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PubMed1997

Functional organization of cone bipolar cells in the rat retina.

The responses of cone bipolar cells in slices of rat retina to ionotropic glutamate receptor agonists were recorded with the whole cell voltage-clamp technique in the presence of 5 mM Co2+ and nominally 0 mM Ca2+ extracellularly. Application of the non-N-methyl-D-aspartate (non-NMDA) receptor agonists kainate and (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate had a series of effects on cone bipolar cells (types 1-9), and the different cell types could be classified as ON- or OFF-type cells according to which type(s) of responses they displayed. First, direct responses were observed in cell types 1-4 as short-latency inward currents at -70 mV with reversal potentials (E(rev)s) close to 0 mV, characteristic of nonselective cation channels. Second, some cells, among types 5-9, did not display short-latency inward currents to kainate at -70 mV. Other type 5-8 cells displayed short-latency kainate responses, but the currents could not be reversed (E(rev) of +40 mV or greater). I suggest that these responses are conveyed to the cone bipolar cells through gap junctions, most likely with AII amacrine cells. The lack of reversal is likely due to a substantial voltage drop across the gap junctions resulting in an inadequate voltage control of AII amacrine cells when the recording pipette is on the cone bipolar cell. Kainate responses recorded directly from AII amacrine cells had E(rev) approximately 0 mV. Third, long-latency indirect responses selective for chloride ions (E(rev) approximately chloride equilibrium potential) were observed in many cone bipolar cells during longer-lasting application of kainate. The long-latency response component was suppressed by coapplication of the gamma-aminobutyric acid-A (GABA(A)) receptor antagonist picrotoxin and the GABA(C) receptor antagonist 3-aminopropyl(methyl)phosphinic acid. This long-latency component was absent in axotomized bipolar cells, suggesting that it was due to external Ca2+-independent release of GABA onto the axon terminals of the cone bipolar cells. All kainate-evoked response components were blocked by the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. Application of NMDA evoked no response in cone bipolar cells. These results suggest that cone bipolar cells types 1-4 are OFF cone bipolar cells, whereas cone bipolar cells types 5-9 are ON cone bipolar cells.

Animals↗
PubMed2000

Determination of optical purity of phosphonic acid analogues of aromatic amino acids by capillary electrophoresis with alpha-cyclodextrin.

A simple and efficient method for the determination of enantiomeric purity of structurally diverse phosphonic and phosphinic acid analogues of phenylalanine and phenylglycine using capillary electrophoresis is presented. These preliminary studies indicated that the enantiomer separation is strongly dependent on the structure of the aminophosphonic acid.

Amino Acids↗
PubMed1998

Different contributions of GABAA and GABAC receptors to rod and cone bipolar cells in a rat retinal slice preparation.

Whole cell currents were recorded from rod and cone bipolar cells in a slice preparation of the rat retina. Use of the gramicidin D perforated-patch technique prevented loss of intracellular compounds. The recorded cells were identified morphologically by injection with Lucifer yellow. During the recordings, the cells were isolated synaptically by extracellular cobalt. To distinguish the gamma-aminobutyric acid (GABA) receptors pharmacologically, the GABAA receptor antagonist, bicuculline, and the GABAC receptor antagonist, 3-aminopropyl(methyl)phosphinic acid, were used. In all bipolar cells tested, application of GABA induced postsynaptic chloride currents that hyperpolarized the cells from their resting potential of about -40 mV. GABA was applied at different concentrations to allow for the different affinity of GABA at GABAA and GABAC receptors. At a GABA concentration of 25 microM, in the case of rod bipolar cells, approximately 70% of the current was found to be mediated by GABAC receptors. In the case of cone bipolar cells, only approximately 20% of the current was mediated by GABAC receptors. Furthermore, this GABAC-mediated fraction varied among the different morphological types of cone bipolar cells, supporting the hypothesis of distinct functional roles for the different types of cone bipolar cells. There is evidence that the efficacy of GABAC receptors is modulated by glutamate through metabotropic glutamate receptors. We tested this hypothesis by applying agonists of metabotropic glutamate receptors (mGluR)1/5 to rod bipolar cells. The specific agonist (+/-)-trans-azetidine-2, 4-dicarboxylic acid and the potent mGluR agonist quisqualic acid reduced the amplitude of the GABAC responses by 10-30%. This suggests a functional role for the modulation of GABAC receptors by the metabotropic glutamate receptors mGluR1/5.

