bluuebunny/crossref_metadata_2025 huggingface dataset:
THE EFFECT OF RECEPTOR DESENSITIZATION ON THE ACTION OF α‐BUNGAROTOXIN ON CULTURED SKELETAL MUSCLE
Authors: DRYDEN W.F. , HARVEY A.L.
Published: July 2012

The effect of receptor desensitization produced by carbachol on the antagonist action of α‐bungarotoxin has been studied in cultured skeletal muscle from chick embryos. In control preparations, α‐bungarotoxin irreversibly blocked depolarization produced by carbachol. However, after receptor desensitization, α‐bungarotoxin was no longer effective in blocking the response to carbachol. It is concluded that desensitization protects cholinoceptors from the action of α‐bungarotoxin.
THE EFFECT OF Δ1‐TETRAHYDROCANNABINOL ON THE UPTAKE OF [3H]‐(—)‐NORADRENALINE BY THE ISOLATED PERFUSED HEART OF THE RAT
Authors: GRAHAM J.D.P. , LEWIS M.J. , LI D.M.F.
Published: July 2012

Forty‐eight isolated rat hearts were perfused with Krebs solution and with [3H]‐(–)‐noradrenaline ([3H]‐NA) containing 4.5 nCi/ml in 50 ng/ml, as described by Iversen (1963). To groups of six, cocaine was added to [3H]‐NA in concentrations of 400 Nm, 2 and 10 μm. To the rest Tween 80, 25 μg/ml was added to [3H]‐NA and in three groups Δ1‐THC additionally in concentrations of 560 Nm and 2.8 or 14 μm. Cocaine caused a linear concentration‐related inhibition of uptake; Tween caused a 38.7% inhibition; THC caused additionally a linear concentration‐related inhibition.
EVIDENCE FOR PROSTAGLANDIN MEDIATED PREJUNCTIONAL CONTROL OF RENAL SYMPATHETIC TRANSMITTER RELEASE AND VASCULAR TONE
Authors: FRAME MADELINE H. , HEDQVIST P.
Published: July 2012

Prostaglandin E2 dose‐dependently and reversibly inhibited the noradrenaline overflow resulting from nerve stimulation of the rabbit kidney.

The magnitude of this inhibition varied inversely with the frequency of stimulation employed.

The prostaglandin synthesis inhibitors, indomethacin and meclofenamic acid, both increased the transmitter overflow resulting from renal nerve stimulation, suggesting that endogenous prostaglandin has a role in the regulation of transmitter release.

In the presence of indomethacin, the inhibitory effect of exogenous prostaglandin E2 was enhanced.

The prostaglandin precursor, arachidonic acid, also caused a significant, dose‐dependent and reversible inhibition of transmitter overflow. This inhibition became insignificant when arachidonic acid was applied in the presence of indomethacin, suggesting that the inhibition was mediated by newly formed prostaglandin rather than by arachidonic acid itself.

It is proposed that newly formed prostaglandin controls noradrenaline release primarily from inner cortical nerve endings, thereby maintaining juxtamedullary blood flow under periods of increased sympathetic nerve activity.
EFFECT OF AMODIAQUINE ON GASTRIC HISTAMINE METHYLTRANSFERASE AND ON HISTAMINE‐STIMULATED GASTRIC SECRETION
Authors: BARTH H. , LORENZ W. , TROIDL H.
Published: July 2012

Amodiaquine was found to be a potent inhibitor in vitro of gastric histamine methyltransferase from human and canine corpus and from pig antrum. The ID50 for the enzyme, purified from pig antrum mucosa by ultracentrifugation and chromatography on DEAE‐cellulose, was 2.5 μM.

In six dogs with Heidenhain pouches the maximum secretory response to histamine (40 μg/kg i.m.) was augmented by i.m. injection of amodiaquine. The augmentation depended on the dose of amodiaquine, the optimum effect (40% increase in volume of gastric juice, 80% in acid output) being achieved with 2 mg/kg. The maximum secretory response to betazole was also enhanced by amodiaquine.

It was suggested that amodiaquine may enhance the histamine and betazole stimulated gastric secretion by an inhibition of gastric histamine methyltransferase in vivo.
CALCIUM AND PANCREATIC SECRETION‐DYNAMICS OF SUBCELLULAR CALCIUM POOLS IN RESTING AND STIMULATED ACINAR CELLS
Authors: CLEMENTE F. , MELDOLESI J.
Published: July 2012

Pulse‐chase experiments were carried out on pancreatic tissue lobules incubated in vitro, with 45Ca as the tracer, in order to shed some light on the functional significance of the calcium pools associated with the various cell organelles of the acinar cell, especially in relation to stimulus‐secretion coupling.

The kinetics of tracer uptake and release which were observed in the intact lobules suggest the existence of a number of intracellular pools, whose rate of exchange is slower than that across the plasmalemma.

The various subcellular fractions accumulate the tracer in different amounts: some (rough microsomes and postmicrosomal supernatant) showed little radioactivity and some (smooth microsomes and zymogen granule membranes) were heavily labelled; mitochondria and zymogen granules showed intermediate values.

The fractions are heterogeneous also in relation to the time course of uptake and release of the tracer: in rough and smooth microsomes and, especially, in the postmicrosomal supernatant both rates were fast; zymogen granules and zymogen granule membranes showed slow rates of uptake and little release during chase; intermediate rates were found in mitochondria.

In agreement with previous findings we observed that in 45Ca preloaded lobules, stimulation of secretion (brought about by the secretagogue polypeptide caerulein) results in an increase of the tracer release which seems to be due primarily to the rise of the intracellular concentration of free Ca2+ and to the consequent increase of the transmembrane Ca2+ efflux. Among the cell fractions isolated from stimulated lobules only the mitochondria exhibited a significantly lower 45Ca level relative to the unstimulated controls.

