bluuebunny/crossref_metadata_2025 huggingface dataset:
INCREASED CENTRAL 5‐HYDROXTRYPTAMINE RECEPTOR MECHANISMS IN RATS AFTER CHRONIC NEUROLEPTIC TREATMENT
Authors: DAWBARN D. , LONG S.K. , PYCOCK C.J.
Published: July 2012

The behavioural responses of drugs known to act through central 5‐hydroxytryptamine (5‐HT) mechanisms have been investigated in rats receiving a neuroleptic (trifluoperazine) in their drinking water for 4 to 6 months.

5‐Hydroxytryptophan (5‐HTP) induced 5‐HT‐dependent behaviours including head bobbing and lateral head weaving, reciprocal forepaw treading, tremor, backward walking, body writhing and ‘wet‐dog’ shakes. In doses of 50 to 150 mg/kg, 5‐HTP induced more intense behavioural effects in neuroleptic‐treated rats than in the control animals.

Similarly the putative 5‐HT agonist, quipazine (1 to 20 mg/kg) and the 5‐HT releasing drug, fenfluramine (5 to 20 mg/kg), both induced significantly greater motor responses in the chronically neuroleptic‐treated rats.

A 5‐HT uptake inhibitor (femoxetine, 2.5 to 10 mg/kg) had little behavioural effect in either control or trifluoperazine‐treated rats.

Total specific high‐affinity binding of radiolabeled 5‐HT was significantly increased in crude membrane fractions prepared from the cortex, striatum and substantia nigra of neuroleptic‐treated rats compared to control animals.

High‐affinity uptake of radiolabeled 5‐HT into striatal slices was similar in experimental and control animals.

Behavioural and biochemical data would indicate that postsynaptic 5‐HT mechanisms are enhanced in rats treated chronically with trifluoperazine. Chronic neuroleptic therapy may thereby induce cerebral 5‐HT receptor supersensitivity in addition to the well‐documented cerebral dopamine receptor supersensitivity.
THE EFFECTS OF THE SUBCUTANEOUS INJECTION OF THE CRUDE VENOM OF THE AUSTRALIAN COMMON BROWN SNAKE, Pseudonaja textilis ON THE SKELETAL NEUROMUSCULAR SYSTEM
Authors: HARRIS J.B. , MALTIN C.A.
Published: July 2012

The effects of the crude venom of the Australian common brown snake on the mammalian neuromuscular system have been investigated.

The venom was injected subcutaneously into the dorso‐lateral aspect of one hind limb of the rat. The limb was paralysed within 90 min and remained paralysed for 2 to 3 days.

The exposed muscles failed to respond to indirect excitation, and individual fibres were not depolarized at the nerve‐muscle junction by exposure to carbachol.

The wet weight, histological appearance, resting potential and input resistance of the muscle fibres and their ability to generate directly elicited action potentials were unaffected by exposure to the venom.

Administration of venom to isolated preparations caused a reduction in the amplitude of miniature endplate potentials, with no change in frequency. The quantal content of evoked endplate potentials was unchanged.

It was concluded that the crude venom was largely devoid of presynaptic activity and myotoxicity, and that its primary site of neurotoxicity was directed to the postsynaptic membrane.
SOME PHARMACOLOGICAL STUDIES ON THE SPASTIC MOUSE
Authors: BISCOE T.J. , FRY J.P.
Published: July 2012

Full‐wave rectification and integration of the EMG signal recorded from the hamstring muscles of the spastic mouse was used to evaluate the actions of a variety of drugs on the muscle rigidity of these mutants, animals in which no histological lesion has yet been found.

Profound and long‐lasting muscle relaxant responses were consistently observed upon the injection of diazepam (2 mg/kg, i.p.) and flunitrazepam (2 mg/kg, i.p.). Such responses were always greater than those obtained upon injection of 40% (v/v) propylene glycol (10 ml/kg) alone, the vehicle for the benzodiazepines.

The muscle relaxant action of a low dose (0.25 mg/kg, i.p.) of the benzodiazepine Roll‐6896 was not shared by the same dose of its enantiomer Roll‐6893.

Profound and long‐lasting muscle relaxation was caused by sodium valproate (696 mg/kg, i.p.). Consistent muscle relaxant responses were also observed upon the injection of pentobarbitone (30 mg/kg, i.p.), but not phenobarbitone (30 mg/kg, i.p.).

Other drugs that had little or no detectable effect on the muscle rigidity of the spastic mouse included diphenylhydantoin (30 mg/kg, i.p.) and bromocriptine (10 mg/kg, s.c.) while, in some animals, benztropine (2 mg/kg, i.p.) and baclofen (10 mg/kg, i.p.) increased muscle rigidity.

The development of full muscle relaxant responses to flunitrazepam (2 mg/kg, i.p.) and to sodium valproate (696 mg/kg, i.p.) was shown to depend upon mild warming of the animals with radiant heat, a procedure which can increase muscle spindle afferent input to the spinal cord.

The results suggest a hyperactivity of stretch reflexes in the spastic mouse, ameliorated selectively by those drugs that enhance the GABA‐mediated presynaptic inhibition of such pathways.
ANDROGEN‐INDUCED SEXUAL DIMORPHISM IN HIGH AFFINITY DOPAMINE BINDING IN THE BRAIN TRANSCENDS THE HYPOTHALAMIC‐LIMBIC REGION
Authors: JALILIAN‐TEHRANI MOHAMMAD H. , KARAKIULAKIS GEORGE , LE BLOND CHRISTINE B. , POWELL RUTH , THOMAS PATRICK J.
Published: July 2012

High affinity binding of [3H]‐dopamine and [3H]‐5‐hydroxytryptamine ([3H]‐5‐HT) was measured in membrane fractions prepared from cerebral cortex, amygdala, hypothalamus, thalamus and brain stem of rats of either sex and of rats which had been either neonatally castrated or androgenized.

Binding was measured in rats of 8, 20 and 30 days old as well as in adults.

[3H]‐dopamine bound with approximately 30 nm affinity and [3H]‐5‐HT with approximately 10 nm affinity to all areas of the brain tested. The relative inhibitory effects of haloperidol, apomorphine, cis‐flupenthixol, unlabelled dopamine, noradrenaline, spiroperone, (+)‐butaclamol, fluphenazine, pimozide and 5‐HT on [3H]‐dopamine binding in the cerebral cortex was consistent with receptor status for the binding components there as were the relative inhibitory effects of methysergide, dopamine, fluoxetine and ouabain on [3H]‐5‐HT binding in the fore brain.

