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R A Webster

Publications and source records attributed to R A Webster.

At least 55 records · Page 3Linked to original sources
PubMed1986

Third Report on the Organization of Pharmacology in Great Britain.

The results presented in this Report on the Organization of Pharmacology in the United Kingdom are based on replies to questionnaires sent out in 1983. In addition to academic and industrial research and development (R&D) departments we also surveyed industrial departments of toxicology, sales, clinical liaison and medical information, as well as specialized research units with no formal teaching function. The overall response rate was 87%. Since the last Report in 1971, the total number of pharmacologists has doubled to 2220, and they are now almost equally distributed between Universities and Industry. The most striking feature has been a major (3 fold) increase in the total number of industrial pharmacologists to 1014. In contrast, there was only a 1.3 fold increase in the number (99) of pharmacologists in established academic posts, over half of which are in the new departments of clinical pharmacology. Of the established pharmacologists in academic departments only 8% were less than 30 years of age and 22% over 50, whereas in industrial R&D departments the corresponding figures were 44% and 6% respectively. Since 1971 the proportion of pharmacy graduates in established academic or industrial R&D posts has fallen from 30% to 13% but the proportion with a medical qualification is almost unchanged. In academic departments, there was a net loss of established staff during 1982 and 1983 compared with a net gain of almost 100 appointments in industrial departments. The major single cause of academic pharmacologists leaving posts was early retirement, whilst in the industrial sector the major single destination was another industrial department. In 1983, 227 students graduated with a special B.Sc. degree in Pharmacology compared with 67 in 1971. The same period saw a decline in pharmacy students specializing in pharmacology (293 to 204) and the emergence of Joint Honours courses that include pharmacology. Pharmacology students who graduated in 1983 were also sent a questionnaire. From those responding (57%) over 90% were satisfied with their course and over 80% considered it adequate preparation for their future occupation. At the time of the survey in 1983, only 8% of students graduating in 1982 were unemployed, but all of the 1982 postgraduates were employed.

Employment↗
PubMed1985

GABA and benzodiazepine-induced modification of [14C]L-glutamic acid release from rat spinal cord slices.

The spontaneous and potassium-evoked release of [14C]-label from rat spinal cord slices preloaded with [14C]L-glutamic acid and its modification by GABA and related drugs, such as flurazepam, was studied as a possible indirect measure of presynaptic inhibition and of the ability of benzodiazepines to augment it. GABA (100 microM) reduced the spontaneous release of [14C]-label (glutamate) provided that GABA metabolism was blocked by amino-oxyacetic acid (AOAA), but failed to reduce the potassium-evoked release of glutamate, although muscimol (10 microM) had some effect. In contrast, flurazepam (1-100 microM) did not affect spontaneous release but produced some inhibition of the evoked release (through a system insensitive to 10 microM bicuculline). This inhibition became more marked in the presence of both GABA and AOAA, and was then overcome by bicuculline. It is concluded that either some benzodiazepine receptors must be occupied for GABA to produce an effect on evoked release and/or, that the benzodiazepines can only augment GABA function once a certain amount has been released. Studies of the rapid distribution of [14C]-label from glutamate, to GABA, glutamine and other amino acids, using high voltage electrophoresis, showed the importance of blocking metabolic pathways in studies of this kind.

Aminooxyacetic Acid↗
PubMed1984

Stimulation of uterine ornithine decarboxylase in organ culture by decreasing osmolality: possible relation to in vivo mechanisms.

Ornithine decarboxylase (ODC) activity increases during many growth responses. Some cells and tissues in culture also exhibit elevated enzyme activity with decreasing osmolality of the culture medium. We have found that this also occurs with uterine tissue from ovariectomized rats. Organ culture incubation under hypotonic conditions caused maximal stimulation of uterine ODC activity at 4 hr. This stimulation was observed when either NaCl or sucrose was used to adjust the osmolality. Incubation under isotonic conditions also increased ODC activity relative to hypertonic conditions. This increase was similar in magnitude to that seen with unincubated uterine tissue from animals receiving systemic estradiol or intrauterine cholera toxin. Both estradiol and cholera toxin increase vascular permeability, and the resultant edema changes the extracellular microenvironment of the uterine cells. We suggest that this change somehow is mimicked by organ culture under hypotonic or isotonic conditions and is responsible for the stimulation of uterine ODC activity.