It is concluded that, of the organelle‐bound calcium pools, that associated with the mitochondria might be involved in the regulation of the calcium‐dependent functions, including stimulus‐secretion coupling; the calcium associated with the zymogen granule content probably has a role in the architecture of the organelle and in the functionality of the pancreatic juice, while the calcium bound to the membrane of the granules might be concerned with the regulation of its permeability properties.
THE USE OF RADIOACTIVE MICROSPHERES TO COMPARE THE EFFECTS OF HYDRALAZINE, GUANETHIDINE AND SK&F 24260 ON THE REDISTRIBUTION OF CARDIAC OUTPUT IN ANAESTHETIZED RABBITS
Authors: JOHNSTON BARBARA M.
Published: July 2012

The use of radioactive microspheres is described for the measurement of cardiac output in anaesthetized rabbits and its redistribution after the administration of drugs which lower blood pressure.

Hydralazine increased peripheral vascular conductance by 123%. The vascular beds in which it had most effect were those of the carcass (mainly muscle) and the kidneys.

SK&F 24260, (1,4 dihydro‐2, 6‐dimethyl‐4‐(2‐trifluormethylphenyl)‐3,5,‐pyridinedicarboxylic acid diethyl ester), had similar vasodilator actions. Its effect in the carcass contributed relatively more to the increase of total peripheral conductance. It also caused a remarkable degree of cerebral vasodilatation.

Guanethidine had a relatively small effect on total peripheral conductance and lowered blood pressure mainly by reducing stroke volume and cardiac output.
EFFECTS OF MONOAMINE OXIDASE INHIBITION BY CLORGYLINE, DEPRENIL OR TRANYLCYPROMINE ON 5‐HYDROXYTRYPTAMINE CONCENTRATIONS IN RAT BRAIN AND HYPERACTIVITY FOLLOWING SUBSEQUENT TRYPTOPHAN ADMINISTRATION
Authors: GREEN A.R. , YOUDIM M.B.H.
Published: July 2012

The effect of various doses of tranylcypromine on the degree of inhibition of rat brain monoamine oxidase (MAO) using 5‐hydroxytryptamine (5‐HT), dopamine and phenylethylamine as substrates has been examined 120 min after injection of the inhibitor. The concentration of brain 5‐HT was also examined both after tranylcypromine alone and also when L‐tryptophan (100 mg/kg) had been given 30 min after the tranylcypromine.

All doses of tranylcypromine greater than 2.5 mg/kg totally inhibited MAO oxidation of 5‐HT, phenylethylamine and dopamine as measured in vitro and produced a similar rise of brain 5‐HT in vivo. When tryptophan was also given, there was a further rise of brain 5‐HT, which was comparable after all doses of tranylcypromine above 2.5 mg/kg and the characteristic syndrome of hyperactivity made its appearance.

Clorgyline (a ‘Type A’ MAO inhibitor), in doses up to 10 mg/kg, did not totally inhibit MAO activity towards phenylethylamine although it did inhibit 5‐HT oxidation by 100%. Deprenil (a ‘Type B’ MAO inhibitor) at doses up to 10 mg/kg did not fully inhibit 5‐HT oxidation although phenylethylamine oxidation was inhibited almost completely. Administration of either compound alone did not produce as great an accumulation of brain 5‐HT as that seen after tranylcypromine (2.5 mg/kg) and subsequent administration of tryptophan did not cause hyperactivity or the rise of brain 5‐HT seen after tranylcypromine (2.5 mg/kg) plus tryptophan.

Administration of clorgyline plus deprenil (2.5 mg/kg of each) almost totally inhibited oxidation of both 5‐HT and phenylethylamine; subsequent tryptophan administration resulted in a rise of brain 5‐HT nearly as great as that seen following tranylcypromine (2.5 mg/kg) plus tryptophan and the animals became hyperactive.

No evidence was found pointing to the formation of any other 5‐substituted indole in the brain following tranylcypromine plus L‐tryptophan administration as suggested by others.

It is concluded that while 5‐HT may normally be metabolized in the brain by ‘Type A’ MAO in vivo, when this form is inhibited, 5‐HT can still be metabolized by ‘Type B’ enzyme. It is only when both forms are almost totally inhibited that the largest rise of brain 5‐HT is seen and subsequent tryptophan administration produces the hyperactivity syndrome.
THE IRREVERSIBLE BINDING OF ACETYLCHOLINE MUSTARD TO MUSCARINIC RECEPTORS IN INTESTINAL SMOOTH MUSCLE OF THE GUINEA‐PIG
Authors: ROBINSON D.A. , TAYLOR J.G. , YOUNG J.M.
Published: July 2012

Acetylcholine mustard (N‐2‐chloroethyl‐N‐methyl‐2‐acetoxyethylamine), a potent muscarinic agonist, binds virtually irreversibly to muscarinic receptors in longitudinal muscle strips from guinea‐pig small intestine, as shown by the inhibition of the binding of [3H]‐propylbenzilylcholine mustard ([3H]‐PrBCM), an affinity label for the muscarinic receptor.

A value for the apparent binding affinity of acetylcholine mustard and a value for the rate constant for the receptor alkylation reaction have been deduced from the rate of onset of the inhibition of [3H]‐PrBCM binding.

The kinetic constants obtained may refer largely to the interaction between acetylcholine mustard and the desensitized receptor.

At high concentrations acetylcholine mustard practically abolishes the contractile response to carbachol. At these concentrations acetylcholine mustard appears to have multiple actions on the tissue.
THERMOREGULATORY CHANGES INDUCED BY CHOLINOMIMETIC SUBSTANCES INTRODUCED INTO THE CEREBRAL VENTRICLES OF SHEEP
Authors: JOHNSON K.G.
Published: July 2012

Thermoregulatory responses have been recorded from Welsh Mountain sheep exposed to warm, neutral or cold environments while injections of cholinomimetic drugs and/or their antagonists have been given into a lateral cerebral ventricle.

Carbachol and physostigmine inhibited panting of animals at high ambient temperature (ta), caused vasoconstriction and initiated shivering at neutral ta, and accentuated shivering at low ta. Rectal temperature (tre) invariably increased. Oxotremorine had apparently identical effects.

Nicotine and another ganglionic stimulant, the quaternary methyl derivative of dopamine, had no effects on thermoregulation.

