bluuebunny/crossref_metadata_2025 huggingface dataset:
THE PHARMACOKINETICS OF PYRIDOSTIGMINE AND 3‐HYDROXY‐N‐METHYLPYRIDINIUM IN THE RAT: DOSE‐DEPENDENT EFFECTS AFTER PORTAL VEIN ADMINISTRATION
Authors: BARBER H.E. , BOURNE G.R. , CALVEY T.N. , MUIR K.T.
Published: July 2012

The elimination kinetics of [14C]‐pyridostigmine iodide and [14C‐methyl]‐3‐hydroxypyridinium bromide (3‐OH NMP) have been studied in the rat.

For pyridostigmine, at a given dose level, the fraction of the dose eliminated unchanged was reduced and the metabolite fraction was increased after portal vein administration when compared to jugular vein administration. This indicates that pyridostigmine is subject to metabolism during the first passage through the liver.

When doses of pyridostigmine 1.25 μmol/kg and higher were injected via the portal vein, the proportion excreted in urine as unchanged drug remained constant; in contrast, the percentage of the dose eliminated as the metabolite was significantly reduced. This indicates that a dose‐dependent process is involved in the urinary excretion of 3‐OH NMP.

This conclusion was supported by studies involving the portal and systemic venous injection of 3‐OH NMP at different dose levels. After 4 h, approximately 85% of the lowest dose was eliminated unchanged in urine; in contrast, only 63% of the higher dose was excreted during this period. The proportion of the dose eliminated in urine was not related to the route of administration.

After the injection of pyridostigmine into the jugular vein, the initial rate of drug excretion fell rapidly for approximately 10 min; in contrast, after injection into the portal vein, the rate of excretion of the drug rose to a maximum at 30 minutes. This suggests that the hepatoportal system behaves as a distinct region during the distribution of this drug.
ANTIARRHYTHMIC, HAEMODYNAMIC AND METABOLIC EFFECTS OF 3α‐AMINO‐5α‐ANDROSTAN‐2β‐OL‐17‐ONE HYDROCHLORIDE IN GREYHOUNDS FOLLOWING ACUTE CORONARY ARTERY LIGATION
Authors: MARSHALL R.J. , PARRATT J. R.
Published: July 2012

The antiarrhythmic, haemodynamic and metabolic effects of a new amino steroid, ORG6001, have been investigated in experimental acute myocardial infarction in anaesthetized greyhounds.

ORG6001 administered either intravenously (1–10 mg/kg) or orally (50 mg/kg) significantly reduced the incidence of ventricular ectopic beats in the first 30 min after ligation of the left anterior descending coronary artery.

In dogs pretreated with ORG6001, metabolic changes indicative of myocardial ischaemia (lactate production and potassium efflux) were less marked than those occurring in control animals.

Antiarrhythmic doses of ORG6001 caused only minimal transient haemodynamic effects.

These results suggest that ORG6001 may possess distinct advantages over presently‐used antiarrhythmic drugs in the prevention and treatment of the early arrhythmias which occur after myocardial infarction.
ACTIONS OF PROSTAGLANDIN E2 ON MYOCARDIAL MECHANICS, CORONARY VASCULAR RESISTANCE AND OXYGEN CONSUMPTION IN THE GUINEA‐PIG ISOLATED HEART PREPARATION
Authors: KREBS R. , SCHRÖR K.
Published: July 2012

In isolated, electrically driven (3 Hz) hearts of guinea‐pigs the action of prostaglandin E2 on left ventricular pressure (LVP), oxygen consumption (Qo2) and coronary vascular resistance (CVR) was studied by establishing cumulative concentration‐response curves. The hearts were perfused at a constant flow (10 ml/min) with Tyrode solution (Ca++ 1.8 mM) at 32° C.

Under control conditions prostaglandin E2 (2.86 × 10−11 − 1.43 × 10−7 M) decreased LVP, Qo2 and CVR in a concentration‐dependent manner by maximally 27, 18 and 38%, respectively (P < 0.05).

After reserpine pretreatment there were lower initial values for all parameters measured. The effect of prostaglandin E2 on LVP and Qo2 was abolished, but CVR was further diminished, depending on the concentration.

The results seem to support the hypothesis of an interaction of prostaglandin E2 with endogenous catecholamines as far as the effects on LVP and Qo2 are concerned. In contrast, prostaglandin E2 seems to have a direct action on CVR, which is independent of the presence of catecholamines.
NORADRENALINE AND MOTOR TRANSMISSION IN THE VAS DEFERENS OF THE MOUSE
Authors: JONES MARGARET E.L. , SPRIGGS T.L.B.
Published: July 2012

A comprehensive investigation of the innervation of the vas deferens of the mouse was made using pharmacological, histochemical and electronmicroscopical techniques.

Guanethidine inhibited the response of the vas to transmural stimulation and potentiated the response to noradrenaline (NA). Phentolamine abolished responses to NA and to transmural stimulation.

After chemical sympathectomy degenerative changes were seen in presumptive noradrenergic axons; histochemical fluorescence due to catecholamines was absent. The vas failed to respond to transmural stimulation, and a 10‐fold increase in sensitivity of the vas to exogenous NA was observed.

NA is shown to diffuse slowly through this tissue whose muscle cells are densely packed. This is discussed in relation to the apparent ‘insensitivity’ of the vas to exogenous NA.

A cholinergic component was identified histochemically which did not contribute significantly to the motor response of the vas as chemical sympathectomy abolished completely the motor response elicited by transmural stimulation.