Neither [3H]‐dopamine nor [3H]‐5‐HT binding varied with the state of the sexual cycle in females.

There were no sexual differences in [3H]‐5‐HT binding in any of the brain areas tested nor was it affected by neonatal androgenization or neonatal castration.

[3H]‐dopamine binding was greater in the cerebral cortex and amygdala of male than of female rats. These differences could be mimicked artificially by neonatal castration of males (female type development) or neonatal androgenization of females (male type development). Sexual dimorphism did not become overt until 20 days of age and did not extend to hypothalamus, thalamus or brain stem.

It is concluded that neonatal sex differences in exposure to steroid hormones has permanent effects on the number of dopamine binding sites in the cerebral cortex and is suggested that this sexual dimorphism extends to the amygdala.
THE EFFECTS OF A SERIES OF ω‐PHOSPHONIC α‐CARBOXYLIC AMINO ACIDS ON ELECTRICALLY EVOKED AND EXCITANT AMINO ACID‐INDUCED RESPONSES IN ISOLATED SPINAL CORD PREPARATIONS
Authors: EVANS R.H. , FRANCIS A.A. , JONES A.W. , SMITH D.A.S. , WATKINS J.C.
Published: July 2012

The depressant actions on evoked electrical activity and the excitant amino acid antagonist properties of a range of ω‐phosphonic α‐carboxylic amino acids have been investigated in the isolated spinal cord preparations of the frog or immature rat.

When tested on dorsal root‐evoked ventral root potentials, members of the homologous series from 2‐amino‐5‐phosphonovaleric acid to 2‐amino‐8‐phosphonooctanoic acid showed depressant actions which correlated with the ability of the substances to antagonize selectively motoneuronal depolarizations induced by N‐methyl‐d‐aspartate.

2‐Amino‐5‐phosphonovalerate was the most potent substance of the series giving an apparent KD of 1.4 μm for the antagonism of responses to N‐methyl‐d‐aspartate.

A comparison of the (+)‐ and (—)‐forms of 2‐amino‐5‐phosphonovalerate indicated that the N‐methyl‐d‐aspartate antagonist activity and the neuronal depressant action of this substance were both due mainly to the (—)‐isomer.

The (—)‐ and (+)‐forms of 2‐amino‐4‐phosphonobutyrate had different actions. The (—)‐form of this substance had a relatively weak and non‐selective antagonist action on depolarizations induced by N‐methyl‐d‐aspartate, quisqualate and kainate and a similarly weak depressant effect when tested on evoked electrical activity. The (+)‐form was more potent than the (—)‐form in depressing electrically evoked activity but did not antagonize responses to amino acid excitants. At concentrations higher than those required to depress electrically evoked activity, the (+)‐form produced depolarization. This action was blocked by 2‐amino‐5‐phosphonovalerate.
THE EFFECT OF TUBOCURARINE COMPETITION ON THE KINETICS OF AGONIST ACTION ON THE NICOTINIC RECEPTOR
Authors: COLQUHOUN D. , SHERIDAN R.E.
Published: July 2012

The rates at which tubocurarine associates with, and dissociates from, the nicotinic receptor, while exerting its classical competitive effect, are still in doubt. We have investigated this problem by observing the effect of low concentrations of tubocurarine on the re‐equilibration rate, following a step change in membrane potential, of the current produced by carbachol in voltage‐clamped endplates of frog muscle.

It is expected, and observed, that in order to see the effects of competition (as opposed to ion channel block), sufficiently high agonist concentrations must be used so that the relaxation rate becomes faster than that seen at low agonist concentrations.

Small concentrations of tubocurarine were found to reduce this relaxation rate, towards a value appropriate to a lower agonist concentration.

The results suggest that tubocurarine equilibrates very rapidly with the nicotinic receptor.

Some of the possible technical problems of this sort of experiment are discussed. The results are similar to those already published for nicotinic receptors in eel electric tissue.
EVIDENCE FOR STEREOSPECIFICITY OF THE P1‐PURINOCEPTOR
Authors: BROWN C. , BURNSTOCK G. , CUSACK N.J. , MEGHJI P. , MOODY C.J.
Published: July 2012

The effects of adenosine, 5′‐N‐ethylcarboxamidoadenosine (NECA), 2‐chloroadenosine, 2‐azidoadenosine, and their l‐enantiomers were examined on driven left atria, trachea and transmurally stimulated ileum of the guinea‐pig.

In each tissue the order of potency of the d‐enantiomers for producing inhibitory effects was NECA > 2‐chloroadenosine > 2‐azidoadenosine > adenosine.

The log concentration‐response curve of each agonist was shifted to the right in the presence of the P1‐purinoceptor antagonist, theophylline.

Dipyridamole, which blocks adenosine uptake, potentiated the effects of adenosine but not those of the d‐enantiomers of adenosine analogues.

The greater potency of the adenosine analogues therefore, is at least partly due to their resistance to tissue uptake and subsequent enzymatic destruction.

The l‐enantiomers of adenosine and its analogues did not produce inhibitory responses in the driven left atria or transmurally stimulated ileum. At high concentrations relaxations of the tracheal muscle were obtained, with the potency series l‐NECA > 2‐chloro‐l‐adenosine > 2‐azido‐l‐adenosine > l‐adenosine.

It is concluded that the postsynaptic P1‐purinoceptors in the guinea‐pig atria and trachea and the presynaptic P1‐purinoceptors on cholinergic nerve terminals in guinea‐pig ileum are stereospecific for the d‐enantiomers of adenosine and its analogues.
CYTOCHROME P‐450‐DEPENDENT O‐DEALKYLASE ACTIVITY IN MAMMALIAN SKIN
Authors: DAMEN FRANK J.M. , MIER P.D.
Published: July 2012

A modified technique for the measurement of O‐dealkylase (ODA) activity in crude homogenates is reported, and its application to skin is described.

Large differences in ODA levels were found between different species, no activity being observed in the skin of primates.

Induction of cutaneous ODA in mice was achieved by the subcutaneous injection of phenobarbitone, hexachlorobenzene or 20‐methylcholanthrene.