Animals↗
PubMed2004

Platinum-catalyzed selective hydration of hindered nitriles and nitriles with acid- or base-sensitive groups.

Hindered tertiary nitriles can be hydrolyzed under neutral and mild conditions to the corresponding amides using platinum(II) catalysts with dimethylphosphine oxide or other secondary phosphine oxides (SPOs, phosphinous acids) as ligands. We have found that this procedure also works well for nitriles with acid- or base-sensitive groups, which is unprecedented in terms of yield and selectivity. The catalyst loading can be as low as 0.5 mol %. Amides are isolated as the only product in high yield, and no further hydrolysis to the corresponding acids takes place. Reactions are carried out at 80 degrees C but take place even at room temperature. When enantiopure secondary phosphine oxide ligands are used in the hydrolysis of racemic nitriles, no kinetic resolution is observed, presumably due to racemization of the ligand during the reaction.

Journal Article↗
PubMed2003

Thiopental inhibits tumor necrosis factor alpha-induced activation of nuclear factor kappaB through suppression of kappaB kinase activity.

BACKGROUND: Thiopental is frequently used for the treatment of intracranial hypertension after severe head injury and is associated with immunosuppressive effects. The authors have recently reported that thiopental inhibits activation of nuclear factor (NF) kappaB, a transcription factor implicated in the expression of many inflammatory genes. Thus, it was the aim of the current study to examine the molecular mechanism of this inhibitory effect. METHODS: The authors tested gamma-aminobutyric acid (GABA), the GABA(A) antagonist bicuculline, and the GABA(B) antagonist dichlorophenyl-methyl-amino-propyl-diethoxymethyl-phosphinic acid (CGP 52432) in combination with thiopental for their influence on the activation of NF-kappaB. In addition, they investigated the direct effect of thiopental on activated NF-kappaB DNA binding activity. These experiments were conducted in Jurkat T lymphocytes using electrophoretic mobility shift assays. The presence of the phosphorylated and dephosphorylated NF-kappaB inhibitor IkappaBalpha (Western blotting) and IkappaB kinase activity were studied in Jurkat T cells and human CD3+ T lymphocytes. In addition, the authors tested the effect of the structural barbiturate analog pairs thiopental-pentobarbital and thiamylal-secobarbital and of thiopental in combination with the thio-group containing chemical dithiothreitol on the activation of NF-kappaB. RESULTS: GABA did not inhibit NF-kappaB activation, and the GABA(A) and GABA(B) antagonists bicuculline and CGP did not diminish the thiopental-mediated inhibitory effect on NF-kappaB activation. Thiopental did not inhibit activated NF-kappaB directly in a cell-free system. The phosphorylation of IkappaBalpha was prevented after incubation with 1,000 microg/ml thiopental. The same concentration of thiopental also inhibited IkappaB kinase activity in tumor necrosis factor-stimulated Jurkat T cells and human CD3+ T lymphocytes (60% suppression, P < 0.05 vs. tumor necrosis factor alpha alone). Thiobarbiturates (4 x 10(-3) m) inhibited NF-kappaB activity, whereas equimolar concentrations of the structural oxyanalogs did not. Preincubation of thiopental with dithiothreitol diminished the inhibitory effect. CONCLUSION: Thiopental-mediated inhibition of NF-kappaB activation is due to the suppression of IkappaB kinase activity and depends at least in part on the thio-group of the barbiturate molecule.