It is concluded that NA is the motor transmitter for the smooth muscle of the vas deferens of the mouse.
TETRAMETHYLENEDISULPHOTETRAMINE: AN INHIBITOR OF γ‐AMINOBUTYRIC ACID INDUCED DEPOLARIZATION OF THE ISOLATED SUPERIOR CERVICAL GANGLION OF THE RAT
Authors: BOWERY N.G. , BROWN D.A. , COLLINS J.F.
Published: July 2012

Tetramethylenedisulphotetramine (TETS), a potent convulsant, antagonized the depolarizing action of γ‐aminobutyric acid (GABA) in the isolated superior cervical ganglion of the rat. No antagonism of responses to the cholinomimetic agent carbachol was observed. TETS appeared to act in a non‐competitive manner and was reversible. Its activity profile was comparable to that of bicuculline in the same tissue except that the latter appears to act in a competitive manner.
CHANGES OF HUMAN PLASMA DOPAMINE‐β‐HYDROXYLASE ACTIVITY AFTER INTRAVENOUS ADMINISTRATION OF THEOPHYLLINE
Authors: AUNIS D. , MANDEL P. , MIRAS‐PORTUGAL M.T. , COQUILLAT G. , ROHMER F. , WARTER J.M.
Published: July 2012

The intravenous administration of theophylline to ten healthy human subjects produced either an increase of circulating plasma dopamine‐β‐hydroxylase or no change. The rise of plasma enzyme activity may reflect the increased peripheral catecholamine release induced by theophylline.
SENSITIVITY OF NEONATAL RABBIT ILEUM TO HISTAMINE
Authors: BOTTING J.H.
Published: July 2012

Segments of ileum from newborn rabbits contracted in response to histamine but sensitivity declined from age 11 days. Intestine from adult animals barely contracted to histamine, even in a concentration of 3 × 10−3 M. Such variation with age was not observed with acetylcholine. The response to histamine was effected by mepyramine‐sensitive receptors which appeared to decrease in number as the animals aged.
E. coli ENDOTOXIN SHOCK IN THE CAT; TREATMENT WITH INDOMETHACIN
Authors: PARRATT J.R. , STURGESS R.M.
Published: July 2012

An earlier study had demonstrated that indomethacin, administered before E. coli endotoxin, abolished the initial pulmonary vasoconstriction and delayed the onset of the secondary shock phase that results from the intravenous injection of this agent in cats. The object of the present study was to determine whether indomethacin modified the shock phase when administered after endotoxin.

All the cats (whether or not they received indomethacin, 10 mg/kg) exhibited the characteristic features of the delayed shock phase that result from the administration of endotoxin (2 mg/kg). These included systemic hypotension, hypoglycaemia, reductions in arterial pH, cardiac output and systolic ejection time and an increase in arterial lactate. Five out of the ten animals given indomethacin survived 4 h compared with four out of twelve in the control (endotoxin alone) group.

These results do not support the suggestion that antipyretic‐analgesic drugs like indomethacin may be of benefit when given during bacteraemic or septic shock. They do support the suggestion that the acute pulmonary changes (hypertension and decreased compliance) that occur in this species within a few minutes of endotoxin administration ultimately contribute to the severity of the shock phase.
THE EFFECTS OF CATECHOLAMINES AND ADRENOCEPTOR BLOCKING DRUGS ON THE CANINE PERIPHERAL LYMPH FLOW
Authors: DE MICHELI P. , GLÄSSER A.H.
Published: July 2012

Blood flow through the femoral artery, lymph flow in a lymphatic vessel in the femoral triangle and metatarsal distal venous pressure were measured simultaneously in a canine moving hind limb.

Low intra‐arterial doses of adrenaline and noradrenaline increased lymph flow even in the presence of marked arterial vasoconstriction. In contrast, isoprenaline increased arterial blood flow without affecting lymph flow rate.

Phenoxybenzamine, dihydroergotoxine, and nicergoline did not inhibit the lymphatic flow increase induced by adrenaline at doses active on arterial or venous vascular alpha‐adrenoceptors.

Propranolol given intra‐arterially into animals pretreated with alpha‐adrenoceptor blocking agents restored the vasoconstrictor effect of adrenaline (reversal of adrenaline reversal).
AN INDIRECT SYMPATHOMIMETIC EFFECT OF BURIMAMIDE ON KITTEN ISOLATED ATRIA
Authors: HOOD A.J.C. , SMY J.R. , WEETMAN D.F.
Published: July 2012

Burimamide (34‐1080 μM) caused a concentration‐dependent increase in the force and frequency of contraction of kitten isolated atria.

Metiamide (467 μM) had no stimulant action on kitten atria and did not modify the effects of burimamide.

The atrial stimulation produced by burimamide was reduced by (‐)‐propranolol (34‐68 nM) and by cocaine (3 μM).

The atrial stimulant effect of burimamide was prevented by pretreatment of kittens with reserpine (1 mg/kg, 24 h before the experiment).

It is concluded that burimamide causes atrial stimulation by releasing catecholamines.
THE EFFECT OF RESERPINE ON HYPOTHALAMO‐PITUITARY‐ADRENOCORTICAL FUNCTION IN THE RAT
Authors: HODGES J.R. , VELLUCCI SANDRA V.
Published: July 2012

The effect of reserpine on hypothalamo‐pituitary‐adrenocortical (HPA) function in the rat was investigated by the use of direct and indirect indices of pituitary adrenocorticotrophic activity.

Administration of a single dose of the drug induced prolonged hypersecretion of corticotrophin (ACTH).

Corticotrophin release in response to the drug no longer occurred after repeated daily injections, indicating that some form of ‘adaptation’ occurred.

The increase in HPA activity normally caused by exposure to cold was prevented by reserpine once ‘adaptation’ to the drug had been produced.

Inhibition of stress‐induced ACTH release was due neither to depletion of pituitary stores of the hormone, nor to a corticosteroid feedback effect.
INTERACTION OF HISTAMINE H1‐ AND H2‐RECEPTOR ANTAGONISTS WITH HISTAMINE UPTAKE AND METABOLISM BY GUINEA‐PIG ISOLATED ATRIUM AND MOUSE NEOPLASTIC MAST CELLS in vitro
Authors: FANTOZZI R. , FRANCONI FLAVIA , MANNAIONI P.F. , MASINI EMANUELA , MORONI F.
Published: July 2012

Burimamide, metiamide, chlorpheniramine, triprolidine and cocaine, were tested as inhibitors of histamine uptake and metabolism in the guinea‐pig atrium and in mouse neoplastic mast cells.

