bluuebunny/crossref_metadata_2025 huggingface dataset:
A histochemical study of extraneuronal accumulation of noradrenaline in the guinea‐pig trachea
Authors: O'DONNELL STELLA R. , SAAR NILI
Published: July 2012

Accumulation of noradrenaline in extraneuronal tissue of the guinea‐pig trachea has been studied by the use of the fluorescence histochemical technique of Falck and Hillarp.

After incubation in solutions of noradrenaline, fluorescence developed in cellular structures (tracheal smooth muscle, vascular smooth muscle and endothelium, fibroblasts and chondroblasts), in the intercellular matrix of the cartilage and throughout the loose connective tissue of the adventitia and submucosa.

The effect of various experimental procedures on the development of this fluorescence has been examined i.e. incubation with noradrenaline at reduced temperature (0° C), removal of fluorescence by washing with Krebs solution at 37° C or 0° C, incubation with phenoxybenzamine (10−4m) or metanephrine (10−4m).

From these observations it has been concluded that noradrenaline accumulates in the trachea:

(a) in cellular structures where it is firmly bound, i.e. not easily removed by washing at 0° C, and where the accumulation is prevented by phenoxybenzamine, metanephrine or cold.

(b) in the intercellular matrix of the cartilage where it is also firmly bound, but where the accumulation is not prevented by phenoxybenzamine, metanephrine or cold. This probably represents binding to sulphated mucopolysaccharides.

(c) in the adventitia and submucosa where it is loosely bound and easily removed by washing.

Some implications of these findings in pharmacological experiments with guinea‐pig trachea are discussed.
On the pharmacology and biochemistry of the amine‐uptake mechanism in human blood platelets
Authors: CAMPBELL I. C. , TODRICK A.
Published: July 2012

The uptake of 5‐hydroxytryptamine (5‐HT) by human blood platelets in vitro has been studied with the object of identifying the biochemical mechanisms involved.

Drugs active in adrenergic systems are only moderate inhibitors of uptake, although prenylamine is as active as the less potent tricyclic anti‐depressive drugs; phenoxybenzamine is almost inactive as a competitive inhibitor but is effective if pre‐incubated with the platelets beforehand. This parallels its pharmacological pattern of action.

Inhibitors of oxidative phosphorylation do not inhibit 5‐HT uptake, but iodoacetate inhibits, if pre‐incubated with the platelets; p‐chloromercuribenzoate does also, when the platelets are suspended in synthetic medium, but not in plasma.

Ouabain causes significant inhibition at 10−7m; by 10−6m it achieves its maximal effect, namely 40% inhibition; in K+‐deficient medium, uptake falls to 30% of normal; the K+‐dependent fraction of the uptake includes the ouabain‐sensitive component. Mg++ has no effect.

A drug not possessing the imipramine structure, which has been tried in the treatment of depressive illness, 4‐phenyl bicyclo (2,2,2) octan‐1‐amine, is a highly potent inhibitor of 5‐HT uptake.
An analysis of the learning deficit following hyoscine administration to man
Authors: CROW T. J. , GROVE‐WHITE I. G.
Published: July 2012

Twelve volunteer subjects completed a free‐recall word learning test, a number‐colour association test, and a scanning task after the following treatments: saline 1 ml, hyoscine 0·4 mg, or atropine 0·6 mg, administered by intravenous injection.

Performance on all three tests was not significantly impaired after atropine.

Performance on the two learning tests but not on the scanning task, was significantly impaired after hyoscine.

Analysis of the results of the free‐recall word learning test indicates that impairment of learning following hyoscine does not affect recall over intervals of a few seconds, but affects that portion of the learning curve which has been attributed to long‐term (or secondary) rather than short‐term (or primary) memory.

The results suggest that hyoscine 0·4 mg may impair learning processes, without significantly depressing other psychological functions, and that the impairment of learning following hyposcine does not affect recall over intervals memory.
Presynaptic and postsynaptic effects of the venom of the Australian tiger snake at the neuromuscular junction
Authors: DATYNER M. E. , GAGE P. W.
Published: July 2012

Crude venom (TSV) from the Australian tiger snake (Notechis scutatus scutatus) has both presynaptic and postsynaptic effects at the neuromuscular junctions of toads.

TSV (50 μg/ml) rapidly blocked indirectly elicited muscle twitches without affecting the compound action potential in the sciatic nerve or twitches elicited by direct stimulation.

Low concentrations of the venom (1–10 μg/ml) reduced the amplitude of miniature endplate potentials (m.e.p.ps) and inhibited the depolarization of muscle fibres normally caused by carbachol. It was concluded that a fraction of the venom binds to acetylcholine receptors.

The frequency of m.e.p.ps was at first increased by TSV at a concentration of 1 μg/ml. Occasional, high frequency ‘bursts’ of m.e.p.ps were recorded in some preparations. The mean frequency of m.e.p.ps appeared to fall after several hours in the venom.

The quantal content of endplate potentials (e.p.ps) was reduced by the venom. With low concentrations (1 μg/ml), an initial increase in quantal content was often seen. When the quantal content was markedly depressed there was no parallel reduction in the amplitude of nerve terminal spikes recorded extracellularly, though a later fall in size and slowing of time course was often seen.

There was evidence that TSV eventually changed the normal Poisson characteristics of the spontaneous release of quanta and this may be correlated with electronmicroscopic changes in nerve terminals.

Tiger snake antivenene counteracted the postsynaptic, but not the presynaptic effects of TSV when they had developed.
Gastric mucosal blood flow during pentagastrin‐ and histamine‐stimulated acid secretion in the rat
Authors: MAIN I. H. M. , WHITTLE B. J. R.
Published: July 2012

Gastric mucosal blood flow was studied in the rat by means of a [14C]‐aniline clearance technique.

There was a significant correlation between clearance and stimulated acid secretion.

No significant difference was found in the relationship between clearance and acid secretion during submaximal stimulation with either pentagastrin or histamine.

Estimates of mucosal blood flow per unit acid secretion by [14C]‐aniline clearance in the rat were similar to those reported with aminopyrine clearance in the dog and cat.
The continuous bioassay of the release and disappearance of histamine in the circulation
Authors: FERREIRA S. H. , NG K. K. , VANE J. R.
Published: July 2012

The blood‐bathed organ technique was used for the continuous assay of histamine in circulating blood.

