bluuebunny/crossref_metadata_2025 huggingface dataset:
EFFECTS OF MAZINDOL, A NON‐PHENYLETHYLAMINE ANOREXIGENIC AGENT, ON BIOGENIC AMINE LEVELS AND TURNOVER RATE
Authors: CARRUBA M.O. , GROPPETTI A. , MANTEGAZZA P. , VICENTINI L. , ZAMBOTTI F.
Published: July 2012

Mazindol is a new anorexigenic agent which possesses a different chemical structure from that of phenylethylamines, but shows a pharmacological profile similar to that of (+)‐amphetamine.

Mazindol neither altered whole brain monoamine levels (noradrenaline (NA), dopamine, 5‐hydroxytryptamine (5‐HT)) nor changed NA levels in the hypothalamus or dopamine levels in the caudate nucleus.

Mazindol enhanced dopamine turnover rate in the caudate nucleus, as shown by the increased rate of dopamine decline after blockade of catecholamine synthesis by α‐methyl‐p‐tyrosine and decreased the conversion index of [3H]‐tyrosine into brain NA.

Mazindol administration did not modify pargyline‐induced decline of 5‐hydroxyindoleacetic acid suggesting that 5‐HT turnover is not altered by this drug.
UPTAKE OF 5‐HYDROXYTRYPTAMINE IN DIFFERENT PARTS OF THE BRAIN OF THE RABBIT AFTER INTRAVENTRICULAR INJECTION
Authors: DOW R.C. , LASZLO I.
Published: July 2012

The uptake of 5‐hydroxytryptamine (5‐HT) was investigated in different areas of the rabbit brain (anterior hypothalamus, the raphe, the region of the substantia nigra, several cortical areas and the medulla oblongata) after intraventricular injection in pargyline pretreated animals by the formaldehyde‐induced histochemical fluorescence method.

The distribution of fluorescence showed that the uptake of 5‐HT, after circulation in the cerebrospinal fluid, caused a general increase in intensity of green yellow to yellow background fluorescence. There was an increased fluorescence in the nerve terminals, but no uptake occurred either in the cell bodies of neurones or in the glial cells.
THE RELATIONSHIP BETWEEN CALCIUM AND INCREASED SENSITIVITY OF RABBIT AORTAE FOUR HOURS AFTER RESERPINE
Authors: CARRIER O. , HESTER R.K.
Published: July 2012

Four hours after reserpine, rabbit aortic strips were supersensitive to acetylcholine, isoprenaline and noradrenaline. The threshold concentration of the drugs necessary to induce a response was less and the maximum tension developed by the tissues was greater than in control strips.

Reserpine‐treatment potentiated the contractile responses to CaCl2.

Reserpine‐treatment resulted in an increase in calcium uptake and an increase in the slow component of 45Ca2+ efflux.

After resperine‐treatment, the rate of relaxation from a potassium‐induced contraction was decreased.

It is concluded that reserpine‐induced supersensitivity is related to an enhanced ability of the tissue to retain and utilize calcium.
EFFECT OF SAS (A NEW 10‐N‐ACYLAMINOPHENOTHIAZINE) ON GASTRIC SECRETION AND ULCERATION IN RATS
Authors: KUMAR A. , SHARMA H.L. , SHARMA V.N.
Published: July 2012

The antiulcer and antisecretory activity of 2‐chloro‐10‐[4′(N‐β‐hydroxyethyl) piperazinyl‐1′] acetylphenothiazine (SAS) has been investigated. At 10 and 20 mg/kg (s.c.) the drug was found to possess potent antigastric secretory and antiulcer activity (both in shay and stress ulcers) and did not exhibit any peripheral parasympathetic blocking activity. The pronounced antispasmodic activity of SAS was nonspecific rather than a specific parasympatholytic effect.
COMPARISON OF THE ACTIONS OF ACEBUTOLOL, PRACTOLOL AND PROPRANOLOL ON CALCIUM TRANSPORT BY HEART MICROSOMES AND MITOCHONDRIA
Authors: DHALLA N.S. , LEE S.L.
Published: July 2012

The effects of acebutolol, practolol and propranolol (0.5‐3 mm) on calcium uptake, calcium binding and ATPase activities of the rabbit and rat heart microsomal and mitochondrial fractions were investigated.

Dose‐response and time course experiments revealed that propranolol greatly inhibited microsomal and mitochondrial calcium uptake whereas both acebutolol and practolol showed slight depressant effects.

The ATPase activities of microsomal and mitochondrial fractions were decreased by acebutolol, practolol and propranolol; however, the latter agent was more effective than the other two.

The inhibitory effects of acebutolol, practolol and propranolol on mitochondria and microsomes were not antagonized by adrenaline.

Propranolol decreased calcium binding by the microsomal fraction only, whereas acebutolol and practolol had no effect on microsomal or mitochondrial calcium binding.

The sensitivity of the rabbit heart subcellular fractions to the β‐adrenoceptor blocking drugs was similar to that of the rat heart; however, the calcium uptake and ATPase activities of microsomes were more sensitive to propranolol than mitochondria in both species.

Perfusion of rat hearts with 0.2‐1 mm propranolol decreased contractile force, and microsomal and mitochondrial fractions obtained from these hearts accumulated less calcium in comparison to the control. On the other hand, acebutolol and practolol (0.2‐1 nm) had no appreciable effects on contractile force or subcellular fractions under similar conditions.

The negative inotropic effect of propranolol may partly be due to its inhibitory actions on calcium transport by subcellular organelles of the myocardium; the depressant action of propranolol on calcium transport is unlikely to be due to its β‐adrenoceptor blocking property.
INDIRECT AND DIRECT INHIBITION OF DOPAMINE β‐HYDROXYLASE BY AMPHETAMINE IN STORAGE VESICLES AND SYNAPTOSOMES
Authors: LAU C. , SLOTKIN T.A.
Published: July 2012

To elucidate the mechanism by which amphetamine produces a functional inhibition of dopamine β‐hydroxylase (DBH), the actions of amphetamine on amine uptake and β‐hydroxylation were examined in isolated adrenal storage vesicles and in whole brain synaptosomes of the rat.

