bluuebunny/crossref_metadata_2025 huggingface dataset:
THE INHIBITION BY GLUCAGON OF THE VASOCONSTRICTOR ACTIONS OF NORADRENALINE, ANGIOTENSIN AND VASOPRESSIN ON THE HEPATIC ARTERIAL VASCULAR BED OF THE DOG
Authors: RICHARDSON P.D.I. , WITHRINGTON P.G.
Published: July 2012

The hepatic artery of the anaesthetized dog was cannulated and perfused from a femoral artery, the blood flow and perfusion pressure being monitored continuously. The sympathetic periarterial nerves were divided.

Dose‐dependent increases in hepatic arterial vascular resistance (HAVR) resulted from intraarterial injections of noradrenaline, angiotensin and vasopressin.

Single injections of glucagon (100 μg, i.a.) caused a transient significant fall in HAVR of 19.9 ± 3.2%, and infusions of 25 μg/min of glucagon intra‐arterially caused maintained reductions in HAVR of 16.9 ± 4.2%.

After single injections of 100 μg glucagon intra‐arterially the vasoconstrictor responses to noradrenaline, angiotensin, and vasopressin were reduced by about 85–95%. Recovery occurred in 8–10 minutes.

Intra‐arterial infusions of glucagon, 2.5–50.0 μg/min, reduced the effects of test doses of noradrenaline, angiotensin and vasopressin throughout the period of the infusions.

Dose‐response curves to the constrictor agents were constructed before, during and after intraarterial infusions of 25 μg/min of glucagon. Glucagon caused a parallel shift of the curves for noradrenaline and angiotensin to the right, with no suppression of the maximum response.

Infusions of glucagon shifted the dose‐response curve for vasopressin to the right, but, in contrast to noradrenaline and angiotensin, the shift was nonparallel and there was a suppression of the maximum response by about one‐half.

A large dose of insulin, 10 iu, transiently reduced HAVR and caused a weak and very transient inhibition of the effect of test doses of noradrenaline. The characteristics of these effects were quite different from those of glucagon.

It is possible that the antagonism by glucagon of the vasoconstrictor responses of the hepatic arterial vasculature may be important in protecting this vascular bed from the effects of concomitantly released vasoconstrictor agents.
THE DIFFERENT EFFECTS OF D‐600 (METHOXYVERAPAMIL) ON THE RELEASE OF ADRENAL CATECHOLAMINES INDUCED BY ACETYLCHOLINE, HIGH POTASSIUM OR SODIUM DEPRIVATION
Authors: PINTO J.E.B. , TRIFARÓ J.M.
Published: July 2012

Bovine adrenal glands were perfused with Locke solution and catecholamine release was induced by acetylcholine, by a depolarizing concentration of potassium, or by omission of sodium from the perfusion fluid.

D‐600 (methoxyverapamil) at the concentration of 30 μm produced a 23% inhibition of catecholamine release evoked by acetylcholine (0.1 mm) in the presence of physostigmine (10 μm).

A concentration of D‐600 of 0.3 mm produced 86% and 85% inhibition in the output of catecholamines in response to acetylcholine and high potassium respectively.

D‐600 (0.3 mm) failed to block the release of catecholamines evoked by sodium deprivation.

The results suggest the involvement of intracellular calcium in the exocytotic release of catecholamines induced by sodium omission.
EFFECTS OF SYMPATHOMIMETIC AMINES ON 45Ca EFFLUX FROM LIVER SLICES
Authors: HAYLETT D.G.
Published: July 2012

The efflux of 45Ca from slices of guinea‐pig and rabbit liver is greatly increased by α‐adrenoceptor agonists. Isoprenaline is much less effective. The effects of these agents on the efflux of 45Ca mirror their actions on 42K loss and suggest that the two may be related. Glucose release from both rabbit and guinea‐pig liver slices is increased to a similar extent by either α‐ or β‐receptor agonists. The possible relationship between Ca and K movements and the production of glucose is discussed.
MECHANISM OF NEUROTOXICITY OF CARDIOTONIC GLYCOSIDES
Authors: GAITONDÉ B.B. , JOGLEKAR S.N.
Published: July 2012

1In cats intracerebroventricular administration of 5, 10, 20 μg of peruvoside, a cardiac glycoside obtained from the plant, Thevetia neriifolia, and 10 and 20 μg of ouabain, produced marked neurotoxicity. This was dose‐related.

2Prior administration of reserpine (2 mg/kg i.m., 500 μg i.c.v.) or tetrabenazine (25 mg/kg i.v., 50 mg/kg i.v. and 2 mg/kg i.c.v.) suppressed the neurotoxicity, but lithium carbonate (100 mg/kg i.p., 2 mg i.c.v.) and haloperidol (200 μg i.c.v.) were ineffective.

3Prior administration of 2‐bromolysergic acid diethylamide (BOL‐148, 200 μg i.c.v.) or p‐chlorophenylalanine (PCPA) (400 mg/kg i.p.) suppressed the neurotoxicity induced by peruvoside and ouabain.

4Perfusion of the lateral ventricles of cats with 10, 20 and 30 μg of peruvoside or ouabain produced a massive release of 5‐hydroxytryptamine (5‐HT). This was dose‐related. Prior administration PCPA suppressed the release of 5‐HT.

5The results of the findings indicate the involvement of 5‐HT in the genesis of neurotoxicity induced by peruvoside or ouabain.
THE ROLE OF BACTERIAL CONTAMINATION IN THE ISOLATION OF APPARENT ANTI‐INFLAMMATORY FACTORS FROM RABBIT ANTI‐LYMPHOCYTIC SERUM
Authors: MAGUIRE E.D. , WALLIS R.B.
Published: July 2012

1Rabbit anti‐guinea‐pig lymphocytic serum was fractionated by gel filtration to obtain partially purified materials possessing anti‐inflammatory activity. The pharmacological properties of these materials were then studied.