Atropine given 10 min before injections of carbachol, physostigmine or oxotremorine completely inhibited their hyperthermic effects, but pretreatment with the ganglion‐blocking drug, pempidine, caused no inhibition. The cholinergic synapses that respond to cholinomimetic drugs injected into the lateral cerebral ventricles of sheep are therefore muscarinic and not nicotinic.

When atropine was given to sheep exposed to cold, no detectable reduction of shivering occurred and tre decreased only slightly, even with doses of atropine far greater than needed to inhibit shivering induced by physostigmine. This may be because shivering is controlled by neural pathways unaffected by drugs administered intracerebroventricularly or because the cholinergic synapses activated by physostigmine do not carry the input from cold sensors.
EFFECT OF ACETYLCHOLINE ON CHANGES IN CONTRACTILITY, HEART RATE AND PHOSPHORYLASE ACTIVITY PRODUCED BY ISOPRENALINE, SALBUTAMOL AND AMINOPHYLLINE IN THE PERFUSED GUINEA‐PIG HEART
Authors: CHAMALES M.H. , GOURLEY R.D. , WILLIAMS BETTY J.
Published: July 2012

Isolated perfused hearts of guinea‐pigs were given graded doses of isoprenaline, salbutamol and aminophylline, both before and during acetylcholine infusion.

The three agonists produced increases in contractile force, heart rate and ventricular glycogen phosphorylase activity.

Acetylcholine, in the concentration used, had no effect on any of the measured variables but did antagonize the effects of the three agonists on contractility and phosphorylase activity. The positive chronotropic responses were unaltered by acetylcholine infusion.

The ratio of the dose required for a standard heart rate response to the dose producing a standard contractile force response was different for each agonist.

The selective antagonism of the contractile response to isoprenaline, salbutamol and aminophylline suggest that different mechanisms are involved in the initiation of positive inotropic and chronotropic responses.
A CHEMOTACTIC ROLE FOR PROSTAGLANDINS RELEASED FROM POLYMORPHONUCLEAR LEUCOCYTES DURING PHAGOCYTOSIS
Authors: HIGGS G.A. , McCALL ELAINE , YOULTEN L.J.F.
Published: July 2012

Prostaglandin E1 is chemotactic at concentrations down to 10 ng/ml for rabbit polymorphonuclear (PMN) leucocytes. Prostaglandins E2 and F2α have little or no chemotactic effect at concentrations up to 10 μg/ml.

Washed PMN leucocytes produce a chemotactic agent during phagocytosis, but not in the presence of indomethacin (28 μM).

Phagocytosing PMN leucocytes produce up to ten times as much prostaglandin as do resting cells. Some of this is prostaglandin E1 as judged by thin layer chromatography and differential bioassay. This prostaglandin production by PMN leucocytes is abolished by indomethacin (28 μM).

Ultrasonicated suspensions of PMN leucocytes produce prostaglandin from arachidonic acid. This synthesis is inhibited by indomethacin.

Homogenates of PMN leucocytes which have been pre‐incubated with bacteria for 30 min show more prostaglandin synthetase activity than homogenates from PMN leucocytes which have not been exposed to bacteria.

It is concluded that in some forms of inflammation, prostaglandin E1 may play a controlling role in cellular migration.

PMN leucocytes may contribute to the generation of prostaglandins found in some inflammatory lesions.
COMBINED α‐ AND β‐ADRENOCEPTOR BLOCKING DRUG AH 5158: FURTHER STUDIES ON α‐ADRENOCEPTOR BLOCKADE IN ANAESTHETIZED ANIMALS
Authors: KENNEDY I. , LEVY G.P.
Published: July 2012

AH 5158, 5‐[1‐hydroxy‐2‐[(1‐methyl‐3‐phenylpropyl)amino]ethyl]salicylamide, competitively antagonised phenylephrine‐induced vasopressor responses in anaesthetized dogs, thus confirming that the drug possesses α‐adrenoceptor blocking activity.

In contrast, AH 5158 was a relatively ineffective antagonist of vasopressor responses to noradrenaline in anaesthetized dogs. Thus, at the lowest dose‐level tested (1 mg/kg) AH 5158 abolished the increase in pulse width caused by noradrenaline, but otherwise had little or no blocking effect in doses as high as 10 mg/kg. Propranolol (0.1 mg/kg) also abolished the increase in pulse width caused by noradrenaline. With both drugs this effect is thought to be a consequence of blockade of the β‐adrenoceptor‐mediated cardiac stimulant action of noradrenaline.

The interaction between AH 5158 and noradrenaline in spinal dogs, anaesthetized cats and pithed rats was very similar to that seen in anaesthetized dogs.

Noradrenaline pressor responses were effectively antagonized by AH 5158 in anaesthetized dogs pretreated with cocaine. The degree of block was similar to that obtained when phenylephrine was the agonist in untreated dogs.

These results are consistent with the hypothesis that AH 5158 blocks a cocaine‐sensitive inactivation process for noradrenaline in addition to blocking α‐ and β‐adrenoceptors. The resultant increase in the level of circulating noradrenaline would tend to counteract the adrenoceptor blocking action of the drug.

The implications of these findings are discussed.
CENTRAL EFFECTS OF CLONIDINE 2‐(2,6‐DICHLOROPHENYLAMINO)‐2‐IMIDAZOLINE HYDROCHLORIDE IN FOWLS
Authors: MARLEY E. , NISTICÒ G.
Published: July 2012

The effects of clonidine infused into the IIIrd cerebral ventricle, the hypothalamus or intravenously were studied on behaviour, electrocortical activity, body, comb and leg temperatures, respiration and carbon dioxide elimination in adult and young fowls (Gallus domesticus).

Behavioural and electrocortical slow wave sleep were induced by clonidine infused into Illrd cerebral ventricle, the hypothalamus or intravenously. Surprisingly, sleep elicited by intravenous clonidine was much longer‐lasting than that induced by an identical dose given intraventricularly.

Body temperature was lowered by clonidine given intraventricularly or infused into the hypothalamus. Depending on initial comb temperature and ambient temperature, comb temperature was elevated, unaffected or lowered as body temperature fell; temperature of the unfeathered legs also rose as body temperature declined after clonidine.

