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Biomedical subjects

T W Stone

Publications and source records attributed to T W Stone.

At least 217 records · Page 12Linked to original sources
PubMed1983

Structure-activity studies on the potentiation of benzodiazepine receptor binding by ethylenediamine analogues and derivatives.

The effect of ethylenediamine analogues on in vitro binding of [3H]-diazepam to crude cerebral cortical synaptosomal membranes in the rat was studied. Ethylenediamine significantly increased [3H]-diazepam binding to a maximum potentiation of 154% control (EC50 = 1.8 X 10(-4) M) and was the most active compound studied in terms of both potency and the maximum potentiation observed. Potentiation of [3H]-diazepam binding by ethylenediamine analogues is dependent on carbon-chain length, appears to require two terminal amino groups, and is not observed in the rigid analogues studied. Potentiation of [3H]-diazepam binding by ethylenediamine analogues is mediated largely by a change in receptor number and not receptor affinity. Results are discussed in terms of the possible nature of the ethylenediamine binding site.

Animals↗
PubMed1983

Inhibition by purines of the inotropic action of isoprenaline in rat atria.

The effects of a series of adenosine derivatives were examined on the catecholamine-stimulated electrically-driven rat left atrium in vitro. All the purines tested reduced the positive inotropic action of isoprenaline, 0.1 microM, with the potency order: L-N6-phenlylisopropyladenosine (L-PIA) greater than 5'-N-ethylcarboxamide adenosine (NECA) greater than D-PIA greater than 2-chloroadenosine greater than adenosine. Dipyridamole did not change the IC50 of adenosine. The adenosine deaminase inhibitor, 2'deoxycoformycin, produced a small but nonsignificant shift to the left of the adenosine concentration-response curve. The cardiac depressant effects of these purines were reversed by theophylline and the IC50 values were unchanged in the presence of atropine or in atria taken from reserpine-treated rats. It is concluded that the purine receptor mediating these effects should not be classified on the A1/A2 system. The relationship between functionally characterized purine receptors and those originally defined as modulating adenylate cyclase is discussed.

Animals↗
PubMed1983

Purine receptors in the rat anococcygeus muscle.

Adenosine triphosphate (ATP) caused contraction of the resting isolated rat anococcygeus muscle. Non-phosphorylated purines did not cause contraction of the resting muscle but did so in muscles in which the tone was raised by carbachol or guanethidine. Adenosine, (-)N6-phenylisopropyladenosine (PIA) and 5'-N-ethyl-carboxamide adenosine (NECA) were approximately equipotent, and these responses were not prevented by theophylline, quinidine, 2,2'-pyridylisatogen tosylate, phentolamine, methysergide, dipyridamole, hexobendine or indomethacin. The contractions became smaller as muscle tone progressively declined, and it is suggested that this effect may explain the apparent blockade of ATP responses by indomethacin reported previously. Adenosine, 2-chloroadenosine, ATP, PIA and NECA inhibited contractile responses of the anococcygeus to field stimulation of the excitatory adrenergic innervation. This inhibitory action was blocked by theophylline, and as PIA was easily the most potent purine tested, it may involve activation of an A1/Ri receptor. It is also argued, however, that the A/R scheme of classification may be inappropriate for the description of responses of intact tissues. As response to noradrenaline were not changed by the purines, the inhibitory effect on stimulation-evoked contractions is probably mediated at a presynaptic site. None of the purines tested had any effect on the neurally mediated inhibition of the anococcygeus which is seen when intrinsic tone is raised and the excitatory adrenergic nerves are blocked.

Adenosine↗
PubMed1983

Pharmacology and regional variations of quinolinic acid-evoked excitations in the rat central nervous system.

