OF SOME ANTIRHEUMATIC DRUGS ON AN in vitro MODEL OF HUMAN POLYMORPHONUCLEAR LEUCOCYTE CHEMOKINESIS
Authors: SMITH M.J.H. , WALKER J.R.
Published: July 2012

A rapid, reproducible in vitro assay for studying the chemokinetic movement of human polymorphonuclear leucocytes (PMNs) is described. Two synthetic peptides, formyl methionyl‐leucylphenylalanine (FMLP) and formyl methionyl‐phenylalanine (FMP), were used as standard chemokinesins.

Maximal chemokinetic movement was observed with peptide concentrations of 2.5 nm (FMLP) and 100 μm (FMP). EC50 values of 650.0 ± 60.0 pm and 27.0 ± 3.5 μm respectively are similar to those reported for chemotactic activity of the peptides in micropore filter assays.

The PMN chemokinetic response to FMLP was enhanced by histamine (100 nm) and vitamin C (2.5 μm).

Human serum albumin was shown to induce chemokinesis but to antagonize the response to FMLP in a dose‐related fashion. Fibrinogen similarly antagonized the cell response to peptide.

Levamisole (250 nm to 2.5 μm) significantly potentiated the chemokinetic responses to FMLP and FMP in a dose‐related manner. The chemokinetic response to FMLP was unaffected by d‐penicillamine (250 μm to 10 mm) while alclofenac (500 μm to 1 mm), salicylic acid (250 μm to 10 mm) and indomethacin (100 μm to 1 mm) caused dose‐related inhibition.
A CLASSIFICATION OF OPIATE RECEPTORS THAT MEDIATE ANTINOCICEPTION IN ANIMALS
Authors: TYERS M.B.
Published: July 2012

To investigate the opiate receptors that mediate antinociception, the activity profiles of opioid analgesic drugs have been determined against different nociceptive stimuli in the mouse and rat.

In tests that employ heat as the nociceptive stimulus, μ‐opiate receptor agonists, such as morphine, pethidine and dextropropoxyphene, had steep and parallel dose‐response curves and were capable of achieving maximum effects. In addition, the antinociceptive potency ratios of these drugs in heat tests were similar to those for analgesia in man.

The κ‐agonists, such as ethylketazocine, nalorphine, Mr2034 and pentazocine, were essentially inactive against heat nociception except at doses that caused sedation and motor incapacitation.

In the writhing and paw pressure tests both μ‐ and κ‐agonists produced steep and parallel dose‐response curves.

It is concluded that both μ‐ and κ‐opiate receptors mediate antinociception in animals and that the interactions of analgesic drugs with these receptors may be classified in terms of their antinociceptive activities against qualitatively different nociceptive stimuli.
EFFECTS OF DIAZEPAM ON ADENOSINE AND ACETYLCHOLINE RELEASE FROM RAT CEREBRAL CORTEX: FURTHER EVIDENCE FOR A PURINERGIC MECHANISM IN ACTION OF DIAZEPAM
Authors: PHILLIS J.W. , SIEMENS R.K. , WU P.H.
Published: July 2012

Diazepam administered intraperitoneally (0.25 mg/kg) enhanced the rate of efflux of [3H]‐adenosine and its metabolites from rat cerebral cortex. At a lower dose (0.05 mg/kg), this effect could be detected in only one of four rats.

Diazepam (0.05 and 0.25 mg/kg i.p.) depressed acetylcholine release from the rat cerebral cortex. Its effect was reversed by theophylline.

Theophylline (15 and 30 mg/kg) enhanced acetylcholine release from the rat cerebral cortex. Diazepam (0.25 mg/kg) administered after theophylline failed to cause a reduction in the rate of release, rather there appeared to be a further enhancement of release.

Pentobarbitone sodium (5, 10 and 15 mg/kg i.p.) did not elicit any increase in adenosine release.

These results support the proposal that benzodiazepines may exert their pharmacological actions by preventing adenosine uptake, thus enhancing the levels of extracellular adenosine.