Coronary arteriovenous fistula--a local epidemic.
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Coronary Vessel Anomalies↗
Biomedical subjects
M J Neal
Publications and source records attributed to M J Neal.
Taurine uptake processes in the isolated rabbit retina and the effects of light.
As part of a study on the mechanisms involved in regulating photoreceptor taurine levels, we have examined the characteristics of [3H]-taurine uptake by the isolated rabbit retina. The effects of light on taurine accumulation have also been studied. Rabbit retinas quickly accumulated [3H]-taurine and tissue: medium ratios of 50:1 were attained after 60 min incubation at 37 degrees C. Under these conditions no metabolites of [3H]-taurine were detected in the tissue. The efflux of [3H]-taurine from the retina was extremely slow, less than 5% of the accumulated radioactivity being released in a 30 min incubation in fresh medium. Thus, in subsequent experiments the accumulation of radioactivity was taken as a measure of [3H]-taurine uptake. Non-linear regression analysis of kinetic data revealed that taurine was accumulated by separate high- and low-affinity transport processes, the kinetic parameters being Kmh = 93 +/- 12 microM; Vmh = 72 +/- 7; KmL = 8.8 +/- 5 mM; VML = 274 +/- 79 nmol min-1 g-1 wet weight respectively. The properties of the high- and low-affinity taurine uptake processes were very similar. Both were temperature sensitive, particularly between 25 and 37 degrees C and sodium- and chloride-dependent, and were inhibited by metabolic inhibitors. The substrate specificities of the high- and low-affinity uptake processes were also similar, both processes being inhibited by beta-alanine, guanidinoethylsulphonate (GES) and GABA, but not by alpha-alanine or glycine. Hypotaurine selectively inhibited the high-affinity uptake process for [3H]-taurine. Exposure of retinas to continuous light did not affect either the high- or the low-affinity uptake of [3H]-taurine compared with dark-adapted controls. However, flickering light (0.5-30 Hz, 25% duty cycle) reduced the high-affinity accumulation of [3H]-taurine by as much as 50%. The reduction in [3H]-taurine may be due to a localized decrease in uptake (or possibly an increased release) by the photoreceptors because the same reduction was found when synaptic transmission in the retina was blocked by exposure to medium containing high Mg/low Ca. High Mg/low Ca did not itself affect taurine accumulation.
Amino Acids↗
Effect of gamma-aminobutyric acid agonists, glycine, taurine and neuropeptides on acetylcholine release from the rabbit retina.
The light-evoked release of [3H]acetylcholine (ACh) from the rabbit retina in vivo was measured and taken as an index of cholinergic amacrine cell activity. The light-evoked release of [3H]ACh was reduced by locally applied gamma-aminobutyric acid (GABA), muscimol and 3-aminopropanesulphonic acid (3-APS). The concentrations of these drugs which reduced the light-evoked release of [3H]ACh by 50% (EC50) were 900, 0.3 and 5 microM respectively. In contrast, (-)-baclofen (5 mM), but not (+)-baclofen, significantly increased the light-evoked release of [3H]ACh. The GABA antagonist, bicuculline increased the resting release of [3H]ACh but abolished the inhibitory action of muscimol on the light-evoked release of [3H]ACh. Glycine and taurine also reduced the light-evoked release of [3H]ACh from the retina, their EC50 values being 1.5 and 0.3 mM respectively. This action was blocked by strychnine, but not by bicuculline. In contrast to the GABA antagonist, strychnine did not affect the spontaneous resting release of [3H]ACh. Retinal [3H]ACh release was not affected by dopamine, 5-hydroxytryptamine (5-HT) morphine, substance P, somatostatin, cholecystokinin sulphate, thyrotropin releasing hormone, luteinizing hormone releasing hormone or angiotensin. Electroretinographic changes produced by amino acids and GABA agonists involved mainly the b-wave and were not correlated with their effects on ACh release. Thus, GABA increased the b-wave amplitude, 3-APS had no effect, whilst muscimol, taurine and glycine either had no effect, or reduced the b-wave amplitude. No obvious changes in the e.r.g. were produced by baclofen, dopamine, 5-HT, morphine or any of the peptides studied with the exception of somatostatin, which reduced the amplitude of the b-wave. It is concluded that cholinergic amacrine cell activity in the rabbit retina may be affected by inputs from other amacrines using GABA or glycine (taurine) as their transmitters, but probably not by inputs from peptidergic or dopaminergic amacrine cells. Our experiments do not provide evidence on the sites of action of GABA, glycine or taurine but the action of bicuculline on the resting release of ACh implies that the activity of the cholinergic amacrine cells is affected by a tonically active GABAergic input.