Cocaine did not affect the uptake and metabolism of histamine, either in the atrium or in the mast cells. All the antihistamines tested blocked the uptake and metabolism of histamine in both preparations. The order of potency was burimamide > chlorpheniramine > triprolidine > metiamide in the atrium; and burimamide > metiamide > triprolidine > chlorpheniramine, in the mast cells.

Comparison of the present results with the antihistamine activity of these blocking agents suggests that no correlation exists between the receptor blocking activity and the ability of these substances to act as inhibitors of histamine uptake and metabolism.
ANTAGONISM OF ADENOSINE 5′‐TRIPHOSPHATE‐INDUCED RELAXATION BY 2‐2′‐PYRIDYLISATOGEN IN THE TAENIA OF GUINEA‐PIG CAECUM
Authors: SPEDDING M. , SWEETMAN A.J. , WEETMAN D.F.
Published: July 2012

2‐2′Pyridylisatogen tosylate (PIT) (>2.5 μM) relaxed the guinea‐pig isolated taenia caeci by an unknown mechanism.

With higher concentrations of PIT (>12.5 μM) subsequent applications of adenosine 5′‐triphosphate (ATP) (2‐600 μM) revealed a blockade of the ATP receptors. The antagonism was characterized by a delayed onset of action (>10 min incubation with 50 μM PIT) and eventually became irreversible (>50 μM PIT for >30 minutes). The antagonism was specific for ATP, was not competitive, and was not dependent upon the relaxant effect.

The presence of either acetylcholine (0.05‐1.0 μM) or carbachol (0.05‐1.0 μM) increased the antagonistic effect of PIT (50 μM) approximately five‐fold.

Following prolonged exposure, PIT (50 μM for 90 min) did not block the inhibitory effects of field stimulation (2 Hz, 10 s) of the taenia caeci in the presence of hyoscine (0.33 μM). These results do not support the purinergic nerve hypothesis.
EFFECT OF FLUPHENAZINE ON TISSUE NORADRENALINE CONCENTRATIONS AND ITS INTERACTION WITH PARGYLINE
Authors: el‐AZHARY ROKEA A. , KHAYYAL M.T. , SALEH SAMIRA
Published: July 2012

Fluphenazine caused a small decrease in the noradrenaline (NA) concentrations of the rat brain, possibly by impairing granular amine storage. The drug diminished the rise in brain and heart NA concentrations induced by pargyline, suggesting that it might possess inhibitory properties on neuronal uptake mechanisms and/or NA synthesis. Fluphenazine abolished conditioned avoidance responses in rats, an effect which was maintained after the concomitant administration of pargyline, when NA concentrations remained high. This suggests that the fluphenazine‐induced sedation is not mediated via its effect on brain NA content, but is possibly due to the effect of the drug on NA turnover rates in the brain.
INDOMETHACIN POTENTIATION OF THE RESPONSE OF THE RABBIT PORTAL VEIN TO ELECTRICAL STIMULATION: EFFECT OF STIMULUS FREQUENCY AND TRAIN LENGTH
Authors: GREENBERG R.
Published: July 2012

The response of the rabbit isolated portal vein to electrical stimulation was potentiated by indomethacin (10 μg/ml). This potentiation was dependent upon frequency but independent of the number of pulses in a train. It is concluded that these results add further support for the idea that indomethacin increases the release of newly synthesized noradrenaline as a result of inhibition of prostaglandin synthesis.
THE ACTION OF ACETYLCHOLINE ANTAGONISTS ON AMINO ACID RESPONSES IN THE FROG SPINAL CORD in vitro
Authors: NICOLL R.A.
Published: July 2012

The isolated hemisected frog spinal cord has been used to study the action of acetylcholine antagonists on amino acid responses by means of sucrose gap recording.

Primary afferents and motoneurones were shown to contain few, if any, cholinoceptors, since acetylcholine and carbachol responses were essentially abolished when synaptic transmission was blocked with magnesium ions or when action potentials were blocked by tetrodotoxin.

Curare antagonized the γ‐aminobutyric acid (GABA) and β‐alanine depolarizations of primary afferents and the hyperpolarizing action of these amino acids on motoneurones. Nicotine also antagonized β‐alanine depolarizations and to a small extent GABA depolarizations of primary afferents. These actions are similar to but weaker than those obtained previously with picrotoxin.

Atropine selectively antagonized β‐alanine depolarizations of primary afferents and blocked β‐alanine and glycine hyperpolarizations of motoneurones. GABA responses were entirely resistant to the action of atropine. These actions are similar to but 50 times weaker than those obtained previously with strychnine.

Dihydro‐β‐erythroidine, tetraethylammonium, and gallamine were entirely ineffective in antagonizing amino acid responses. Since these agents are known to block the dorsal root potential elicited by ventral root stimulation but have no effect on the amino acid responses of primary afferents, it is evident that a cholinergic step is involved in this pathway.
FURAZOLIDONE‐PETHIDINE INTERACTION IN RABBITS
Authors: ELTAYEB I.B. , OSMAN O.H.
Published: July 2012

The intravenous injection of pethidine in rabbits pretreated with furazolidone administered orally but not systemically resulted in severe interaction and fatal hyperpyrexia.

Treatment with p‐chlorophenylalanine, chloropromazine or cyproheptadine protected the rabbits against the furazolidone‐pethidine interaction, while α‐methyl‐p‐tyrosine was ineffective.

5‐Hydroxytryptophan produced a fatal hyperpyrexia in furazolidone pretreated rabbits.

Pretreatment of rabbits with 1,1,1‐trichloro‐2, 2‐bis(p‐chlorophenyl)ethane (DDT) accelerated and enhanced the furazolidone‐pethidine interaction, while oxytetracycline pretreatment completely prevented the interaction.