Amphetamine produces a competitive inhibition of catecholamine incorporation into adrenal vesicles with a Ki of 279 μm; this action of the drug accounted for slightly less than half of the total inhibition of β‐hydroxylation in the vesicles, indicating that the interference by amphetamine of access of substrate to the enzyme compartment plays an important role in functional inhibition of DBH. The remainder of the effect in vesicles probably represents direct inhibition of the enzyme.

In synaptosomes, similar actions on uptake of substrate and on functional enzyme activity were noted, indicating that amphetamine‐induced inhibition of the neuronal amine pump can also affect DBH activity if the substrate is supplied exogenously.

In addition to the effects of amphetamine in vitro, chronic administration of amphetamine to rats produced an increase in total activity of adrenal DBH.

The net effect of amphetamine on DBH activity thus represents the summation of direct inhibition of the enzyme, indirect inhibition via reduced access of substrate and enhancement of activity via trans‐synaptic induction.
ONTOGENESIS OF ENZYME SYSTEMS DEAMINATING DIFFERENT MONOAMINES
Authors: BLATCHFORD D. , HOLZBAUER MARGARETHE , GRAHAME‐SMITH D.G. , YOUDIM M.B.H.
Published: July 2012

A detailed investigation into the postnatal development of the activity of the enzyme monoamine oxidase (MAO) in the rat and domestic pig was carried out.

MAO activity was measured in littermate male rats aged between 3 and 122 days belonging to six breeding colonies. The tissues studied were three brain regions in which monoamines may play a role in neuronal transmission (septum, hypothalamus, corpus striatum) and, for comparison, in the cerebellum. Liver, heart and adrenal glands were the peripheral organs studied. The following substrates were used to measure MAO activity in each tissue homogenate: kynuramine, tyramine, dopamine, tryptamine and 5‐hydroxytryptamine (5‐HT).

MAO activity towards kynuramine, tyramine and dopamine increased after birth in all brain regions and also in the liver, to reach maximal values between days 40 and 80. In the heart and the adrenal glands enzyme activity remained low up to 30–40 days and then increased steeply. This was the case in all litters examined.

All tissues deaminated more tyramine than dopamine. In the liver, the ratio of the quantities of tyramine deaminated/dopamine deaminated was approx. 2 at all ages. In the homogenates of whole brains (including or excluding the hypothalamus and striatum) this ratio was also 2 at all ages. In contrast in the isolated striatum and hypothalamus it was first much higher and reached a value of 2 only at an age of about 20 days. This may indicate an independent development of a dopamine and a tyramine deaminating enzyme system in discrete brain regions. It was suggested, that the low ability to deaminate dopamine in discrete brain regions may be due to the local presence of an enzyme inhibitor which becomes too diluted to be active in homogenates of whole brain.

Deamination of tryptamine in the striatum decreased between day 5 and 20 in 3 out of 4 colonies tested. There was a large fall in the deamination of 5‐HT in all tissues of one group of rats, but in another 4 groups the tissues of the 5 day old rats deaminated smaller amounts of 5‐HT than those of the older rats.

Purified hypothalamic mitochondria from 40 day old rats deaminated more tyramine and dopamine but not tryptamine per mg protein than those from 5 day old rats.

In the domestic pig there was a significant rise in the values in hippocampal MAO activity towards dopamine and tyramine from the foetus (55 day gestation) to the 1 week old piglet. A further steady rise up to week 6 was indicated, but this rise was not statistically significant. The difference between rat and pig probably reflected the much higher degree of maturity of the latter at birth.

In the hippocampus of the pig the ratio between the amount of tyramine deaminated/dopamine deaminated decreased from > 10 (foetus) to 4.8 in the 6 week old pig and 2 in the adult.
UTERINE RECEPTORS FOR OXYTOCIN: CORRELATION BETWEEN ANTAGONIST POTENCY AND RECEPTOR BINDING
Authors: SOLOFF M.S.
Published: July 2012

The apparent dissociation constants (Kd) of four competitive antagonists of oxytocin were estimated from their ability to compete with [3H]‐oxytocin for binding sites in particulate fractions from rat uterine homogenates.

These apparent Kd values were not significantly different from the Kd values calculated from the published potency of each compound as an antagonist of oxytocin‐induced uterine contractions.

These results support the conclusion that the binding sites for oxytocin are part of the receptor complex. Furthermore, ‘spare receptors' for oxytocin do not appear to be present in significant quantities, and the relative potency of each antagonist appears to depend upon its affinity for the receptor site rather than its intrinsic activity.

The antagonists used in these studies were [N‐acetyl, 2‐O‐methyltyrosine]oxytocin, [1‐(β‐mercapto‐β,β‐diethylpropionic acid)]oxytocin, [1‐(β‐mercapto‐β,β‐pentamethylenepropionic acid)]‐oxytocin, and [1‐(deaminopenicillamine), 4‐threonine]oxytocin.
THE USE OF DIFFERENT AGONISTS IN ANTAGONIST AFFINITY CONSTANT ESTIMATIONS
Authors: ROBERTS F. , STEPHENSON R.P.
Published: July 2012

The affinities of 4 muscarinic antagonists were estimated on intact pieces of guinea‐pig ileum using the agonists carbachol and pentyl trimethylammonium both in separate experiments and in the same experiment.

The apparent affinities were slightly but consistently higher when estimated from the responses produced by pentyl trimethylammonium than when estimated from the responses produced by carbachol.

This difference was greatly reduced or abolished if totally denervated logitudinal muscle strips were used rather than intact pieces of ileum. It is therefore suggested that the difference is due to the presence of receptors in the ganglionic layer.

To explain the difference in apparent affinity of the antagonists these receptors can not be identical to the muscarinic receptors on the smooth muscle.