Animals↗
PubMed1984

Antagonism of caffeine-induced seizures in mice by Ro15-1788.

The effect of the benzodiazepine antagonist Ro15-1788 has been tested against caffeine (200-300 mg/kg i.p.) induced convulsions in mice. It offered protection in lower doses (10 mg/kg i.p.) than had been effective previously against other convulsants such as bicuculline and leptazol. In contrast, diazepam was much less active against caffeine than against the other convulsants and offered no significant protection in doses up to 1 mg/kg i.p. If Ro15-1788 only acts on benzodiazepine receptors then one explanation for the increased activity of Ro15-1788 compared with diazepam against caffeine is that caffeine exerts its convulsant action through a direct effect on benzodiazepine receptors but is more potent at displacing diazepam than Ro15-1788 or alternatively it acts on a sub-class of benzodiazepine receptors that bind Ro15-1788 more effectively than diazepam.

Animals↗
PubMed1984

The role of GABA in the anticonflict action of sodium valproate and chlordiazepoxide.

The anxiolytic effects of chlordiazepoxide (CDP) in the Geller-Seifter rat conflict test have been compared with those of muscimol and sodium valproate in order to evaluate the possible role of GABA in the anxiolytic action of the benzodiazepines. The anticonflict activity of CDP was inhibited by the benzodiazepine antagonist Ro15-1788, as well as by bicuculline and picrotoxin. The weaker anticonflict effect of muscimol was overcome by both bicuculline and picrotoxin. Sodium valproate had a marked anticonflict effect which was only inhibited by picrotoxin. Thus, while the anxiolytic action of CDP depends on GABA function in some way, it can be distinguished from the effects of muscimol and sodium valproate which appear to act at the GABA receptor and the chloride ion channel, respectively.

Aminooxyacetic Acid↗
PubMed1984

Estrogen-like stimulation of uterine ornithine decarboxylase by cholera toxin.

Cholera toxin administered by intrauterine injection to ovariectomized rats increased uterine ornithine decarboxylase activity as much as systemic estradiol at 4 h after treatment. At 45-60 min after treatment, however, cholera toxin did not increase nuclear estrogen receptor or stimulate synthesis of the uterine "induced protein," which is closely correlated with nuclear receptor, whereas estradiol caused substantial increases in both nuclear receptor and induced protein synthesis. Intrauterine injection of cholera toxin also produced an estrogen-like elevation of the uterine protein/DNA ratio at 24 h. Because both cholera toxin and estradiol are known to increase vascular permeability, our results support the hypothesis that some uterine effects of estradiol are not mediated by receptor-genome interaction but involve another mechanism that is associated with increased vascular permeability.

Animals↗
PubMed1983

Effects of dexamethasone and indomethacin on estrogen-induced uterine growth.

Certain aspects of estrogen-induced uterine growth are reminiscent of an inflammatory response. Dexamethasone (DEX) and indomethacin (IND), two anti-inflammatory agents that interfere with arachidonic acid metabolism, were examined with respect to their effects on several growth-associated responses of the uterus to estrogen. Ovariectomized rats were given a s.c. injection of either DEX (2 mg) or IND (8 mg) immediately prior to receiving a s.c. injection of estradiol (10 micrograms). At 4 hr, DEX inhibited estrogen-stimulated uterine wet weight and ornithine decarboxylase (ODC) activity by 100% and 48%, respectively. At 24 hr, 3H-leucine incorporation into protein was inhibited 44% and 3H-thymidine incorporation into DNA was depressed 83%. Estrogen-stimulated increases in uterine protein/DNA ratio and epithelial microvilli density at 24 hr were not inhibited by DEX. IND inhibited estrogen-stimulated wet weight by 64% and 3H-thymidine incorporation into DNA by 42%, yet did not inhibit the increases in ODC activity, 3H-leucine incorporation into protein or protein/DNA ratio. These results suggest that the inflammation-like component of estrogen-induced uterine growth is mediated, at least in part, by arachidonic acid metabolites and is directed primarily toward stimulating cell division, and not cell growth.

Animals↗
PubMed1983

Is Ro15-1788 a partial agonist at benzodiazepine receptors?