Anesthetics, Intravenous↗
PubMed1997

Baclofen reduces GABAA receptor responses in acutely dissociated neurons of bullfrog dorsal root ganglia.

The effect of baclofen on the function of the gamma-aminobutyric acidA (GABAA) receptor was examined in acutely dissociated neurons of bullfrog dorsal root ganaglia (DRG) by using the whole-cell voltage-clamp method. Baclofen (0.1-100 microM) depressed the inward currents produced by GABA (100 microM) and muscimol (100 microM). Baclofen shifted the concentration-response curve for GABA (1 microM-1 mM) downward. Baclofen decreased the maximum response (Vmax) to GABA without changing the apparent dissociation constant (Kd), suggesting a noncompetitive antagonism. The effect of baclofen on the GABA current was blocked by antagonists for the GABAB receptor; the rank order of potency was P-[3-Aminopropyl]-P-diethoxymethylphosphinic acid (CGP 55845A) > > 3-N[1-(S)-(3,4-dichlorophenyl)ethyl]amino-2-(S)-hydroxypropyl-P- benzyl-phosphinic acid (CGP 35348) > saclofen > > phaclofen. Baclofen produced an irreversible depression of the GABA current in neurons dialyzed with an internal solution containing guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S, 100 microM). Intracellular guanosine 5'-O-(2-thiodiphosphate) (GDP beta S, 100 microM) blocked the inhibitory effect of baclofen on the GABA current. Forskolin (10 microM) and dibutyryl N6, 2'-O-dibutyryladenosine 3':5'-cyclic monophophate (db-cyclic AMP) (200 microM) depressed the GABA current. N-(2-aminoethyl)-5-isoquinolinesulfonamide (H-9, 40 microM) and N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA-1004, 50 microM), protein kinase A (PKA) inhibitors, reduced the depressant effect of baclofen on the GABA current. The baclofen-induced depression of the GABA current was blocked by PKI(5-24), a specific PKA inhibitor, but not by PKC(19-36), a specific protein kinase C (PKC) inhibitor. We suggest that GABAB receptors regulate the GABAA receptor function through a G-protein linked to the adenylyl cyclase-PKA pathway in bullfrog DRG neurons.

Animals↗
PubMed1994

Non-peptide renin inhibitors containing 2-(((3-phenylpropyl)phosphoryl)oxy)alkanoic acid moieties as P2-P3 replacements.

A series of novel renin inhibitors containing 2-(((3-phenylpropyl)phosphoryl)oxy)alkanoic acid moieties as P2-P3 surrogates are presented. The P2-P3 mimetics were obtained from (omega-phenylalkyl)-phosphinic acids 1a-c and 2-hydroxyalkanoic acid benzyl esters 2a-f by N,N'-dicyclohexylcarbodiimide-mediated coupling and subsequent oxidation with sodium metaperjodate. Ester cleavage of these derivatives and coupling with P1-P1' transition-state mimetics I-VII provided highly selective compounds with inhibitory potencies in the lower nanomolar range. Small renin inhibitors, such as analogues 8c and 8h with molecular weights of 539 and 537, respectively, could be prepared. These compounds exhibited IC50 values of about 20 nM against human plasma renin. Compound 7i was examined in vivo for its hypotensive effect. In salt-depleted cynomolgus monkeys, 7i inhibited plasma renin activity almost completely and lowered blood pressure after oral administration of a dose of 30 mg/kg.

Amino Acid Sequence↗
PubMed1993

The physiological regulation of synaptic inhibition by GABAB autoreceptors in rat hippocampus.