In addition they can not be nicotinic ganglionic receptors as the difference did not appear to be affected by the presence or absence of hexamethonium.
EFFECTS OF DRUGS AFFECTING ENDOGENOUS AMINES OR CYCLIC NUCLEOTIDES ON ETHANOL WITHDRAWAL HEAD TWITCHES IN MICE
Authors: COLLIER H.O.J. , HAMMOND M.D. , SCHNEIDER C.
Published: July 2012

Twenty‐four hours after ethanol withdrawal, dependent mice exhibited frequent head twitching. Naive mice exhibited similar twitching 15 min after treatment with 5‐hydroxytryptophan (5‐HTP) or 6 h after α‐methyl‐p‐tyrosine (AMPT). Ethanol lessened the incidence of head twitches induced by any of these treatments. 5‐HTP and AMPT each increased the incidence of head twitches induced by withdrawal of ethanol from dependent mice.

Drugs that affect the amount or activity of endogenous amines or cyclic nucleotides modified the incidence of head twitches. Nearly all drugs acted in the same direction on twitching elicited by any of these three treatments.

The incidence was lessened by: (a) methysergide, methergoline, MA 1420, p‐chlorophenylalanine and p‐chloroamphetamine; (b) dopamine, noradrenaline, l‐DOPA, amphetamine and apomorphine; (c) hyoscine and nicotine; and (d) adenosine triphosphate, dibutyryl cyclic adenosine‐3′,5′‐monophosphate (db cyclic AMP) and prostaglandins E1 and E2.

The incidence was increased by: (a) acetylcholine, carbachol and physostigmine; and (b) guanosine triphosphate, dibutyryl cyclic guanosine monophosphate (db cyclic GMP), theophylline and 3‐isobutyl‐1‐methyl‐xanthine.

These findings suggest that head twitching induced by these three treatments arises from a common biochemical mechanism, which may ultimately be a change in favour of cyclic GMP of the balance between this nucleotide and cyclic AMP within appropriate neurones. This imbalance appears to be elicited or increased by 5‐hydroxytryptamine and acetylcholine and to be decreased by dopamine, noradrenaline and E prostaglandins.

Neither actinomycin D nor cycloheximide, given during the induction of ethanol dependence, altered the incidence of head twitches after ethanol withdrawal.
FURTHER STUDIES ON THE MODE OF ACTION OF ISOPRENALINE ON GASTRIC SECRETION IN THE CONSCIOUS RAT
Authors: LUNDELL L. , SVENSSON S.E. , NILSSON G.
Published: July 2012

The effect of isoprenaline on gastric secretion evoked by various means has been studied in conscious rats provided with Pavlov and Heidenhain pouches.

Interdigestive acid secretion in the Pavlov pouch was reduced by isoprenaline, whereas pepsin secretion was unaltered.

Central vagal stimulation effected by 2‐deoxy‐d‐glucose injection evoked a gastric secretory response that was substantially reduced by isoprenaline.

2‐Deoxy‐d‐glucose increased the mobilization of gastric mucosal histamine, an effect that was prevented by isoprenaline.

Isoprenaline infusion alone induced a slight increase in histamine mobilization and also a considerable elevation of immunoreactive serum gastrin concentration.

The secretory response to food in the Pavlov pouch was almost abolished by isoprenaline.

Although the acid response to histamine in the Heidenhain pouch was susceptible to isoprenaline inhibition, that to methacholine was not.

Pepsin secretion in the Heidenhain pouch preparation stimulated by histamine or methacholine seemed to be enhanced by isoprenaline.
THE KINETICS OF COMPETITIVE ANTAGONISTS ON GUINEA‐PIG ILEUM
Authors: ROBERTS FIONA , STEPHENSON R.P.
Published: July 2012

The kinetics of action of some competitive muscarinic and histamine antagonists were examined on guinea‐pig isolated ileum and their behaviour compared with the predictions of the interaction‐limited model described by Paton (1961).

The kinetics of antagonism were not consistent with the predictions of this model: (1) The apparent dissociation rate constant calculated from the decrease in occupancy on washout was not independent of the concentration of antagonist. (2) The dissociation rate constant of a ‘slow’ antagonist calculated from the change in occupancy when a ‘fast” antagonist was superimposed varied with the concentration of fast antagonist. (3) If the concentration of slow antagonist was increased when the fast antagonist was superimposed so that the equilibrium occupancy of the ‘slow” was the same as before, a transitional phase was observed.

The kinetics of antagonism were observed in longitudinal muscle strips and intact pieces of ileum, bathed in Tyrode or Krebs solution, and with isometric and isotonic recording. No evidence was found that the discrepancies between the interaction‐limited model and the observed kinetics could be accounted for by the experimental method used.

It is therefore concluded that either access is rate‐limiting in these circumstances or, if interaction is rate‐limiting, some alternative interaction‐limited model is required to describe the kinetics of antagonism. In either case it would seem unwise at this time to calculate antagonist‐receptor rate constants from the observed kinetics of antagonism.
THE CAT LUNG STRIP AS AN in vitro PREPARATION OF PERIPHERAL AIRWAYS: A COMPARISON OF β‐ADRENOCEPTOR AGONISTS, AUTACOIDS AND ANAPHYLACTIC CHALLENGE ON THE LUNG STRIP AND TRACHEA
Authors: LULICH K.M. , MITCHELL H.W. , SPARROW M.P.
Published: July 2012

A new in vitro preparation, the isolated lung strip of the cat, is described for investigating the direct effect of drugs on the smooth muscle of the peripheral airways of the lung. The preparation comprises a thin strip of lung parenchyma which can be mounted in a conventional organ bath for isometric tension recording. Its pharmacological responses have been characterized and compared with the isolated tracheal preparation of the cat.

The lung strip exhibited an intrinsic tone which was relaxed by catecholamines, aminophylline and flufenamate. It was contracted strongly by histamine, prostaglandin F2α, acetylcholine, compound 48/80, potassium depolarizing solution and alternating current field stimulation. In contrast, the cat trachea was unresponsive to histamine and prostaglandin F2α and did not exhibit an intrinsic tone.