2Two fractions were found which reproducibly contained significant activity. One of these activities caused inflammation at the site of injection and was associated with high molecular weight protein (200,000). The other activity was found in a low molecular weight fraction but was shown to be due to small amounts of endotoxin from Gram negative bacteria. These organisms contaminated the fractions in spite of the recommended precautions for gel filtration having been taken.

3The endotoxin‐containing fraction completely abolished leucocyte infiltration into the rat foot which had been injected with kaolin. It had no apparent effect on circulating haemolytic complement. It caused maximal elevation of serum 11‐hydroxycorticosteroid concentrations and was found to cause the release of pharmacologically active amines. Many of the previously reported naturally occurring anti‐inflammatory substances have similar pharmacological properties to those of the endotoxin‐containing fraction.

4It was concluded that doubt will exist about the presence of anti‐inflammatory factors in mammalian body fluids unless stringent precautions are taken to exclude measurable bacterial contamination.

5These experiments also cast doubt on the validity of accepted procedures for excluding microbial growth from columns used in the fractionation of serum.
THE EFFECT OF CONFORMATIONALLY RESTRICTED AMINO ACID ANALOGUES ON THE FROG SPINAL CORD in vitro
Authors: NICOLL R.A.
Published: July 2012

1The isolated spinal cord of the frog (Rana pipiens) was used to examine the structural requirement for the activity of neutral amino acids. The potencies of the aliphatic amino acids, γ‐aminobutyric acid (GABA), β‐alanine and glycine were compared with the potencies of conformationally restricted cyclopentane and cyclohexane amino acid analogues. Both motoneurone hyperpolarizing and primary afferent depolarizing activity were examined in this study.

2On motoneurones β‐alanine was the most potent aliphatic amino acid and glycine the least potent. Of the substituted aminocyclopentane carboxylic acids, that compound with a separation of amino and carboxylic acid groups closest to that of the extended GABA molecule (4.74 Å) had a potency similar to GABA. As the separation decreased the hyperpolarizing activity fell off rapidly. The substituted aminocyclohexane carboxylic acids were generally inactive even at a concentration of 10 mm.

3Strychnine blocked the motoneurone hyperpolarizing responses to all compounds with a distance between the amino and carboxylic acid groups of 3.66 Å or less, but did not block the response of compounds with a distance of 4.08 Å or greater. Picrotoxin and bicuculline antagonized all the responses to varying degrees and therefore were of little value in characterizing the responses.

4On the primary afferents GABA was the most potent aliphatic amino acid and glycine the least potent. The substituted aminocyclohexane carboxylic acids were generally inactive on primary afferents. The response of the substituted aminocyclopentane carboxylic acid whose separation of amino and carboxylic acid groups was closest to that of the extended GABA molecule was most similar to the GABA response. However, (±)‐cis‐3‐aminocyclopentane‐carboxylic acid (separation=4.08 Å), which mimicked the action of GABA on motoneurones, closely mimicked the depolarizing action of β‐alanine on primary afferents.

5The findings suggest that the hyperpolarizing GABA receptor on motoneurones will accept a molecule whose amino and carboxylic acid groups are separated by a distance of 4.08 Å or greater while the glycine receptor will accept a compound with a distance of 3.66 Å or less. The depolarizing GABA receptors on primary afferents appear to be more selective since they are not activated by (±)‐cis‐3‐aminocyclopentane carboxylic acid (separation=4.08 Å), while the motoneurone receptors are.
REPEATED CHLORPROMAZINE ADMINISTRATION INCREASES A BEHAVIOURAL RESPONSE OF RATS TO 5‐HYDROXYTRYPTAMINE RECEPTOR STIMULATION
Authors: GREEN A.R.
Published: July 2012

1The hyperactivity syndrome produced in rats by administration of tranylcypromine (20 mg/kg i.p.) followed 30 min later by l‐tryptophan (50 mg/kg i.p.) is generally considered to be due to increased 5‐hydroxytryptamine (5‐HT) functional activity. It is inhibited by chlorpromazine (30 mg/kg i.p.) injected 60 min before the tranylcypromine. However, chlorpromazine injection for 4 days either at a dose of 30 mg/kg once daily or 5 mg/kg twice daily results in an enhanced hyperactivity response to tranylcypromine and l‐tryptophan administration 24 h after the final dose of chlorpromazine.

2One injection of chlorpromazine (30 mg/kg) did not produce enhancement 24 h later and the inhibition of the tranylcypromine/l‐tryptophan hyperactivity observed after acute chlorpromazine injection was seen if the rats were given tranylcypromine and l‐tryptophan 1 h after the fourth chlorpromazine (30 mg/kg) dose.

3Chlorpromazine (30 mg/kg) once daily or 5 mg/kg twice daily for 4 days resulted in rats displaying enhanced behavioural responses to the suggested 5‐HT agonist 5‐methoxy N,N‐dimethyltryptamine (2 mg/kg) on day 5.

4Chlorpromazine (30 mg/kg) once daily for 4 days produces a slight increase in brain 5‐hydroxytryptamine (5‐HT) concentration on day 5, but no difference in the rate of brain 5‐HT synthesis or the rate of 5‐HT accumulation after tranylcypromine and l‐tryptophan administration.

5There is some evidence that chlorpromazine blocks 5‐HT receptors. It has also been observed that several other neuroleptic drugs do not produce enhanced 5‐HT responses after repeated administration. It is suggested therefore that the enhanced behavioural response to 5‐HT receptor stimulation following repeated chlorpromazine administration may be because this drug blocks 5‐HT receptors.
THE EFFECT OF CATECHOLAMINES ON THE in vivo AND in vitro RESPONSES OF THE CAT LUNG DURING ANAPHYLAXIS
Authors: MITCHELL H.W. , SPARROW M.P.
Published: July 2012

Anaphylaxis in the lung of cats actively sensitized to Ascaris antigen has been investigated in vivo and in vitro.