A physiological and pharmacological investigation of a novel endogenous excitant, quinolinic acid, was carried out in male rats using conventional iontophoretic techniques. It was established that quinolinic acid responses were preferentially reduced by antagonists acting at the N-methyl-D-aspartate (NMDA) preferring receptor, such as (+/-)-2-amino-7-phosphono-heptanoic acid and 1-hydroxy-3-amino-pyrrolidone-2. Glutamic acid diethyl ester reduced responses to quinolinic acid, quisqualic acid and NMDA with no clear specificity. Streptomycin, thought to act at the quisqualic acid receptor, largely spared quinolinic acid responses, being more effective against quisqualic acid evoked excitations. It is therefore suggested that quinolinic acid acts primarily at the NMDA receptor. In addition, the sensitivity of various components of the neuraxis to quinolinic acid was assessed and compared with glutamate and NMDA. Neurons in the spinal cord and cerebellum were largely unresponsive to quinolinate, whereas cells in the neocortex, striatum and hippocampus responded to this agonist to a similar degree as glutamate. In the cortex quinolinate was about one-fifth as active as NMDA, which together with quinolinic acid was much less active in the spinal cord and cerebellum. It is concluded that the possibility that quinolinic acid has a neurotransmitter type function at central "amino acid" receptors merits further investigation.

Animals↗
PubMed1982

Isomers of 2-amino-7-phosphonoheptanoic acid as antagonists of neuronal excitants.

The D(-)-isomer of 2-amino-7-phosphonoheptanoic acid ( (-)APH) was active as an antagonist of N-methyl-D-aspartate (NMDA) excitation of central neurones. The L(+)-isomer was inactive. The antagonism was also selective, kainate and glutamate responses being relatively unaffected. Excitatory responses to ibotenic acid, a neurotoxic amino acid analogue, were less susceptible to blockade by (-)APH than NMDA, but more so than kainic acid. Ibotenate may therefore act partly on NMDA receptors.

2-Amino-5-phosphonovalerate↗
PubMed1982

Nanomolar concentrations of propranolol inhibit GABA-stimulated benzodiazepine binding to rat cerebral cortex.

The influence of propranolol on GABA-stimulated [3H]diazepam binding in the rat cerebral cortex was investigated. Maximum potentiation of GABA-stimulated binding (20.6 +/- 4.5%, P less than 0.05) was observed at 100 microM propranolol, whilst maximum inhibition (32.5 +/- 2.5%, P less than 0.01) was observed at 1 nM propranolol. Low concentrations (1 nM) of (+)-propranolol were observed to be equipotent with (+/-)-propranolol in shifting the dose-response curve of GABA-stimulated [3H]diazepam binding by approximately 1/2 log unit. The phenomenon does not therefore show the stereospecificity observed towards either beta-adrenergic receptors or 5-hydroxytryptamine receptors.

Animals↗
PubMed1982

Cell-membrane receptors for purines. Review.

Purines are involved in many aspects of cell chemistry - intermediary metabolism, nucleic acid synthesis, and the supply of high-energy phosphates to various active transport systems. In addition, however, there appear to be specific receptor molecules located within the plasma membrane of some cells, which mediate changes of cell function in response to purines present in the extracellular fluid. It is the purpose of this review to summarize the kind of functions subserved by those receptors as well as the basic structural requirements for their activation.

Adenosine Triphosphate↗
PubMed1982

Uptake and calcium-dependent release of ethylenediamine (1,2-diaminoethane) by rat brain slices.

The uptake of [14C]ethylenediamine into slices of rat brain and its subsequent evoked release have been studied. An active uptake process was demonstrated by comparing uptake at 37 and 4 degrees C. This uptake showed a Km of 1.36 mM, was partly sodium-dependent and was reduced by nipecotic acid. Release could be readily evoked by 30 mM potassium, and by electrical stimulation, the release in both cases being calcium-dependent. In view of these findings and the reported interactions of ethylenediamine with gamma-aminobutyric acid-related mechanisms, it might be of interest to determine whether this simple diamine occurs endogenously in the mammalian brain.

Animals↗
PubMed1982

Ethylenediamine as a specific releasing agent of gamma-aminobutyric acid in rat striatal slices.