(–)‐Isoprenaline and (–)‐adrenaline were much more potent in relaxing the lung strip than the trachea. The potency order of relaxation responses to isoprenaline, adrenaline and (±)‐noradrenaline in the lung strip was isoprenaline > adrenaline > noradrenaline but in the trachea was isoprenaline > noradrenaline > adrenaline.

β2‐Adrenoceptor selective agonists salbutamol and terbutaline were more potent in the lung strip than the trachea, suggesting β2‐adrenoceptors predominated in the lung strip. Propranolol was equipotent in inhibiting isoprenaline relexations of the lung strip and trachea, whereas practolol was much less effective in inhibiting lung strip than trachea, further supporting a predominance of β2‐adrenoceptors in lung strip and β‐adrenoceptors in trachea.

Strong Schultz‐Dale type contractions were elicited in both lung strips and trachea by Ascaris lumbricoides antigen in actively sensitized cats. The initial phase of the contractile response of the lung strip following challenge was shown to be due to histamine release and was absent in the trachea. The delayed phase of the contraction which took several minutes to develop in both the mepyramine‐treated lung strip and trachea was not due to prostaglandins E1, F2α or bradykinin, the probable mediator being slow reacting substance of anaphylaxis (SRS‐A).

It is concluded that the isolated lung strip of the cat is useful as an in vitro model for investigating the effect of drugs on the smooth muscle of the peripheral airways of the lungs.
THE ACTIONS OF NATURAL SECRETIN ON THE SMALL INTESTINAL VASCULATURE OF THE ANAESTHETIZED CAT
Authors: RICHARDSON P.D.I.
Published: July 2012

A plethysmographic preparation of cat jejunum was used to measure changes in tissue volume and capillary filtration coefficient (CFC), simultaneously with measurements of arterial and venous pressures, and total blood flow.

Secretin was infused and injected intravenously and also infused intra‐arterially in relatively small doses. Probable resulting blood concentrations were compared with those determined under physiological conditions in other investigations.

By intravenous or intra‐arterial infusion, secretin caused increases in CFC, indicating an increased functional exchange vessel area, and increases in jejunal volume, indicating increased vascular capacitance. The jejunal blood flow increased whilst the blood pressure remained essentially unchanged.

By intravenous injection, secretin caused rises in jejunal volume and reductions in calculated jejunal vascular resistance over the same dose range. Effects were statistically significant at 500 mu/kg and higher doses caused reductions in systemic arterial pressure.

The calculated peak blood concentrations of secretin resulting from the lower doses used in this investigation were of the same order of magnitude as those determined under physiological conditions in man.

It is possible that at physiological concentrations secretin causes an increased functional exchange vessel area in the small intestine, and may also increase the total blood flow through this tissue.
LABELLED DECAMETHONIUM IN CAT MUSCLE
Authors: CREESE R. , MACLAGAN JENNIFER
Published: July 2012

Tritium‐labelled decamethonium was infused intravenously in 12 cats at final rates of 1.3–4.2 nmol kg−1 min−1 to produce a steady plasma concentration which ranged between 0.21‐1.3 μmol/1 in different experiments. Muscle contractions were elicited by nerve stimulation and the potential at the end‐plate regions of superficial fibres was recorded by extracellular electrodes.

Under these conditions, it was not possible to obtain a steady degree of neuromuscular block. The initial decrease in muscle contractions was followed by recovery towards the original value although the concentration of decamethonium in the plasma remained constant, or in some cases rose. The initial depolarization of the end‐plate region also waned during the constant infusion of the drug.

Once the twitch tension had returned to control values during infusion of the drug, prolongation of the infusion for a total of four hours did not produce a secondary neuromuscular block.

Scintillation counting showed that during infusion of labelled decamethonium the radioactivity of the muscles increased progressively with time. The uptake was less in the soleus muscle than in the fast‐contracting flexor longus digitorum and extensor longus digitorum muscles. Muscles which had been denervated 12–13 days previously showed a greater uptake of labelled drug than control muscles from the contralateral limb.

The labelled drug was localized by autoradiography of frozen sections of leg muscles following intra‐arterial injection of decamethonium. Grain counts in individual fibres showed that small amounts of decamethonium had entered the muscle fibres along their entire length, and there was increased uptake of the drug into the cell in the region of the end‐plate.

The mechanisms underlying the waning of the pharmacological response during constant application of depolarizing drugs are discussed.
INHIBITORY INNERVATION OF CAT SPHINCTER OF ODDI
Authors: PERSSON C.G.A.
Published: July 2012

Electrical stimulation with trains of 0.1‐0.2 ms pulses of the cat isolated sphincter of Oddi inhibited the spontaneous contractile activity and lowered base‐line tension considerably. A contraction usually followed the period of stimulation.

These inhibitory effects were prevented by tetrodotoxin 0.1‐0.5 μg/ml but were not reduced by hexamethonium, morphine, or blockade of α‐ or β‐adrenoceptors or cholinoceptors with phenoxybenzamine propranolol or atropine, respectively.

Adenosine‐5′‐triphosphate (ATP) and adenosine‐5′‐diphosphate (ADP) inhibited the spontaneous sphincter activity and caused relaxation thus mimicking the effects of the C‐terminal octapeptide of cholecystokinin (C8‐CCK), isoprenaline and prostaglandins E1 and E2.

ATP alone (> 100 μg/ml) or ATP (> 10 μg/ml) plus dipyridamole (1 μg/ml), relaxed the sphincter to the same degree as did the field stimulation.

In sphincters maximally contracted by acetylcholine, the effect of stimulation was more marked than that recorded in uncontracted preparations.