Following clonidine, but before any considerable decline of body temperature, tachypnoea and wing abduction developed; during recovery of body temperature, the wings were lowered and applied closely to the trunk and the feathers partly erected.

CO2 elimination fell more swiftly than body temperature following intrahypothalamic clonidine in young chicks; initial recovery developed sooner than that of body temperature, but eventual recovery was delayed compared to that for body temperature. The effects of clonidine were much more marked in young chicks studied at an ambient temperature below thermoneutrality as compared to thermoneutrality.

The soporific effects of clonidine were attenuated by intraventricular phentolamine; its hypothermic effects were prevented by phenoxybenzamine and prevented or attenuated by phentolamine. Intraventricular atropine, haloperidol, methysergide and propranolol were ineffective.

Larger doses of intraventricular phentolamine elicited shivering, tachypnoea and wing abduction; body temperature was elevated, to the extent even of lethal hyperthermia. Intraventricular atropine also elevated body temperature.

Clonidine infused intravenously, intraventricularly or into the hypothalamus, replaced the behavioural and electrocortical arousal evoked with dexamphetamine, by sleep associated with slow wave electrocortical activity.
EFFECTS OF DOPAMINE ON SINUS RATE AND VENTRICULAR CONTRACTILE FORCE OF THE DOG HEART in vitro AND in vivo
Authors: ENDOH M.
Published: July 2012

Experiments were carried out on dog isolated papillary muscle and sinus node preparations perfused with arterial blood from a donor dog. The chronotropic and inotropic effects of dopamine were analysed by using reserpine, desmethylimipramine (DMI), cocaine and phenoxybenzamine, and the relative chronotropic and inotropic effects defined, the results being compared with those for noradrenaline (NA).

The effects of dopamine administered intra‐arterially into the isolated preparations were reduced by pretreatment of animals with reserpine both in the papillary muscle and sinus node. The chronotropic effects, however, were affected less by pretreatment with reserpine than were the inotropic effects.

Desmethylimipramine (DMI) reduced the inotropic and chronotropic effects of dopamine, and enhanced the effects of NA and nerve stimulation; the chronotropic effects of the amines were less affected than the inotropic effects.

Cocaine enhanced considerably the inotropic and chronotropic effects of NA, and decreased the inotropic but not the chronotropic effect of dopamine.

Phenoxybenzamine enhanced the inotropic effects of dopamine, NA and nerve stimulation, but did not affect the chronotropic effects of the amines.

When dopamine (1 to 300 μg/kg) was administered intravenously to the donor dog, it increased preferentially the contractile force of the ventricular myocardium with a comparatively small change of the sinus rate in the isolated preparations as well as in the heart in vivo. NA (0.1 to 10 μg/kg) caused effects similar to those of dopamine. The maximal inotropic responses to these catecholamines were reached with lower doses than the chronotropic ones.

It is concluded that both the positive inotropic and the positive chronotropic responses to dopamine are mediated partially by a direct and partially by an indirect stimulant effect on β‐adrenoceptors in the dog heart. The present results suggest that the difference in activity of dopamine and NA between the ventricular myocardium and the sinus node may be ascribed to the unequal innervation with adrenergic nerve fibres of the atrium and the ventricle (Furnival, Linden & Snow, 1971). The sinus node which is densely innervated by adrenergic nerve fibres may inactivate noradrenaline and dopamine more effectively than the ventricular myocardium through the uptake into the nerve and thereby be less sensitive to the exogenous catecholamines.
VENTRAL ROOT RESPONSES OF THE HEMISECTED AMPHIBIAN SPINAL CORD TO PERFUSED AMINO ACIDS IN THE PRESENCE OF PROCAINE
Authors: EVANS R.H. , WATKINS J.C.
Published: July 2012

The use of the procaine‐blocked hemisected spinal cord preparation to identify the primary action of amino acids and their antagonists on amphibian motoneurones is described.

Apart from an anomalous effect of glycine, the responses of frog spinal motoneurones to amino acids were shown to be similar to those of mammalian spinal neurones.

In the presence of procaine, γ‐aminobutyrate (GABA), taurine and β‐alanine caused a hyperpolarizing response, measured in ventral roots, whereas L‐glutamate and, to a lesser extent, glycine caused depolarization.

Picrotoxin and bicuculline specifically blocked ventral root responses to GABA; strychnine blocked responses to taurine and β‐alanine but not responses to L‐glutamate, glycine or GABA.
THE EFFECTS OF LITHIUM IONS ON THE ANTIDIURETIC ACTION OF VASOPRESSIN IN THE RAT
Authors: JENNER F.A. , MACNEIL SHEILA
Published: July 2012

The effect of intravenous infusion of lithium, 2.56 μmol/min on the antidiuretic responses to antidiuretic hormone (ADH), adenosine triphosphate (ATP), 3′‐5′ adenosine cyclic monophosphate (cyclic AMP) and theophylline was studied in water‐loaded, alcohol‐anaesthetized rats.

Lithium reversibly inhibits the antidiuretic response to all concentrations of ADH, depressing the maximum response but not changing the amount required for half maximal response.

The rate of increase of serum lithium relates more clearly to the inhibitory effect than does the serum concentration.

Sodium concentrations in the renal papilla seem to fall when serum lithium levels are rising.

Lithium inhibits the antidiuretic response to ATP and cyclic AMP but does not inhibit the response to theophylline.
THE INFLUENCE OF METYRAPONE ON THE SYNTHESIS AND RELEASE OF PROSTAGLANDINS FROM THE PREGNANT RAT UTERUS in vitro
Authors: PARNHAM M.J. , SNEDDON J.M.
Published: July 2012

Metyrapone (150 mg/kg, s.c. or i.p.) an inhibitor of corticosteroid biosynthesis, significantly reduced the release of prostaglandins of the F‐type from isolated preparations of pregnant rat uteri in vitro, on day 22 ‐ the expected day of delivery.