1. Intracellular recording techniques were used to study the effects of repetitive stimulation on monosynaptically activated inhibitory postsynaptic currents (IPSCs) in rat hippocampal slices. This was achieved by stimulation in stratum radiatum close to a recorded CA1 pyramidal neurone after pharmacological blockade of excitatory synaptic responses, using a combination of the N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonists D-2-amino-5-phosphonopentanoate (AP5; 0.04-0.1 mM) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 0.02-0.04 mM), respectively. 2. Fixed-intensity stimulation at frequencies of less than 0.1 Hz evoked biphasic IPSCs of constant amplitude and waveform. In contrast, when two shocks (paired pulse) or longer trains of ten or more stimuli (i.e. tetani) were delivered at frequencies of between 0.2 and 20 Hz there was marked depression of both phases of every IPSC (by 60-100%) relative to the first or 'priming' IPSC evoked. 3. The gamma-aminobutyric acid (GABA)B receptor antagonists phaclofen (0.4-2 mM), 2-hydroxy-saclofen (0.02-0.4 mM) and 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP 35348; 0.01-1 mM) reduced or abolished, in a concentration-dependent and reversible manner, both the late phase of the IPSC (IPSCB) and paired-pulse depression of the early phase of the IPSC (IPSCA). Expressed in terms of IC50 values, all three antagonists were 5-10 times more potent at blocking IPSCB than paired-pulse depression. 4. Paired-pulse depression, at 5 and 10 Hz, has been shown to be mediated by GABA acting on presynaptic GABAB receptors (i.e. GABAB autoreceptors). We now show that GABAB receptor antagonists reverse paired-pulse depression over the entire range of frequencies (0.1-50 Hz) that it occurs. 5. GABAB receptor antagonists reversed substantially the depression of IPSCs during tetani delivered at 5 or 10 Hz. However at 20 Hz, GABAB receptor antagonists appeared to be less effective. At 100 Hz they appeared to be ineffective at reversing the depression of IPSCA; since the antagonists block IPSCB the net effect was to reduce the level of outward current. 6. At frequencies of 20 Hz or more, there was also the appearance of a slow inward current which increased in size in proportion to the frequency and number of shocks in the tetanus. This current (termed here IPSCI) was more pronounced at hyperpolarized membrane potentials and was blocked by picrotoxin (0.1 mM) or bicuculline (0.05 mM). 7. 'Priming' is considered to represent a more physiological pattern of activity than a tetanus.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2004

Gabapentin activates presynaptic GABAB heteroreceptors in rat cortical slices.

In electrically stimulated rat neocortical brain slices preloaded with [3H]gamma-aminobutyric acid (GABA) or [3H]glutamic acid, the pharmacological actions of 1-(aminomethyl)-cyclohexaneacetic acid (gabapentin, Gp) were compared with the GABAB receptor agonists baclofen (Bac) and (3-amino-2-(S)-hydroxypropyl)-methylphosphinic acid (CGP 44532). Gabapentin, baclofen and CGP 44532 all reduced the electrically stimulated release of [3H]glutamic acid (IC50=20 microM, 0.8 microM and 2 microM, respectively). These effects were sensitive to the GABAB receptor antagonists (+)-(S)-5,5 dimethylmorpholinyl-2-acetic acid (Sch 50911) or N-3-[[1-(S)-(3,4-dichlorophenyl)ethyl]amino]-2-(S)-hydroxypropyl-P-(cyclo-hexylmethyl)-phosphinic acid (CGP 54626). By contrast, gabapentin was without effect on the release of [3H]GABA, whilst baclofen (IC50=8 microM) and CGP 44532 (IC50=1 microM) inhibited [3H]GABA release. It is concluded that gabapentin selectively activates presynaptic GABAB heteroreceptors, but not GABAB autoreceptors, and may be a useful ligand to discriminate between presynaptic GABAB receptor subtypes.

Amines↗
PubMed2005

Stabilization of zwitterions in solution: phosphinic and phosphonic acid GABA analogues.