Longitudinal strips of cat or kitten terminal ileum detect concentrations of histamine of 2–5 ng/ml; these are below the threshold at which hypotension is induced in dogs.

The cat or kitten terminal ileum also contract to bradykinin. However, the simultaneous use of a cat jejunum strip, which is selectively sensitive to bradykinin, will distinguish between histamine and bradykinin.

The utility of the method for detecting and quantitating circulating histamine was exemplified by measuring: (a) its half‐life in the circulation, (b) its disappearance during a passage through the vascular beds of lungs, liver and lower limbs, and (c) its release into the circulation by compound 48/80.
A CENTRAL VASODEPRESSOR EFFECT OF DYFLOS
Authors: EDERY H. , GUERTZENSTEIN P.G.
Published: July 2012

Cats were anaesthetized with pentobarbitone sodium and atropinized peripherally by intravenous injection of atropine methyl nitrate; the effect was examined of topical bilateral application of dyflos to the ventral surface of the medulla oblongata at a region lateral to the pyramids and caudal to the trapezoid bodies. Dyflos was applied by means of perspex rings; the volume of fluid placed in each ring was 10 μl.

The topical application of dyflos (1–20 mg/ml) produced a fall in arterial blood pressure without changes in heart rate and, in experiments without artificial ventilation, tachypnoea with dissociation of thoracic and abdominal respiration.

Atropine methyl nitrate (50 mg/ml) applied topically in the same way as dyflos, prevented or abolished its vasodepressor effect.

The two reactivators of acetylcholinesterase, obidoxime (100–200 mg/ml) and pralidoxime mesylate (100–200 mg/ml), applied topically in the same way as dyflos, abolished its vasodepressor effect. The reactivator compound 30 (100 mg/ml), also a pyridinium aldoxime, did not have this effect.

Obidoxime and pralidoxime mesylate also reversed the vasodepression produced by carbachol applied to the ventral surface of the brain stem but not the vasodepression produced by glycine similarly applied.

The problem is discussed as to whether the reversal of the dyflos and carbachol‐induced vasodepression by obidoxime and pralidoxime is due to acetylcholinesterase reactivation by dephosphorylation and decarbamylation respectively, to a central atropine‐like action of these compounds or to a combination of both.
METABOLISM OF ISOPRENALINE AFTER AEROSOL AND DIRECT INTRABRONCHIAL ADMINISTRATION IN MAN AND DOG
Authors: BLACKWELL E.W. , BRIANT R.H. , CONOLLY M.E. , DAVIES D.S. , DOLLERY C.T.
Published: July 2012

Administration of isoprenaline by aerosol inhalation to man results in over 80% being metabolized to the sulphate conjugate.

The majority of an inhaled dose is probably swallowed since the metabolic pattern resembles that after an oral dose.

Isoprenaline, administered in aqueous solution directly into the bronchial tree in both man and dog, is rapidly O‐methylated to 3‐O‐methyl isoprenaline, which is subsequently conjugated with sulphate.

3‐O‐Methylation is the main metabolic pathway for the small part of an inhaled dose which does enter the bronchial tree.
POTENCY AND SELECTIVITYin vitroOF COMPOUNDS RELATED TO ISOPRENALINE AND ORCIPRENALINE ON β‐ADRENOCEPTORS IN THE GUINEA‐PIG
Authors: O'DONNELL STELLA R. , WANSTALL JANET C.
Published: July 2012

Amines related in structure to either isoprenaline (catechol series) or orciprenaline (resorcinol series) were examined for activity on isolated trachea (relaxation), atria (chronotropic action) and perfused hind‐limb (vasodilatation) of the guinea‐pig.

Compounds with a resorcinol nucleus were less potent on all three preparations but more selective for trachea than were compounds with a catechol nucleus.

In both catechol and resorcinol compounds potency on trachea was enhanced by and selectivity for trachea was favoured by substitution of ap‐OH phenyl group in theN‐isopropyl, or by replacement of theN‐isopropyl with anN‐t‐butyl, with or without ap‐OH phenyl group.

Most of the compounds, particularly the resorcinols, had much lower potencies, relative to isoprenaline, on hind‐limb than on trachea.

Some of the problems associated with the quantitative measurement of selectivity and with sub‐classification of β‐adrenoceptors are discussed.
FURTHER OBSERVATIONS ON THE CARDIOTOXICITY OF ISOPRENALINE DURING HYPOXIA
Authors: McDEVITT D.G. , SHANKS R.G. , SWANTON J.G.
Published: July 2012

In dogs respired with 10% oxygen: 90% nitrogen, only five out of 16 dogs survived repeated intravenous doses of isoprenaline (either 0.5 or 1.0 μg/kg) and only one out of six dogs survived repeated isoprenaline inhalations from a pressurized aerosol.

In dogs respired with 15% oxygen: 85% nitrogen, five out of six dogs survived repeated intravenous doses of isoprenaline (2.5 μg/kg).

The fatal response in these animals consisted of a fall in heart rate, arterial and pulse pressures. Sinus rhythm persisted even after the arterial pressure had fallen, though occasionally a slow A‐V nodal rhythm or irregular ventricular ectopic beats occurred. Ventricular fibrillation did not occur.

Eight out of 10 dogs brought to the verge of a fatal response with 10% oxygen: 90% nitrogen and repeated doses of isoprenaline (2.5 μg/kg) were resuscitated by the administration of 100% oxygen and, when necessary, cardiac massage.

A group of five dogs survived the combined effects of repeated doses of isoprenaline (2.5 μg/kg) and respiration with 10% oxygen: 90% nitrogen when the time interval between doses was 11 min, instead of the usual 5 minutes.

Control of pH by infusion of sodium bicarbonate did not protect the dogs from the combined effects of hypoxia and repeated isoprenaline challenge.

After a 60 min period of continuous isoprenaline infusion in dogs breathing room air, only one of 10 dogs survived artificial respiration with 10% oxygen: 90% nitrogen and repeated challenge with intravenous isoprenaline (1.0 μg/kg) at 5 min intervals. At the higher infusion levels of isoprenaline (0.1 and 1.0 μg kg−1min−1), two dogs out of four died after the hypoxic mixture was started but before any isoprenaline challenge was given.