In vivo there was a 100% increase in airways resistance and a 50% decrease in dynamic lung compliance following intravenous challenge with Ascaris antigen. Prostaglandin F2α induced similar changes but with histamine only dynamic lung compliance was affected. (‐)‐Isoprenaline prevented these prostaglandin F2α‐ and histamine‐induced changes and caused a delay of about 2 min in the onset of the mechanical changes following anaphylactic challenge.

In vitro the isolated lung strip contracted within seconds of challenge whereas there was a delay of 2 to 3 min in the onset of the tracheal anaphylactic response. (‐)‐Isoprenaline, (‐)‐adrenaline and (+)‐noradrenaline reduced the magnitude of anaphylactic contractions of the isolated trachea but did not significantly affect those of the isolated lung strip. This indicated lack of inhibition of mediator release from the lung parenchyma.

Histamine was released from sensitized lung fragments following challenge with the Ascaris extract. This release constituted 6.3% of the total tissue histamine and was not inhibited by (‐)‐isoprenaline (1 μM).

(‐)‐Isoprenaline abolished 5‐hydroxytryptamine (5‐HT)‐induced contractions of the isolated trachea but not those elicited in response to acetylcholine. The isolated lung strip responses to histamine, prostaglandin F2α and 5‐HT were highly resistant to inhibition by (‐)‐isoprenaline.
RESPIRATORY AND CIRCULATORY EFFECTS OF SAXITOXIN IN THE CEREBROSPINAL FLUID
Authors: BORISON H.L. , McCARTHY L.E.
Published: July 2012

In cats anaesthetized with pentobarbitone, saxitoxin and, on a few occasions, tetrodotoxin were injected into a lateral cerebral ventricle or into the subarachnoid space of the lower brain stem. Observations were made on frequency and tidal volume of breathing, on CO2 responsiveness and on electrical responsiveness of the respiratory centre. Effects on the blood pressure were observed simultaneously.

A single large dose of toxin, e.g., 250 ng, produced within minutes apneustic breathing and a rise in blood pressure which were converted rapidly to respiratory failure and hypotension. In contrast, repeated small doses, e.g., 25 ng, yielded only progressive slowing of the respiration together with circulatory hypotension. Bulbar depression was produced as effectively by subarachnoid injection as by intraventricular injection of the toxins. Onset of action was detectable within seconds.

Slowing of the respiration occurred independently of change in tidal volume and whether or not the vagus nerves were cut. The reduction in breathing frequency is attributed to direct toxin‐induced depression of the central respiratory oscillator.

Steady‐state measurements of tidal volume at controlled levels of alveolar CO2 pressure in intermediate stages of respiratory depression showed that the toxins produced an increase in CO2 stimulation threshold as well as a reduction in gain of CO2 responsiveness, whether or not the vagus nerves were cut. Carotid arterial chemoreceptor reactivity to O2 was demonstrable when central sensitivity to CO2 was depressed. These effects are attributed to a direct influence of the toxins upon the brainstem CO2‐tidal volume controller.

Responsiveness of the medullary inspiratory centre to electrical stimulation persisted after the failure of spontaneous breathing was caused by the toxins. Conversely, restitution of electrical responsiveness preceded the reappearance of spontaneous respiratory activity in the recovery phase of toxic depression. Circulatory effects paralleled the changes in respiratory behaviour.

On the basis of the relatively prompt and discrete alterations in the central respiratory and circulatory control mechanisms produced by saxitoxin and tetrodotoxin placed in the cerebrospinal fluid, it is concluded that the agents rapidly penetrated to deep target loci in the lower brain stem.
EFFECT OF APOMORPHINE AND ITS N‐PROPYL HOMOLOGUE ON ETHANOL WITHDRAWAL HEAD TWITCHES IN MICE
Authors: PEARL J. , WOODWARD W.A.
Published: July 2012

Collier, Hammond & Schneider (1976) reported that apomorphine, given orally, decreased the incidence of head twitches induced by ethanol withdrawal. These results were confirmed in the present study. Moreover, the N‐propyl homologue of apomorphine was about 45 times more potent than apomorphine in affecting head twitching.

Discussion Apomorphine inhibited head twitching in mice after ethanol withdrawal in accordance with the results of Collier et al. (1976). That the N‐propyl compound was considerably more potent than apomorphine in preventing head twitching agrees with the majority of results of previous studies in which different tests were used (Ashton et al., 1976; Pearl, 1977).
THE MODE OF ACTION OF TETRABENAZINE ON PERIPHERAL NORADRENERGIC NERVES
Authors: TOMLINSON D.R.
Published: July 2012

Tetrabenazine (100 mg/kg i.p. in rats) greatly decreased catecholamine‐induced histofluorescence in the iris, hepatic portal vein, inferior vena cava and mesenteric blood vessels 4 h after injection. Fluorescence returned to normal by 24 h after injection.

The extent of this depletion (4 h after tetrabenazine) was similar to that seen 18 h after reserpine (0.5 mg/kg i.p.)

Incubation of tissues taken from rats 4 h after this dose of tetrabenazine with noradrenaline 5 × 10−6M restored the intraneuronal fluorescence as well as the electron density of noradrenergic vesicle cores viewed with the electron microscope. No such repletion was seen on incubation of tissues from reserpine‐treated rats with noradrenaline under the same conditions.

Incubation of tetrabenazine‐treated hepatic portal veins with noradrenaline also reinstated the normal response to electrical stimulation of the intramural nerves. This did not occur with reserpine‐treated veins.

The interpretation that tetrabenazine exerts a reversible depleting effect on the noradrenergic vesicle is supported by the demonstration that it exerts no monoamine oxidase inhibition.
TRANSIENT CHANGES IN PLASMA DIGOXIN CONCENTRATION AND THE DEVELOPMENT OF CARDIOTOXICITY
Authors: CHAPPLE D.J. , HUGHES R. , JOHNSON B.F.
Published: July 2012

Eight dogs were given two infusions of digoxin 0.1 mg/kg, one over 9 min and the other one over 90 min in a randomized sequence, allowing at least 12 days between each experiment.