Attempts to induce ODA in vitro were unsuccessful.
THE EFFECT OF INHIBITORS OF ARACHIDONIC ACID METABOLISM ON DRUG‐INDUCED CONTRACTIONS IN ISOLATED TRACHEAL SMOOTH MUSCLE OF THE PIG
Authors: MITCHELL H.W.
Published: July 2012

The regulation of drug‐induced tone in airways smooth muscle was examined in an isolated preparation of swine tracheal smooth muscle.

The trachea contracted (isometric) to histamine, 2‐pyridylethylamine (2‐PEA), acetylcholine and K+ but no responses to histamine H2‐receptor agonists were observed.

Histamine‐induced contractions (100 μm) were potentiated by 213.3% by indomethacin (1 μm) and by 126.9% by sodium salicylate (250 μm). These inhibitors had only slight or no effects on acetylcholine‐induced tone. 2‐PEA responses were also potentiated by indomethacin but there were no changes in the response to H2‐receptor agonists in the presence of indomethacin. The indomethacin‐mediated potentiation of histamine was blocked by 5, 8, 11, 14‐eicosatetraynoic acid (10 μm). FPL 55712 had no effect on these responses.

Mepacrine (100 μm) inhibited responses to histamine but not those to acetylcholine. No effect was observed with dexamethasone (up to 100 μm).

Prostaglandin E2 caused relaxation but arachidonic acid did not.

The possibility that histamine H1‐agonist‐induced contractions are regulated by contractile products of the arachidonic acid lipoxygenase pathway is discussed.
STIMULATION OF RENIN RELEASE BY 6‐OXO‐PROSTAGLANDIN E1 AND PROSTACYCLIN
Authors: MCGIFF JOHN C. , SPOKAS ERIC G. , WONG PATRICK Y‐K
Published: July 2012

Renin release induced by 6‐oxo‐prostaglandin E1 (6‐oxo‐PGE1) was compared to release in response to prostacyclin (PGI2) and 6‐oxo‐PGF1α in slices of rabbit renal cortex.

Krebs‐Ringer medium bathing slices of renal cortex was collected for renin assay after four successive 20 min intervals (periods I‐IV). Renin release did not increase during periods I to IV in untreated slices. Agonists were added, only once, at the beginning of period III. Between periods III and IV, the incubation solution was aspirated and replaced with fresh medium.

PGI2 increased renin release during period III while 6‐oxo‐PGE1 stimulated release during periods III and IV. 6‐oxo‐PGE1 stimulated renin release (24%–74%) in concentrations ranging from 1–33 μm while PGI2 stimulated release at 10 μm (60%) but not at 5 μm. 6‐oxo‐PGF1α, 10 μm, did not release renin during period III (period III, 9%), but caused a small rise in period IV (29%).

6‐oxo‐PGE1, unlike PGI2, was stable under the incubation conditions (pH 7.4, 37°C) as indicated by recovery of undiminished platelet anti‐aggregatory material after 20 min.

In the rabbit kidney, activity of 9‐hydroxyprostaglandin dehydrogenase was greatest in the cortex and negligible in the papilla, corresponding to the zonal distribution of renin.

The prominent and sustained in vitro renin releasing effect of 6‐oxo‐PGE1, as well as the cortical localization of enzyme activity capable of generating this stable prostacyclin metabolite, suggest that formation of 6‐oxo‐PGE1 may contribute to PGI2‐induced renin release and may explain the delayed stimulation caused by 6‐oxo‐PGF1α.
THE ACTION OF GANGLIONIC BLOCKING DRUGS ON THE SYNAPTIC RESPONSES OF RAT SUBMANDIBULAR GANGLION CELLS
Authors: RANG H.P. , COLQUHOUN D. , RANG H.P.
Published: July 2012

The effects of tubocurarine, hexamethonium and trimetaphan on the synaptic currents of rat submandibular ganglion cells have been measured at 20°C by means of a two‐microelectrode voltage‐clamp system. The aim was to distinguish between the receptor‐blocking and channel‐blocking actions of those drugs, and to test for possible selectivity of action on the ‘fast’ and ‘slow’ acetylcholine‐operated channels.

Tubocurarine had no effect on the amplitude of evoked synaptic currents (e.s.cs) or miniature synaptic currents (m.s.cs), except at concentrations exceeding 20 μm. The slow component of the e.s.c. was shortened by tubocurarine, this effect becoming more marked as the cell was hyperpolarized. The timecourse of m.s.cs, which have no slow component, was unaffected.

Hexamethonium (2–30 μm) caused a voltage‐dependent reduction of e.s.c. amplitude, and voltage‐dependent shortening of both fast and slow components of the e.s.c. M.s.cs were also shortened.

Trimetaphan (2–10 μm) reduced the amplitude of e.s.cs and m.s.cs. Neither component of the e.s.c. was shortened by trimetaphan; however, the slow component was reduced in amplitude more than the fast component, so that the overall duration of the e.s.c. appeared to be reduced. At higher concentrations (15–25 μIM) trimetaphan clearly shortened the fast component.

It is concluded that tubocurarine acts selectively on the slow ionic channels, the association rate constant being 2.8 × 106 m−1 s−1 at −80mV. Hexamethonium acts on both fast and slow channels, the association rate constants, at — 80 mV, being respectively 5.3 × 106 m−1 s−1 and 1.3 × 107 m−1 s−1. With both drugs, the association rate constant increases if the cell is hyperpolarized, this effect being more pronounced with hexamethonium than with tubocurarine.

The marked voltage‐dependent reduction of e.s.c. amplitude by hexamethonium cannot be accounted for by open channel block, and requires an additional mechanism, the nature of which is discussed.

Trimetaphan, at low concentrations, acts in a way consistent with receptor block, and shows a degree of selectivity for the slow component of the e.s.c.

In an appendix, the effect of temporal dispersion of the time of opening of ionic channels on the amplitude and time‐course of the composite synaptic response is analysed. It is concluded that the shortening of the time‐constant of the e.s.c. decay by hexamethonium cannot, by itself, account for the drug's effect on e.s.c. amplitude.
THE HUMAN ERYTHROCYTE Cl‐DEPENDENT Na‐K COTRANSPORT SYSTEM AS A POSSIBLE MODEL FOR STUDYING THE ACTION OF LOOP DIURETICS
Authors: ELLORY J.C. , STEWART G.W.
Published: July 2012

The recent demonstration of the chloride‐dependence of the red cell Na‐K cotransport system suggests an analogy between this process and the active Cl− absorption in the ascending loop of Henle, which is the target transport system for loop diuretics.