The possible relevance of these findings in dogs to the recently observed increase in mortality in young asthmatics is discussed.
A COMPARISON OF THE ACTIONS OF SOME DRUGS ON DECEREBRATE RIGIDITY, MUSCLE SPINDLE ACTIVITY AND α‐ADRENOCEPTORS
Authors: MAXWELL D.R. , SUMPTER EILEEN A.
Published: July 2012

The relative potencies of methotrimeprazine, (+)‐methotrimeprazine, (±)‐10‐(3‐dimethylamino‐2‐methylpropyl)‐2‐valeroyl phenothiazine hydrochloride (M & B 18,706) and (+)‐M & B 18,706 in reducing the pressor action of noradrenaline in the spinal cat, reducing intercollicular decerebrate rigidity, and muscle spindle afferent activity have been studied.

Methotrimeprazine was eight times as potent as (+)‐methotrimeprazine in reducing the pressor action of noradrenaline and six times as potent in reducing decerebrate rigidity. M & B 18,706 was also eight times as potent as (+)‐M & B 18,706 in reducing the pressor action of noradrenaline and six times as potent in reducing decerebrate rigidity.

For the above compounds and chlorpromazine there was a significant correlation between the effective doses for the inhibition of the pressor action of noradrenaline and for the reduction of decerebrate rigidity.

The doses which reduced decerebrate rigidity were similar to those that reduced muscle spindle afferent discharge. It is likely that these drugs reduce decerebrate rigidity by inhibiting fusimotor activity.

Desipramine increased decerebrate rigidity and increased spindle afferent discharge.

It is thought that the phenothiazine derivatives studied reduce decerebrate rigidity and spindle afferent discharge by inhibiting receptors for noradrenaline in the central nervous system.
A PHARMACOLOGICAL STUDY OF THE ADRENERGIC MECHANISMS INVOLVED IN THE STRETCH REFLEX OF THE DECEREBRATE RAT
Authors: COMMISSIONG J.W. , SEDGWICK E.M.
Published: July 2012

The effects of catecholamine precursors, enzyme inhibitors, and monoamine depletors have been studied on the stretch reflex in the decerebrate rat.

l‐DOPA alone had a biphasic effect, facilitation followed by inhibition and recovery of the reflex.

About 10% of the preparations did not develop decerebrate rigidity. These preparations did not have a stretch reflex. Within 1 to 5 min of the injection of l‐DOPA in these inactive preparations, a stretch reflex could be elicited.

Control experiments indicate that l‐DOPA was acting centrally after decarboxylation.

dl‐dihydroxyphenylserine had an inhibitory effect, without a preceding facilitation.

When l‐DOPA was preceded by diethyldithiocarbamate (i.v.) or FLA‐63 (i.p.), the predominant response was a sustained facilitation, without an accompanying inhibition.

It is concluded that in the decerebrate rat, increased stretch reflex activity is associated with increased central levels of dopamine, and decreased stretch reflex activity with increased central levels of noradrenaline. The results are discussed with reference to the possibility that dopamine acts by liberating 5‐hydroxytryptamine.
THE ROLE OF PROSTAGLANDINS IN RABBIT MONOARTICULAR ARTHRITIS
Authors: BLACKHAM A. , FARMER J.B. , RADZIWONIK H. , WESTWICK J.
Published: July 2012

Old English (OE) rabbits produced more severe monoarticular arthritis (MAA) after sensitization and intra‐articular challenge with ovalbumin than did either New Zealand White (NZW) or Dutch rabbits. NZW rabbits were better responders than Dutch rabbits.

The swelling of the joint in all three strains of rabbits was triphasic. There was an initial acute swelling which appeared to peak at 2–4 days after challenge. This was followed by a decrease in joint size, and then a secondary increase in size beginning 1–2 weeks after challenge.

An investigation of MAA in OE rabbits showed that there was an increase in E‐type prostaglandins, total leucocyte counts and free acid phosphatase activity in the synovial fluid of the challenged joints at 6 h, 19 h, 47 h, 7 days and 46 days following challenge. There were also histopathological changes at these times. In addition, there was an increase in the surface temperature of both the challenged and non‐challenged knees, and a rise in the body temperature.

Prostaglandin levels peaked at 19 h and were equivalent to 19 ng E2 per joint. In a separate experiment, the prostaglandin present at 18 h was shown to be mainly E1. Maximum levels of prostaglandin appeared to coincide with maximum joint temperature, but preceded maximum joint swelling and a significant rise in both the number of inflammatory cells and the free acid phosphatase activity in the synovial fluid, all of which occurred at 47 hours.

Indomethacin, 7.5 mg/kg orally twice daily, almost completely inhibited the increase in prostaglandin levels in the challenged joints and produced a moderate reduction in joint swelling. It also reduced the increased surface temperature of both knee joints and the raised body temperature. However, indomethacin had no effect on the number of leucocytes present, the free acid phosphatase levels, or the histopathological changes in the joint.

The mean plasma level of indomethacin ranged from 0.5 to 3 μg/ml at the time when the animals were killed.

Lysosomal enzymes may be more important than prostaglandins in rabbit MAA, and the lack of effect of indomethacin on joint histopathology may be due to its inability to prevent the release of these enzymes.
THE ACTIONS OF A NEW β‐ADRENOCEPTOR BLOCKING DRUG, ICI 66082, ON THE RABBIT PAPILLARY MUSCLE AND ON THE DOG HEART
Authors: HARRY J.D. , KNAPP M.F. , LINDEN R.J.
Published: July 2012

The actions of 4‐(2‐hydroxy‐3‐isopropylaminopropoxy) phenyl acetamide (ICI 66082), a new β‐adrenoceptor blocking drug, on the twitch response of the isolated papillary muscle of the rabbit and on dP/dt max and free heart rate of a denervated dog heart preparation, are described.

ICI 66082 (up to 1 mg/ml) did not produce any depression of the twitch response of the rabbit papillary muscle. ICI 66082 antagonized the action of isoprenaline on this preparation at a concentration of 0.01 μg/ml.