Digoxin plasma profiles reflected the rate of digoxin infusion, the peak concentration of drug attained at the end of each infusion being considerably higher but more transient after the 9 min than after the 90 min transfusion.

Digoxin reduced the amount of acetylstrophanthidin required to produce electrocardiographic evidence of cardiotoxicity. This increase in cardiac sensitivity at 150 and at 360 min after the start of the digoxin infusion was independent of rate of infusion.

These results suggest that the development of cardiotoxicity is dependent upon the quantity of digoxin delivered into the systemic circulation regardless of the plasma concentration.

By inference, cardiotoxicity is related solely to the amount and not the rate of absorption from a given dose of digoxin.
A PHARMACOLOGICAL STUDY OF THE SPONTANEOUS CONVULSIVE ACTIVITY INDUCED BY 1,2‐DIHYDROXYBENZENE (CATECHOL) IN THE ANAESTHETIZED MOUSE
Authors: ANGEL A. , CLARKE K.A. , DEWHURST D.G.
Published: July 2012

The convulsive activity induced by catechol has been examined in anaesthetized mice either by determining the CD50 for the convulsions in drug‐treated and control animals, or by studying the effects of various drugs on the total whole body activity.

The results indicate that catecholamines play no part in the mechanism of action of catechol. Drugs which alter cerebral catecholamine levels had no effect on the convulsions, nor did the α‐ and β‐adrenoceptor blocking drugs.

5‐Hydroxytryptamine (5‐HT) could possibly be important, though results with drugs which either change brain 5‐HT levels, or block 5‐HT receptors were inconsistent.

γ‐Aminobutyric acid also appears not to be involved in the mechanism of action of catechol.

The results strongly suggest that catechol primarily activates a central cholinergic system, in that muscarinic and nicotinic receptor blocking drugs inhibit, and anticholinesterases potentiate the convulsions.
HISTAMINE H2‐RECEPTORS IN THE BRAIN AND SLEEP PRODUCED BY CLONIDINE
Authors: VOGT MARTHE
Published: July 2012

Sleep was induced in chicks aged 4‐7 days by intravenous injection of clonidine hydrochloride 0.04 μmol/kg. Sleep was not prevented or altered by a preceding intramuscular injection of blockers of histamine H2‐receptors which were used in doses (as μmol/kg) of up to 800 (metiamide) and 2400 (cimetidine). Clonidine, therefore, does not cause sleep by stimulating H2‐receptors in the brain. The highest dose of cimetidine used had a hypnotic action of its own.
THE DEPENDENCE OF THE LIPID BILAYER MEMBRANE: BUFFER PARTITION COEFFICIENT OF PENTOBARBITONE ON pH AND LIPID COMPOSITION
Authors: MILLER K.W. , YU S‐C. T.
Published: July 2012

The membrane/buffer partition coefficient of [14C]‐pentobarbitone has been determined as a function of the lipid composition of bilayer membranes.

A new technique based on ultrafiltration gave comparable results to conventional techniques but required less time for equilibration.

The membrane/buffer coefficient was independent of pentobarbitone concentration in the range studied.

The apparent partition coefficient varied with pH and was a linear function of the degree of dissociation of pentobarbitone.

Both the charged and uncharged forms of pentobarbitone partitioned into the membrane, the latter to a much greater extent than the former.

At low pH the highest partition coefficient observed was in egg phosphatidylcholine bilayer membranes.

Incorporation of cholesterol or phosphatidic acid into phosphatidylcholine membranes greatly reduced the partition coefficient.

High pressures do not greatly change these partition coefficients.
DO CENTRAL DOPAMINE RECEPTORS HAVE A PHYSIOLOGICAL ROLE IN THERMOREGULATION?
Authors: COX B. , LEE T.F.
Published: July 2012

Core and tail skin temperature was measured in rats which had guide cannulae implanted into their brains to allow drug injections directly into the preoptic anterior hypothalamus.

Apomorphine and dopamine (10 μg in 1 μl) injected into the area of the preoptic anterior hypothalamus caused a fall in core temperature which was preceded by a rise in tail skin temperature.

The decrease in core temperature following central injection of either apomorphine or dopamine was significantly reduced by pretreating rats for 2 h with pimozide (0.5 mg/kg i.p.).

Bilateral intrahypothalamic injection of pimozide (0.5 μg in 1 μl) significantly reduced the hypothermic effect of systemic apomorphine (1.25 mg/kg i.p.).

Control rats placed 65 cm below a 250 W infrared lamp responded with vasodilatation of tail skin blood vessels as indicated by an increase in tail skin temperature. Pimozide pretreatment (0.5 mg/kg i.p.) significantly reduced this response.

These results suggest that the preoptic anterior hypothalamus contains dopamine receptors which mediate hypothermia in rodents and raise the possibility that endogenous dopamine has a physiological role in thermoregulation.
HYPERTHERMIC EFFECTS OF MORPHINE: SET POINT MANIPULATION BY A DIRECT SPINAL ACTION
Authors: RUDY T.A. , YAKSH T.L.
Published: July 2012

Rats were implanted with chronic indwelling catheters in the lumbar spinal subarachnoid space in order to study the effects of morphine on body temperature.

Morphine administered intrathecally produced a dose‐dependent rise in body temperature that was antagonized by naloxone.

The rise in body temperature evoked by a given dose of morphine appeared to be independent of the environmental temperature (4°C to 32°C) and was consistently associated with coordinated thermoregulatory responses (i.e. shivering and tail vasoconstriction). The fall in body temperature observed in these hyperthermic animals, following naloxone, was associated with a vasodilatation which coincided with the fall to the premorphine temperature level.

Morphine administered systemically also produced hyperthermia. This was only partially reversed by intrathecal naloxone. In animals made tolerant to the hyperthermic effects of systemic morphine, the intrathecal administration of naloxone produced a fall in body temperature.

Naloxone alone, administered either intrathecally or systemically, had no effect upon body temperature.

