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Biomedical subjects

A Doble

Publications and source records attributed to A Doble.

At least 19 recordsLinked to original sources
PubMed1992

Pertussis toxin pretreatment abolishes the inhibitory effect of riluzole and carbachol on D-[3H]aspartate release from cultured cerebellar granule cells.

The release of D-[3H]aspartate from cultured cerebellar granule cells evoked by glutamic acid can be inhibited by riluzole and the muscarinic agonist carbachol. The combined application of maximally efficacious concentrations of riluzole and carbachol produces no greater inhibition than that seen with either agent alone, indicating that a common mechanism is involved. The effects of both agents are abolished when the cells have been pretreated with pertussis toxin, which suggests that this mechanism may involve a GTP-binding protein. The effect of pertussis toxin pretreatment is not mimicked by cholera toxin, nor does pertussis toxin pretreatment interfere with the inhibitory effect of the competitive excitatory amino acid receptor antagonist D-alpha-aminoadipic acid.

Anesthetics↗
PubMed1992

Multiple benzodiazepine receptors: no reason for anxiety.

Since the introduction of the benzodiazepines into clinical practice in 1960, these drugs have been widely employed as anxiolytics, sedative/hypnotics and anticonvulsants. In recent years, concern has been expressed about their side-effects, and their use has declined. During this latter period many advances have been made in understanding the molecular mechanisms by which these drugs produce their effects. Adam Doble and Ian Martin review this progress and highlight the possibilities that these advances may hold for the development of more efficacious and specific medicines.

Animals↗
PubMed1992

Measurement of nerve growth factor-like immunoreactivity in human brain using an anti-mouse-NGF enzyme immunoassay.

Nerve growth factor (NGF) like immunoreactivity, expressed as mouse 2.5S nerve growth factor equivalents, was evaluated in three structures of the human brain post-mortem using a commercially available enzyme immunoassay. Regional differences in NGF-like immunoreactivity were observed. Highest levels were found in hippocampus (148 pg/g) compared to putamen (76 pg/g) and frontal cortex (34 pg/g). In addition, these results suggest differences in the distribution of brain NGF between human and rodent, where relatively high levels of NGF are found in the cortex.

Aged↗
PubMed1992

The trophic effect of beta-amyloid 25-35 peptide is not mediated by NK1 or bombesin receptors.

beta-Amyloid peptide and spantide have previously been described to have trophic effects on hippocampal neurones in vitro. We report here that bombesin and [Pro9]-substance P also show a neurotrophic effect on cultured hippocampal neurones. The neurotrophic effect of spantide or a beta-amyloid fragment containing amino acids 25 to 35 was not blocked by addition of the NK1 receptor agonist, substance P or the nonpeptide NK1 antagonist, RP 67580. For the bombesin-related peptides, the antagonist [Tyr4-DPhe12]-bombesin also provokes a trophic response, but the agonist alytesin and the antagonist [Leu13-psi-(CH2NH) Leu14]-bombesin have no effect on neurite growth. These results suggest that the observed trophic responses are unlikely to be mediated by a classical NK1 or bombesin receptor.

Amino Acid Sequence↗
PubMed1992

KATP channels modulate GABA release in hippocampal slices in the absence of glucose.

We studied the effects of KATP channel blockers on [3H]GABA release in the absence of glucose in rat hippocampal slices. The omission of glucose induced a marked increase in the efflux of [3H]GABA, which was antagonized by TTX (1 microM), but not by MK 801 (1 microM) or DNQX (100 microM). Glibenclamide (10-100 microM) increased dose-dependently the release of [3H]GABA evoked in the absence of glucose. An increase in [3H]GABA release was also observed with gliquidone (100-300 microM), another sulfonylurea. The potentiation of [3H]GABA release induced by glibenclamide (100 microM) was antagonized by DNQX but not by MK 801. Thus, in the absence of glucose, KATP channel blockers enhance the release of GABA from rat hippocampal slices; this effect seems to be mediated by an overstimulation of non-NMDA glutamate receptors. On the basis of results reported in the present paper, we suggest that KATP channels may play a role in the regulation of GABAergic activity during hypoglycemia.

Adenosine Triphosphate↗
PubMed1992

Pharmacological characterization of RP 62203, a novel 5-hydroxytryptamine 5-HT2 receptor antagonist.