The present findings suggest that the sphincter of Oddi receives inhibitory nerves that are neither cholinergic nor adrenergic.
EFFECT OF MORPHINE AND NALOXONE ON PRIMING‐INDUCED AUDIOGENIC SEIZURES IN BALB/c MICE
Authors: CHEN C.S. , GATES G.R. , REYNOLDSON J.A.
Published: July 2012

Morphine (1–200 mg/kg, s.c.) reduced the incidence and prolonged the latency of priming‐induced audiogenic seizures in a dose‐dependent manner.

This effect was reversed by naloxone (1 and 2 mg/kg) although naloxone was itself inactive.

This priming‐induced seizure model may be useful in the study of tolerance and physical dependence.
ON THE FUNCTIONAL COUPLING OF NEUROTRANSMITTER UPTAKE AND RELEASE IN BRAIN
Authors: COTMAN C.W. , HAYCOCK J.W. , LEVY W.B.
Published: July 2012

Isolated synaptosomal fractions from mouse forebrains were incubated with [14C]‐γ‐aminobutyric acid ([14C]‐GABA). Release of the accumulated label in high potassium solution was measured.

The fractional release dependent upon calcium was decreased by raising the concentration of [14C]‐GABA during labelling but was not affected by altering the time allowed for labelling or the time between labelling and stimulation.

These data suggest that extracellular GABA gains rapid access to available intraterminal pools. The relative distribution of the accumulated GABA in different pools can be influenced by the concentration of GABA in the incubation medium but, once ‘stored’, there is no net redistribution of accumulated GABA in the absence of stimulation.
THE EFFECT OF DIBUTYRYL CYCLIC ADENOSINE‐3′,5′‐MONOPHOSPHATE ON PROTEIN SECRETION FROM THE RAT EXOCRINE PANCREAS in vitro
Authors: FAST D. , TENENHOUSE A.
Published: July 2012

The mechanism by which dibutyryl cyclic adenosine‐3′‐5′‐monophosphate (dibutyryl cyclic AMP) potentiates the secretory effect of carbachol in rat exocrine pancreas was investigated.

Dibutyryl cyclic AMP potentiated the secretory effect of carbachol only at carbachol concentrations ⋝10−7 mol/l; was independent of carbachol at concentrations > 10−7 mol/l and was inversely proportional to extracellular [Ca2+].

Carbachol increased and dibutyryl cyclic AMP reduced the rate of 45Ca efflux from the tissue.

A‐23187 stimulated 3H‐protein release in the presence of Ca2+ and this effect was potentiated by dibutyryl cyclic AMP; the degree of potentiation was inversely proportional to extracellular [Ca2+]. At 10−3 mol/l [Ca2+] the potentiation occurred only at ionophore concentrations ⋜ 10−6 mol/litre.

These results support the hypothesis that dibutyryl cyclic AMP potentiates the effect of secretagogues in rat exocrine pancreas by maintaining an elevated intracellular calcium concentraion. It does so by inhibiting Ca2+ efflux. The results also suggest that the limiting factor in carbachol‐stimulated secretion, at all concentrations of carbachol, is intracellular [Ca2+].
TOLERANCE PATTERN OF THE ANOREXIGENIC ACTION OF AMPHETAMINES, FENFLURAMINE, PHENMETRAZINE AND DIETHYLPROPION IN RATS
Authors: GHOSH M.N. , PARVATHY S.
Published: July 2012

The tolerance pattern to anorectic drugs was studied in starved rats by measuring two consecutive 2 h food intakes.

There was a reduction in the first 2 h food intake with development of complete tolerance after fenfluramine and phenmetrazine, and of partial tolerance after amphetamine, (+)‐amphetamine and diethylpropion.

During the second 2 h intake, the anorectic effect was transient after fenfluramine and diethylpropion; while there was an absolute increase in the intake after amphetamine and (+)‐amphetamine.

A pair‐feeding experiment revealed that the increase in the second 2 h food intake was not a direct effect of the drug but a consequence of the deficit in food intake during the preceding 2 hours.

There was an overall correlation between the food and water intake.

A significant loss in body weight was observed after amphetamine, fenfluramine and phenmetrazine but not after (+)‐amphetamine or diethylpropion.

The results indicate that so‐called tolerance to the anorexigenic effect of drugs is apparent rather than real and that the duration of food access is a determining factor. The body weight changes may be brought about by the metabolic effects of these drugs rather than their effect on food and water intake.
DUAL EFFECTS OF ASPIRIN IN GUINEA‐PIG LUNGS
Authors: MIELENS Z. E. , ROSENBERG F. J.
Published: July 2012

Dual effects of aspirin were demonstrated in guinea‐pig lungs: (a) aspirin (3.3 mg/kg i.v.) antagonized bronchoconstriction induced by slow reacting substance of anaphylaxis (SRS‐A); (b) aspirin produced bronchoconstriction when injected in the presence of propranolol into guinea‐pigs in vivo at 330 mg/kg, or into guinea‐pig isolated lungs in vitro as a 4% solution (40 mg/ml).

The severity of bronchoconstriction following administration of aspirin was directly related to the degree of β‐adrenoceptor blockade and to the age of the guinea‐pigs. Aspirin‐induced bronchoconstriction was prevented in vivo and in vitro by atropine and it could be reversed in vivo by atropine. Aspirin‐induced bronchoconstriction was not inhibited by vagotomy or phenoxybenzamine.

These data suggest that the mechanism involved in aspirin‐induced bronchoconstriction may be local cholinergic stimulation and that reduced β‐adrenergic drive may be a predisposing factor.
OBSERVATIONS ON THE PHARMACOLOGY OF CHOLINOCEPTIVE NEURONES IN THE RAT BRAIN STEM
Authors: BRADLEY P.B. , DRAY A.
Published: July 2012

The pharmacology of spontaneously active cholinoceptive neurones in the brain stem of rats anaesthetized with urethane has been investigated using microiontophoresis to administer muscarinic and nicotinic agonists and antagonists.

