bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.