Metyrapone and indomethacin administered in vitro both inhibited the conversion of 14C‐arachidonic acid to prostaglandin E2 by homogenates of day 22 pregnant rat uteri. Metyrapone was approximately 150 times less potent than indomethacin. Although indomethacin also inhibited prostaglandin F2α production, metyrapone stimulated synthesis of this prostaglandin. The differential inhibition of prostaglandin synthesis by metyrapone may reflect sensitivity of the inhibitor to changes in experimental conditions.

Inhibition of prostaglandin synthesis may explain the effects of metyrapone on parturition in the rat.
TOLERANCE TO SYMPATHOMIMETIC BRONCHODILATORS IN GUINEA‐PIG ISOLATED LUNGS FOLLOWING CHRONIC ADMINISTRATION in vivo
Authors: BENOY CHRISTINE J. , EL‐FELLAH M.S. , SCHNEIDER R. , WADE O.L.
Published: July 2012

Pretreatment of the guinea‐pig subcutaneously three times daily with either 5 μg/kg isoprenaline or adrenaline reduced the response of the isolated perfused histamine‐constricted lung when challenged with either the same or a different sympathomimetic bronchodilator. The longer the animals were pretreated and the higher the dose of bronchodilator the greater was the degree of tolerance developed.

Tolerance was developed to aminophylline in the same preparation when the guinea‐pig had been pretreated with aminophylline or isoprenaline. Cross‐tolerance also developed to adrenaline when the guinea‐pig had been pretreated with aminophylline.

Tolerance was still persistent in guinea‐pigs one and two weeks after pretreatment three times daily with either isoprenaline or adrenaline (5 μg/kg s.c.) for seven days in the same preparation. Only after three weeks was the tolerance diminished.

These results suggest that asthmatic patients who use bronchodilators excessively may become refractory to the bronchodilator effect of these drugs. They also support the hypothesis that induced cross‐resistance to endogenous sympathetic stimulation could lead to a deterioration of the asthmatic state in patients using the sympathomimetic bronchodilators and that this may explain the increase in asthma mortality rate.

A mechanism of tolerance to sympathomimetic bronchodilators is postulated.
THE ACTIONS OF FLUPENTHIXOL UPON 5‐HYDROXYTRYPTAMINE‐INDUCED AGGREGATION AND THE UPTAKE OF 5‐HYDROXYTRYPTAMINE AND DOPAMINE BY HUMAN BLOOD PLATELETS
Authors: BOULLIN D.J. , GRIMES R.P.J. , ORR M.W.
Published: July 2012

The effects of the α‐ and β‐isomers of flupenthixol on 5‐hydroxytryptamine (5‐HT)‐induced platelet aggregation and on 5‐HT and dopamine uptake were investigated. α‐Flupenthixol was 185 times more potent than the β‐isomer as an inhibitor of platelet aggregation. In contrast both isomers were equipotent as inhibitors of uptake of 5‐HT and dopamine. The data suggest that 5‐HT‐induced aggregation and uptake are separate processes.
INNERVATION BOTH OF PERI‐ORBITAL STRUCTURES AND OF THE HEART BY THE CERVICAL SYMPATHETIC NERVES IN MOUSE, RAT, GUINEA‐PIG, RABBIT AND CAT
Authors: LARGE B.J.
Published: July 2012

In anaesthetized rats electrical stimulation of the intact cervical sympathetic nerve produced frequency‐dependent lower eyelid contractions and tachycardia.

The tachycardia was caused by excitation of efferent fibres since it was equally evident in the pithed rat preparation, and the right nerve was more effective than the left. By contrast, no differences were seen between the responses to right and left vagal stimulation in either rats or rabbits.

Guanethidine inhibited both cardiac and eyelid responses, propranolol only the former and phentolamine only the latter, thereby revealing the adrenergic nature of the nerves. Hexamethonium caused partial inhibition and the block was intensified by atropine.

The inferior eyelid of mice, guinea‐pigs and rabbits as well as the nictitating membrane of rabbits and cats were contracted by cervical sympathetic nerve stimulation. In these species too, tachycardia occurred; this was more pronounced with the right than the left sympathetic nerve. The order of cardiac responsiveness was mouse > rat > guinea‐pig > rabbit > cat.

In guinea‐pigs histamine‐induced bronchoconstriction was reduced by cervical sympathetic nerve stimulation.

That discrete cardiac pathways exist in the cervical sympathetic nerves is suggested by the reproducibility of the effects within any one species. The accessibility of the nerves greatly simplifies the examination of drugs in vivo on two different structures innervated by the sympathetic nervous system.
DEPOLARIZING EFFECTS OF THE IONOPHORES X‐537A AND A23187 AND THEIR RELEVANCE TO SECRETION
Authors: COCHRANE D.E. , DOUGLAS W.W.
Published: July 2012

The ionophore X‐537A depolarized frog skeletal muscle fibres about 10 mV in 10 min and a further 30 mV or so over the next 50 minutes. With A23187, depolarization was relatively feeble and delayed in onset but was hastened when calcium was removed from the bathing medium. The results support conjecture that some functional responses to these ionophores are attributable, in part, to depolarization.
In vitro INHIBITION OF BRAIN MITOCHONDRIAL MONOAMINE OXIDASE BY 6‐HYDROXYDOPAMINE
Authors: YOUDIM M.B.H.
Published: July 2012

6‐Hydroxydopamine (6‐OHDA) inhibits rat brain mitochondrial monoamine oxidase (MAO) when kynuramine or dopamine are used as substrates. The effect is competitive and reversible giving Ki values of 74 and 176 μM with the respective substrates. At high concentrations (5 mM) of each substrate, inhibition of MAO was not observed.
THE γ‐AMINOBUTYRIC ACID SYSTEM IN RAT CEREBELLUM DURING CANNABINOID‐INDUCED CATALEPTOID STATE
Authors: EDERY H. , GOTTESFELD ZEHAVA
Published: July 2012

Repeated, but not single, intraperitoneal injections of Δ1,6‐tetrahydrocannabinol (Δ1,6‐THC) 20 mg/kg to rats administered daily for two weeks, produced increased γ‐aminobutyric acid (GABA) concentration and decreased glutamic acid decarboxylase (GAD) activity in the cerebellum, as well as enhancement of [3H]‐GABA uptake by cerebellar crude synaptosomes. It seems that the motor impairment elicited by Δ1,6‐THC was not associated with the GABA system, but presumably might be related to changes in brain excitability.
TEMPERATURE AND BEHAVIOURAL RESPONSES INDUCED IN THE UNANAESTHETIZED CAT BY THE CENTRAL ADMINISTRATION OF RX72601, A NEW ANTICHOLINESTERASE
Authors: METCALF G. , MYERS R.D. , REDGRAVE P.C.
Published: July 2012

The central effects produced by a new anticholinesterase RX72601 injected into the cerebral ventricles or perfused within circumscribed forebrain structures have been investigated in the unanaesthetized cat.