1. RP 62203 (2-[3-(4-(4-fluorophenyl)-piperazinyl)propyl]naphto[1,8- ca]isothiazole-1,1-dioxide) is a novel naphtosultam derivative which shows very high affinity for 5-HT2 receptors in the rat cerebral cortex (Ki = 50.0 pM). 2. RP 62203 is relatively selective for this sub-type of 5-hydroxytryptamine (5-HT) receptor, having lower affinity for the 5-HT1A receptor and very low affinity for the 5-HT, receptor. RP 62203 displayed low to moderate affinity for alpha 1-adrenoceptors, dopamine D2 receptors and histamine H1 receptors. 3. In vivo binding experiments demonstrated that oral administration of low doses of RP 62203 led to a long-lasting (greater than 6 h) occupation of cortical 5-HT2 receptors (ID50 = 0.39 mgkg-1). 4. In cortical slices from the neonatal rat, RP 62203 potently inhibited inositol phosphate formation evoked by 5-HT, with an IC50 of 7.76 nM. 5. The activity of neurones in the raphé and their responses to microiontophoretically applied 5-HT were studied with extracellular recording electrodes in the anaesthetized rat. RP 62203 potently and dose-dependently blocked excitations evoked by 5-HT when administered at doses of 0.5-4.0 mg kg-1, i.p. In contrast, neither 5-HT-evoked depressions nor glutamate-evoked excitations of raphé neuronal firing were blocked by RP 62203 at doses as high as 8.0 mg kg-1, i.p. 6. Head twitches induced by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) could be abolished by low doses of RP 62203 in mice (ED50 = 0.44 mg kg-1, p.o.) and in rats (ED50 = 1.54 p.o.). Similar results were obtained with mescaline and 5-hydroxytryptophan (5-HTP). 7. The potency of RP 62203 was compared with that of three other 5-HT2 receptor antagonists, ritanserin, ICI 169,369 and ICI 170,809. In all models, RP 62203 showed similar activity to ritanserin, whilst either ICI 169,369 or ICI 170,809 was several fold less active. 8. It is concluded that RP 62203 is a potent and selective antagonist at 5-HT2 receptors in the rodent central nervous system.

Action Potentials↗
PubMed1992

A rapid filtration assay for the glycine binding site on the NMDA receptor in rat cortical membranes using [3H]dichlorokynurenic acid.

A filtration binding assay using [3H]dichlorokynurenic acid to label the glycine binding site on the N-methyl-D-aspartic acid receptor has been evaluated on rat cortical membranes. This ligand binds to a single population of binding sites following mass action kinetics with a KD of 29 nM and a capacity of 5.73 pmol (mg protein)-1. The pharmacological specificity of the binding site is identical to that previously reported for this binding site using [3H]glycine as a radioligand. Agonists showed lower affinity and antagonists higher affinity when [3H]dichlorokynurenic acid was used compared with [3H]glycine. The higher affinity of [3H]dichlorokynurenic acid compared with [3H]glycine make it the more suitable compound with which to label the glycine site.

Animals↗
PubMed1992

Potassium markedly potentiates the effect of veratridine on dopamine release from rat superfused striatal ribbons.

The effects of veratridine-induced depolarization on [3H]dopamine ([3H]DA) release in the presence of a physiological (5 mM) or a depolarizing (25 mM) concentration of K+ were studied in-vitro in rat superfused striatal ribbons. A combination of the two depolarizing agents induced a marked potentiation in the overflow of [3H]DA, giving an overall 3- to 5-fold increase in veratridine activity. This potentiation was completely antagonized by tetrodotoxin (100 nM). These studies indicated that K(+)-induced depolarization can increase the potency of veratridine in releasing dopamine from terminals.

Animals↗
PubMed1991

Possible involvement of nitric oxide in long-term potentiation.

Long-term potentiation (LTP) in the hippocampus is known to involve NMDA (N-methyl-D-aspartate) receptors. Since activation of NMDA receptors in the cerebellum results in the formation of nitric oxide (NO), we studied the possible involvement of this messenger in hippocampal synaptic plasticity. We report here that the NO-synthase inhibitor, L-N omega-nitro-arginine, blocks LTP and that sodium nitroprusside, which releases NO, produces a long-lasting enhancement in synaptic efficacy which is not additive with tetanus-induced LTP.

Animals↗
PubMed1991

Prostatodynia and herpes simplex virus infection.

The etiology of chronic abacterial prostatitis remains obscure, although viral agents have been postulated. Herpes simplex virus was isolated from the prostatic fluid of a patient with symptoms of prostatitis and the implications are reviewed.

Adult↗
PubMed1991

Naphthosultam derivatives: a new class of potent and selective 5-HT2 antagonists.

A series of 2-(aminoalkyl)naphth[1,8-cd]isothiazole 1,1-dioxides was synthesized and examined in various receptor binding tests. Most compounds demonstrated high affinity for the 5-HT2 receptor with moderate to high selectivity. A member of this series, compound 24 (RP 62203), displays high 5-HT2 receptor affinity (Ki = 0.26 nM), which is respectively more than 100 and 1000 times higher than its affinity for alpha 1 (Ki = 38 nM) and D2 (Ki greater than 1000 nM) receptors. This compound is a potent orally effective and long lasting 5-HT2 antagonist in the mescaline-induced head-twitches test in mice and rats.

Animals↗
PubMed1991

Differential effects of potassium channel blockers on dopamine release from rat striatal slices.