We suggest that morphine exerts a direct, pharmacologically specific effect on the spinal cord, which results in an altered thermoregulatory set point in the rat.
SUBCELLULAR DISTRIBUTION OF ETORPHINE IN RAT BRAIN AND EVIDENCE FOR in vivo STEREOSPECIFIC BINDING
Authors: CERLETTI CHIARA , COCCIA P. , MANARA L. , MENNINI TIZIANA , RECCHIA M.
Published: July 2012

Control experiments were carried out by homogenizing rat brain at 0°C with sucrose containing various concentrations of [3H]‐etorphine. Subcellular fractionation of this homogenate showed that the distribution of the labelled drug amongst the primary fractions was dependent on the concentration of etorphine in the homogenate.

Rats were injected intravenously with 0.2 and 20 μg/kg of [3H]‐etorphine. The brains were homogenized and fractionated in sucrose containing 4.2 times 10−5 M unlabelled etorphine in order to control redistribution artifacts. Different distribution profiles in the subcellular fractions were observed at these two dose levels.

Concurrent administration of either cyprenorphine or naloxone with intravenous etorphine, caused a shift of the labelled drug from the P3 fraction to the supernatant fraction.

The subcellular distribution of intravenously administered [3H]‐etorphine was also studied by homogenizing brains in etorphine‐free sucrose, and sucrose containing either levorphanol or dextrorphan. From these experiments it was concluded that the P3 microsomal fraction is a major site to which in vivo etorphine is stereospecifically bound in the rat brain.
THE EFFECTS OF REPLACING ESTER BY AMIDE ON THE BIOLOGICAL PROPERTIES OF COMPOUNDS RELATED TO ACETYLCHOLINE
Authors: BARLOW R.B. , BREMNER J.B. , SOH K.S.
Published: July 2012

Replacement of ester by amide in series of derivatives of diphenylacetic acid reduces the affinity for muscarine‐sensitive. acetylcholine receptors of the guinea‐pig ileum from 40‐ to 100‐fold. With similar series of phenylacetic acid the reduction is only 2‐ to 4‐fold. In both series changes in the composition of the onium group produce similar changes in the affinity of amides and esters and it appears that the stiffness of the amide bond reduces the binding of the phenyl groups at the far end of the molecule from the onium atom.

Replacement of ester by amide in similar series of acetyl compounds reduces activity on the guinea‐pig ileum over 1000‐fold and on the frog rectus over 50‐fold. Compounds with larger onium groups are antagonists on both preparations with log affinity constant around 3. The amides have similar affinity for electric eel acetylcholinesterase.

The amides are slightly bigger than the esters in solution and slightly more hydrophilic.

Replacement of ester by amide in acetylcholine reduces the proportion of gauche conformer about the C—C—bond from 100% to 39%.

The ability of acetylcholine to activate receptors is thought to depend on some degree of flexibility in the —CO—O— bond, though the hydration of the bond may also be important.
THE CARDIOVASCULAR EFFECTS OF CYCLOPROPANE IN THE INTACT, DECEREBRATE AND PITHED RABBIT PREPARATIONS
Authors: HUGHES R.L. , MACKENZIE J.E.
Published: July 2012

The anaesthetic cyclopropane was given to intact, decerebrate and pithed unanaesthetized rabbit preparations to determine the relative importance in vivo of its central and peripheral cardiovascular effects.

Cyclopropane elevated both the heart rate and the mean arterial pressure in the intact rabbit.

In the decerebrate rabbit, cyclopropane elevated the heart rate and efferent cervical preganglionic nerve activity and diminished the magnitude of these components of the aortic baroreceptor reflex, the mean arterial pressure being unaffected.

Apart from slight myocardial depression, cyclopropane was largely without effect in the pithed rabbit.

It is concluded that cyclopropane produces its cardiovascular effects by supra‐collicular activation eliciting an elevation of mean arterial pressure, a central sub‐collicular activation producing an increase in heart rate, and that in vivo the peripheral effects of cyclopropane are of minimal importance in comparison to these central effects.
REVERSAL OF GUANETHIDINE BLOCKADE OF SYMPATHETIC NERVE TERMINALS BY TETRAETHYLAMMONIUM AND 4‐AMINOPYRIDINE
Authors: KIRPEKAR MADHURI , KIRPEKAR S.M. , PRAT J.C.
Published: July 2012

The effect of tetraethylammonium (TEA) and 4‐aminopyridine (4‐AP) on the inhibitory effect of guanethidine on noradrenaline (NA) release was investigated in the perfused spleen of the cat.

Guanethidine blocked the release of NA evoked by nerve stimulation. TEA and 4‐AP readily reversed this inhibitory effect, and the NA output was nearly doubled after repeated stimulation of the nerves. On subsequent perfusion with Krebs solution without TEA or 4‐AP, the inhibitory effect of guanethidine reappeared

The reversal of guanethidine blockade of sympathetic nerves by TEA and 4‐AP is discussed.
THE EFFECT OF THE IONOPHORES X‐537A AND A23187 ON THE NORADRENALINE OUTPUT FROM PERIPHERAL ADRENERGIC NEURONES IN THE PRESENCE OF VARIOUS DIVALENT CATIONS
Authors: ITO S. , NAKAZATO Y. , OHGA A.
Published: July 2012

The effects of the ionophores, X‐537A and A23187 on the noradrenaline output from peripheral adrenergic neurones of isolated vas deferens of the guinea‐pig were investigated in the presence of various divalent cations.

X‐537A (17 μM) caused an increase in the noradrenaline output in the presence of barium, calcium and strontium. The effectiveness of the cations was Ba > Ca ≥ Sr.

In the absence of calcium and in the presence of ethyleneglycol‐bis(2‐aminoethylether)‐N, N, N′, N′,‐tetraacetic acid (EGTA, 1 mM), the response was reduced by about 50% of that obtained in the presence of calcium.