Following incubation with [14C]gamma-aminobutyric acid (GABA) or [3H]dopamine, slices of rat striatum were superfused with media containing 36 mM K+ or ethylenediamine (EDA), 1 or 5 mM. Both K+ and EDA induced a release being largely Ca2+-dependent, while the EDA-induced release was not. Whereas K+ also evoked a Ca2+-dependent release of [3H]dopamine, EDA evoked no release of dopamine. EDA may therefore have potential as a specific GABA releasing agent.

Animals↗
PubMed1982

Ethylenediamine and GABA potentiation of [3H]diazepam binding to benzodiazepine receptors in rat cerebral cortex.

Specific binding of [3H]diazepam at a free concentration of 2 nM was found to be maximally potentiated by 117% in Tris-HCl buffer and 160% in Tris-citrate buffer by ethylenediamine (EDA), but only at relatively high concentrations of EDA (ED50 = 5 X 10(-5) M), although this potentiation was susceptible to a low dose (6 microM) of bicuculline. Dose-response curves show that EDA differs from GABA with respect to both potency and efficacy. In additivity experiments no evidence was found that EDA could act as a partial agonist at GABA receptors, and it was concluded that EDA and GABA apparently do not potentiate [3H]diazepam binding by acting on the same receptor. Scatchard analysis lends support to this hypothesis, indicating that the potentiation of [3H]diazepam binding by 3.16 X 10(-3) M EDA is due to an increase in receptor number (from 930 to 1170 fmol/mg protein) and not receptor affinity (remaining constant about 20 nM). Subsequent studies showed the potentiation to be reversible. It is concluded that EDA can act on the GABA-benzodiazepine receptor ionophore complex but that this is probably not a direct action on the GABA receptor. It is suggested that EDA can be used to differentiate GABA receptors linked to benzodiazepine receptors from those not so linked.

Animals↗
PubMed1982

Comparison of the effects of ethylenediamine analogues and gamma-aminobutyric acid on cortical and pallidal neurones.

1 The actions of ethylenediamine (EDA) and structurally related compounds were investigated by microiontophoresis in Wistar rats. 2 EDA inhibited, via a bicuculline-sensitive mechanism, the spontaneous firing rate of all cortical and pallidal cells tested. 3 The results with the analogues suggest that two amine groups are required for this neuronal depressant action whereas a carboxyl grouping is not. N-substitution reduces the depressant effect. The length of the molecule is also critical, more than 3 methylene components seriously reducing its effectiveness. A rigid analogue of EDA, piperazine, was also active. In addition the apparent transport numbers of EDA and gamma-aminobutyric acid (GABA) were calculated, showing a close similarity between the two. 4 The results are discussed wih respect to the possibility that EDA may represent a new class of GABA-mimetics, or may indicate the existence of a novel diamine receptor mediating bicuculline-sensitive inhibition in the rat CNS.

Animals↗
PubMed1982

The effects of cyclic dicarboxylic acids on spontaneous and amino acid-evoked activity of rat cortical neurones.

1 A series of cyclic dicarboxylic acids were applied by microiontophoresis to neurones in the cerebral cortex of rats anaesthetized with urethane. The object was to examine effects on spontaneous firing rates and any ability to antagonize responses to excitatory amino acids. 2 At relatively low ejecting currents (10-25 nA) cis-2,3-piperidine dicarboxylic acid (cis-2,3-PDA) had no effect on spontaneous firing but selectively antagonized the excitation evoked by n-methyl-D-aspartate (NMDA) without affecting responses to quisqualaife or kainate. At higher ejecting currents (60-100 nA) responses to all three agonists were reduced. 3 Other cis-piperidine dicarboxylic acids and piperazine-2,3-dicarboxylic acid had only weak and variable effects on cell firing and responses to NMDA, quisqualate, kainate, glutamate and aspartate. 4 2, 3-Pyridine dicarboxylic acid (quinolinic acid) produced excitation of all cortical neurones tested. 5 2-Amino-5-phosphono-valeric acid, an NMDA antagonist, reduced responses to quinolinate, implying that this compound can act at NMDA receptors. 6 It is suggested that quinolinic acid may be of physiological interest as a potential endogenous excitant in the nervous system and that cis-2,3-PDA and its N-methyl derivative may be of use in studies of receptor pharmacology and the identification of synaptic transmitters.