The effects of different potassium channel blockers on tritiated dopamine [( 3H]DA) release were investigated in rat striatal slices in the presence of pargyline and nomifensine (10 microM each). 4-Aminopyridine (4-AP; 10 and 30 microM) and 3,4-diaminopyridine (3,4-DAP; 30 microM) markedly increased the basal tritium outflow, whereas tetraethylammonium (TEA; 100-1000 microM) was without effect. The facilitating effect of 4-AP (10 microM) on spontaneous release was Ca(2+)- and K(+)-dependent. Moreover, the 4-AP-induced increase in spontaneous release was abolished in the presence of tetrodotoxin, indicating that voltage-dependent Na+ channels were involved in the release mechanism. 4-AP (10 and 30 microM) induced a dose-dependent decrease in K(+)-evoked [3H]DA release. This effect was confirmed with 3,4-DAP (30 microM). When striatal slices were depolarized with veratridine (5 microM), these two aminopyridines increased the evoked release of [3H]DA. TEA increased both K(+)- and veratridine-evoked [3H]DA release. These biochemical results are consistent with electrophysiological differences between the mechanism of action of aminopyridines and that of TEA.

4-Aminopyridine↗
PubMed1991

A comparative study between Michel and Proximate clips for the closure of neck incisions.

A prospective study comparing two types of surgical clip, the Proximate II (Ethicon) staple and the Michel clip, was performed on 30 thyroidectomy (horizontal) and 50 carotid endarterectomy (vertical) incisions with reference to their ease of handling, patient comfort, complication rate, cosmetic result and cost. In each patient half of the wound was approximated with one type of clip and half with the other. The Proximate II staple was more comfortable for the patient in the vertical wounds (P less than 0.02), easier to remove as judged by the nurse in both horizontal (P less than 0.001) and vertical (P less than 0.02) wounds, and by the patient in the horizontal wounds (P less than 0.02) only. The incidence of inflammation was significantly higher with the Michel clip (P less than 0.001). In both the horizontal (P less than 0.05) and the vertical (P less than 0.001) wounds, when the scar was assessed at the time of discharge from hospital, the Proximate II staple achieved a significantly better result. However, assessment of the wounds by patient and researcher 6 weeks postoperatively, revealed no significant difference between the wounds with regard to cosmetic outcome. The Proximate II design, however, costs between seven and ten times more than the Michel clip depending on the size of the dispenser used, and since the late cosmetic result offers no advantage over the latter design, we feel these financial variables deserve consideration.

Adult↗
PubMed1990

Intraprostatic antibody deposition in chronic abacterial prostatitis.

Sixty patients with chronic abacterial prostatitis and 21 men without prostatitis were studied. Transperineal prostatic biopsies taken under transrectal ultrasound control were examined for antibody, complement (C3) and fibrinogen deposition using a direct immunofluorescence (IF) technique; 34 patients (57%) had prostatic tissue that displayed IF staining compared with only 1 (5%) in the non-prostatitis group. IF staining for IgM was found in 85%, for C3 in 44%, for IgA in 35% and for fibrinogen in 24%, but the IgG subclass was not detected. Antibody deposition was mainly periglandular and glandular and in the wall of vessels. Five symptoms, particularly poor urinary flow, irritative voiding and urgency, were significantly correlated with IgM and C3 deposition and, to a lesser extent, fibrinogen deposition. The aetiology of chronic abacterial prostatitis remains obscure but several possible mechanisms are discussed. The link between symptomatology and immunology could rest with functional outflow obstruction causing intraprostatic reflux of urine, this in turn inciting an immunological response, the inducing antigens being organism remnants or products, urinary constituents or autoantibodies.

Adult↗
PubMed1990

Preferential decrease in dopamine utilization in prefrontal cortex by zopiclone, diazepam and zolpidem in unstressed rats.

This study has compared the effects of a cyclopyrrolone, zopiclone, a benzodiazepine, diazepam, and an imidazopyridine, zolpidem, on dopamine (DA) and DOPAC levels, and DA utilization (DOPAC/DA ratio) in rat striatum and prefrontal cortex. The endogenous levels of DA were significantly increased by both zopiclone (2.5, 10 and 40 mg kg-1 p.o.) and diazepam (10 and 40 mg kg-1 p.o.) in the prefrontal cortex, whereas striatal DA content was significantly increased only with the highest dose of diazepam (40 mg kg-1 p.o.). Diazepam (10 and 40 mg kg-1 p.o.) decreased cortical level of DOPAC more markedly than striatal levels, whereas zopiclone (40 mg kg-1 p.o.) only slightly decreased striatal DOPAC levels. Zopiclone and diazepam dose-dependently decreased DA utilization, an effect which was more marked in prefrontal cortex than in striatum. This result was confirmed with zolpidem, another benzodiazepine ligand. Zopiclone was most potent at decreasing DA utilization at the cortical level. The diazepam-induced decreases in DA metabolism and utilization were antagonized by Ro 15-1788, suggesting that the effects seen were mediated by specific benzodiazepine receptors. Thus, our results clearly show that ligands acting on the benzodiazepine receptor GABA receptor chloride ionophore complex can decrease the utilization of dopamine in unstressed rats. The preferential decrease in cortical DA utilization induced by benzodiazepine ligands may be compared to the well-known activation by stress of the mesocortical DAergic system.

3,4-Dihydroxyphenylacetic Acid↗