When injected into the cerebral ventricles in doses of 1–10 μg, RX72601 produced a dose‐related hyperthermia together with behavioural and autonomic responses.

Experiments designed to localize the site or sites of these actions demonstrated that hyperthermia could be produced from several diencephalic sites but that the other effects were not normally produced from these same sites.
EFFECTS OF IPRINDOLE ON RESPONSES OF SINGLE CORTICAL AND CAUDATE NEURONES TO MONOAMINES AND ACETYLCHOLINE
Authors: BEVAN P. , BRADSHAW C.M. , SZABADI E.
Published: July 2012

The technique of microelectrophoresis was used to study the effects of iprindole on single neurones in the cerebral cortex and caudate nucleus of the rat.

Iprindole, when applied for a brief period, did not affect the firing rate of the vast majority of neurones tested.

Both potentiation and antagonism of neuronal responses to noradrenaline, dopamine, and 5‐hydroxytryptamine could be observed after a brief application of iprindole. Potentiation and antagonism often occurred after the same application of iprindole, antagonism always preceding potentiation.

Responses to acetylcholine were affected by iprindole similarly: both potentiation and antagonism of the responses could be observed.

Responses to glutamate were not affected by iprindole.

It is concluded that the potentiation of responses to monoamines by iprindole cannot be explained on the basis of uptake blockade; this potentiation may be due to the blockade of masked receptors on the post‐synaptic cell.

It is suggested that the common pharmacological action of the tricyclic antidepressants may be the ability to block both monoamine and acetylcholine receptors in the brain.
MECHANICAL RESPONSES OF RAT ISOLATED UTERINE HORNS TO TRANSMURAL STIMULATION
Authors: HOLLINGSWORTH M.
Published: July 2012

Transmural stimulation of rat isolated uterine horns at low pulse width produced contractions. These were antagonized by hyoscine or tetrodotoxin and potentiated by physostigmine.

In the presence of hyoscine, and during bradykinin‐induced contractions, transmural stimulation produced inhibition. This inhibition was antagonized by guanethidine, propranolol or tetrodotoxin.

Hexamethonium or pempidine did not affect responses to transmural stimulation.

It is suggested that transmural stimulation is a method of exciting cholinergic motor and noradrenergic inhibitory postganglionic neurones to the rat myometrium.
MEDIATORS OF PASSIVE LUNG ANAPHYLAXIS IN THE RAT
Authors: FARMER J.B. , RICHARDS I.M. , SHEARD P. , WOODS AUDREY M.
Published: July 2012

Passive lung anaphylaxis (PLA) was investigated in rats sensitized by the intravenous injection of high titre reaginic antiserum prepared in rats.

The effect of various pharmacological antagonists on anaphylactic bronchoconstriction in vivo were examined. An antihistamine (mepyramine), a kallikrein inactivator (aprotinin) or a prostaglandin synthesis inhibitor (aspirin) did not inhibit PLA, whereas an anti‐5‐hydroxytryptamine agent (methysergide) and an anti‐slow reacting substance‐A agent (FPL, 55712) significantly reduced the response.

Isolated perfused lungs taken from sensitized rats released, on challenge with the sensitizing antigen, histamine, 5‐hydroxytryptamine, slow reacting substance of anaphylaxis (SRS‐A) and prostaglandins, but no rabbit aorta contracting substance (RCS).

Disodium cromoglycate inhibited both anaphylactic bronchoconstriction in vivo and the anaphylactic release of mediators in vitro. Inhibition in vivo was dose‐related.

Mediators from the intestine, the primary shock organ of anaphylaxis in the rat, did not contribute to the lung response.

Vagal reflex pathways were found not to be important in PLA in vivo.

The relationship between the mediators released following antigen challenge of passively sensitized rat lung in vitro and passive lung anaphylaxis in vivo is discussed.
ANTI‐INFLAMMATORY ACTION OF GLUCAGON IN RATS
Authors: LEME J. GARCIA , MORATO M. , SOUZA MARIA ZENILDE A.
Published: July 2012

Subcutaneous administration of glucagon (1 and 0.5 mg/kg) 30 min before the injection of carrageenin or dextran into the rat's paw reduced oedema and the local exudation of Evans blue previously given intravenously.

The effect persisted after removal of the adrenal medulla but not after adrenalectomy.

When glucagon (1 mg/kg, s.c.) was given daily after a local reaction to Freund's adjuvant injected into the paw had developed, a decrease in the reaction was observed up to 12 days. Blood sugar levels remained within the normal range.

Glucagon may exert an anti‐inflammatory effect through the release of adrenal corticosteroids and thus help modulate inflammatory reactions.
FORMATION OF DOPAMINE AND NORADRENALINE IN RAT VAS DEFERENS: COMPARISON WITH GUINEA‐PIG VAS DEFERENS
Authors: BOADLE‐BIBER MARGARET C. , ROTH R.H.
Published: July 2012

The formation of [14C]‐3,4‐dihydroxyphenylalanine (DOPA) from [14C]‐tyrosine, in the presence of the amino acid decarboxylase inhibitor, brocresine (3‐hydroxy‐4‐bromobenzyloxy‐amine dihydrogen phosphate), was greatly enhanced in rat vasa deferentia depolarized by a KCl‐enriched Krebs‐Henseleit solution (52 mM KCl) compared with tissues maintained in unmodified Krebs‐Henseleit solution.