Amino Acids↗
PubMed1982

Anticonvulsant actions of the putative gamma-aminobutyric acid (GABA)-mimetic, ethylenediamine.

1 Ethylenediamine, 31.6-1000 mg/kg intraperitoneally, inhibited the convulsive effects of pentylenetetrazol, 100 mg/kg (i.p.) in mice. 2 Ethylenediamine, 100-1000 mg/kg (i.p.) increased the convulsion threshold to the intravenous infusion of three convulsants in the order pentylenetetrazol greater than bicuculline greater than strychnine. 3 The benzodiazepine antagonist R0 15-1788, 10 mg/kg (i.p.), significantly inhibited the anticonvulsant action of diazepam, 50 micrograms/kg, but not ethylenediamine, 1000 mg/kg. 4 These results clearly indicate that ethylenediamine has anticonvulsant properties and are consistent with the hypothesis that ethylenediamine is a gamma-aminobutyric acid (GABA)-mimetic.

Animals↗
PubMed1982

Inhibitory action of gamma-aminobutyric acid on the excitatory but not inhibitory innervation of the rat anococcygeus muscle.

1 The effects of gamma-aminobutyric acid (GABA), ethylenediamine, 3-aminopropane sulphonic acid and (+/-)-baclofen have been examined on the responses to stimulation of the adrenergic excitatory and non-adrenergic non-cholinergic inhibitory innervation of the rat anococcygeus muscle in vitro. 2 GABA produced a dose-related depression of the contractile responses to field stimulation. Ethylenediamine and baclofen also depressed the contractile responses, though they were less potent than GABA. 3-Aminopropane sulphonic acid was almost inactive. The inhibitory action of GABA was not modified by phentolamine, propranolol or bicuculline methylbromide. 3 GABA did not affect the contractile responses of the anococcygeus muscle to noradrenaline, phenylephrine or carbachol in untreated muscles or those treated with 6-hydroxydopamine in vitro. 4 In preparations in which tone was raised by continuous perfusion with carbachol in the presence of phentolamine, field stimulation relaxed the muscle. GABA had no effect on this inhibitory response, and did not itself produce any relaxation. 5 It is concluded that GABA exerts a presynaptic inhibitory action on the excitatory adrenergic but not on the inhibitory innervation of the anococcygeus muscle, and that the GABA receptor involved exhibits properties of the previously described GABAB site.

Animals↗
PubMed1981

Actions of adenine dinucleotides on the vas deferens, guinea-pig taenia caeci and bladder.

Adenine dinucleotides such as beta-NAD, alpha-NAD, NADP, 3-aminopyridine adenine dinucleotide, flavin adenine dinucleotide, 3',5'-and 2',5'-adenylyladenosine mimicked the inhibitory effects of adenosine and adenine nucleotides on electrically evoked contractions of the rat and mouse isolated superfused vas deferens. The inhibitory effects were blocked by theophylline or adenosine deaminase, unaffected by the nucleotidase inhibitor alpha, beta-methylene ADP and enhanced by inhibition of adenosine deaminase. The inhibitory effects were associated with a release of purines from the vasa after preloading with [3H]adenosine. It is suggested that these compounds activate a receptor, causing the release of adenosine which is largely responsible for the inhibitions. Diadenosine pyrophosphate and triphosphate caused only depression of the vas twitch, whereas the pentaphosphate and hexaphosphate derivatives caused contraction, followed by inhibition at higher concentrations. These inhibitions were only partly reduced by theophylline or deaminase, but both contractile and inhibitory effects were enhanced by alpha, beta-methylene ADP. Noradrenaline contractions were also reduced by the higher polyphosphates. It is suggested that there may be a receptor for these dinucleotides, located at least in part postjunctionally. The pentaphosphate and hexaphosphate compounds mimicked the effects of nerve stimulation on the guinea-pig bladder, being substantially more potent than beta, gamma-methylene-ATP, and on the taenia caeci, where contraction or relaxation could be produced depending on resting tone.

Adenine Nucleotides↗