Calcium was the most effective cation in stimulating noradrenaline output when reintroduced after pretreatment with A23187 (191 μM). The response increased in an almost linear fashion with the concentration of calcium 1 mM to 10 mM.

Excess magnesium (20 mM) reduced the response induced by X‐537A in the presence of barium. However, it was without effect on the response produced by reintroduction of calcium after pretreatment with A23187.

The response induced by X‐537A in the presence of barium increased with an increase in the concentration of external sodium from 25 mM to 143 mM.

It is suggested that X‐537A may cause an increase in the noradrenaline output by depolarization as well as by transferring cations as an ionophore. On the other hand, A23187 may produce an increase in the noradrenaline output, transferring calcium across the membrane as a specific calcium ionophore.
THE EFFECTS OF GLYCEROL DETUBULATION, OF MANGANESE IONS, OF DANTROLENE AND OF NITRATE IONS ON THE RESPONSES OF ISOLATED CHRONICALLY DENERVATED SOLEUS MUSCLES OF THE MOUSE TO ACETYLCHOLINE
Authors: HALL MOIRA T. , MALEQUE M.A. , WADSWORTH R.M.
Published: July 2012

In the isolated chronically denervated soleus muscle of the mouse acetylcholine produced a biphasic contraction.

In muscles detubulated by glycerol treatment, the first phase of the acetylcholine contraction was almost abolished, but the second was only slightly reduced or was unaffected.

Manganese ions (10 mM) reduced the first phase of the acetylcholine response, but enhanced the second.

Dantrolene sodium (5.94 times 10−5 M) reduced the first phase of the acetylcholine response, but not the second.

Nitrate ions (118 mM) augmented the first phase but not the second.

It was concluded that the first phase requires the excitation‐contraction‐coupling sequence: membrane depolarization‐T‐tubules‐Ca2+ release from sarcoplasmic reticulum. In contrast, the second phase appears to occur independently of these processes.
EVIDENCE FOR THE ROLE OF ADRENOCORTICAL HORMONES IN THE REGULATION OF NORADRENALINE AND DOPAMINE METABOLISM IN CERTAIN BRAIN AREAS
Authors: RASTOGI R.B. , SINGHAL R.L.
Published: July 2012

Bilateral adrenalectomy suppressed body growth and increased the activity of tyrosine hydroxylase in rat striatum in a time‐dependent manner. Fifteen days after adrenalectomy, the concentrations of noradrenaline were decreased significantly in hypothalamus and striatum, as were those of dopamine in brain stem and striatum.

Catechol‐O‐methyltransferase failed to change in response to adrenalectomy, but the activity of monoamine oxidase in cortex was significantly increased 7 days after surgery. These changes in various neurochemical parameters were even more pronounced 15 days after adrenal ablation.

Administration of corticosterone (10 mg/kg i.p.) to adrenalectomized rats effectively reversed the observed effects on brain amine metabolism. Corticosterone treatment for 7 days beginning from the 8th day of adrenalectomy virtually restored the concentrations of noradrenaline and dopamine as well as the activities of striatal tyrosine hydroxylase and cerebrocortical monoamine oxidase to the values seen for sham‐operated controls.

Our data suggest that changes seen in brain noradrenaline and dopamine of adrenalectomized rats are specific to adrenocortical steroids and that these hormones play a role in the regulation of catecholamine formation.
EFFECTS OF MINOXIDIL AND NITROPRUSSIDE ON REFLEX INCREASES IN MYOCARDIAL CONTRACTILITY
Authors: ROBIE N.W.
Published: July 2012

The effects of nitroprusside and minoxidil on increases in myocardial contractility resulting from carotid artery occlusion were investigated in anaesthetized dogs. The results were compared with those produced by intravenous influsion of noradrenaline.

Nitroprusside and minoxidil attenuated the pressor responses produced by carotid artery occlusion.

Nitroprusside, but not minoxidil, attenuated the maximal myocardial contractility resulting from carotid occlusion.

The pressor and contractility responses to noradrenaline infusion were unaffected by either agent.

Nitroprusside failed to alter the myocardial responses produced by dimethylphenylpiperazinium.

These results, in conjunction with those of other investigators who have demonstrated that nitroprusside does not affect the release of noradrenaline from adrenergic neurones, suggest that nitroprusside may inhibit sympathetic nervous system reflex activity via an afferent and/or central component.
EFFECTS OF MONOCROTALINE PRETREATMENT OF RATS ON REMOVAL OF 5‐HYDROXYTRYPTAMINE AND NORADRENALINE BY PERFUSED LUNG
Authors: GILLIS C.N. , HUXTABLE RYAN J. , ROTH ROBERT A.
Published: July 2012

The alkaloid, monocrotaline, causes significant pulmonary damage in many species, including the rat. We, therefore, determined whether the inactivation of biogenic amines by perfused lungs of rats was modified by prior treatment of the animals with monocrotaline.

Young rats (45 to 50 g) treated for 21 days with monocrotaline (22 μg/ml) in their drinking water developed right ventricular hypertrophy. Treated animals gained weight more slowly and consumed less food and water than control rats that drank tap water. Lungs from monocrotaline‐treated animals were heavier and had a higher protein content than control lungs.

Isolated lungs from treated animals removed and metabolized 50% less perfused 5‐hydroxytryptamine than did controls.

The diminished 5‐hydroxytryptamine metabolism was probably due to impaired delivery of substrate to intrapulmonary monoamine oxidase (MAO) since MAO activity in 600 g supernatant fractions of homogenates of lungs from monocrotaline‐treated rats was not different from control values.

Pulmonary removal of perfused noradrenaline was decreased about 60% by the 21‐day treatment, suggesting that the effects of monocrotaline were somewhat nonspecific.

These effects were not caused by monocrotaline directly, since perfusion of lungs from untreated animals with this drug did not alter removal of co‐perfused 5‐hydroxytryptamine.