When the conversion of tyrosine was allowed to proceed as far as catecholamine (brocresine absent) no significant difference was observed between the accumulation of [14C]‐catecholamines (CA) in depolarized rat vasa deferentia and the accumulation in control (non‐depolarized) tissues.

Endogenous CA levels in the depolarized rat vasa deferentia fell to 67% of the controls after a 1 h incubation period and to 53% at the end of 2 hours.

Chromatographic separation on Amberlite CG‐120 columns of the newly synthesized CA and catechol metabolites from the rat vas deferens revealed that a very high proportion was present as dopamine. The percentage distribution after 1 h incubation in control Krebs‐Henseleit was: noradrenaline (NA): 30.6 ± 5.2; dopamine 56.9 ± 5.9; acid metabolites: 12.8 ± 1.1; and in KCl‐rich Krebs‐Henseleit, NA: 32; dopamine: 44.7 and acid metabolites 23.3. In contrast to the newly synthesized (14C‐labelled) CA, endogenous dopamine comprises only 10% of the endogenous CA stores in rat vas deferens.

The distribution of newly synthesized NA and dopamine in rat vas deferens is strikingly different from that of guinea‐pig vas deferens where more than 80% of newly formed amine is present as NA. In the latter tissue depolarization with K+ causes a striking increase in CA biosynthesis.
MECHANISM OF MECHANICAL INHIBITION OF SMOOTH MUSCLE BY OUABAIN
Authors: BOSE D.
Published: July 2012

Ouabain (10 μg/ml) caused an initial increase followed by a decrease in tension in guinea‐pig taenia coli bathed in normal sodium and potassium containing medium.

The excitatory effect of ouabain was prevented by the elevation of extracellular potassium while the inhibitory effect was abolished in the absence of sodium in the bathing medium.

In the presence of sodium, the inhibitory effect of ouabain disappeared when the drug was washed out, but in the presence of lithium (which is not extruded by the Na‐K pump) the inhibition was not abolished.

The inhibitory effect of ouabain was accompanied by an increase in tissue Na and a decrease in tissue K concentration. The increase in intracellular [45Ca] which occurred when extracellular [K] was varied, was also reduced by ouabain.

It is concluded that a high intracellular level of sodium inhibits contractions in visceral smooth muscle probably by a mechanism involving decreased Ca influx.
A COMPARISON OF THE EFFECT OF MESCALINE ON ACTIVITY AND EMOTIONAL DEFAECATION IN SEVEN STRAINS OF MICE
Authors: LUSH I.E.
Published: July 2012

Mescaline hemi‐sulphate (35 mg/kg body weight) was injected intraperitoneally into male mice (Mus musculus) from seven genetically diverse laboratory strains.

The effect of mescaline was found by comparison of the emotional defaecation and open field activity of mice after mescaline injection with the performance of the same mice after a subsequent saline (0.9% w/v NaCl solution) control injection.

In strains A2G, C3H/He, C57BR/cd, CBA/Cam and F/St, mescaline inhibited emotional defaecation and stimulated open field activity. These effects did not occur in strains ICFW and Schneider.

A positive relationship was found between the degree of emotional defaecation characteristic of each strain in the saline control experiment and the inhibitory effect of mescaline on emotional defaecation.

Pre‐treatment of mice with tranylcypromine (20 mg/kg body weight, i.p.) had no effect on emotional defaecation or on its inhibition by mescaline.
MEIOSIS: A PROSTAGLANDIN RESPONSE THAT IS NOT INHIBITED BY ASPIRIN
Authors: DELLOW P.G. , MILES T.S.
Published: July 2012

Antidromic stimulation of the sensory nerve to the rabbit eye produces pupillary meiosis, supposedly by release of prostaglandins into the aqueous humour. The analogy between this phenomenon and neurogenic inflammation is drawn. It is shown that aspirin and indomethacin, known blockers of prostaglandin synthesis and release, fail to block the meiosis thus produced.
EFFECTS OF OESTRADIOL AND PROGESTERONE ON THE in vitro PRODUCTION OF PROSTAGLANDIN F2α BY THE GUINEA‐PIG UTERUS
Authors: NAYLOR B. , POYSER N.L.
Published: July 2012

The effects of oestradiol and progesterone on the production of prostaglandin F2α by the guinea‐pig uterus in vitro have been studied.

Ovariectomized guinea‐pigs were treated with oestradiol benzoate, progesterone, or a combination of these hormones. The uteri were homogenized and incubated and the prostaglandin F2α produced was measured by radioimmunoassay or combined gas chromatography‐mass spectrometry (g.c.‐m.s.). Oestradiol treatment or progesterone followed by oestradiol caused a significant increase in prostaglandin F2α synthesis compared with control values, whereas progesterone treatment caused no significant increase.

The uteri from guinea‐pigs on day 7 of the oestrous cycle were split into four parts, and each part homogenized and incubated either alone or in the presence of oestradiol‐17β, progesterone, or a combination of these hormones. Prostaglandin F2α was measured by g.c.‐m.s. Oestradiol was found to increase prostaglandin F2α synthesis by the uterus whereas progesterone had no effect. However, progesterone did inhibit the response to oestradiol.

Oestradiol treatment of the guinea‐pig uterus causes an increase in capacity to produce prostaglandin F2α in vitro. The role of progesterone is difficult to interpret.
PRESSOR EFFECTS OF TRYPTAMINE ANALOGUES
Authors: BOSIN T.R. , HIXSON E. JANE , MAICKEL R.P.
Published: July 2012

Methylation of tryptamine in the 1‐position had little effect on the potency of the drug as a pressor agent in the intact anaesthetized rat.

In contrast, substitution of a benzo[b]thiophene ring system for the indole ring decreased the pressor activity.

Pretreatment of the animals with reserpine reduced the pressor effect of tryptamine and its benzo[b]thiophene analogue while increasing the effect of the 1‐methylindole analogue.