Acetylcholine↗
Evidence for a cholinergic inhibitory feed-back mechanism in the rabbit retina.
The effects of muscarine, atropine and nicotinic antagonists on the light-evoked release of radioactivity from rabbit retinas previously exposed to [3H]choline (Ch) was studied. On the basis of previous experiments, this light-evoked release of total radioactivity was taken as a measure of the light-evoked release of [3H]acetylcholine (ACh) from the cholinergic amacrine cells. Atropine (1 microM) in the presence, but not the absence, of eserine more than doubled the light-evoked release of [3H]ACh. Eserine (30 microM) itself had no significant effect on either the spontaneous resting release or the light-evoked release of [3H]ACh. Muscarine (10 microM) in the presence or absence of eserine reduced the light-evoked release of [3H]ACh from the retina by 50%. This effect of muscarine was blocked by atropine used in the absence of eserine. The nicotinic antagonists pempidine, hexamethonium and gallamine had no significant effect on retinal [3H]ACh release. Strychnine (20 microM), which alone had no effect on retinal [3H]ACh release, abolished the effects of both muscarine and atropine on the light-evoked release of [3H]ACh. Bicuculline (5 microM) did not affect the actions of muscarine or atropine on the light-evoked release of [3H]ACh. Previous experiments had shown that glycine and gamma-aminobutyric acid (GABA) reduce the light-evoked release of [3H]ACh from the retina and that these inhibitory effects are selectively blocked by strychnine (20 microM) and bicuculline (5 microM) respectively. These results suggest the presence in the retina of a cholinergic inhibitory feed-back mechanism which involves a neuronal loop, rather than presynaptic or post-synaptic inhibitory muscarinic receptors on the cholinergic amacrine cells themselves. Our experiments do not provide evidence on the nature of the proposed inhibitory loop, except that it apparently includes a glycinergic or taurinergic (amacrine) cell.
Acetylcholine↗
The contrasting effects of neuroleptics on transmitter release from the nucleus accumbens and corpus striatum.
The effects of haloperidol, chlorpromazine and clozapine on transmitter release have been studied by measuring the simultaneous release of dopamine and acetylcholine from tissue slices of nucleus accumbens and striatum in vitro following in vivo drug application, either a single dose or daily for periods of up to 25 days. In the striatum, both single and chronic injections of haloperidol (1 and 2 mg. kg-1) caused a large and significant enhancement (up to 83%) of the K+-evoked release of [3H]acetylcholine synthesized from [3H]choline. In contrast, in the nucleus accumbens, the K+-evoked release of [3H]acetylcholine was not significantly affected by neuroleptics when compared with the controls which received injection of vehicle. Clozapine (50 mg.kg-1) also enhanced the K+-evoked release of [3H]acetylcholine relative to the resting release but the effect was smaller than that with haloperidol or chlorpromazine. The evoked release of preloaded [14C]dopamine from either nucleus accumbens or striatum was unaffected by treatment with haloperidol. However, chlorpromazine (25 mg.kg-1) and clozapine (50 mg.kg-1) significantly enhanced the evoked release of preloaded [14C]dopamine from tissue slices of striatum. A similar but reduced effect of enhancing release was also seen in the nucleus accumbens in response to chlorpromazine. In support of these results, dopamine itself applied in vitro induced an opposite effect to that of the neuroleptics. Thus in the striatum, dopamine (4 x 10(-4) M) markedly reduced the release of [3H]acetylcholine (45%). A smaller inhibition was also seen in the nucleus accumbens (25%).
Acetylcholine↗
Potassium activation of [3H]-choline accumulation by isolated sympathetic ganglia of the rat.