Acetylcholine (ACh) excited most cells but occasionally depressed their activity. Muscarine, and the muscarinic agonists methacholine and bethanechol produced prolonged excitation or inhibition of cells whereas nicotine produced prolonged excitations but no inhibitions.

Atropine selectively antagonized ACh excitations and both excitation and inhibition of neuronal activity produced by muscarine and muscarinic agonists, but not the excitations produced by nicotine, glutamate or dl‐homocysteic acid.

Dihydro‐β‐erythroidine (DHBE) and tubocurarine antagonized both ACh and nicotine excitations but not those induced by glutamate or dl‐homocysteic acid. Inhibitions by ACh or muscarine were not affected.

It is concluded that excitations of cholinoceptive neurones in the rat brain stem may be mediated by activation of both muscarinic and nicotinic receptors whereas inhibitions are mediated by activation of a muscarinic receptor.
EFFECTS OF CONTRACEPTIVE AGENTS ON DRUG METABOLISM IN VARIOUS ANIMAL SPECIES
Authors: BRIATICO G. , GUISO G. , JORI A. , RAVAZZANI C.
Published: July 2012

The effect on liver microsomal enzyme activity of three steroid contraceptive drug (SCD) combinations was compared in rats, mice and guinea‐pigs. Lynestrenol plus mestranol, norethisterone plus mestranol and norethynodrel plus mestranol were given orally for 4 consecutive days (acute treatment) or 30 days (chronic treatment) at various doses eliciting an experimentally controlled antifertility activity which varied in its extent.

In rats and mice all the combined treatments (with the exception of norethynodrel plus mestranol in mice) were active as inducers of liver microsomal enzymes. This induction seems to be mediated mainly by the progestogenic compounds. Oestrogens showed a very poor effect bordering on significance only in a few cases.

No effect on liver microsomal protein or cytochrome P 450 concentration was obtained after treatment with doses capable of increasing the microsomal enzyme activity.

The activity of the liver microsomal enzymes did not appear to be reduced immediately (2 h) after the last administration of the SCD given during 4 or 30 days.

Contraceptive treatments at doses capable of eliciting complete antifertility activity were inactive on liver microsomal enzyme activity in guinea‐pigs.
STIMULATION OF PROSTAGLANDIN BIOSYNTHESIS BY DRUGS: EFFECTS in vitro OF SOME DRUGS AFFECTING GUT FUNCTION
Authors: COLLIER H.O.J. , McDONALD‐GIBSON WENDY J. , SAEED S.A.
Published: July 2012

Low concentrations of several emetic, purgative or irritant drugs in the absence of added co‐factors stimulated conversion of arachidonic acid to prostaglandin E2 and F2α by prostaglandin synthetase extracted from bull seminal vesicles (BSV prostaglandin synthetase). Their effect was dependent on concentration and time.

Stimulation of BSV prostaglandin synthetase by apomorphine, aloes, tyramine or zingerone was increased several‐fold by addition of reduced glutathione to the incubation medium, whereas hydroquinone, a phenolic co‐factor of prostaglandin synthetase caused slight depression.

From this finding and from the observation that many of the stimulant drugs possess a phenolic group, whereas their inactive relatives lack such a group, it is suggested that these stimulant drugs act as co‐factors for prostaglandin synthetase in place of hydroquinone.

Aloes, tyramine, ethanol and quipazine also produced a dose‐related increase in resting tone of the isolated fundus of the rat stomach. This increase occurred at concentrations comparable to those effective in stimulating BSV prostaglandin synthetase, and was abolished by acetylsalicylate.

These findings support the view that certain drugs exert some of their pharmacological effects by stimulating prostaglandin synthetase.
BRADYKININ AND FUNCTIONAL VASODILATATION IN THE SALIVARY GLAND
Authors: FERREIRA S.H. , SMAJE L.H.
Published: July 2012

Blood flow through the submandibular gland of the dog was measured and the venous effluent monitored for potential mediators of the functional vasodilatation by passing it over a series of assay tissues.

On chorda lingual nerve stimulation there was salivation, an increased blood flow and the release of a bradykinin‐like substance (kinin) into the venous effluent.

In about half of the preparations, increasing the frequency of stimulation from 2 to 10 Hz led to an increased output of kinin, whereas in the others successive stimulations led to a decreasing output of kinin in the face of normal secretory and vascular responses.

Following the administration of atropine, the vasodilatation persisted, salivation was abolished and after several stimulations kinin release could no longer be detected.

Release of prostaglandin did not appear to be responsible for the vasodilatation.

It is concluded that neither kallikrein nor kinin is the main mediator of parasympathetic vasodilatation in the salivary gland.
THE DENERVATED CREMASTER MUSCLE OF THE GUINEA‐PIG AS A PHARMACOLOGICAL PREPARATION
Authors: DALE M. MAUREEN , EVINÇ AKGÜN , VINE PAULINE
Published: July 2012

The pharmacological responses of both denervated and innervated cremaster muscle preparations from the guinea‐pig have been investigated and compared. Acetylcholine (ACh) dose‐response curves were obtained in both preparations. The affinity constants for (+)‐tubocurarine and for atropine were calculated and indicated that the ACh receptors in both preparations were nicotinic.

Histamine dose‐response curves could be obtained only in the denervated preparation. The response was unaltered by metiamide, and the affinity constant for mepyramine fitted in with those previously obtained by others on ileum and trachea, indicating that the histamine receptors are H1 in type.

Sustained contractions were obtained to adrenaline and noradrenaline but not isoprenaline, with the denervated preparations.

Schultz‐Dale responses were obtained with denervated muscle in sensitized guinea‐pigs. This preparation did not respond to 5‐hydroxytryptamine, bradykinin, or the slow‐reacting substance of anaphylaxis.
EFFECTS OF KETAMINE ON THE PERIPHERAL AUTONOMIC NERVOUS SYSTEM OF THE RAT
Authors: CLANACHAN A.S. , McGRATH J.C.
Published: July 2012

The effects of ketamine (2‐(o‐chlorophenyl) 2‐methylaminocyclohexanone) (2–50 mg/kg) on the responses of the pithed rat arterial pressure, anococcygeus muscle and colon to selective stimulation of the spinal autonomic outflows were examined.