Using red cell K influx, four known loop diuretics, six experimental frusemide analogues, two thiazides, two K‐retaining diuretics and one organomercurial were compared for inhibitory potency on the red cell Na‐K cotransport system.

Except for mersalyl, whose exact mode of action in the kidney is still in doubt, the inhibition of the red cell system by various loop diuretics was consistent with both published whole body diuretic data and isolated perfused tubule studies, while the system did not respond to the thiazides or the K‐retaining diuretics.

It is concluded that the human red cell Na‐K cotransport system is a possible valid model process on which to study the activity of loop diuretics.
UPTAKE OF 6‐FLUORO‐5‐HYDROXYTRYPTAMINE AND 4,6‐DIFLUORO‐5‐HYDROXYTRYPTAMINE INTO RELEASABLE AND NON‐RELEASABLE COMPARTMENTS OF HUMAN PLATELETS
Authors: COSTA J.L. , KIRK K.L. , STARK H.
Published: July 2012

The ring‐fluorinated compounds, 6‐fluoro‐5‐hydroxytryptamine and 4,6‐difluoro‐5‐hydroxytryptamine, are sterically similar to 5‐hydroxytryptamine (5‐HT) but have pKas for their 5‐hydroxyl groups (9.7 and 8.0 respectively) which are lower than that of 5‐HT.

The rates at which [3H]‐5‐HT, [3H]‐6‐fluoro‐5‐HT, and [3H]‐4,6‐difluoro‐5‐HT entered the releasable (vesicular) and non‐releasable compartments of washed human platelets during a 1 min incubation period at 37°C were similar. These portions of the uptake process therefore appear to be relatively independent of the pKa of the 5‐hydroxyl group.

The [3H]‐4,6‐difluoro‐5‐HT was unique since material accumulating in the non‐releasable compartment during uptake did not migrate into the vesicular compartment under appropriate incubation conditions.

The data suggest that the zwitterionic form of 5‐HT is not the transported species, but that the electronic configuration about the 5‐hydroxyl group may be critical for translocation from a non‐releasable to a releasable compartment.
RELAXANT EFFECTS OF LITHIUM ON GUINEA‐PIG TRACHEAL SMOOTH MUSCLE in vitro
Authors: SAMPSON SANFORD R. , WEISS‐ROTEM CARMELA
Published: July 2012

The esffect of lithium was studied on resting tesion of guinea‐pig spiral tracheal strips and their responses to carbachol and histamine in vitro.

Lithium reversibly relaxed tracheal smooth muscle in a dose‐dependent manner. In addition, lithium increased the ED50 for carbachol 10 fold and that for histamine by over 100 fold; maximum responses for each agonist were also reduced.

Lithium‐induced relaxation of tracheal smooth muscle was unaffected by changes in extracellular calcium concentration over the range 0–11 mm, verapamil, ouabain, procaine, propranolol or reduction in extracellular sodium concentration.

The ability of lithium to reduce carbachol‐ and histamine‐induced contraction of tracheal smooth muscle was also not altered by propranolol, procaine, ouabain, verapamil or lowered extracellular sodium.

We conclude that lithium acts directly on tracheal smooth muscle to relax it by an as yet unknown mechanism. This may or may not be related to the ability of this agent to alter agonist‐induced contraction of tracheal smooth muscle.
STUDIES ON THE BRADYCARDIA INDUCED BY BEPRIDIL
Authors: BEAUGHARD M. , FERRIER M. , LABRID C. , LAMAR J.C. , LEBOEUF J. , PIRIS P.
Published: July 2012

Bepridil, a novel active compound for prophylactic treatment of anginal attacks, induced persistent bradycardia and a non‐specific anti‐tachycardial effect, the mechanisms of which were investigated in vitro and in vivo.

In vitro perfusion of bepridil in the life‐support medium for isolated sino‐atrial tissue from rabbit heart, caused a reduction in action potential (AP) spike frequency (recorded by KCl microelec‐trodes) starting at doses of 5 × 10−6 m. This effect was dose‐dependent up to concentrations of 5 × 10−5 m, whereupon blockade of sinus activity set in.

Bepridil at a dose of 5 × 10−6 m, induced a concomitant reduction in AP amplitude (falling from 71±8 mV to 47±6 mV), maximum systolic depolarization velocity (phase 0) which fell from 1.85 ± 0.35 V/s to 0.84 ± 0.28 V/s, together with maximum diastolic depolarization velocity (phase 4) which fell from 38 ± 3 mV/s to 24 ± 5 mV/s.

In vivo injection of bepridil at a dose of 5 mg/kg (i.v.) into 6 anaesthetized dogs which had undergone ablation of all the extrinsic cardiac afferent nerve supply, together with a bilateral medullo‐adrenalectomy, caused a marked reduction in heart rate which fell from 98·7 ± 4.2 beats/min to 76 ± 5.3 beats/min sustained for more than 45 min.

It is concluded that bepridil reduces heart rate by acting directly on the sinus node. This effect, which results in a flattening of the phase 0 and phase 4 slope, together with a longer AP duration, may be due to an increase in the time constants of slow inward ionic currents (already demonstrated elsewhere), but also to an increased time constant for deactivation of the outward potassium current (Ip).
EFFECTS OF CIMETIDINE ON HAEMATOPOIESIS in vitro
Authors: CALZADO M.C. , GARCIA‐CASTELLANO J.M. , MANZANARES R.M. , MARTINEZ F. , PRIETO B. , TORRES A.
Published: July 2012

The possible modifications in haematopoiesis induced by cimetidine were studied in normal bone marrow cultures in vitro.

When cimetidine was added in the therapeutic range, there was no significant change in either granulocytic‐macrophagic (CFU‐GM) or erythroid (BFU‐E) colony growth. However, when cimetidine was added to the culture at 2 to 25 times the therapeutic range, a small but significant inhibition of both types of colony growth was found.