The ability of the imidazodiazepine derivative Ro15-1788, a potent and specific displacer of benzodiazepine binding, to induce and reduce benzodiazepine-like activity has been evaluated against the convulsant activity evoked by leptazol, bicuculline and the convulsant benzodiazepine Ro5-3663, in mice. Ro15-1788 (10-50 mg/kg) produced a dose dependent reduction in the activity of all 3 convulsants (significant at 50 mg/kg), when they were given at just maximal convulsant doses, but this effect was lost with supramaximal doses of the convulsants, as used in other reported experiments. In addition to this weak benzodiazepine-like activity, Ro15-1788 also reduced the anticonvulsant activity of diazepam and a triazolopyridazine derivative but not that of phenobarbitone. This effect was more marked at 10 than 25 or 50 mg/kg Ro15-1788. It is concluded that although Ro15-1788 has a specific effect on drugs acting at the benzodiazepine receptor it should be classified as a weak partial agonist rather than an antagonist at this site.

Animals↗
PubMed1983

Intrauterine injection of cholera toxin induces estrogen-like uterine growth.

Uterine growth in response to estrogen involves nuclear interaction of cytoplasmic estrogen receptors. The magnitude of the uterine growth response, however, and other observations have led to the suggestion that an additional mechanism or mechanisms of estrogen action may be at work in the uterus. This was investigated indirectly by examining estrogen-like growth responses of the uterus to the intrauterine (i.u.) injection of cholera toxin and water. Ovariectomized rats received either a subcutaneous injection of estradiol or vehicle and an i.u. injection of cholera toxin, water, or nothing. At 4 h after treatment of uterine wet weight was determined, and at 24 h the uterine protein/DNA ratio, [3H] leucine incorporation into protein, and [3H] thymidine incorporation into DNA were measured. Estradiol caused a 1.5-fold increase in the protein/DNA ratio and cholera toxin caused a 2.0-fold increase. Similarly, estradiol increased uterine wet weight 2.1-fold and cholera toxin increased it 1.9-fold. Estradiol and cholera toxin caused similar increases in the incorporation of [3H]leucine into protein: 3.3-fold and 2.3-fold, respectively. The effects of the treatments on the incorporation of [3H] thymidine into DNA were even greater, with estradiol producing a 10.3-fold increase, cholera toxin a 12.0-fold increase, and water a 3.6-fold increase. Since vascular permeability is known to be increased in the uterus by estrogen and in other systems by cholera toxin, these results support the idea of a relationship between uterine growth and increased vascular permeability.

Animals↗
PubMed1983

Reduced cortical glutamine concentrations in electrically kindled rats.

The effect of kindling rats (with an electrical stimulus applied daily to the frontal cortex) on the concentrations of taurine, aspartate, glutamate, glutamine, and gamma-aminobutyric acid has been investigated. When compared with control groups, cortical glutamine concentrations were significantly decreased in kindled rats by approximately 20%. This decrease in glutamine directly correlated with the after-discharge duration (r = 0.84, p = 0.005). The significance of this in relation to glutamate metabolism and kindling is discussed here.

Amino Acids↗
PubMed1983

The evaluation of different types of anti-convulsant drug activity against leptazol-induced epileptogenic activity in the anaesthetized rat.

1 The effects of various anticonvulsant drugs were evaluated quantitatively on the development of the epileptogenic EEG, induced by the intravenous infusion of leptazol in rats anaesthetized with urethane. 2 Leptazol alone produced five distinct phases of EEG activity developing from early wave and small spike and wave activity to larger spikes which later grouped and led to full body convulsion (FBC). 3 Drugs effective in petit mal such as clonazepam (0.1 and 0.25 mg kg-1) and ethosuximide (100 and 200 mg kg-1), significantly delayed the time to FBC by prolonging the early phases of the epileptogenic EEG and delaying the appearance of spiking. 4 Drugs effective in grand mal such as sodium valproate (60 mg kg-1) and phenytoin (5 mg kg-1) significantly prolonged the time to FBC by extending the later phases of the EEG and the development and grouping of spikes. Higher doses of these compounds were without effect. Carbamazepine and phenobarbitone produced mixed effects but were generally not markedly anticonvulsant. 5 The model is sensitive to drugs effective in both petit mal and grand mal, and appears able to differentiate usefully between them.