It is concluded that furazolidone‐pethidine interaction might depend mainly on potentiation of the effects of 5‐hydroxytryptamine in the CNS and that the transformation of furazolidone into an active monoamine oxidase inhibitor metabolite might occur mainly in the gut microflora in the gut lumen.
THE DEVELOPMENT OF ANTISERA TO PROSTAGLANDINS B2 AND F2α AND THEIR ANALYSIS USING SOLID‐PHASE AND DOUBLE ANTIBODY RADIOIMMUNOASSAY METHODS
Authors: DIGHE K.K. , EMSLIE H.A. , HENDERSON L.K. , SIMON L. , RUTHERFORD F.
Published: July 2012

A method for the production of highly substituted prostaglandin‐bovine serum albumin conjugates has been developed.

Antisera to prostaglandins B2 and F2α were raised in rabbits immunized with prostaglandin‐bovine serum albumin conjugates.

The antisera were assessed for specificity and sensitivity by the double antibody radioimmunoassay method and after they were covalently linked to powdered cellulose to form a ‘solid‐phase’ system.

Solid phase radioimmunoassays were developed using conventional shaking and in the presence of sucrose which obviates the need for continuous mixing of the incubates.
POSTNATAL DEVELOPMENT OF DOPAMINE DEAMINATION IN THE STRIATUM OF THE RAT
Authors: DAVIS A.J. , HOLZBAUER MARGARETHE , SHARMAN D.F. , YOUDIM M.B.H.
Published: July 2012

In the striata of litter‐mate rats the development of the monoamine oxidase (MAO) activity towards dopamine in vitro followed a similar time course with age as the tissue concentrations of homovanillic acid and dihydroxyphenylacetic acid, the two acid metabolites of dopamine formed by the action of MAO.
AN INHIBITORY EFFECT OF ATROPINE ON RESPONSES OF THE VAS DEFERENS OF THE MOUSE TO FIELD STIMULATION
Authors: JONES MARGARET E.L. , SPRIGGS T.L.B.
Published: July 2012

Atropine is shown to impair responses of the vas deferens of the mouse to field stimulation by acting at a site proximal to the smooth muscle cells.

The inhibitory effect of atropine is prevented by desmethylimipramine and reversed by dexamphetamine, and appears similar to the adrenergic‐neurone blockade of guanethidine.

Electronmicroscopical studies show the presence in vas of presumptive noradrenergic axons which have acetylcholinesterase reaction product associated with their axolemmae.

These results are discussed in relation to the controversial hypothesis of a ‘cholinergic link’ in noradrenergic transmission.
SOME CHARACTERISTICS OF PRE‐ AND POST‐SYNAPTIC INHIBITORY RECEPTORS AT THE HERMIT CRAB NEUROMUSCULAR JUNCTION
Authors: BALASHOV N. , EARL JANET , LARGE W.A.
Published: July 2012

The effects of γ‐aminobutyric acid (GABA), β‐guanidinopropionic acid (βGP) and picrotoxin on the pre‐ and post‐synaptic receptors of the hermit crab neuromuscular junction were studied quantitatively using electrophysiological techniques. Reductions in excitatory junction potential (e.j.p.) amplitude and membrane resistance were measured simultaneously from the same cells.

The pre‐ and post‐synaptic receptors were activated by the same order of concentration of GABA, whereas βGP stimulated the pre‐synaptic receptors at a concentration ten times lower than was required to affect the post‐synaptic membrane.

Picrotoxin appeared to antagonize the pre‐synaptic action of βGP in a competitive manner. The affinity constants (± s.e. mean) for picrotoxin 5 × 10−6 M and 2 × 10−4 M were 6.80 (± 0.46) × 105 M−1 and 6.42 (± 1.8) × 105 M−1 respectively.

The effect of GABA on e.j.p. amplitude also appeared to be antagonized competitively by picrotoxin whereas the post‐synaptic effect was antagonized in a non‐competitive manner.

Possible differences in the nature of the pre‐ and post‐synaptic receptors are discussed.
RAPID EFFECTS OF ENVIRONMENTAL DISTURBANCE ON RAT PLASMA UNESTERIFIED FATTY ACID AND TRYPTOPHAN CONCENTRATIONS AND THEIR PREVENTION BY ANTILIPOLYTIC DRUGS
Authors: CURZON G. , KNOTT P.J.
Published: July 2012

Changes of plasma unesterified fatty acid (UFA) and tryptophan concentration in group‐housed rats following removal of their cage‐mates and the effects of antilipolytic drugs on these changes were investigated.

Removal of group‐housed 24 h fasted rats but not fed rats from cages resulted in increased plasma UFA concentration in the remaining rats which was associated with significant increases of the proportion of free tryptophan but significant falls of total tryptophan concentration. These rapid changes were not associated with brain tryptophan changes. Plasma tyrosine concentration was unaffected.

The fall of plasma tryptophan did not appear to be due to passage into red cells as erythrocyte tryptophan concentration remained unchanged.

Plasma UFA concentrations correlated positively and significantly with corticosterone concentrations which were also increased following removal of cage‐mates.

Plasma UFA increases and tryptophan changes in the fasting rats were both prevented by nicotinic acid or propranolol. Corticosterone concentration was increased by nicotinic acid but unaffected by propranolol.

The possible importance of these rapid changes of plasma tryptophan and of their prevention by antilipolytic drugs is discussed.
AN ELECTROPHYSIOLOGICAL ANALYSIS OF THE EFFECT OF Ca IONS ON NEUROMUSCULAR TRANSMISSION IN THE MOUSE VAS DEFERENS
Authors: BENNETT M.R. , FLORIN T.
Published: July 2012

A study has been made of the effects of changing the external calcium concentration [Ca] 0 and the external magnesium concentration [Mg] 0 on the synaptic potential due to noradrenaline release.

When [Ca] 0 was varied in the range 0.7 to 1.8 mM, the synaptic potential increased as about the second power of [Ca] 0.

Increasing [Mg] 0 depressed the synaptic potential; however, variation of [Ca] 0 in the presence of high [Mg] 0 did not significantly change the power relationship between the synaptic potential and [Ca] 0.