Ketamine depressed the vasopressor response produced by stimulation of the lumbar sympathetic outflow in a dose‐dependent manner but did not significantly affect the pressor response to intravenous noradrenaline (NA) administration.

Ketamine depressed the motor responses of the anococcygeus to stimulation of the pre‐ganglionic lumbar sympathetic outflow or to stimulation of post‐ganglionic fibres in the sacral region in a dose‐dependent manner, the response to preganglionic stimulation being relatively more sensitive to such depression. The anococcygeus response to NA was significantly potentiated with doses of ketamine of 20 mg/kg and 50 mg/kg.

Ketamine depressed the motor response of the smooth muscle of the colon to stimulation of the sacral parasympathetic outflow in a dose‐dependent manner and at lower doses than were required to produce an equivalent depression of the sympathetic responses in the other tissues.

A comparison was made of the effects of ketamine and cocaine on the motor responses of the anococcygeus muscle in vitro to NA, carbachol and field stimulation. Both ketamine and cocaine produced a non‐specific depression of all responses at high doses whereas cocaine but not ketamine produced a large potentiation of NA and motor nerve responses at lower doses.

The results are discussed in relation to the hypothesis that ketamine might elevate blood pressure in conscious animals and man by potentiating vascular adrenergic responses.
RENAL FUNCTION AND RENAL VENOUS PROSTAGLANDIN CONCENTRATIONS DURING DIFFERENT STAGES OF EXPERIMENTAL RENAL HYPERTENSION IN THE RAT
Authors: SMITH G.W. , SOMOVA LILIANA I.
Published: July 2012

Renal hypertension was produced in rats and the changes in renal function, renal venous prostaglandin E2 and F2α concentrations and secretion rates were studied at various times.

Renal plasma flow transiently fell in the ischaemic kidney 2 weeks after clamping, whilst that of the other kidney did not change. Glomerular filtration rate remained constant in both kidneys throughout the entire study.

Prostaglandins E2 and F2α concentrations rose in the venous plasma from the ischaemic kidney, but did not change in the other kidney and appeared to be inversely related to renal plasma flow.

Calculated secretion rate of both prostaglandins fell in the ischaemic kidney and did not change in the other kidney.

Clamping the second kidney, two weeks after the first, caused a further elevation in blood pressure, a fall in renal plasma flow and a fall in prostaglandin secretion rate in both kidneys.

The implications of these prostaglandin changes are discussed.
EFFECTS OF ADRENOCEPTOR BLOCKADE ON PLASMA CATECHOLAMINE LEVELS DURING ADRENALINE INFUSION
Authors: BRITTON B.J. , IRVING M.H. , WOOD W.G.
Published: July 2012

The present experiments investigate the effects of phenoxybenzamine and propranolol, singly and in combination, on plasma catecholamine levels in sheep receiving a three‐hour adrenaline infusion.

Five groups of five anaesthetized sheep were studied for a period of 3 h each. One group acted as a control and received only a saline (0.9% w/v NaCl solution) infusion. A second group received a constant infusion of adrenaline (2 μg kg body weight−1 min−1). A third group received a similar adrenaline infusion, having been premedicated with phenoxybenzamine (1 mg/kg body weight). A fourth group received a similar adrenaline infusion following premedication with (±)‐propranolol hydrochloride (7 μg/kg body weight). The fifth group received the adrenaline infusion following premedication with both the α‐ and β‐blocker in the above doses.

Plasma catecholamines were measured on blood samples taken at seven intervals before, during and following the infusion.

Control animals receiving only a saline infusion remained physiologically and biochemically stable throughout the experimental period.

Adrenaline infusion in animals not receiving adrenoceptor blocking drugs caused a rise in plasma adrenaline levels from a low basal value of 1 μg/litre to a maximum level of 19.8 μg/litre. Animals premedicated with phenoxybenzamine exhibited a similar response.

Animals premedicated with propranolol before the infusion of adrenaline did not demonstrate as marked a rise of plasma adrenaline levels as the two previous groups. The maximum mean plasma adrenaline level recorded in this group was 6.88 μg/litre.

Animals premedicated with phenoxybenzamine and propranolol before the infusion of adrenaline showed only a small rise in plasma adrenaline levels compared with animals receiving adrenaline infusion alone. The maximum mean plasma adrenaline level in the group was only 3.43 μg/litre.

The studies demonstrate that by an unknown mechanism β‐adrenoceptor blockade with (±)‐propranolol, either alone or in combination with phenoxybenzamine, lowers the plasma adrenaline response evoked by adrenaline infusion.
POTENTIATION OF THE RESPONSE TO VASOPRESSIN (PITRESSIN) BY TREATMENT WITH A COMBINATION OF CHLORPROPAMIDE AND CHLOROTHIAZIDE IN BRATTLEBORO RATS WITH HEREDITARY HYPOTHALAMIC DIABETES INSIPIDUS
Authors: LAYCOCK J.F. , LEWIS A.F.
Published: July 2012

The effect of a combination of chlorpropamide and chlorothiazide in Brattleboro rats with hereditary hypothalamic diabetes insipidus (DI) treated with low doses of vasopressin (Pitressin tannate in oil) was investigated with particular reference to the time course of response from the initiation of treatment.

Analysis of the relationship between water intake and body weight indicated no real correlation and body weight accounted for only 4.4% of the variation in water intake. It was therefore decided to use whole body responses as the index in preference to the response per unit body weight.

The daily administration of 5 mg chlorpropamide combined with chlorothiazide in the drinking water (4 mg/l) to Pitressin‐treated DI rats potentiated the response to small doses of vasopressin (25 and 50 mu Pitressin/24 hours). Water intake was reduced by the drug combination by an average of 12.35 ml/24 h, but only on the second day of treatment was the decrease of any real magnitude (30 ml/24 h but otherwise 9 ml/24 h or less). Analysis of urine volume measurements gave similar results to those obtained for water intake and the potency ratio measured in terms of free water clearance was 1.26 (agreeing closely with the ratio for water intake which was 1.24).