We conclude that cimetidine in the therapeutic range does not induce inhibition of haematopoiesis in vitro but does in doses above the therapeutic range when inhibition is dose‐dependent.
EFFECTS OF DESENSITIZATION TO ADENOSINE 5′‐TRIPHOSPHATE AND ADENOSINE ON NON‐ADRENERGIC INHIBITORY RESPONSES IN THE CIRCULAR MUSCLE OF RABBIT COLON
Authors: CREMA A. , D'ANGELO L. , FRIGO G.M. , LECCHINI S. , ONORI L. , TONINI M.
Published: July 2012

An approximate eight fold desensitization of the circular coat of the distal rabbit colon to adenosine 5′‐triphosphate (ATP) and adenosine could be achieved by repeatedly exposing the organ to relatively low concentrations (10–100 μm) of these compounds.

The desensitization was specific and reversible after prolonged washing. It could be overcome by increasing the concentrations of the purine agonists.

Dipyridamole potentiated the non‐adrenergic inhibition in response to transmural stimulation but failed to influence the caudad relaxation evoked by radial distension.

Desensitization to ATP and adenosine (and to ATP + adenosine simultaneously) did not affect the non‐adrenergic inhibition in response to radial distension or transmural stimulation.

These results suggest that neither ATP nor adenosine are the final transmitters mediating the non‐adrenergic inhibitory responses in the distal colon of the rabbit.
ANTIARRHYTHMIC EFFECTS OF ORG 6001 IN RATS: CORRELATION WITH PLASMA AND TISSUE DRUG CONCENTRATIONS
Authors: KANE KATHLEEN , McDONALD FIONA , PARRATT JAMES , TIMMER CEES , VINK JAN
Published: July 2012

The antiarrhythmic effects of Org 6001 following oral administration in the rat have been assessed and correlated with plasma, myocardial and skeletal muscle drug concentrations.

Arrythmias were induced by coronary artery ligation in anaesthetized rats. Org 6001 (10,20,50 and 100 mg/kg given 1h before ligation) significantly reduced mortality and the incidence of ventricular fibrillation in the 0–30 min post ligation period. Only the highest dose of drug also significantly reduced the number of ventricular ectopic beats following ligation.

A linear relationship was observed between the oral dose and the Org 6001 concentrations in plasma and skeletal muscle determined 90 min after drug administration.

The Org 6001 concentration in the myocardium was not linearly related to the administered dose and Org 6001 appeared to be concentrated to a higher extent in cardiac than in skeletal muscle at that time.

No statistically significant difference in drug levels in the ischaemic left ventricle and normal right ventricle plus septum was observed.

The antiarrythmic effect of Org 6001, as measured by changes in the incidence of ventricular fibrillation, correlated with myocardial concentrations of the drug.
RELATIONSHIP BETWEEN LESION FORMATION AND PERMEABILITY OF RAT GASTRIC MUCOSA TO H+ AND OTHER CATIONS
Authors: BUNCE K.T. , McCARTHY J.J. , SPRAGGS C.F. , STABLES R.
Published: July 2012

The relationship between lesion formation and ionic permeability has been investigated in rat gastric mucosa in vivo. Changes in these parameters were measured in the mucosa treated topically with prostaglandins E2 and A2 and/or aspirin. Particular attention was paid to the net flux of H+ ions across the gastric mucosa.

The effect of aspirin concentrations of 5 mm, 20 mm and ‘40 mm’ (the latter, a suspension in a saturated solution) was investigated. Aspirin concentrations of 20 mm and ‘40 mm’ produced a marked increase in lesion formation and increased the net mucosal to serosal flux of H+ ions. Aspirin 5 mm produced a significant increase in lesion formation but did not cause a significant change in net H+ ion flux. This result suggests that aspirin can have a direct irritant effect on the gastric mucosa and that the back diffusion of H+ ions is not a pre‐requisite for the development of overt mucosal ulceration.

The effect of topically applied prostaglandin E2 (PGE2) on aspirin‐induced gastric mucosal damage was investigated. Concentrations of PGE2 of 10−5m and 10−4m ameliorated aspirin‐induced damage, but these changes were not necessarily accompanied by a significant reduction in net H+ ion flux. Again, this result is not consistent with a direct relationship between lesion formation and mucosal permeability to H+ ions.

Since PGA2 did not ameliorate aspirin‐induced mucosal damage, the protective effect of PGE2 could not be attributed to its conversion to PGA2 in the acidic environment of the gastric lumen.

Changes in gastric mucosal potential difference (p.d.) and net fluxes of Na+ and K+ ions may occur without a concomitant change in the permeability of the gastric mucosa to acid back‐diffusion. Thus, the assumption cannot be made that a change in the permeability of the gastric mucosa to one particular ion reflects a general increase in ionic permeability.
INHIBITION OF TRYPSIN AND PAPAIN BY SODIUM AUROTHIOMALATE MEDIATED BY EXCHANGE REACTIONS
Authors: GRIFFIN M.M. , STEVEN F.S.
Published: July 2012

Sodium aurothiomalate has been shown to participate in exchange reactions leading to the inhibition of trypsin; for this exchange to take place it was necessary to include in the test system a suitable thiol, such as N‐acetyl‐cysteine.

Neither N‐acetyl‐cysteine nor aurothiomalate on their own had any inhibitory action on trypsin.

The results indicate that aurothiomalate dissociates in the presence of a carrier to form thiosuccinate and gold.

The gold is responsible for trypsin inhibition since independent experiments demonstrated that the total concentration of thiosuccinate was insufficient to cause the observed inhibition of trypsin.

Bovine serum albumin was shown to act as a carrier in place of N‐acetyl‐cysteine.

It is known that histidine in the active centre of trypsin binds heavy metal ions with consequent inhibition of the enzyme. In this study, imidazole was shown to act as a carrier for gold from aurothiomalate to trypsin resulting in inhibition. This inhibition by gold was reversed when higher concentrations of imidazole were added to the test system due to competition for the trypsin‐bound gold by imidazole.

Conversely, the thiol enzyme papain was re‐activated in the presence of low concentrations of sodium aurothiomalate and inhibited by higher concentrations of this reagent in a biphasic manner. This observation will be discussed in relation to the dissociation of sodium aurothiomalate.