Reduced pulmonary removal of circulating biogenic amines following pretreatment with monocrotaline may reflect damage to capillary endothelium, which could also affect other metabolic functions of lung.
THE LOCAL ANAESTHETIC ACTIVITY OF A BENZOTRIAZINIUM SALT
Authors: FRENCH A.M. , KHAN M.T. , SCOTT N.C.
Published: July 2012

The local anaesthetic properties of 2‐w‐propyl‐4‐p‐tolylamino‐1,2,3‐benzotriazinium iodide (TnPBI) were compared with those of lignocaine hydrochloride on intact and desheathed sciatic nerves of the frog, on the phrenic nerve‐hemidiaphragm preparation of the rat, and by the intradermal wheal test in the guinea‐pig.

Both TnPBI and lignocaine were more potent* on desheathed than on intact sciatic nerves. The potency of TnPBI was affected more than that of lignocaine by the presence of the sheath in intact nerves.

Both drugs inhibited conduction in the rat phrenic nerve, as shown by the reduction in twitch tension of the diaphragm elicited by nerve stimulation. TnPBI also caused an initial augmentation of the twitch tension of the diaphragm when applied directly to the muscle.

TnPBI was shown to be approximately twice as potent as lignocaine by the guinea‐pig intradermal wheal test.

These results are discussed in view of the known effects of TnPBI on intracellular calcium storage.
PRESYNAPTIC ACTIONS OF β‐AMINOBUTYRIC ACID AND SOME ANTAGONISTS IN A SLICE PREPARATION OF CUNEATE NUCLEUS
Authors: SIMMONDS M.A.
Published: July 2012

A slice preparation of the rat cuneate nucleus is described which is suitable for electrophysiological studies on the presynaptic action of drugs.

Superfusion of a slice with γ‐aminobutyric acid (GABA) depolarized the afferent nerves in a concentration‐related manner. The responses were CI “‐dependent. Depolarizations to high concentrations of GABA often faded. Glycine and l‐glutamate had little effect.

(‐h)‐Bicuculline antagonized GABA in an apparently competitive manner (pA2 = 5.35) at low response levels. Strychnine was 10 times less potent. Responses to high concentrations of GABA were sometimes potentiated by (+)‐biculline and strychnine.

Bemegride and leptazol both antagonized GABA, but with low potency and in a manner which was clearly not competitive.
BRAIN TRYPTOPHAN METABOLISM ON THE 5‐HYDROXYTRYPTAMINE AND KYNURENINE PATHWAYS IN A STRAIN OF RATS WITH A DEFICIENCY IN PLATELET 5‐HT
Authors: JOSEPH MICHAEL H.
Published: July 2012

Brain 5‐hydroxytryptamine (5‐HT) metabolism has been compared in albino (Sprague‐Dawley; SD) and in Fawn‐Hooded (FH) rats, which have an inherited platelet 5‐HT deficiency.

It was confirmed that blood 5‐HT levels in the FH rats were about one quarter of those in the SD rats.

Brain 5‐HT and 5‐HIAA were however higher in FH rats on a per gram basis; there was no difference between the strains on a per brain basis, because of the smaller brain weights of the FH rats.

Brain and plasma tryptophan were not significantly different in the two strains. Plasma kynur‐enine was higher in the FH rats, and brain kynurenine was also higher either on a per gram or on a per brain basis.

The reserpine‐releasable brain 5‐HT was the same proportion of total brain 5‐HT in the two strains.

Experiments with pargyline suggested that the turnover of 5‐HT was somewhat higher in the FH rats on a per gram basis, but not significantly so on a per brain basis.

It is concluded that although brain tryptophan metabolism may be somewhat accelerated along both the 5‐HT and kynurenine pathways in the FH rats there is no gross deficiency in the binding of 5‐HT in their brains analogous to that found in their platelets.
THE EFFECTS OF ACETYLCHOLINE ON THE MEMBRANE AND CONTRACTILE PROPERTIES OF SMOOTH MUSCLE CELLS OF THE RABBIT SUPERIOR MESENTERIC ARTERY
Authors: KURIYAMA HIROSI , SUZUKI HIKARU
Published: July 2012

Effects of acetylcholine (ACh) on the membrane potential and mechanical properties of rabbit superior mesenteric artery were investigated by the use of microelectrode and isometric tension recording methods. The membrane potential was −62.5 ± 3.0 mV (s.d.). The maximum slope of the membrane depolarization produced by tenfold increase in [K]0 plotted on a log scale was 48 mV. Excess [K]0 and low [K]0 depolarized the membrane and produced contraction (contracture). The minimum depolarization to produce contraction was 10 mV.

Low concentrations (10 and 100 ng/ml) of ACh hyperpolarized the membrane. Increased concentrations of ACh (1 and 10 μg/ml) hyperpolarized the membrane further in adult rabbit, while increased concentrations of ACh produced a smaller hyperpolarization in young rabbit. These potential changes produced by ACh in immature and adult rabbits were suppressed by treatment with atropine (0.1 μg/ml).

ACh (10 ng to 1 μg/ml) consistently generated contraction in Krebs solution. However, ACh relaxed the contraction induced by either K+ or noradrenaline in the adult rabbit, and it enhanced contraction produced by this treatment in the immature rabbit. In Ca‐free EGTA solution, the action of ACh on the mechanical response was markedly suppressed, although high concentrations of ACh still evoked contraction. However, treatment with atropine (1 μg/ml) completely prevented these actions of ACh.

ACh‐induced relaxation during either K+‐induced or noradrenaline‐induced contraction was not caused by the hyperpolarization of the membrane.

It is concluded that ACh possesses dual actions on smooth muscle cells of the rabbit superior mesenteric artery in Krebs solution, i.e. ACh hyperpolarizes the membrane, while it consistently generates contraction. These ACh actions on the muscle cells were modified by aging.
ANTAGONISTIC EFFECT OF COMPOUND 48/80 ON THE INHIBITORY ACTIONS OF MORPHINE AND METHIONINE‐ENKEPHALIN ON ELECTRICALLY‐INDUCED CONTRACTIONS OF THE GUINEA‐PIG ILEUM
Authors: KAMIKAWA YUICHIRO , SHIMO YASUO
Published: July 2012

The effect of compound 48/80 was studied on the twitch‐like contractions of the longitudinal muscle of guinea‐pig ileum induced by electrical stimulation of intramural cholinergic nerves.