The facilitated increase in the synaptic potential during short trains of impulses at different frequencies was quantitatively predicted on the assumption that each impulse leaves residual Ca ions bound to release receptors in the nerve terminal.
INTERACTION OF MONO‐ AND DIVALENT METALLIC CATIONS AND OF INDOMETHACIN ON THE MEMBRANE POTENTIAL OF VASCULAR ENDOTHELIAL CELLS in vitro
Authors: NORTHOVER B.J.
Published: July 2012

Endothelial cells depolarized progressively when heated for 5 h at 45° C in the presence of calcium (1 mM), cupric (0.08 mM) or ferrous (0.04 mM) ions. In the absence of these ions, heating caused only slight depolarization. Higher concentrations of these ions caused depolarization even at normal body temperature (37° C).

Cuprous and potassium ions, although producing depolarization at 37° C, failed to augment the depolarization due to heating to 45° C.

Hydrogen peroxide caused depolarization which was potentiated by the presence of calcium, cupric or ferrous ions, but not by the presence of cuprous or potassium ions.

Indomethacin (0.25 mM) reduced the depolarization caused by calcium, cupric or ferrous ions at 37° C and also reduced the potentiation of heat‐induced and hydrogen peroxide‐induced depolarization which these divalent metallic cations produced. However, indomethacin failed to modify the depolarization caused by cuprous or potassium ions.
FORECASTING THE ANTIMALARIAL ACTIVITIES OF ARYLAMIDINOUREAS FROM THEIR MEASURED PHYSICOCHEMICAL PROPERTIES
Authors: GILBERT D. , GOODFORD P.J. , NORRINGTON F.E. , WEATHERLEY B.C. , WILLIAMS S.G.
Published: July 2012

The octanol: water partition coefficient (PC), protein binding coefficients to albumin (Ba) and haemoglobin (Bh), proton magnetic resonance (PMR) chemical shifts and pKa of 8 arylamidinoureas have been measured.

There were statistically significant correlations for 7 of the 8 compounds between the predicted lipophilicity parameter π and log PC, Ba and Bh, and also between Hammett's electronic parameter π and the PMR and pKa observations.

3‐Chloro, 4‐nitrophenylamidinourea showed a larger deviation from these correlations than any other compound. Geometric calculations based on the covalent radii and bond angles of the molecule suggested that the neighbouring chloro and nitro substituents were interacting sterically.

Molecular orbital calculations and the observed ultra‐violet spectrum provided further evidence for such an interaction, and suggested that the nitro group is twisted out of the plane of the benzene ring in this molecule.

Such steric interactions can introduce an additional source of error when attempts are made to correlate the biological and predicted physicochemical properties of compounds.

Generalized parameters such as π and π cannot be used with confidence to predict the properties of compounds in which such steric interactions occur.
STUDIES UPON THE MECHANISM BY WHICH ACETYLCHOLINE RELEASES SURPLUS ACETYLCHOLINE IN A SYMPATHETIC GANGLION
Authors: COLLIER B. , KATZ H.S.
Published: July 2012

Acetylcholine (ACh) releases surplus ACh from the superior cervical ganglion of the cat and the experiments described in this paper tested whether this results from exchange of endogenous ACh with exogenous ACh; the experiments also attempted to characterize pharmacologically the mechanism of this action of ACh.

The surplus ACh in the ganglion was radioactively labelled by perfusion of the ganglion with [3H]‐choline‐Krebs solution containing diisopropylphosphofluoridate, and the release of surplus [3H)‐ACh by [14C]‐ACh injected close arterially to the ganglion measured. The amount of [3H]‐ACh released by [14C]‐ACh was 33 ± 5 times greater than was the amount of [14C]‐ACh accumulated by ganglia. The amount of exogenous ACh accumulated by ganglia that had first formed surplus ACh was not different from exogenous ACh accumulation by ganglia that had not formed surplus ACh. Thus, it is concluded that surplus ACh release by ACh is not the result of ACh exchange.

In other experiments, surplus [3H]‐ACh was accumulated in ganglia exposed to physostigmine. Nicotine, pilocarpine or ACh released surplus ACh; the effect of both nicotine and ACh was blocked by hexamethonium; atropine blocked the effect of ACh but not that of nicotine. It is concluded that both nicotinic and muscarinic receptors can be involved in the release of surplus ACh by cholinomimetic agonists.
EFFECTS OF DRUGS ACTING ON CEREBRAL 5‐HYDROXYTRYPTAMINE MECHANISMS ON DOPAMINE‐DEPENDENT TURNING BEHAVIOUR IN MICE
Authors: MILSON J.A. , PYCOCK C.J.
Published: July 2012

The effects of drugs acting on cerebral 5‐hydroxytryptaminergic mechanisms on drug‐induced turning behaviour in mice with unilateral destruction of nigro‐striatal dopaminergic nerve terminals have been studied.

Administration of l‐tryptophan (400 mg/kg) or 5‐hydroxytryptophan (200 mg/kg) increased brain 5‐hydroxytryptamine and decreased the turning induced by both apomorphine (2 mg/kg) and amphetamine (5 mg/kg).

Parachlorophenylalanine (3 × 500 mg/kg) decreased brain 5‐hydroxytryptamine and increased both apomorphine and amphetamine‐induced circling behaviour.

Varying the protein content of dietary intake significantly altered brain 5‐hydroxytryptamine and tryptophan levels, spontaneous locomotor activity and amphetamine‐induced circling behaviour in these mice.

Systemic administration of methysergide (0.5–4 mg/kg), lysergic acid diethylamide (0.025‐0.2 mg/kg), cyproheptadine (2.5–20 mg/kg) or clomipramine (0.6–20 mg/kg) produced no consistent effect on drug‐induced turning behaviour.

The results suggest that circling behaviour due to striatal dopamine receptor stimulation is depressed by an elevation of brain 5‐hydroxytryptamine and enhanced by a reduction in brain 5‐hydroxytryptamine.

The possible physiological relationship between dopamine and 5‐hydroxytryptamine neurones in the basal ganglia is discussed.
THE EFFECT OF LITHIUM CHLORIDE ON ONE‐TRIAL PASSIVE AVOIDANCE LEARNING IN RATS
Authors: JOHNSON F.N.
Published: July 2012

Expression of a one‐trial passive avoidance learning response in rats was examined following injections of lithium chloride or sodium chloride before and after initial training and before the first day of testing. Five tests were given at daily intervals, 24 h after training being the time of the first test.