These observations can also be explained in terms of exchange reactions involving thiols and free metal ions.
RELATIVE ACTIVITIES OF SUBSTANCE P‐RELATED PEPTIDES IN THE GUINEA‐PIG ILEUM AND RAT PAROTID GLAND, in vitro
Authors: GATER P.R. , JORDAN C.C. , OWEN D.G.
Published: July 2012

The relative potencies of a series of substance P analogues have been determined for spas‐mogenic activity in the guinea‐pig ileum in vitro and for the release of 86Rb and α‐amylase activity from rat parotid gland slices in vitro. Equipotent molar ratios (EMR), relative to substance P, were determined for all the compounds.

In the rat carotid gland, EC50 values for amylase release were, on average, 35.5 times greater than those for 86Rb release. Analysis of Hill plots suggests that spare receptors exist for 86Rb release but not for amylase release and it is suggested that the stimulus‐response coupling for amylase release may be less efficient than that for 86Rb release.

In the parotid gland, the octapeptide and [<Glu6]‐hexapeptide C‐terminal fragments of substance P were less active than substance P itself, whereas in the ileum, the octapeptide was as active as substance P.

Substitutions at the Phe7 or Phe8 positions in general reduced activity relative to substance P. This effect was particularly apparent in C‐terminal hexapeptide analogues.

Substitutions at the Phe7 and Phe8 positions in C‐terminal hexapeptide analogues produced a greater reduction in activity in the parotid gland than in the ileum. The most marked difference was observed with eledoisin‐related peptide for which the ratio of EMRs for ileum and 86Rb release was 18.1. The unsubstituted C‐terminal octapeptide fragment similarly showed a discrepancy between the two assay systems (EMR ratio, ileum: Rb release = 7.75).

It is suggested that the results may indicate the presence of sub‐populations of ‘substance P receptors’ which are represented at least in different proportions in the two tissues studied, although alternative explanations such as differences in metabolism of agonists are possible.
SELECTIVE POTENTIATION OF NORADRENALINE IN THE GUINEA‐PIG VAS DEFERENS BY 2‐(4‐METHYLAMINOBUTOXY) DIPHENYLMETHANE HYDROCHLORIDE (MCI‐2016), A NEW PSYCHOTROPIC DRUG
Authors: OHIZUMI YASUSHI , TAKAHASHI MASAMI , TOBE AKIHIRO
Published: July 2012

In the isolated vas deferens of the guinea‐pig, the effects of 2‐(4‐methylaminobutoxy) diphenyl‐methane hydrochloride (MCI‐2016), a new psychotropic drug, on the contractile response to various agonists or transmural electrical stimulation and on the release of noradrenaline (NA) from the tissue were examined and compared with cocaine.

MCI‐2016 (3 × 10−6m) and cocaine (3 × 10−5m) produced a leftward shift (15 and 20 times, respectively) of the dose‐response curves for the contractile effect of NA and increased the maximum contractile response to NA by approximately 7 and 14% respectively.

MCI‐2016 had no apparent effect on the dose‐response curves for methoxamine, acetylcholine and high K, while cocaine markedly shifted those for these agents to the left and increased the maximal responses (10, 16 and 16%, respectively).

MCI‐2016 and cocaine abolished the tyramine (3 × 10−4m)‐induced contraction and inhibited the twitch response to transmural electrical stimulation in a dose‐dependent manner. The inhibitory effects of both drugs on the twitch were reversed by yohimbine (10−5 m).

The spontaneous outflow of NA from the vas deferens was unaffected by MCI‐2016(3 × 10−6m) and cocaine (10−5 m), while the high‐K‐evoked release of NA was increased by both drugs.

In the presence of cocaine (10−5 m), the high‐K‐evoked release of NA was markedly increased by yohimbine (10−5 m) and decreased by clonidine (3 × 10−8m), but only slightly increased by MCI‐2016 (3 × 10−6m).

In phaeochromocytoma cells, both MCI‐2016 and cocaine at concentrations of 10−7 to 10−5 m caused a dose‐dependent inhibition of the [3H]‐NA uptake.

These results suggest that MCI‐2016‐induced supersensitivity is specific for NA and is due to interference with the neuronal uptake process for NA.
MODIFICATION OF ENDORPHIN/ENKEPHALIN ANALGESIA AND STRESS‐INDUCED ANALGESIA BY DIVALENT CATIONS, A CATION CHELATOR AND AN IONOPHORE
Authors: CHAPMAN D.B. , WAY E. LEONG
Published: July 2012

The possibility that divalent cations may antagonize opiate peptide analgesia and stress‐induced analgesia was examined.

Intracerebroventricular injection of low doses of Ca2+, Mn2+ and Mg2+ antagonized β‐endorphin and methionine‐enkephalin analgesia. Ba2+ and Cd2+ were without effect.

The ionophore, A23187, significantly antagonized β‐endorphin analgesia and the effect was increased when a low dose of Ca2+ was injected at the same time as the ionophore.

Ethylene glycol tetraacetic acid (but not ethylenediamine tetraacetic acid) significantly potentiated endorphin analgesia.

Stress‐induced analgesia, as determined by increased tail‐flick latencies following intraperitoneal injection of acetic acid, was effectively antagonized by naloxone, Ca2+ and Mn2+. The frequency of writhing following acetic acid injection was increased by both naloxone and divalent metal ions, again suggesting antagonism of endogenous opiates.

These results confirm previous findings indicating that divalent metal ions (and especially Ca2+) may be involved in the actions of opiates.
SPECIFIC BUT NONCOMPETITIVE INHIBITION BY 2‐ALKYLTHIO ANALOGUES OF ADENOSINE 5′‐MONOPHOSPHATE AND ADENOSINE 5′‐TRIPHOSPHATE OF HUMAN PLATELET AGGREGATION INDUCED BY ADENOSINE 5′‐DIPHOSPHATE
Authors: CUSACK N.J. , HOURANI S.M.O.
Published: July 2012

Some 2‐alkylthio derivatives of adenosine 5′‐monophosphate (AMP), adenosine 5′‐monophosphorothioate (AMPS) and adenosine 5′‐triphosphate (ATP) were examined as inhibitors of human platelet aggregation.

2‐Methylthio‐AMP, 2‐ethylthio‐AMP, 2‐(pentan‐l‐yl)thio‐AMP, 2‐ethylthio‐AMPS, 2‐methylthio‐ATP and 2‐ethylthio‐ATP (100 μm) each inhibited aggregation induced by adenosine 5′‐diphosphate (ADP) but not by 11α,9α‐epoxymethano prostaglandin H2, a stable endoperoxide analogue.