ICI 66082 (0.5–1.0 mg/kg intravenously) reduced the control value of dP/dt max in four dog preparations by a mean value of 529 mmHg/s (s.e. mean ± 139 mmHg/s), with no significant change in free heart rate. Antagonism of the effect of isoprenaline on dP/dt max and on free heart rate was demonstrated with ICI 66082 (0.1 mg/kg).

ICI 66082 (1.0–1.5 mg/kg) produced no significant changes in dP/dt max or in free heart rate in four dogs pretreated with reserpine. A significant reduction (16% of the control value) in dP/dt max was observed with ICI 66082 at a high dose of 40–50 mg/kg.

It is concluded that ICI 66082 is a competitive antagonist against the actions of isoprenaline on cardiac muscle, has no negative inotropic action (unless the dose exceeds 40 mg/kg) and lacks intrinsic sympathomimetic activity.
EFFECTS OF PROPRANOLOL ON GASTRIC SECRETION IN ALBINO RATS
Authors: DEBNATH P.K. , GODE K.D. , DAS D. GOVINDA , SANYAL A.K.
Published: July 2012

Effects of graded doses of propranolol have been studied on gastric secretion and gastric ulcers in pylorus‐ligated rats.

A dose‐dependent action of propranolol was observed; small doses increased total volume, acid output and pepsin secretion along with an increase in the incidence of ulcers but high doses were inhibitory.
MODIFICATION BY DRUGS OF THE SECRETAGOGUE EFFECT OF DOPAMINE ON THE PANCREAS
Authors: FURUTA Y. , HASHIMOTO K. , ISHII Y. , IWATSUKI K.
Published: July 2012

The specific stimulating action of dopamine and l‐DOPA on exocrine pancreatic secretion was further investigated in the isolated blood‐perfused canine pancreas.

6‐Hydroxydopamine (100 μg, i.a.) stimulated the secretion but was far less potent than dopamine. Epinine (0.3–1 mg. i.a.), α‐methyldopamine (10–300 μg, i.a.) and octopamine (10–300 μg, i.a.) were ineffective.

α‐Methyldopa (30 mg, i.a.) inhibited the stimulating effect of l‐DOPA (1–3 mg) on pancreatic secretion.

Apomorphine (1 mg, i.a.) attenuated dopamine‐induced (1–30 μg) pancreatic secretion but did not antagonize secretin‐induced (0.03–0.3 units) or pancreozymin‐induced (0.3–1 units) secretion.

These observations suggest that l‐DOPA is probably converted to dopamine to stimulate the exocrine pancreas, and that dopamine interacts with the specific receptors.

The noradrenaline and dopamine content of the canine pancreas was estimated in controls and in dogs treated with secretin, reserpine, l‐DOPA or α‐methyldopa. The values for dopamine and noradrenaline in controls were 139 ± 6 and 375 ± 40 ng/g tissue (n = 13), respectively. Reserpine reduced the noradrenaline content of the pancreatic tissue without affecting the dopamine content. l‐DOPA or secretin caused a significant increase in the dopamine, but not in the noradrenaline content. It is suggested that dopamine has a physiological function in the pancreas which is independent of that of the noradrenaline‐containing nerve fibres.
THE NATURE OF THE BINDING BETWEEN LSD AND A 5‐HT RECEPTOR: A POSSIBLE EXPLANATION FOR HALLUCINOGENIC ACTIVITY
Authors: BERRIDGE M.J. , PRINCE W.T.
Published: July 2012

(+)‐Lysergic acid diethylamide (LSD) mimicked 5‐hydroxytryptamine (5‐HT) in its ability to stimulate fluid secretion, to change transepithelial and intracellular potentials as well as to increase the cyclic 3′,5′‐adenosine monophosphate (cyclic AMP) concentrations of isolated salivary glands of Calliphora.

Unlike 5‐HT, LSD disengages slowly from the receptor and fluid secretion continues despite repeated washing.

Both 5‐HT and tryptamine prevented LSD from acting on the glands.

LSD bound to the receptor was slowly displaced when glands were treated with agonists (tryptamine) or antagonists (gramine).

The property of LSD which permits it to function as an agonist despite remaining tightly bound to the receptor is discussed as a possible basis for its profound effects within the central nervous system.
MODIFICATION OF RESPONSES TO SYMPATHETIC NERVE STIMULATION BY THE RENIN‐ANGIOTENSIN SYSTEM IN RATS
Authors: JOHNSON E.M. , MARSHALL G.R. , NEEDLEMAN P.
Published: July 2012

Angiotensin I (AI) and AII elicited a dose‐dependent potentiation of contractions by rat vas deferens produced by low frequency nerve stimulation without enhancing the contraction produced by exogenous noradrenaline. The All‐induced presynaptic potentiation was blocked by the specific antagonist cysteine8‐AII.

The vasoconstrictor response to periarterial stimulation of rat isolated perfused kidney was potentiated by AII and there was a lesser enhancement of the effect of exogenous noradrenaline.

The response to stimulation of complete sympathetic outflow from the spinal cord to blood vessels in the pithed rat was enhanced by angiotensin or vasopressin in direct proportion to the increase in prestimulus muscular tone. The blood pressure in the pithed rats is primarily maintained by the renin‐angiotensin system since the converting‐enzyme inhibitor (SQ‐20881) or bilateral nephrectomy caused further substantial lowering of systemic blood pressure after spinal cord destruction and after treatment with curare and atropine.
ACTIONS OF PUTATIVE TRANSMITTERS IN THE CHICKEN VAGUS NERVE/OESOPHAGUS AND REMAK NERVE/RECTUM PREPARATIONS
Authors: BARTLET A.L.
Published: July 2012

Histamine (0.02–0.1 μg/ml) contracted the chicken rectum preparation. This effect was antagonized by mepyramine (0.01 μg/ml) but not by hyoscine (0.02 μg/ml).

5‐Hydroxytryptamine (0.05–0.25 μg/ml) relaxed the rectum preparation and at higher concentration produced a biphasic response. These responses were not antagonized by methysergide (0.01 μg/ml), and the relaxation was not antagonized by tetrodotoxin (0.1 μg/ml) or a combination of propranolol (0.05 μg/ml) and phentolamine (0.1 μg/ml).