Lithium given before the first day of testing impaired response expression on the first and all subsequent days of testing; the rate of extinction was unaffected.

Given both before and immediately after initial training, lithium impaired response expression on the first day of testing but slowed down the subsequent rate of extinction, leading eventually to improved performance on the fifth day, as compared with placebo‐treated control subjects.

The results are interpreted in the light of the hypothesis that lithium impaired the central processing of sensory information.
THE EFFECT OF EDROPHONIUM ON ERYTHROCYTE ACETYLCHOLINESTERASE AND NEUROMUSCULAR FUNCTION IN THE RAT
Authors: BARBER H.E. , CALVEY T.N. , MUIR K.T. , TAYLOR K.
Published: July 2012

The relation between the concentration of edrophonium in plasma, inhibition of red cell acetylcholinesterase, and neuromuscular transmission was studied in the rat.

In both in vivo and in vitro conditions, red cell acetylcholinesterase activity was predictably related to the concentration of the quaternary amine.

After low doses of edrophonium (1.0 μmol/kg) there was a significant correlation between the monophasic potentiation of twitch tension and the plasma concentration of the drug. In contrast, with higher doses of edrophonium (4.0 or 10.0 μmol/kg) a biphasic potentiation of twitch tension was observed; this was only correlated with the plasma concentration of the drug during the secondary decline in neuromuscular facilitation. Subsequent recovery of normal neuromuscular transmission invariably occurred at a constant plasma concentration of edrophonium.
EFFECT OF ATROPINE ON THE DECAY OF MINIATURE END‐PLATE CURRENTS AT THE FROG NEUROMUSCULAR JUNCTION
Authors: FELTZ ANNE , LARGE W.A.
Published: July 2012

The effect of atropine on the time constant of decay (τ) of miniature end‐plate currents was investigated.

The atropine‐induced shortening of τ was accompanied by a reduction in the voltage‐sensitivity of τ.

This effect of atropine was reversible and dose‐dependent, the voltage sensitivity being abolished with high concentrations of atropine (2.5 × 10−5 m).
METABOLISM OF PHENYLETHYLAMINE IN RAT ISOLATED PERFUSED LUNG: EVIDENCE FOR MONOAMINE OXIDASE ‘TYPE B’ IN LUNG
Authors: BAKHLE Y.S. , YOUDIM M.B.H.
Published: July 2012

Phenylethylamine is inactivated in a single passage through rat lung tissue by a process of uptake and deamination by a monoamine oxidase ‘type B’. This enzyme is particularly susceptible to inhibition by deprenil and less sensitive to clorgyline. The monoamine oxidase of the lung, like that of other rat tissues, can be differentiated into ‘type A’ and ‘type B’ which appear to operate independently in the organized tissue.
A NOTE ON THE EFFECT OF DITHIOTHREITOL (DTT) ON THE DEPOLARIZATION OF ISOLATED SYMPATHETIC GANGLIA BY CARBACHOL AND BROMO‐ACETYLCHOLINE
Authors: BROWN D.A. , KWIATKOWSKI D.
Published: July 2012

The S‐S reducing agent, dithiothreitol (DTT) altered the properties of nicotinic receptors in rat superior cervical ganglia such that (i) carbachol became less active as a depolarizing agent and (ii) bromo‐acetylcholine produced an irreversible depolarization. The latter was temporarily annulled by hexamethonium (which retained antagonist properties), but returned when hexamethonium was removed. It is concluded that ganglionic nicotinic receptors might be quite similar to those for mono‐quaternary agonists in leech dorsal muscle.
LITHIUM OROTATE, CARBONATE AND CHLORIDE: PHARMACOKINETICS, POLYDIPSIA AND POLYURIA IN RATS
Authors: SMITH D.F.
Published: July 2012

The pharmacokinetics of the lithium ion administered as lithium orotate were studied in rats. Parallel studies were carried out with lithium carbonate and lithium chloride.

No differences in the uptake, distribution and excretion of the lithium ion were observed between lithium orotate, lithium carbonate and lithium chloride after single intraperitoneal, subcutaneous or intragastric injections (0.5‐1.0 mEq lithium/kg) or after administration of the lithium salts for 20 days in the food.

The findings oppose the notion that the pharmacokinetics of the lithium ion given as lithium orotate differ from lithium chloride or lithium carbonate.

Polyuria and polydipsia developed more slowly in rats given lithium orotate than in those given lithium carbonate or lithium chloride, perhaps due to an effect of the orotate anion.
ISOTONIC AND ISOMETRIC RESPONSES OF DIFFERENTTONIC MUSCLES TO AGONISTS AND ANTAGONISTS
Authors: MICHELSON M.J. , SHELKOVNIKOV S.A.
Published: July 2012

With isotonic recording the percentage of muscle shortening as compared with the maximal possible shortening, and with isometric recording the percentage of developed tension were determined. In relatively ‘thick’ muscles, such as dorsal leech muscle, frog rectus abdominis or protractor pharynx of holothuria (0.3‐0.8 mm thick), the concentrations of a full agonist (carbachol) producing a given percentage of tension, (e.g. 50%) are about 5 times greater than the concentrations, producing the same percentage of shortening. In ‘thin’ muscles the difference between the percentage of shortening and tension is either small (retractor dentis of the sea urchin, 0.1 mm thick, response to carbachol) or absent (guinea‐pig ileum, 0.06 mm thick, responses to methylfurmethide). The possible mechanism underlying this difference is discussed.

With partial agonists (dodecamethonium and heptamethonium) the fractional tension of the frog rectus abdominis is always less than the fractional shortening and the correlation between shortening and tension is the same as in the case of full agonists.

The blocking activity of (+)‐tubocurarine on the frog rectus abdominis is the same in isotonic and in isometric conditions.