Compound 48/80 alone, at concentrations up to 30 μg/ml, had no effect on the twitch contractions. The contraction to exogenously applied acetylcholine was slightly depressed by the compound.

At 100 μg/ml, compound 48/80 caused a weak but long‐lasting increase in tone and irregular contractile activity in the ileum, part of which was reduced but not completely abolished by pretreatment with chlorpheniramine (1 μm) or by repeated applications of compound 48/80.

The inhibitory effects of morphine and methionine‐enkephalin on the twitches were antagonized by the presence of compound 48/80 (3 to 30 μg/ml), possibly in a competitive manner. The antagonism was not affected by pretreatment with the antihistaminics, chlorpheniramine and/or metiamide.

The inhibitory effects of noradrenaline and adrenaline on the twitches were slightly but significantly increased by the presence of compound 48/80 (10 or 30 μg/ml), whereas that of ATP was not modified.

These results indicate that compound 48/80 acts as a selective and competitive antagonist at opiate receptors located in the intramural cholinergic nerves of guinea‐pig ileum.
MECHANISMS OF INACTIVATION OF NORADRENALINE IN THE IRIS SPHINCTER, TRACHEAL MUSCLE AND FACIAL ARTERY OF CATTLE: IMPLICATIONS FOR β‐ADRENOCEPTOR‐MEDIATED RESPONSES
Authors: KALSNER STANLEY
Published: July 2012

The rôle of neuronal and extraneuronal pathways of amine inactivation in regulating the inhibitory actions of noradrenaline was investigated in three bovine smooth muscle preparations in which the primary adrenoceptor is of the j?‐type.

The extraneuronal uptake inhibitor, 17β‐oestradiol, sensitized the inhibitory responses to noradrenaline in the facial artery, the iris sphincter and in tracheal muscle preparations, indicating a major rôle for non‐neuronal processes in agonist‐inactivation in all three preparations. Cocaine also increased responses to noradrenaline, pointing to a rôle for neuronal uptake either as a terminating mechanism or as a process limiting access of exogenous agonist molecules to their site of action.

Cocaine did not enhance significantly responses to isoprenaline, a potent β‐adrenoceptor agonist which is not taken up neuronally. Further, relaxations to metaraminol, a sympathomimetic amine which is taken up extraneuronally, but much less so than noradrenaline, were also less enhanced by 17β‐oestradiol in the three preparations tested. These findings support the specificity of action of cocaine and 17β‐oestradiol as neuronal and extraneuronal uptake inhibitors in the present experiments.

Studies of the uptake of [3H]‐noradrenaline revealed that 17β‐oestradiol reduced the uptake of amine in the presence of cocaine, confirming a cocaine‐resistant site of action for the steroid in all three preparations.

It is concluded that extraneuronal uptake sites are located sufficiently close to the β‐adrenoceptors to modulate the concentration and duration of action of noradrenaline at these sites of action. It is proposed that in smooth muscles which contain a preponderance of β‐receptors, extraneuronal metabolism is a key event in terminating the inhibitory effects produced.
SYMPATHOMIMETIC EFFECTS OF PANCURONIUM BROMIDE ON THE CARDIOVASCULAR SYSTEM OF THE PITHED RAT: A COMPARISON WITH THE EFFECTS OF DRUGS BLOCKING THE NEURONAL UPTAKE OF NORADRENALINE
Authors: DOCHERTY J.R. , McGRATH J.C.
Published: July 2012

The effects of pancuronium bromide on the cardiovascular system of the pithed rat were examined. Pancuronium had two effects, a short‐lasting cardiovascular stimulation following injection and a longer‐lasting potentiation of responses to sympathetic nerve stimulation.

The initial effect of pancuronium was compared with that of tyramine. The cardioaccelerator but not the pressor responses to both pancuronium and tyramine were significantly reduced following sympathectomy with 6‐hydroxydopamine (6‐OHDA).

The action of pancuronium in potentiating sympathetic nerve responses was compared with that of known blockers of the neuronal uptake of noradrenaline (NA). Pancuronium (1 mg/kg) and cocaine (0.5 mg/kg) potentiated cardioaccelerator and pressor responses to sympathetic stimulation. These effects of pancuronium could be obtained following adrenalectomy and during neuromuscular blockade with gallamine. Pancuronium and uptake blockers potentiated the cardioaccelerator response to NA, reduced the response to tyramine, but did not affect the response to isoprenaline. Pancuronium and uptake blockers potentiated the pressor response to NA, but did not affect the response to tyramine or clonidine.

Following sympathectomy with 6‐OHDA, pancuronium failed to potentiate cardioaccelerator and pressor responses to NA.

These results are discussed in relation to two main cardiovascular effects of pancuronium; an indirect sympathomimetic action and blockade of the neuronal uptake of NA.
INTERACTIONS OF (+)‐AMPHETAMINE AND CHLORPROMAZINE ON NEURONES IN THE LOWER BRAIN STEM OF THE RAT
Authors: BOAKES R.J. , BRADLEY P.B. , CANDY J.M.
Published: July 2012

The ability of chlorpromazine to antagonize the effects of iontophoretic application of (+)‐amphetamine to single neurones in the medulla and lower pons of anaesthetized rats has been studied.

Chlorpromazine, administered systemically or iontophoretically, consistently and specifically antagonized the excitatory actions of (+)‐amphetamine, but not those of noradrenaline on the same neurone.

It is concluded that chlorpromazine reduces the effect of (+)‐amphetamine by a presynaptic mechanism.

(+)‐Amphetamine did not mimic the prolonged inhibitory response of some neurones to noradrenaline but often excited these neurones and chlorpromazine blocked these excitatory responses to (+)‐amphetamine.