The influence of treatment of electron correlation, size of basis set and choice of solvation model on the predicted stabilization of zwitterionic phosphinic and phosphonic acid gamma-aminobutyric acid (GABA) analogues is investigated using ab initio molecular orbital methods and density functional theory. Density functional theory with the B3LYP functional and a composite basis set composed of the 6-31+G(2df) basis for phosphorus atoms and the 6-31+G(d,p) basis set for all other atoms is found to give an acceptable tradeoff between accuracy and computational expense. Either directly optimizing zwitterionic conformers within the conductor-like screening solvation model (COSMO) or pre-optimizing as dihydrates and then applying the COSMO solvation model give an acceptable treatment of solvation in terms of determining stable solvated structures, although directly optimizing within COSMO is simpler and less computationally expensive. With this protocol, cis-constrained phosphinic and phosphonic acid GABA analogues, which exhibit lower affinities for GABAC receptors, are found to possess only folded, intramolecularly hydrogen bonded low energy conformers. Trans-constrained analogues, on the other hand, exhibit higher affinities for GABAC receptors and are found to exist only as partially folded stable conformers. Conformationally flexible analogues can attain folded, partially folded or fully extended conformations and also have high biological activity. These results imply that the partially folded conformation is likely to be the most biologically active.

Amines↗
PubMed2002

Highly active, air-stable palladium catalysts for the C-C and C-S bond-forming reactions of vinyl and aryl chlorides: use of commercially available [(t-Bu)(2)P(OH)](2)PdCl(2), [(t-Bu)(2)P(OH)PdCl(2)](2), and [[(t-Bu)(2)PO...H...OP(t-Bu)(2)]PdCl](2) as catalysts.

Air-stable palladium complexes [(t-Bu)(2)P(OH)](2)PdCl(2), [(t-Bu)(2)P(OH)PdCl(2)](2), and [[(t-Bu)(2)PO...H...OP((t-Bu)(2)]PdCl](2) serve as efficient catalysts for a variety of cross-coupling reactions of vinyl and aryl chlorides with arylboronic acids, arylzinc reagents, and thiols to yield the corresponding styrene derivatives, biaryls, and thioethers. (31)P NMR and mechanistic studies argue that the phosphinous acid ligands in the complexes can be deprotonated in the presence of a base to yield an electron-rich anionic species, which is likely a catalyst intermediate, and dimeric [[(t-Bu)(2)PO...H...OP((t-Bu)(2)]PdCl](2) was isolated and cystallographically characterized. These anionic complexes are anticipated not only to accelerate the rate-determining oxidative addition of aryl chlorides but also to stabilize the palladium complexes in the catalytic cycle.

Journal Article↗
PubMed1991

Subpopulations of GABA-mediated synaptic potentials in slices of rat dorsal striatum are differentially modulated by presynaptic GABAB receptors.

gamma-Aminobutyric acid (GABA)-mediated synaptic potentials in rat dorsal striatum in vitro were reduced in amplitude by the GABAB receptor agonists baclofen and 3-aminopropyl-(methyl)-phosphinic acid (SK&F 97541), without any detectable postsynaptic effect. Synaptic potentials in 40% of neurones were distinctly multiphasic, the components of which exhibited a differential sensitivity to GABAB agonists. One population of GABA-releasing neurones within the striatum had presynaptic GABAB autoreceptors, whereas others were not directly affected by GABAB agonists.

Animals↗
PubMed2004

Catalysis with phosphine-containing amino acids in various "turn" motifs.

We have been actively involved in the development of parallel approaches for the discovery of phosphine ligands. Our approach has been based on the incorporation of phosphine-containing amino acids into peptide sequences that are designed to have stable secondary structures. We have examined helical and turn secondary structures and have reported that alkylation of cyclopentenyl acetate with dimethylmalonate can be catalyzed in high enantiomeric excess (ee) with a beta-turn-based ligand. The importance of the peptide secondary structure was demonstrated through the synthesis of a series of peptide ligands where the nature of the turn-forming residues was probed. Additionally, other turn-forming units and a variety of different phosphine-containing amino acids have been examined for their ability to control the selectivity of the allylation reaction. This paper reports the results obtained through the examination of different turn motifs as well as different phosphine substitutions on the "best" turn sequence, Pps-Pro-d-Xxx-Pps.