On the frog rectus abdominis the alkylating agent, decamethonium mustard, does not produce any ‘parallel shift’ of the dose‐response curve for carbachol, the only result of alkylation being a decrease in maximal response, which is more pronounced in isometric than in isotonic conditions. The degree of decrease is in accordance with the correlation between percentage of shortening and percentage of tension in the absence of alkylating agent. Probably this muscle does not possess any ‘spare receptors’.

On the frog muscle the dose‐isometric response curve for acetylcholine (ACh) is shifted toward greater concentration about 33‐fold as compared with the dose‐isotonic response curve but after the inhibition of cholinesterases the shift is only about 6‐fold. The same shift (5‐fold) is observed for carbachol, which is not hydrolysed by cholinesterases. The results with ACh are due to the fact, that after cholinesterase inhibition the sensitivity to ACh increases in isotonic conditions only 13‐fold, but in isometric conditions it increases 71‐fold. Probably under isometric conditions, when the muscle remains in the extended state, the rate of hydrolysis of ACh is much greater than under isotonic conditions when the muscle is shortened during contraction.
PROSTAGLANDIN PRODUCTION BY RABBIT ISOLATED JEJUNUM AND ITS RELATIONSHIP TO THE INHERENT TONE OF THE PREPARATION
Authors: FERREIRA S.H. , HERMAN A.G. , VANE J.R.
Published: July 2012

Pieces of rabbit jejunum were bathed in Krebs solution at 37°C in an isolated organ bath bubbled with O2 and 5% CO2. The bathing fluid was collected regularly and assayed for prostaglandins.

The preparations maintained a continuous sub‐maximal muscle contraction, referred to as inherent ‘tone’. Prostaglandins E2 and F2α were continuously generated by the intestine and released into the bathing fluid. The amounts released first declined over 2 h and then steadily increased. The release was also greater after 48 h storage in the refrigerator and after mechanical damage.

There was no change in prostaglandin release when the rabbit jejunum was contracted by acetylcholine or physostigmine or relaxed by adrenaline, hyoscine, papaverine, dinitrophenol, or calcium‐free Krebs solution.

Addition to the bathing fluid of the prostaglandin precursor, arachidonic acid, did not increase the release of prostaglandins although it contracted the tissue. Thus, output of prostaglandins from the tissue was not limited by substrate concentration but more probably by the capacity of the prostaglandin synthetase.

Prostaglandin output was decreased by bubbling the bathing fluid with N2 rather than O2; at the same time the preparation relaxed.

Aspirin‐like drugs such as indomethacin also decreased or abolished prostaglandin formation and this, too, was accompanied by loss of tone of the isolated preparation.

Pieces of rabbit jejunum stored in Krebs solution containing indomethacin initially released little or no prostaglandin into the bathing fluid. However, prostaglandin release increased with repeated washing of the preparation.

The results suggest that intra‐mural prostaglandin production contributes to the inherent tone of the rabbit jejunum, that trauma increases prostaglandin production and that the inhibitory effects of anoxia are linked with the lack of prostaglandin production and activity. The relevance of these findings to intestinal activity in vivo is discussed.
THE EFFECT OF QUINIDINE ON MEMBRANE ELECTRICAL ACTIVITY IN FROG AURICULAR FIBRES STUDIED BY CURRENT AND VOLTAGE CLAMP
Authors: DUCOURET P.
Published: July 2012

The action of quinidine sulphate 50 μm has been investigated on frog auricular trabeculae transmembrane currents recorded with a double sucrose gap apparatus. Results were obtained either in current or in voltage clamp conditions.

Quinidine modified the time course of repetitive activity elicited by long lasting depolarizing currents and reduced the range of current over which repetitive activity could be triggered, eventually abolishing repetitive responses altogether.

Several authors have emphasized the limitations of the voltage clamp method. Taking into account these limitations, the numerical values of the parameters obtained in the present work must not be considered as exact values but may be interpreted as indicators of the variations of the parameters.

The results are in agreement with previous findings that the main features of the action of quinidine are to produce (a) a reduced maximum rate of depolarization (MRD), (b) a reduced total amplitude of action potential, (c) a flattening of the plateau of the action potential, (d) a slight prolongation of the tail of the action potential, (e) an increased effective refractory period without greatly prolonging action potential duration, (f) no change of resting potential and of 50% repolarization time.

The analysis of ionic conductances has provided explanations for the above effects.

Quinidine reduced the reactivation kinetics of the sodium inward current, and decreased sodium conductance and the steady state of activation. These effects account for (a) and (b).

Quinidine increased the activation and inactivation time constants of sodium conductances, which account in part for (e).

Quinidine delayed reactivation of slow inward current, reduced calcium conductance, and decreased the steady state of activation of calcium conductance. These effects could account for (c).

The amplitudes of the two components of the delayed conductances responsible for repolarization were decreased by quinidine, and the time constant of activation for the faster of the two was slowed. These effects could account for (d) and in part for (e).
ANALYSIS OF THE EFFECTS OF p‐METHOXY‐PHENYLETHYLAMINE ON SPINAL CORD NEURONES
Authors: JORDAN L.M. , McCREA D.A.
Published: July 2012

Para‐methoxyphenylethylamine (PMPEA) was applied microiontophoretically onto interneurones and motoneurones in the spinal cords of acute spinal cats anaesthetized with α‐chloralose. Its effects were compared with those of noradrenaline (NA) and 5‐hydroxytryptamine (5‐HT).

PMPEA had effects on interneurones which were similar to those of NA and/or 5‐HT; its action was predominantly depressant, and it rarely affected interneurones which could not be influenced by NA or 5‐HT.

The actions of PMPEA on interneurones excited by electrical stimulation of leg nerves showed that the population of interneurones influenced by the drug coincides with the population affected by NA and 5‐HT and by intravenously administered PMPEA.

Renshaw cells, which are excited by intravenous PMPEA, were either not affected or depressed by microiontophoretically applied PMPEA.

Alpha motoneurones, which are depolarized by intravenous PMPEA, were hyperpolarized by microiontophoretically applied PMPEA. Antidromic firing of the cells could be blocked by PMPEA.