Neither mepyramine (0.1 μg/ml) nor methysergide (0.01 μg/ml) antagonized the contractions produced by nerve stimulation in vagus nerve/oesophagus and Remak nerve/rectum preparations.

5‐Hydroxytryptamine (2 μg/ml) in the presence of methysergide (0.01 μg/ml), inhibited the contractions produced by nerve stimulation in Remak nerve/rectum and vagus nerve/oesophagus preparations.

Adenosine, adenosine 5′‐phosphate (AMP), adenosine 5′‐diphosphate (ADP) and adenosine 5′‐triphosphate (ATP), in order of decreasing potency, produced slow contractions in most oesophagus preparations. The action of ATP in this preparation was antagonized by tetrodotoxin (0.1 μg/ml), hyoscine (0.1 μg/ml) and strychnine (5 μg/ml).

Desensitization of the vagus nerve/oesophagus preparation to ATP did not produce any antagonism of the contractions to nerve stimulation.

Adenosine and AMP produced relaxations and ADP and ATP contractions in the rectum preparation. ATP was about 100 times as potent as ADP in producing fast contractions which were not antagonized by tetrodotoxin, hyoscine or strychnine.

Desensitization of the Remak nerve/rectum preparation to ATP resulted in the contractions to nerve stimulation and acetylcholine being inhibited to the same extent.

Prostaglandin E2 produced slow contractions in the oesophagus and rectum preparations which were not antagonized by tetrodotoxin (0.1 μg/ml). Polyphloretin phosphate (10 μg/ml) antagonized spontaneous movements and responses to prostaglandin E2 in the rectum but not the oesophagus.

Neither polyphloretin phosphate (60 μg/ml) nor indomethacin (20–100 μg/ml) antagonized the contractions produced by nerve stimulation in vagus nerve/oesophagus (with hyoscine in the bathing solution) and Remak nerve/rectum preparations.

These experiments seem to exclude histamine, 5‐hydroxytryptamine, adenosine and its nucleotides and prostaglandin E2 as possible motor transmitters in synapses and neuromuscular junctions in the chicken vagus nerve/oesophagus and Remak nerve/rectum preparations.
THE EFFECT OF PROSTAGLANDIN E2 ON THE ARTERIAL BLOOD PRESSURE OF NORMOTENSIVE AND SPONTANEOUSLY HYPERTENSIVE RATS
Authors: SIMPSON L.L.
Published: July 2012

In anaesthetized rats, injection of prostaglandin E2 (0.5–5.0 μg/kg i.v.) caused a dose‐dependent vasodepressor response. The magnitude of response was significantly greater in spontaneously hypertensive rats than in normotensive rats.

In spontaneously hypertensive rats, the magnitude of the prostaglandin‐induced depressor response was closely correlated with blood pressure. The higher the blood pressure, the greater was the response evoked by prostaglandin.

In spontaneously hypertensive rats, a combination of guanethidine plus hydralazine reduced both blood pressure and prostaglandin‐induced depressor responses.

Spontaneously hypertensive rats and normotensive rats did not differ in the magnitude of their vasodepressor responses to intravenously administered acetylcholine or isoprenaline.
EFFECTS OF BENZOCTAMINE AND CHLORDIAZEPOXIDE ON TURNOVER AND UPTAKE OF 5‐HYDROXYTRYPTAMINE IN THE BRAIN
Authors: LIPPMANN W. , PUGSLEY T.A.
Published: July 2012

Benzoctamine, a new psychoactive drug, known to exert in man an anti‐anxiety effect resembling that of chlordiazepoxide, decreased the disappearance of intraventricularly‐injected [14C]‐5‐hydroxytryptamine (5‐HT) from rat brain, as did chlordiazepoxide.

Both drugs partially inhibited the α‐ethyl‐3‐hydroxy‐4‐methylphenylethylamine‐induced depletion of rat brain 5‐HT.

It is concluded that benzoctamine, like chlordiazepoxide, decreases 5‐HT turnover in the brain and that this action may play a role in the anti‐anxiety effect of these drugs observed in man.
STRUCTURE‐ACTIVITY RELATIONS FOR THE INHIBITION OF 5‐HYDROXYTRYPTAMINE UPTAKE BY TRICYCLIC ANTIDEPRESSANTS INTO SYNAPTOSOMES FROM SEROTONERGIC NEURONES IN RAT BRAIN HOMOGENATES
Authors: HORN A.S. , TRACE R.C.A.M.
Published: July 2012

The inhibitory effects of various analogues of imipramine on [3H]‐5‐hydroxytryptamine (5‐HT) uptake into homogenates of rat hypothalamus were examined.

For structures with a three carbon side chain the tertiary amine derivative was more potent than the compound with a secondary amine function.

Potency was reduced by increasing or decreasing the length of the three carbon side chain by one carbon atom.

Substitution of a methyl group in the α or β position in the side chain reduced potency.

Replacement of the dimethylene bridge in imipramine by a sulphur atom or substitution of a C=C double bond for the exocyclic N‐C bond of imipramine both led to a fall in potency.

3‐Chlorimipramine was the most potent inhibitor of [3H]‐5‐hydroxytryptamine uptake of the compounds tested.
EFFECTS OF PROCAINE AND LIGNOCAINE ON ELECTRICAL AND MECHANICAL ACTIVITY OF SMOOTH MUSCLE OF SHEEP CAROTID ARTERIES
Authors: JACOBS A. , KEATINGE W.R.
Published: July 2012

Procaine in concentrations up to 20 Mm facilitated or induced electrical and mechanical activity in arterial smooth muscle, even with tetrodotoxin present.

Procaine (up to 20 Mm) caused relaxation when electrical activity was blocked by prior potassium depolarization.

Procaine (1 Mm) reduced mechanical responses to noradrenaline (1 μm) which were not accompanied by action potentials. It generally reduced mechanical responses to noradrenaline (1 Mm) while increasing electrical activity induced by this.

Lignocaine (1 Mm) did not facilitate electrical activity significantly; it relaxed arteries in saline or potassium‐rich solution and reduced mechanical responses to noradrenaline.