Log dose‐response curves to ADP in the absence and presence of each inhibitor were not parallel and the inhibition could not be overcome by high concentrations of ADP.

The ATP analogues achieved greater inhibition of aggregation induced by ADP (5 μm) than did the AMP analogues.

The order of potency of the AMP analogues was 2‐ethylthio‐AMPS > 2‐ethylthio‐AMP > 2‐(pentan‐l‐yl)thio‐AMP > 2‐methylthio‐AMP, and 2‐methylthio‐ATP was more potent than 2‐ethylthio‐ATP.

These 2‐alkylthio substituted analogues of AMP and ATP are specific but noncompetitive inhibitors of ADP‐induced human platelet aggregation.
STIMULATION OF SODIUM AND OF CHLORIDE TRANSPORT IN EPITHELIA BY FORSKOLIN
Authors: CUTHBERT A.W. , SPAYNE J.A.
Published: July 2012

The diterpene, forskolin, is shown to produce a concentration‐dependent, increase in short circuit current in two epithelial preparations, amphibian skin and rat colon. In the amphibian tissue the increase is sensitive to amiloride and due to an increase in electrogenic transepithelial sodium transport towards the serosal side. In the rat colon piretanide attenuated the forskolin effect, suggesting the terpene increases electrogenic transepithelial chloride transport towards the mucosal side. Half‐maximal activation of both processes was achieved with concentrations of 1–3 μm, similar to those required to activate half‐maximally the catalytic subunit of adenylate cyclase.
RATE‐LIMITING STEP IN THE METABOLISM OF POLAR AND NON‐POLAR MONOAMINES IN LUNG AND LIVER
Authors: BEN‐HARARI RUBEN R. , PELEG R. , YOUDIM M.B.H.
Published: July 2012

Uptake of the non‐hydroxylated amines, [14C]‐tryptamine and [14C]‐benzylamine in rat lung, infused through the pulmonary circulation, was not saturable over the concentration range 2.5–1,000 μm.

The kinetic constants for deamination of a variety of hydroxylated and non‐hydroxylated monoamines in liver, perfused via the portal circulation, with monoamine oxidase activity in homogenates of liver were similar.

In lung, uptake of both [14C]‐tryptamine and [14C]‐benzylamine was inhibited by the monoamine oxidase inhibitor deprenyl and competition occurred between tryptamine, benzylamine and β‐phenylethylamine for uptake.

These results indicate that tryptamine and benzylamine metabolism in lung is not limited by uptake, unlike that of the hydoxylated amines 5‐hydroxytryptamine and noradrenaline and that uptake resembles that of β‐phenylethylamine in lung.

The selectivity of the lung in handling monoamines is not shown by the liver, suggesting that lung has a specific role in clearing certain biogenic monoamines.
THE MECHANISM OF THE POSITIVE INOTROPIC ACTION OF KETAMINE ON ISOLATED ATRIA OF THE RAT
Authors: BARRIGON SANTOS , DE MIGUEL BEATRIZ , TAMARGO JUAN , TEJERINA TERESA
Published: July 2012

The effect of ketamine (10−7 m‐5 × 10−4 m) on electrical and mechanical properties of isolated atria of the rat was investigated.

On spontaneously beating right atria, ketamine produced a dose‐dependent positive inotropic effect which was accompanied by a progressive reduction in atrial rate.

In electrically driven left atria, ketamine produced a dose‐dependent positive inotropic effect which was accompanied by a parallel increase in df/dtmax and by a prolongation in the time to peak tension and in the time for total contraction. The positive inotropic effect occurred concomitantly with an increase in the height and duration of the plateau phase of the action potential of atrial fibres.

The positive inotropic effect of ketamine varied with the concentration of Ca and Na in the bathing media and the rate of stimulation.

Ketamine decreased post‐extrasystolic potentiation and the amplitude‐interval relationship.

The positive inotropic effect of ketamine was inhibited by verapamil (10−6 m) and by caffeine (4 × 10−3 m).

Ketamine, 5 × 10−5 m and 10−4 m, increased 45Ca uptake in electrically driven left atria. At 10−4 m and 5 × 10−4 m, ketamine also increased 45Ca efflux.

These results suggest that ketamine produces its positive inotropic effect by two possible mechanisms. One of these is presumed to be an effect on the cell membrane which leads to an increased Ca influx into atrial fibres; the other is probably related to the inhibition of Ca sequestration by the sarcoplasmic reticulum.
ALTERATION IN THE LEVEL OF ENDOGENOUS HYPOTHALAMIC PROSTAGLANDINS INDUCED BY Δ9‐TETRAHYDROCANNABINOL IN THE RAT
Authors: COUPAR IAN M. , TAYLOR DAVID A.
Published: July 2012

Whole brain and regional brain levels of prostaglandin E2 (PGE2)‐like material have been determined following administration of Δ9‐tetrahydrocannabinol (Δ9‐THC) in rats.

Intravenous administration of Δ9‐THC 2 mg/kg, resulted in marked behavioural changes and hypothermia. The behavioural changes consisted mainly of catatonia (most apparent at 30 min after administration of Δ9‐THC), followed by sedation (most evident at 60 min). Hypothermia was marked from 30 min after administration of Δ9‐THC.

Δ9‐THC did not alter the whole brain levels of PGE2‐like material 30, 60 or 120 min after administration.

Δ9‐THC did not alter the levels of PGE2‐like material in the medulla oblongata/pons, midbrain, cortex and cerebellum, 30 min after administration. However, there was a significant reduction of PGE2‐like material in the hypothalamus, 30 min after Δ9‐THC.

It is suggested that the Δ9‐THC‐induced decrease in hypothalamic PGE2‐like material may contribute to the hypothermia observed following Δ9‐THC administration.
PROTECTIVE EFFECTS OF THE GLUCOCORTICOID, BUDESONIDE, ON LUNG ANAPHYLAXIS IN ACTIVELY SENSITIZED GUINEA‐PIGS: INHIBITION OF IgE — BUT NOT OF IgG — MEDIATED ANAPHYLAXIS
Authors: ANDERSSON P. , BRATTSAND R.
Published: July 2012

The effect of glucocorticoid pretreatment on antigen‐induced bronchoconstriction was studied in guinea‐pigs actively sensitized to two different ovalbumin regimens (one producing IgE‐ and IgG‐like antibodies and the other exclusively IgG‐like antibodies).