The differences between the effects of intravenous infusion and the iontophoretic application of PMPEA upon motoneurones is most easily explained by inhibition of interneurones and a concomitant disinhibition of motoneurones. A similar mechanism may also account for the different effects seen with intravenous and iontophoretic application of PMPEA on Renshaw cells.
EFFECTS OF SEVERAL INHALATION ANAESTHETICS ON THE KINETICS OF POSTSYNAPTIC CONDUCTANCE CHANGES IN MOUSE DIAPHRAGM
Authors: GAGE P.W. , HAMILL O.P.
Published: July 2012

Miniature endplate currents were recorded with extracellular electrodes in mouse diaphragms in order to measure the kinetics of the conductance change produced by acetylcholine. Miniature endplate potentials (m.e.p.ps) were recorded intracellularly in the same fibres in which the currents were being recorded.

The general anaesthetics, ether, halothane, chloroform and enflurane at low (anaesthetic) concentrations increased the rate of decay of miniature endplate currents (m.e.p.cs) and reduced the amplitude of m.e.p.ps in this way.

At high concentrations the anaesthetics caused a reduction in the amplitude of both m.e.p.cs and m.e.p.ps, and a decrease in the rate of decay of the currents. With halothane and enflurane the decay of some currents became biphasic, with a prolonged tail.

It was proposed that the increased rate of decay of the conductance caused by the four agents at anaesthetic concentrations is due to an increase in the fluidity of the subsynaptic membrane. Prolongation of the currents at higher concentrations may be caused by an increase in membrane dielectric constant.

The effectiveness of the four anaesthetics in producing a 30% decrease in the time constant of decay of m.e.p.cs was shown to be related to their oil/water partition coefficients and followed closely the relationship between anaesthetic potency and oil/water partition coefficient. It is suggested therefore that the four anaesthetics may produce anaesthesia by changing the kinetics of postsynaptic conductance changes at synapses, perhaps by increasing membrane fluidity.
INHIBITION OF PERISTALSIS IN GUINEA‐PIG ISOLATED ILEUM AND COLON BY DRUGS THAT BLOCK PROSTAGLANDIN SYNTHESIS
Authors: BENNETT A. , ELEY K.G. , STOCKLEY HELEN L.
Published: July 2012

Methods of analysing peristaltic activity have been evaluated by the use of recordings of longitudinal and circular muscle activity and of propulsion in whole segments of guinea‐pig ileum and colon.

Some prostaglandin synthesis inhibitors, and antagonists of prostaglandin action were tested for their suitability for studying the role of prostaglandins in peristalsis. Aspirin was suitable; at 10–200 μg/ml it had little effect on responses of longitudinal muscle strips of the guinea‐pig ileum to acetylcholine (ACh), histamine, nicotine or prostaglandin E2. Indomethacin (1–4 μg/ml) reduced responses to nicotine and prostaglandin E2. The prostaglandin antagonists polyphloretin phosphate and SC‐19220 reduced contractions of ileal longitudinal muscle caused by nerve excitation with either nicotine or transmural stimulation.

Aspirin (20–100 μg/ml) or indomethacin (1–4 μg/ml) applied serosally greatly inhibited all aspects of peristalsis in guinea‐pig ileum and colon. Inhibition of peristalsis of the ileum by aspirin was antagonized by prostaglandin E2 and that by indomethacin was removed by prostaglandin F2α or ACh. Inhibition of colonic peristalsis by aspirin was antagonized by prostaglandin E2 but rarely by ACh, and that by indomethacin by prostaglandin E1 or E2. Mucosal application of aspirin had little effect on either ileum or colon but indomethacin caused some inhibition.

These results support the supposition that prostaglandins contribute to peristaltic activity.
A COMPARATIVE STUDY OF THE ACTION OF γ‐AMINOBUTYRIC ACID AND PIPERAZINE ON THE LOBSTER MUSCLE FIBRE AND THE FROG SPINAL CORD
Authors: CONSTANTI A. , NISTRI A.
Published: July 2012

The effects of γ‐aminobutyric acid (GABA) and piperazine were compared on two in vitro preparations, the lobster muscle fibre and the frog spinal cord.

Both GABA and piperazine increased the membrane conductance of single lobster muscle fibres without changing the membrane potential; sigmoidal log dose‐conductance curves for these agents were obtained and a similar model expressed the receptor interaction of both substances.

The actions of GABA and piperazine on lobster muscle were antagonized by picrotoxin and were Cl−‐dependent.

In the frog spinal cord GABA depolarized the dorsal roots presumably by mimicking the activity of the transmitter depolarizing the primary afferents; sigmoidal log dose‐response curves for GABA were obtained.

On the dorsal roots piperazine produced either depolarizations or biphasic responses; these were mainly indirect effects as was shown by experiments in the presence of tetrodotoxin (TTX).

The effects of GABA on the dorsal root (in TTX‐treated cords) were antagonized by picrotoxin whereas those of piperazine were more resistant to this alkaloid. The GABA‐induced responses appeared to be largely Na+‐dependent while both Na+ and Cl− seemed to mediate the effects of piperazine.

It is proposed that piperazine has GABA‐agonist activity on lobster muscle but little GABA‐like activity on the frog spinal cord.
A COMPARATIVE STUDY OF THE EFFECTS OF GLUTAMATE AND KAINATE ON THE LOBSTER MUSCLE FIBRE AND THE FROG SPINAL CORD
Authors: CONSTANTI A. , NISTRI A.
Published: July 2012

The depolarizing actions of glutamate and its conformationally restricted analogue kainate were investigated on the lobster muscle fibre and the frog spinal cord using intracellular and extracellular recordings, respectively.

Bath‐applied kainate was less potent than glutamate on the lobster fibre but more potent on the frog cord. From the log‐log transformation of dose‐response curves it was proposed that more than one glutamate molecule was necessary to activate both the lobster and the frog receptor sites. In the frog, at least three kainate molecules were thought to be required for receptor activation.

The ionic dependence of glutamate and kainate responses appeared different for the two tissues.

Some possible explanations of the differential tissue sensitivity to kainate are discussed.