High concentrations of procaine (at least 80 Mm) or lignocaine (at least 20 Mm) blocked electrical activity and caused contraction followed by relaxation and complete unresponsiveness.
THE RESPONSES OF THE ISOLATED, BLOOD‐PERFUSED SPLEEN OF THE DOG TO ANGIOTENSIN, OXYTOCIN AND VASOPRESSIN
Authors: DAVIES B.N. , WITHRINGTON P.G.
Published: July 2012

The responses of the smooth muscle of the capsule and blood vessels of the isolated, blood‐perfused spleen of the dog to angiotensin, oxytocin and vasopressin have been investigated and compared to the actions of the catecholamines, adrenaline and noradrenaline.

Increasing doses of each of the three polypeptides cause graded increases in splenic vascular resistance and reductions in spleen volume.

Doses of the polypeptides which evoked increases in splenic vascular resistance not significantly different from increases produced by chosen doses of each catecholamine caused significantly smaller reductions in spleen volume.

The time‐course of action of the polypeptides on the splenic vascular smooth muscle is different since the time to 50% recovery from vasopressin is highly significantly longer than that for equieffective doses of either angiotensin or oxytocin.

Phenoxybenzamine, in a dose which almost blocked the actions of the catecholamines, increased the responses of the vascular and capsular smooth muscle to oxytocin, vasopressin and angiotensin. This increase was not observed with another α‐adrenoceptor blocking agent, phentolamine.

The significant species variation in the responses of the smooth muscle of the spleen to polypeptides and catecholamines are discussed and the results are considered in the context of the possible physiological roles of the polypeptides in haemorrhage.
EVIDENCE FOR NORADRENALINE AND ADRENALINE AS SYMPATHETIC TRANSMITTERS IN THE CHICKEN
Authors: DeSANTIS V.P. , LÄNGSFELD W. , LINDMAR R. , LÖFFELHOLZ K.
Published: July 2012

The concentrations of noradrenaline and adrenaline in various organs, arterial plasma and venous outflow from isolated hearts of adult chickens have been determined.

The relative adrenaline concentrations (percentage of the sum of noradrenaline and adrenaline) in the heart (33%), spleen (16%) and brain (26%) were higher than those found in mammalian organs. Chemical sympathectomy by pretreatment with 6‐hydroxydopamine caused a decrease of the noradrenaline and adrenaline concentrations in the heart to 20 and 23% and in the spleen to 16 and 29%, respectively.

Stimulation of the right sympathetic nerves, infusion of tyramine or infusion of a modified Tyrode solution containing 108 mM K+ and 44 mM Na+ caused an output of both noradrenaline and adrenaline into the perfusate of isolated hearts. The relative adrenaline concentration in the perfusate (20–28%) was not significantly different from the relative adrenaline concentration remaining in these hearts (19–22%). In the individual experiments, the noradrenaline: adrenaline ratios of the stimulation perfusates were positively correlated with the ratios found in the hearts.

The effects of noradrenaline and adrenaline on cardiac rate and tension development were studied in spontaneously beating right atria and electrically driven left atria, respectively. In addition, the arterial pressure rise in response to noradrenaline or adrenaline was measured in chickens. It was found that the cardio‐vascular potency of noradrenaline, as reflected by the increases in heart rate, cardiac tension development and arterial blood pressure, was not significantly different from that of adrenaline.

It is concluded that, in the chicken heart and spleen, both noradrenaline and adrenaline act as sympathetic neurotransmitters.
BEHAVIOURAL CHANGES INDUCED IN CONSCIOUS MICE BY INTRACEREBROVENTRICULAR INJECTION OF CATECHOLAMINES, ACETYLCHOLINE AND 5‐HYDROXYTRYPTAMINE
Authors: HERMAN Z.S.
Published: July 2012

A simple method of injecting soluble substances into the lateral ventricle of the brain of the conscious mouse is described.

The effect of various doses of noradrenaline, dopamine, acetylcholine, 5‐hydroxytryptamine given into the right lateral brain ventricle were tested on locomotor and exploratory activities of mice.

Noradrenaline in a dose of 0.1 μg increased locomotor activity. This effect was prevented by phenoxybenzamine but not by propranolol.

Higher doses of noradrenaline (1 or 10 μg) decreased locomotor and exploratory activities. Propranolol but not phenoxybenzamine abolished these effects.

Dopamine (0.1 or 1 μg) increased locomotor activity. The higher doses also induced tremor.

The highest dose of dopamine tested (10 μg) elicited stereotypical behaviour.

All the behavioural phenomena induced by 0.1 μg and 10 μg of dopamine were blocked by pimozide.

Acetylcholine (1 and 10 μg) and 5‐hydroxytryptamine (1 μg) inhibited locomotor and exploratory activity.

The effects of 1 and 10 μg of acetylcholine were abolished by atropine (5 mg/kg i.p.). Methysergide (5 mg/kg i.p.) had no influence on the effects of 5‐hydroxytryptamine (1 μg).
INHIBITION BY APOMORPHINE OF THE METOCLOPRAMIDE‐INDUCED CATALEPSY AND INCREASE IN STRIATAL HOMOVANILLIC ACID CONTENT
Authors: AHTEE LIISA
Published: July 2012

The mechanism of the cataleptic effect of metoclopramide was analyzed by using drugs which alter the activity of dopaminergic or cholinergic neurones or the content of γ‐aminobutyric acid in the central nervous system of rats.

The cataleptic effect of metoclopramide (20 mg/kg) was antagonized by apomorphine (10 mg/kg) and by atropine (50 mg/kg). Aminooxyacetic acid (AOAA, 25–50 mg/kg) potentiated the catalepsy induced by metoclopramide (5 mg/kg).

Metoclopramide alone did not alter the rectal temperature of rats. It did not alter the AOAA‐induced hypothermia, but it partially antagonized apomorphine‐induced hypothermia.

Metoclopramide induced a six‐fold increase in striatal homovanillic acid (HVA) concentration, but it did not change the dopamine or noradrenaline content in the brain of rats. Apomorphine decreased the striatal HVA concentration in control and in metoclopramide‐treated rats. Atropine and AOAA did not alter the metoclopramide‐induced increase in striatal HVA concentration.