Budesonide (50 mg/kg) and hydrocortisone (50 mg/kg) given as one intraperitoneal injection 15–20 h before the anaphylactic test or as two consecutive intraperitoneal injections 5 and 6 days before, led to a decreased bronchial capacity. In this respect glucocorticoid pretreatment was effective only in guinea‐pigs sensitized to produce both IgE‐like and IgG‐like antibodies.

Budesonide pretreatment also reduced the capacity of anaphylactically‐challenged chopped lung tissue to release histamine in guinea‐pigs sensitized to produce both IgE‐ and IgG‐like antibodies.

Budesonide pretreatment did not change the levels of circulating IgG1a and IgE‐like homocytotropic antibodies as measured by passive cutaneous anaphylaxis; nor did it affect histamine or methacholine‐induced bronchoconstriction in vivo or the capacity of histamine or methacholine to contract the guinea‐pig isolated trachea preparation or the isoprenaline‐induced relaxation of this preparation.

The selective inhibitory effects of budesonide and hydrocortisone on IgE‐mediated but not IgG‐mediated anaphylaxis and the relevance to human atopic disease are discussed.
ULCERATIVE COLITIS: EFFECT OF SULPHASALAZINE, ITS METABOLITES AND INDOMETHACIN ON THE ABILITY OF HUMAN COLONIC MUCOSA TO METABOLIZE PROSTAGLANDINS in vitro
Authors: HILLIER KEITH , MASON P.J. , PACHECO S. , SMITH C.L.
Published: July 2012

Homogenates of mucosa from human colon metabolize [3H]‐prostaglandin E1 in the presence of nicotinamide adenine dinucleotide to 15‐oxo prostaglandin E1 or 15‐oxo, 13,14 dihydro prostaglandin E1.

Metabolic capacity of tissue from patients with active ulcerative colitis under treatment with sulphasalazine (0.021 ± 0.004 nmol/mg protein ± s.e. mean) did not differ from mucosa of normal patients (0.02 ± 0.004 nmol/mg protein) during 1 h incubation.

Sulphasalazine inhibits prostaglandin E1 metabolism by mucosal homogenates in a dose‐dependent manner with an ID50 of 125 μm. Its therapeutically active metabolite, 5‐aminosalicylic acid (2.6 mm) was without significant inhibitory activity.

Indomethacin inhibits prostaglandin E1 metabolism by colonic mucosa with an ID50 of 388 μm.

At present we cannot clearly relate the therapeutic benefit of sulphasalazine and its therapeutically active metabolite, 5‐aminosalicylic acid, in ulcerative colitis to their effects on prostaglandin E synthesis or metabolism in vitro.
RELATION OF PLASMA RENIN ACTIVITY TO THE ANTIHYPERTENSIVE EFFECT OF MK 421 IN THE RAT
Authors: BRADSHAW DAVID , FRANZ PETER H. , SUGDEN A. LOUISE
Published: July 2012

The effect of the angiotensin converting enzyme inhibitor, MK 421 (N‐((S)‐1‐(ethoxycarbonyl)‐3‐phenylpropyl)‐l‐Ala‐l‐Pro), on the blood pressure of two‐kidney Goldblatt hypertensive rats has been investigated in relation to the initial plasma renin activity (PRA) and the initial blood pressure of the individual animals.

Blood pressure was monitored by an indirect tail‐cuff method at 1, 3, 6 and 24 h after dosing. MK 421 produced a fall in blood pressure in the majority of animals, but the extent of this reduction varied considerably between individuals.

The change in blood pressure showed a significant correlation with both the initial PRA and the initial blood pressures of the animals. However, only a modest correlation was found between the initial PRA and the degree of hypertension.

MK 421 (10 mg/kg, orally) produced a mean blood pressure change which was statistically significant (P< 0.001) at all times tested.

It is concluded that the degree of antihypertensive activity of MK 421 is related to the degree of activity of the renin‐angiotensin system which, in this model at least, is reflected by the PRA.
NALOXONE INHIBITS EARLY ARRHYTHMIAS RESULTING FROM ACUTE CORONARY LIGATION
Authors: FAGBEMI OLU , LEPRÁN ISTVAN , PARRATT JAMES R. , SZEKERES LASZLO
Published: July 2012

The intravenous administration of naloxone 15 min before acute coronary artery ligation in both anaesthetized and conscious male rats markedly reduced the incidence and severity of the ventricular arrhythmias that occur within 30 min of the onset of myocardial ischaemia. The incidence of ventricular fibrillation was especially reduced and, in conscious rats, the survival 16 h after ligation was increased from 27% (in the controls) to 58 and 73% after 2 and 4 mg/kg naloxone respectively. One possible explanation of these results implies a detrimental effect of released endorphin in the early stages of myocardial ischaemia.
PHARMACOLOGICAL RESPONSES OF HUMAN AND PORCINE LUNG PARENCHYMA, BRONCHUS AND PULMONARY ARTERY
Authors: GOLDIE ROY G. , PATERSON JAMES W. , WALE JANET L.
Published: July 2012

Responses of preparations of human and porcine isolated bronchus and pulmonary artery to carbachol (CCh), methacholine, histamine, 5‐hydroxytryptamine (5‐HT), (−)‐noradrenaline (NA), (−)adrenaline (Adr) and (±)‐isoprenaline (Iso) were compared with responses to the same agonists in isolated lung parenchyma strips.

All preparations from both human and porcine lung contracted in response to histamine and all, except preparations of porcine pulmonary artery, contracted in response to CCh. Human and porcine pulmonary artery and parenchyma strip contracted in response to NA while bronchial preparations invariably relaxed. Iso caused relaxation of human and porcine bronchus and parenchyma strip. Although 5‐HT was completely inactive in tissues isolated from pig lung, this amine was a powerful spasmogen in human pulmonary artery, relaxed human bronchus and caused variable responses in human parenchyma.

Results indicate that the pharmacological characteristics of human and porcine parenchyma strips may be explained in terms of responses of vascular or airways smooth muscle.