Amino Acid Sequence↗
PubMed1995

Role of peripheral GABAB receptors in the regulation of pepsinogen secretion in anaesthetized rats.

The purpose of the present study was to investigate the role played by GABAB receptors in the regulation of gastric basal pepsinogen secretion in anaesthetized rats. Following parenteral administration, the GABAB receptor agonists (-)-baclofen and 3-aminopropylphosphinic acid (3-APPA) caused a dose-dependent increase in basal pepsinogen secretion which was associated with a parallel increment in acid output. The gastric stimulant effects induced by both agonists were not affected by intracerebroventricular injection of the GABAB receptor antagonists 2-hydroxy-saclofen, 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP 35348) or phaclofen, whereas the excitatory actions were antagonized by intravenously administered 2-hydroxy-saclofen or CGP 35348, but not phaclofen. In addition, the (-)-baclofen-induced increases in both pepsinogen and acid output, were fully prevented by omeprazole or cimetidine, partly reduced by atropine and unaffected by pretreatment with capsaicin. When tested on rats undergoing bilateral cervical vagotomy, both (-)-baclofen and 3-APPA were still able to stimulate the basal pepsinogen and acid secretions, although at a lesser extent than in animals with intact vagus nerves. The stimulant actions elicited by (-)-baclofen in vagotomized rats were antagonized by 2-hydroxy-saclofen or CGP 35348, but not phaclofen. Moreover, these gastric excitatory effects were prevented by cimetidine or compound 48/80, while being unaffected by atropine. The present results show that peripheral GABAB receptors mediate an excitatory effect on gastric pepsinogen secretion which totally depends on an increase in acid output. It is also suggested that both vagal cholinergic and extravagal pathways, probably histaminergic in nature, take part in these GABAB receptor-mediated gastric stimulant actions.

Anesthesia↗
PubMed1998

The gamma-aminobutyric acid uptake inhibitor NO-711 potentiates 3-aminopropylphosphinic acid-induced actions in rat neocortical slices.

In rat neocortical slices maintained in Mg2+-free Krebs medium, the GABAB receptor agonists baclofen and 3-aminopropylphosphinic acid dose-dependently reduced the frequency of spontaneous discharges, 3-aminopropylphosphinic acid being 10 times less potent than baclofen. These were sensitive to the antagonist CGP 52432 (3-[[3,4-dichloro-phenyl)methyl]-amino]propyl](-P-diethoxymethyl)- phosphinic acid) (1, 5 and 10 microM). The GABA uptake inhibitor NO-711 (1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,5,6-tetrahydro-3-+ ++pyridinecarboxylic acid) (5 and 10 microM) produced 2.9 and 9 fold increases in the potency of 3-aminopropylphosphinic acid without affecting baclofen-induced responses. In this study, the low potency of 3-aminopropylphosphinic acid when compared to baclofen, may be attributed to its uptake by NO-711-sensitive GABA transporters.

Animals↗
PubMed1999

Synthesis and anticonvulsant activity of N-benzyloxycarbonyl-amino acid prodrugs of phenytoin.

Glycine, which has weak anticonvulsant properties, has been shown to potentiate the activity of several antiepileptic drugs but not phenytoin. Recently, studies have shown that N-(benzyloxycarbonyl)glycine (Z-glycine) antagonized seizures more than glycine in addition to possessing activity in the maximal electroshock test, a convulsive model in which glycine is inactive. In the present study esters of 3-hydroxymethylphenytoin, a phenytoin prodrug, and Z-glycine as well as the homologous N-(benzyloxycarbonyl)-omega-amino acids, Z-beta-alanine and Z-gamma-aminobutyric acid (Z-GABA), were prepared and tested for their anticonvulsant and acute neurotoxic activities. The phenytoin prodrugs were obtained by esterification of bis(2-oxo-3-oxazolidinyl)-phosphinic acid chloride-mediated esterification of 3-hydroxymethylphenytoin with the respective N-benzyloxycarbonyl-protected amino acid. The Z-glycine-phenytoin ester was the most active anticonvulsant derivative. Compared with phenytoin the compound exhibited a decreased median effective dose (ED50) in the MES test and an increased median toxic dose (TD50), resulting in an significantly improved protective index expressed as the ratio between TD50 and ED50. The present data suggest that covalent binding of phenytoin to Z-glycine results in an improved pharmacological profile of the drug.