The results suggest that metoclopramide produces catalepsy by blocking striatal dopamine receptors.
TOLERANCE TO MORPHINE‐INDUCED CALCIUM DEPLETION IN REGIONAL BRAIN AREAS: CHARACTERIZATION WITH RESERPINE AND PROTEIN SYNTHESIS INHIBITORS
Authors: ROSS D.H.
Published: July 2012

Administration of a single dose of morphine sulphate (25 mg/kg) induces tolerance to calcium depletion lasting seven days.

There are no apparent changes in calcium content in any of eight discrete brain regions throughout this seven day period.

Pretreatment with reserpine (5 mg/kg) did not alter the ability of morphine to induce tolerance. Reserpine alone produced no tolerance to its own calcium depleting action.

Cycloheximide (500 μg/kg) but not chloramphenicol (200 mg/kg) effectively prevented development of tolerance.

It is concluded that the induction of tolerance to calcium depletion seen after morphine may involve changes in various proteins in membranes of synaptic origin.
AN INVESTIGATION OF THE TACHYCARDIA PRODUCED BY INTRACEREBRO‐VENTRICULAR INJECTIONS OF ISOPRENALINE IN MICE
Authors: BURDEN D.T. , PARKES M.W.
Published: July 2012

Isoprenaline, 3.5–20 ng, injected intracerebroventricularly in atropinized mice under pentobarbitone anaesthesia produced a dose‐dependent tachycardia.

Pretreatment with either reserpine or pempidine blocked nervously‐mediated tachycardia as shown by marked reduction of that due to stimulation of the spinal outflow in pithed mice. After pretreatment with these drugs, intracerebroventricular isoprenaline caused tachycardia of a similar degree and time course to that in mice not so pretreated.

Pretreatment with either reserpine or pempidine caused supersensitivity to the tachycardia due to intravenous isoprenaline.

When allowance was made for this supersensitivity in the effect of intracerebroventricular isoprenaline in pretreated mice, a small dose‐dependent residual effect remained that could be attributed to leakage of isoprenaline into the peripheral circulation.

This was confirmed by the appearance of a late‐developing tachycardia on intracerebroventricular injection of isoprenaline in spinal mice.

It is therefore concluded that the tachycardia caused by intracerebroventricular isoprenaline in mice is, at least initially, of central origin.
EFFECTS OF RESERPINE ON THE ADRENAL MEDULLA OF THE SPONTANEOUSLY HYPERTENSIVE RAT
Authors: SLOTKIN T.A.
Published: July 2012

Reserpine administration resulted in a larger initial decline in adrenal catecholamines in spontaneously hypertensive rats (SHR) than in normotensive Wistar rats (NWR); the difference was eliminated by pretreatment with chlorisondamine.

Reserpine also produced a larger increase in SHR catecholamines and dopamine β‐hydroxylase several days later; chlorisondamine pretreatment did not prevent the increases, although it did slightly slow the increases.

Vesicles from SHR or NWR incubated with reserpine in vitro demonstrated equivalent inhibition of adenosine 5′‐triphosphate (ATP)‐Mg2+ ‐stimulated adrenaline uptake.

Recovery of uptake was more rapid in SHR than in NWR after reserpine inhibition, and this was associated with a burst of new vesicle synthesis in the SHR; chlorisondamine pretreatment reduced the number of new, immature vesicles in reserpine‐treated SHR.

Both SHR and NWR secreted equal proportions of their adrenal catecholamine contents after nicotine administration.

These data suggest that the sympatho‐adrenal system of the SHR exhibits an enhanced reflex response to reserpine but that reserpine is equally effective in SHR and NWR in producing blockade of vesicular catecholamine transport; these alterations can affect markedly the actions of autonomic drugs in the SHR.
NICOTINE‐INDUCED STIMULATION OF STEROIDOGENESIS IN ADRENOCORTICAL CELLS OF THE CAT
Authors: RUBIN R.P. , WARNER W.
Published: July 2012

The effect of nicotine on steroid production and release from trypsin‐dispersed cat adrenocortical cells was investigated.

Nicotine, like adrenocorticotrophin (ACTH), elicited a dose‐dependent increase in steroidogenesis, which depended upon the presence of calcium in the medium.

Augmented steroid production evoked by submaximal concentrations of ACTH, monobutyryl cyclic adenosine 3′,5′‐monophosphate (AMP), or prostaglandin E2 was further enhanced by steroidogenic concentrations of nicotine.

These results are discussed in relation to the possible mode of action of nicotine on cortical cells and to the potential consequences of smoking during stress.
ACTION OF β‐ADRENOCEPTOR ANTAGONISTS ON THE RESPONSE TO ISOPRENALINE IN THE OESTROGEN DOMINATED RABBIT UTERUS
Authors: NESHEIM BRITT—INGJERD
Published: July 2012

Log dose‐response curves to isoprenaline from spontaneously contracting muscle strips from rabbit uterus have been obtained. The effects of the α‐adrenoceptor antagonists phentolamine and phenoxybenzamine, the β‐adrenoceptor antagonists propranolol and practolol, and (+)‐propranolol on the log dose‐response curves were studied.

Phentolamine 5.3 × 10−7 M had a stimulating effect on the muscle strips, moving the log dose‐response curve of isoprenaline to the right. Phenoxybenzamine 2.9 × 10−5 M had no effect on the curves.

Propranolol 3.4 × 10−6 M had no effect on the curves from circular muscle strips, with either phentolamine 5.3 × 10−7 M or with phenoxybenzamine 2.9 × 10−5 M as α‐blocker. The curves from the longitudinal muscle strips were shifted somewhat to the right, the same shift, however, being obtained with (+)‐propranolol 3.4 × 10−6 M.

Practolol 3.8 × 10−6, 3.8 × 10−5 and 3.8 × 10−4 M was without effect on the curves, either in the circular or in the longitudinal strips.