Pretreatment with phenoxybenzamine reduced the pressor effect of all three compounds.
TOLERANCE TO THE CARDIOVASCULAR EFFECTS OF Δ9‐TETRAHYDROCANNABINOL IN THE RAT
Authors: ADAMS M.D. , CHAIT L.D. , EARNHARDT J.T.
Published: July 2012

Daily intraperitoneal injections of Δ9‐tetrahydrocannabinol (Δ9‐THC, 10 mg/kg) resulted in tolerance to the effects of the cannabinoid on body weight and body temperature within 1–2 weeks of treatment.

Tolerance failed to develop to the suppression of spontaneous motor activity produced by Δ9‐THC during 28 days of treatment with the cannabinoid (10 mg/kg, i.p. per day).

Following treatment with vehicle for 28 days, intravenous administration of Δ9‐THC in anaesthetized rats produced a transient pressor response followed by a sustained hypotension and bradycardia.

Tolerance to the hypotensive and negative chronotropic responses to intravenous Δ9‐THC was readily apparent in animals which had received daily intraperitoneal injections of Δ9‐THC (10 mg/kg) for 28 days.

Tolerance failed to develop to the pressor actions of intravenous Δ9‐THC after 28 days of pretreatment.

There was no difference in the pressor response to intravenous noradrenaline in vehicle‐treated animals (1.0 ml/kg, i.p., per day for 28 days) and Δ9‐THC‐treated animals (10 mg/kg, i.p., per day for 28 days).
RESPONSES OF NEURONES IN THE CEREBRAL CORTEX AND CAUDATE NUCLEUS TO AMANTADINE, AMPHETAMINE AND DOPAMINE
Authors: STONE T.W.
Published: July 2012

Dopamine, amantadine and amphetamine have been applied directly by microiontophoresis to single neurones in the caudate nucleus ana cerebral cortex of rats anaesthetized with urethane.

The predominant response to all three agents was a depression of neuronal firing rate. The responses to dopamine and amantadine could be antagonized by the dopamine receptor blocking agent, chlorpromazine.

Amantadine did not cause any potentiation of dopamine responses, suggesting that inhibition of amine uptake was not responsible for its effects.

The responses of pyramidal tract cells in the cerebral cortex to dopamine, amphetamine and amantadine were compared in control groups of rats and rats pretreated with reserpine (10 mg/kg i.p.) or α‐methyl‐p‐tyrosine methyl ester (200 mg/kg i.p.). The reduction of cortical catecholamine concentrations was confirmed by a direct fluorimetric assay method.

Responses to dopamine were unaltered in the amine‐depleted animals compared with controls. Responses to amantadine and amphetamine were reduced but not abolished.

It is concluded that amantadine acts partly by releasing catecholamines from neuronal stores. The residual responses to amantadine and amphetamine may be the result of a direct postsynaptic receptor stimulation.
THE INFLUENCE OF MOTOR NERVE TETANIZATION ON THE EFFECT OF ORGANOPHOSPHORUS CHOLINESTERASE INHIBITORS ON NEUROMUSCULAR TRANSMISSION
Authors: DANILOV A.F. , IVANOV YU.J. , MICHELSON M.J.
Published: July 2012

The changes in the activity of synaptic cholinesterases (ChE) of the ant. tibial muscle in the anaesthetized cat were detected by recording the changes of the blocking activity of acetylcholine (ACh) and comparing them with the blocking activity of carbaminoylcholine (carbachol) injected intra‐arterially or intravenously. After the administration of organophosphorus inhibitors (OPI) of ChE the ACh blocking dose diminished 500 to 2000‐fold but the carbachol blocking dose did not change. In 4–6 h after the injection of OPI the ACh blocking dose increased again 8 to 15‐fold, but the dose of carbachol still remained unchanged. The transmission of high frequency impulses improved after OPI in parallel with the decrease of the ACh blocking activity. Thus the synaptic ChE is partly restored in a few hours after its irreversible inhibition with OPI.

Tetanization of the motor nerve (50–60 Hz, 10 min), started simultaneously with the intravenous injection of OPI (armine, Gd‐42), diminished the impairment of neuromuscular transmission. On the side of tetanization the ACh blocking action was less pronounced and the transmission of high frequency impulses better than on the control side. Thus the tetanization produced some protection of synaptic ChE against inhibition by OPI. The protective effect of tetanization was absent when the tetanization was performed before the injection of OPI or was started 10–20 min after the injection of OPI.

The protective effect of tetanization was also observed on the isolated phrenic nerve diaphragm preparation of the rat.

The possible mechanisms of the protective effect of tetanization are discussed.
UPTAKE OF 5‐HYDROXYTRYPTAMINE BY RAT BLOOD PLATELETS AND ITS INHIBITION BY ADENOSINE 5‘‐DIPHOSPHATE
Authors: DRUMMOND A.H. , GORDON J.L.
Published: July 2012

The uptake of 5‐hydroxytryptamine (5‐HT) by rat blood platelets in citrated plasma was linear for at most 10 s and was substantially complete within 3 minutes.

Adenosine 5′‐diphosphate (ADP) was a potent inhibitor of 5‐HT uptake (Ki = 0.38 μm) and kinetic analysis revealed that the inhibition was not competitive.

Inhibition of 5‐HT uptake by ADP was abolished in the presence of prostaglandin E1 and 2‐n‐amylthio‐AMP, which also inhibit the stimulant actions of ADP on blood platelets.

It is concluded that ADP could inhibit 5‐HT uptake by changing the Na+/K+ distribution across the cell membrane, and the biological significance of this is discussed.
THE DISTRIBUTION AND KINETICS OF SULPHACETAMIDE IN LEUKAEMIC MICE
Authors: MARCHAND C. , NADEAU D.
Published: July 2012

During the first 90 min following oral administration of sulphacetamide, there was a rapid decline in plasma drug concentration in control mice whereas a progressive increase in sulphacetamide concentration was observed in leukaemic mice.

Similar changes in the kinetics of sulphacetamide distribution were observed in the liver, spleen and muscle.

While the concentration of sulphacetamide remained quite constant in the brain and fat tissue of control mice, a progressive increase in drug concentration was observed in the brain and fat tissue of leukaemic mice.

Some of these changes in the kinetics of sulphacetamide tissue distribution are compatible with delay in gastrointestinal absorption of the drug and its accumulation in the ascitic fluid.