1 The effect of K-depolarization on the uptake of low and high concentrations of [3H]-choline by isolated superior sympathetic ganglia of the rat has been studied. 2 In unstimulated ganglia, the uptake of [3H]-choline (0.1 microM) ('high affinity uptake') was unaffected by denervation or by hemicholinium-3 (HC-3), suggesting uptake by structures other than cholinergic nerve terminals. 3 K-depolarization of the ganglia increased [3H]-choline accumulation by the high affinity uptake process but in contrast the 'low affinity' accumulation of [3H]-choline (100 microM) was decreased. 4 The K-activated, 'high affinity' component of choline uptake was highly sodium-dependent, inhibited by HC-3, and was abolished by denervation. 5 In incubation conditions designed to prevent transmitter release (Ca-free medium and high-Mg medium), the K-activated uptake of [3H]-choline was abolished. 6 It is concluded that in unstimulated ganglia, there is little choline uptake by nerve terminals. However, when the terminals are depolarized, choline uptake is increased by the activation of a sodium-dependent, HC-3-sensitive transport process. The activation of this uptake process is apparently associated with the release of acetylcholine from the terminals, or by changes in ionic fluxes, and not by the depolarization per se.
Animals↗
Effect of potassium depolarization and preganglionic nerve stimulation on the metabolism of [3H]-choline in rat isolated sympathetic ganglia.
1 The effects of potassium depolarization and preganglionic nerve stimulation on the metabolism of [(3)H]-choline in the isolated superior sympathetic ganglion of the rat have been studied.2 When unstimulated (resting) ganglia were incubated for 10 min with a low concentration (0.1 muM) of [(3)H]-choline (high affinity uptake), approximately 75% of the accumulated radioactivity was present as [(3)H]-phosphorylcholine, 11% was [(3)H]-acetylcholine ([(3)H]-ACh) and the remainder was unchanged [(3)H]-choline.3 Depolarization of the ganglia with K (46 mM) before their incubation with [(3)H]-choline, increased [(3)H]-choline uptake by 70% and increased [(3)H]-ACh synthesis by more than 700%, so that [(3)H]-ACh represented almost 50% of the total radioactivity recovered. In contrast, the proportion of [(3)H]-phosphorylcholine fell to 36% of the total radioactivity recovered.4 The striking effect of K-depolarization on [(3)H]-ACh synthesis in ganglia occurred at a concentration of 30 mM or above, and the maximum effect was seen at 45-50 mM.5 Chronic denervation of the ganglia abolished all the effects of high-K on [(3)H]-choline metabolism. In resting ganglia, [(3)H]-ACh formation was reduced by over 80% but [(3)H]-phosphorylcholine synthesis and the level of unchanged [(3)H]-Ch were not affected by denervation.6 Exposure of the ganglia to low-Na or hemicholinium-3 (HC-3) greatly reduced [(3)H]-ACh synthesis in control resting ganglia and almost abolished the effects of high-K on [(3)H]-ACh synthesis.7 Prevention of transmitter release with high-Mg or low-Ca medium also prevented K-depolarization from stimulating [(3)H]-ACh synthesis.8 Preganglionic nerve stimulation had an effect on [(3)H]-choline metabolism similar to that of K-depolarization. Thus, at all the frequencies studied (1-30 Hz), [(3)H]-ACh synthesis was greatly increased and [(3)H]-phosphorylcholine was reduced, the maximum effects occurring at 3 Hz.9 When ganglia were incubated with a high concentration (100 muM) of [(3)H]-choline (low affinity uptake), a different pattern of metabolism was observed. Most of the radioactivity in resting ganglia was present as unchanged [(3)H]-choline (70%) with [(3)H]-phosphorylcholine and [(3)H]-ACh representing 23% and 6% of the total radioactivity respectively. K-depolarization decreased [(3)H]-choline uptake but increased the proportions of [(3)H]-phosphorylcholine and [(3)H]-ACh to 32% and 24% of the total radioactivity respectively.10 It is concluded that in unstimulated (resting) rat sympathetic ganglia most of the [(3)H]-choline transport and metabolism occurs in postsynaptic structures. However, depolarization of the presynaptic nerve terminals appears to trigger a sodium-dependent, HC-3 sensitive, high-affinity uptake process, and causes a dramatic increase in presynaptic [(3)H]-ACh synthesis together with a fall in postsynaptic [(3)H]-phosphorylcholine synthesis. These changes in choline metabolism cannot be due to the depolarization of the nerve terminals per se, because they were abolished by high-Mg or low-Ca, i.e. when transmitter release was prevented. Thus, the increase in ACh synthesis may be triggered by a fall in the intraterminal concentration of ACh or by the changes in Ca flux induced by depolarization. Our experiments do not provide evidence on these possible mechanisms.