A reduction in the solute excretion was observed only in those DI rats treated with the higher dose of Pitressin (50 mu/24 h) combined with the two drugs.

Possible reasons for the discrepancy between the effect of the combination of chlorpropamide and chlorathiazide on water metabolism in the DI rat and the DI patient are discussed.
MODIFICATION BY CAPSAICIN AND COMPOUND 48/80 OF DYE LEAKAGE INDUCED BY IRRITANTS IN THE RAT
Authors: ARVIER P.T. , CHAHL LORIS A. , LADD R.J.
Published: July 2012

Concentration‐related dye leakage produced by intracutaneous injections of irritants was measured in rats by an Evans blue technique.

In rats pretreated with a total dose of 50 mg capsaicin over 4 days, the response to capsaicin, formalin, HCl, KCl, prostaglandin E1, bradykinin and bradykinin with prostaglandin E1 (10−6 m) were greatly reduced, the responses to histamine and 5‐hydroxytryptamine were slightly reduced and those to adenosine 5′‐triphosphate (ATP) and compound 48/80 were unaffected.

Pretreatment with intracutaneous injections of compound 48/80 (0.5 μg, 24 and 48 h previously) recuded the responses to ATP, compound 48/80, HCl, KCl, prostaglandin E1, and bradykinin but did not affect those to histamine, 5‐hydroxytryptamine or bradykinin with prostaglandin E1 (10−6 m).

Responses to capsaicin and formalin produced spotted blueing extending over a large area and were suppressed by compound 48/80 in the smaller pretreated area only. Capsaicin responses were reduced with larger doses of compound 48/80 (total dose 15 μg).

It is concluded that the production of neurogenic oedema involves both sensory nerves and mast cells.
THE PHARMACOLOGICAL PROPERTIES OF THE CHOLINERGIC FALSE TRANSMITTER, N‐2‐ACETOXYETHYL‐N‐METHYLPYRROLIDINIUM, AND ITS PRECURSOR, N‐2‐HYDROXYETHYL‐N‐METHYLPYRROLIDINIUM
Authors: VON SCHWARZENFELD I. , WHITTAKER V. P.
Published: July 2012

The pharmacological properties of N‐2‐hydroxyethyl‐N‐methyl pyrrolidinium (pyrrolcholine) and its acetate ester, recently shown to be a false transmitter at the cholinergic electromotor synapses in Torpedo marmorata, also those of the corresponding morpholinium compounds (morpholinecholine, acetylmorpholinecholine), have been studied on the guinea‐pig ileum, frog heart, frog rectus abdominis muscle, rat blood pressure, rat gastrocnemius muscle and dorsal muscle of the leech.

Acetylpyrrolcholine and acetylmorpholinecholine are full cholinoceptor agonists with dose‐response curves parallel to that of acetylcholine. They are, however, less potent. Acetylpyrrolcholine is relatively more potent as a muscarinic drug (molar potency about 30% of that of acetylcholine in the ileum but only 4% on the leech) whereas acetylmorpholinecholine is more strongly nicotinic. The unacetylated compounds are very weak agonists with potencies comparable to that of choline.

Pyrrolcholine in high concentration showed a distinct neuromuscular blocking effect in the rat gastrocnemius muscle preparation. It is likely that this is a direct effect and not due to uptake by the presynaptic nerve terminals followed by conversion to a false transmitter since it was not reduced by hemicholinium‐3, which is known to block uptake of choline and choline analogues by the presynaptic high affinity choline uptake system.
THE SELECTIVE ACTION OF β‐ADRENOCEPTOR BLOCKING DRUGS AND THE NATURE OF β1 and β2 ADRENOCEPTORS
Authors: COLEMAN A.J. , SOMERVILLE A.R.
Published: July 2012

Purified membranes retaining a catecholamine responsive adenylate cyclase have been prepared from rabbit heart, lung and (pseudo‐pregnant) uterus.

These preparations have the characteristics of plasma membranes and both heart and lung respond to β‐adrenoceptor agonists in the order:

(±)‐isoprenaline> (—)‐noradrenaline> (—)‐adrenaline> (+)‐isoprenaline> salbutamol.

The sensitivity of the adenylate cyclase to β‐adrenoceptor stimulation is improved by pre‐treatment of the animals with reserpine and syrosingopine.

Dose‐ratios for several concentrations of propranolol (non‐selective β‐adrenoceptor blocker), practolol and atenolol (cardio‐selective β‐adrenoceptor blockers) have been measured on all three membrane preparations. Schild plots of log (dose ratio — 1) vs. log dose were virtually coincident for heart and lung with a dissociation constant (Kb) for propranolol very close to the pharmacological value. The ratio of Kb values was 0.65 for practolol and 1.23 for atenolol compared with pharmacological cardio‐selectivity ratios (measured on isolated atria and tracheal chain) of 67.6 and 110 respectively. The uterus/heart Kb ratio was 51.5 for atenolol. Inhibition of the uterus by practolol gave a Schild plot with slope significantly less than 1, indicating a different mechanism of action from the heart.

Kb values obtained by measuring adenylate cyclase stimulation in chopped tissue (including preparations of bronchial tree and alveolar tissue as well as whole lung) resembled the membrane values rather than those found in whole organs.

The results show that the pharmacological selectivity of practolol and atenolol is maintained at the receptor‐adenylate cyclase level, at least as far as heart and uterus are concerned, though the smaller selectivity ratios in the biochemical system suggest that receptor difference is not the only factor and that phase distribution of the drug may also be important. Membranes prepared from whole lung show an overall β1 response which may simply reflect the predominance of β1 cell types containing β1‐adrenoceptors over bronchial smooth muscle.