It is concluded that neither propranolol at 3.4 × 10−6 M nor practolol act as β‐adrenoceptor antagonists in oestrogen dominated rabbit uterus. In all other tissues investigated, propranolol or practolol block the effect of isoprenaline. Whether the effect of isoprenaline in this tissue may be termed a β‐effect, is then a question of definition. In addition there is no evidence for any extraneuronal uptake mechanisms for isoprenaline.

Variations in sensitivity to β‐stimulation with the time of the year were observed, the sensitivity being greatest in the winter and lowest in the summer.
THE EFFECT OF PROPRANOLOL ON VASCULAR RESPONSES TO SYMPATHETIC NERVE STIMULATION
Authors: DAWES P.M. , FAULKNER D.C.
Published: July 2012

In an attempt to clarify the rǒle of the sympathetic neurone in the antihypertensive action of propranolol, the effect of this drug on responses to lumbar sympathetic nerve stimulation has been studied in the perfused hind‐limb of the dog.

No consistent reduction of maximal or submaximal responses to nerve stimulation was produced by propranolol (10 to 100 μg/kg). In contrast, potentiation of nerve‐evoked responses, as well as those to injected noradrenaline, usually occurred. Dexpropranolol (50 μg/kg) had no effect.

When neuronal uptake of noradrenaline was inhibited by desmethylimipramine or cocaine, no reduction in responses to sympathetic nerve stimulation was observed with propranolol.

No evidence was found, using α‐adrenoceptor blocking drugs, that released transmitter stimulates β‐adrenoceptors in the blood vessels of the hind‐limb.

No evidence has been found for the existence of an adrenergic neurone‐blocking action of propranolol that might contribute to the antihypertensive activity in man.
ENHANCED INACTIVATION OF PROSTAGLANDIN E2 BY THE RABBIT LUNG DURING PREGNANCY OR PROGESTERONE TREATMENT
Authors: BEDWANI J.R. , MARLEY P.B.
Published: July 2012

The inactivation of prostaglandin E2 by the rabbit lung was estimated in vivo by comparing its depressor potency following intravenous and intra‐aortic injections, and in vitro by measuring the rate of disappearance of smooth muscle stimulating activity when the prostaglandin was incubated with high speed supernatant fractions from lung homogenates.

The ability of the lung to inactivate prostaglandin E2 in vivo increased gradually throughout pregnancy, and then decreased rapidly during the three days post‐partum.

An increased lung inactivation was also seen in pseudopregnant (day 12) rabbits, and in non‐pregnant rabbits treated with progesterone for 12 days. A further increase occurred when progesterone treatment was prolonged to 26 days.

Treatment with oestradiol monobenzoate or cortisol for 12 days, and deprivation of ovarian hormones for 14‐17 days by ovariectomy, were without effect on the lung inactivation of prostaglandin E2.

The in vitro experiments revealed a striking increase in the activity of lung prostaglandin metabolizing enzymes during pregnancy.

The results are discussed in relation to the hormonal changes occurring during pregnancy, and it is suggested that an enhanced lung inactivation of prostaglandins might have an important protective function at this time.
EFFECT OF TETRAMETHYLENEDISULPHOTETRAMINE ON THE MEMBRANE CONDUCTANCE INCREASE PRODUCED BY γ‐AMINO‐BUTYRIC ACID AT THE CRAB NEUROMUSCULAR JUNCTION
Authors: LARGE W.A.
Published: July 2012

The effect of tetramethylenedisulphotetramine (TETS) on the increase in membrane conductance produced by γ‐aminobutyric acid (GABA) at the hermit crab neuromuscular junction was investigated. TETS produced a dose‐dependent antagonism of GABA, which was characterized by a non‐parallel shift of the log dose‐conductance curve for GABA with a reduced maximal conductance change.
INDOMETHACIN‐INDUCED INCREASE IN NORADRENALINE TURNOVER IN SOME RAT ORGANS
Authors: FREDHOLM B.B. , HEDQVIST P.
Published: July 2012

The effect of a prostaglandin synthesis inhibitor, indomethacin, on noradrenaline turnover rate in various rat tissues was determined from the product of the endogenous noradrenaline concentration and of the rate constant of (—)‐[3H]‐noradrenaline decline after injection of the labelled amine in tracer doses.

Treatment of the rats with indomethacin (5 mg/kg p.o. five times during 2.5 days) increased noradrenaline turnover rate 32–36% in submandibular gland, spleen and heart, and 4–17% in epididymal and subcutaneous adipose tissue.

The extrapolated [3H]‐noradrenaline content at time 0 was greater in heart and adipose tissue of indomethacin‐treated animals than in controls, while it was not significantly changed in spleen and salivary gland.

There was no apparent relationship between tissue concentrations of intravenously injected [14C]‐indomethacin and the effect of indomethacin on noradrenaline uptake and turnover rate in the different tissues.

Indomethacin treatment did not affect monoamine oxidase and catechol O‐methyl‐transferase activities in the different tissues.

The results are consistent with the hypothesis that indomethacin increases noradrenaline turnover in the rat by blockade of a locally operating feed back inhibition of transmitter release by prostaglandins. However, additional effects, such as an increased impulse traffic, cannot be ruled out.
INHIBITION OF THE PULMONARY INACTIVATION OF PROSTAGLANDINS in vivo BY DI‐4‐PHLORETIN PHOSPHATE
Authors: CRUTCHLEY D.J. , PIPER PRISCILLA J.
Published: July 2012

Inactivation of prostaglandin E2 in the pulmonary circulation of rabbits in vivo was measured by comparing the hypotensive effects of doses given intravenously and intra‐arterially.

Di‐4‐phloretin phosphate (DPP) 25–100 μg kg−1 min−1 inhibited the inactivation of prostaglandin E2 in the pulmonary circulation.

These doses of DPP caused a marked shift to the left of the dose‐response curve to prostaglandin E2 given intravenously but did not affect the dose‐response curve to prostaglandin E2 given intra‐arterially.

Inhibition of pulmonary inactivation of prostaglandins E2 and E2α caused marked potentiation of their gastrointestinal effects.

At these doses antagonism of the hypotensive action of prostaglandin E2 by DPP was seldom seen but the gastrointestinal effect of prostaglandin E2α was sometimes antagonized.

After treatment with DPP 100 μg kg−1 min−1, high doses of prostaglandin were sometimes lethal.