Anesthesia↗
PubMed1982

Antagonism of the anticonflict effects of chlordiazepoxide by beta-carboline carboxylic acid ethyl ester, Ro 15-1788 and ACTH(4--10).

The antagonism of the anticonflict effect of chlordiazepoxide (CDP) by beta-carboline carboxylic acid ethyl ester (BCCE), Ro 15-1788 and ACTH(4--10) has been evaluated in the Geller-Seifter rat conflict test in which CDP increases punished (conflict), but not unpunished responding. BCCE (0.5--10 micrograms ICV) produced a dose-dependent reduction in the anticonflict activity of CDP. This was also significantly reduced by Ro 15-1788 (25 mg/kg IP) and a high dose of ACTH(4--10) (5 micrograms ICV). None of these test compounds had a marked direct effect on punished or unpunished responding in the dose used. These experiments provide further physiological support for the suggestion from binding studies that BCCE and Ro 15-1788 act on benzodiazepine receptors. However, the ability of ACTH(4--10) to reduce the anticonflict effect of CDP may be by some other, possibly opioid, mechanism.

Adrenocorticotropic Hormone↗
PubMed1982

Release of [3H]noradrenaline from descending tracts in the cat spinal cord in vivo.

The release of [3H]noradrenaline into the perfused central canal of the cat lumbar-sacral spinal cord was monitored in vivo. Stimulation of descending tracts produced an increase efflux into artificial cerebrospinal fluid containing 10(-6) M phenoxybenzamine which could be dissociated from any concurrent rise in blood pressure. No release was produced by stimulating dorsal roots over the length of cord perfused. It appears, therefore, that noradrenaline can be released from descending nerve terminals, but not from dorsal root afferents in the spinal cord.

Afferent Pathways↗
PubMed1981

Modification of diazepam's antileptazol activity by endogenous tryptophan-like compounds.

Three possible endogenous ligands for benzodiazepine receptors, beta-carboline-3-carboxylic acid ethyl ester (beta CCE), tryptophylglycine (Trp-Gly) and ACTH peptides, have been tested, following intracerebroventricular (i.c.v.) administration in mice, for their direct effects on the CNS and the modification of diazepam's antileptazol activity. Whilst beta CCE and ACTH both reduced diazepam's antileptazol activity, only beta CCE had direct stimulant effects. Trp-Gly produced sedation and augmented the antileptazol effect of diazepam. Despite these differing effects, it remains possible that the endogenous ligand for the benzodiazepine receptors has a tryptophan-like structure.

Adrenocorticotropic Hormone↗
PubMed1980

Isolation and characterization of the estrogen receptor in hen oviduct: evidence for two molecular species.

Isolation of the estrogen receptor was undertaken for comparison with the progesterone receptor with respect to seasonal variations in receptor level and function and the specificity of nuclear binding sites in the hen oviduct. The estrogen receptor in the chick and hen oviduct has been only partially characterized, with conflicting or incomplete information on its properties. We have isolated a binding protein and have partially purified it by ammonium sulfate precipitation. The binding protein displays a single, high affinity class of sites (Kd similar to 10(-10) M) with a low capacity (35 fmol/mg protein) for 17beta-estradiol, shows a marked specificity for estrogenic compound, and is tissue specific. The protein sediments at approximately 8S in low salt and at approximately 4S in high salt conditions. The protein elutes from molecular sieve chromatography (agarose-0.5 m) in high salt conditions (0.3 M KCI) in a molecular weight range of approximately 60,000. DEAE chromatography and isoelectric focusing suggest that there are two molecular species, one focusing at pH 6.8 and the other at pH 7.3. Estrogen complexed to this protein will bind to nuclear acceptor sites in a cell-free assay in which free estrogen, estrogen bound to serum proteins, and [3H]estradiol receptor exchanged with a 100-fold excess of cold estradiol do not bind. Binding to nuclei is saturable and displaceable by an excess of nonradioactive estrogen receptor complexes under conditions of constant protein concentration. The above results represent the most detailed characterization to date of the cytosol estrogen receptor of hen oviduct This is the first demonstration of saturable, receptor-dependent, cell-free binding to target organ nuclei.

Animals↗