Animals↗
PubMed2004

Limited usefulness of the PFA-100 for the monitoring of ADP receptor antagonists--in vitro experience.

We have evaluated the usefulness of the PFA-100 system (collagen/ADP and collagen/epinephrine cartridges) to assess the in vitro effects of a few platelet function inhibitors: Aspisol (60 microg/ml), 4-[4-[4-(aminoiminomethyl]-1-piperazinyl]-1-piperidineactetic acid, hydrochloride trihydrate (GR144053F, fibrinogen receptor antagonist, 100 nM), adenosine-3',5'-diphosphate (A3P5P, P2Y1 ADP receptor antagonist, 500 microM) and Bis[(adenosine-5'-O-phosphorodithioyl)methylene]-phosphinic acid (APTMPA, P2Y12 ADP receptor antagonist, 500 microM) on platelet function, as compared with the other commonly used diagnostic technique, a whole blood electrical aggregometry (20 microM ADP or 0.5 mM arachidonic acid). The in vitro studies were carried out on a group of 38 subjects. Whereas all the examined platelet antagonists and inhibitors almost completely blocked the 20 microM ADP- or 0.5 mM arachidonic acid-induced (in the case of acetylsalicylic acid) whole blood aggregation, only two inhibitors (Aspisol and GR144053F) remained effective in a significant prolongation of the PFA-100 occlusion time. Otherwise, using the PFA-100 system we were not able to detect the inhibitory actions of ADP receptor antagonists- P2Y1 and P2Y12. Our findings point to a limited usefulness of the PFA-100 system for the monitoring of the effectiveness of ADP receptor antagonists. The outcomes of this study show that platelet aggregometry in whole blood is characterised by the highest sensitivity in the monitoring of the investigated blood platelet inhibitors.

Adenosine Diphosphate↗
PubMed2000

Lack of coupling between GABA release and GABA synthesis in the rat brain via GABA(B) autoreceptors.

GABA is synthesized within GABA terminals through a highly compartmentalized process in which glial-derived glutamine is a major precursor and its release is modulated by GABA(B) autoreceptors. The aim of this work was to ascertain whether or not GABA synthesis and release are coupled in the rat brain through a GABA(B) autoreceptor-mediated modulation. It was found that (-)baclofen (30microM) reduces the K+ stimulated release of [3H]GABA in synaptosomes and prisms (10microM) from cerebral cortex, while at the same concentrations (-)baclofen failed to modify the synthesis of [3H]GABA from [3H]glutamine in cortical and hypothalamic slices, prisms and in cortical synaptosomes. In this latter preparation, identical results were observed when (-)baclofen was added to Krebs-Tris media, containing 5 or 15 mM K+ concentration. In agreement with these latter results, glutamic acid decarboxylase (GAD) activity from cortical and hypothalamic prisms was not affected by 1-100 microM (-)baclofen. Similar results on GABA synthesis were also observed when 1-100 microM 3-aminopropil(methyl)phosphinic acid or GABA was used instead of (-)baclofen to stimulate GABA(B) autoreceptors. [3H]GABA release, [3H]GABA synthesis from [3H]glutamine and GAD activity were also insensitive to the action of the GABA(B) antagonist CGP 52432 (10-100microM). Likewise, muscimol (0.3-100microM) did not affect GABA synthesis. Our results indicate that unlike GABA release, GABA synthesis is not modulated by GABA(B) autoreceptors.

Animals↗