Animals↗
The effect of 2-amino-4-phosphonobutyrate (APB) on acetylcholine release from the rabbit retina: evidence for on-channel input to cholinergic amacrine cells.
The light-evoked release of acetylcholine (ACh) from the rabbit retina was taken as a measure of cholinergic amacrine cell activity. The glutamate analogue DL-(+/-)-2-amino-4-phosphonobutyric acid (APB) prevented the light-evoked release of ACh and also selectively abolished the ON-responses of ganglion cells and the ERG b-wave. It is concluded that the input to cholinergic amacrine cells involves mainly the depolarizing bipolar cells, which subserve ON-channels. L-(+)-stereoisomer of APB was 15 times more potent than the D-(-)-isomer in suppressing ACh release and the b-wave, suggesting that the mechanism of action of APB does not involve antagonism of excitatory amino acids.
2-Amino-5-phosphonovalerate↗
The radioautographical localization in the vertebrate retina of [3H]-(+ or -)-cis-aminocyclohexane carboxylic acid (ACHC); a selective inhibitor of neuronal GABA transport.
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Amino Acids↗
Interaction of chlorpromazine with tea and coffee.
1 The interaction between phenothiazine neuroleptics with tea and coffee was studied in vitro. 2 Filtered infusions of tea and coffee caused precipitation of all the neuroleptics studied. Tea always caused a heavier precipitate than coffee. 3 The constituent or constituents of tea and coffee responsible for precipitating the neuroleptics was not identified. Solutions of caffeine, caffeine citrate and sodium chloride did not form a precipitate with chlorpromazine but precipitates were formed by sodium salicylate, sodium benzoate and trisodium citrate. 4 The interaction between chlorpromazine (CPZ) and tea was studied quantitatively using radiolabelled drug and it was found that the precipitation of [3H]-CPZ with a given quantity of tea was 'saturable'. The proportion of CPZ precipitated by a 'standard cup of tea' was 80% at low doses of the drug (10-40 mg) whilst at high doses (800 mg), the proportion of the drug precipitated was approximately 20%. 5 The interaction was further studied in vivo by the oral administration of tea and CPZ to rats. The cataleptic effect of CPZ was significantly reduced by the simultaneous administration of tea and this was apparently not due to the caffeine present in tea. 6 The results suggest that a substantial proportion of orally administered neuroleptic may be precipitated as a highly insoluble compound if coffee, or more especially tea, is taken close to drug administration. This interaction might affect the absorption of phenothiazines given orally to patients.
Animals↗
On the mechanism by which veratridine causes a calcium-independent release of gamma-aminobutyric acid from brain slices.
1 The mechanisms by which veratridine increases the release of gamma-aminobutyric acid (GABA) from brain slices have been studied.2 Exposure of superfused cerebro-cortical, nigral or cerebellar slices to veratridine (5 muM) or KCl (50 mM) caused large increases in the efflux of [(3)H]-GABA.3 Reduction of the external Ca concentration [Ca](o) to zero had strikingly different effects on the veratridine and K-evoked release of [(3)H]-GABA. The K-evoked release from all three areas was greatly reduced in Ca-free medium, but the veratridine-evoked release from cerebeller slices was not affected, and the release of [(3)H]-GABA from cortical and nigral slices was increased three fold. The potentiation of the veratridine evoked release of GABA which occurred in Ca-free medium was not due to the reduction in divalent ions, because it still occurred in medium in which the Ca was replaced by an equivalent amount of Mg.4 The veratridine-evoked release of [(14)C]-glycine from slices of spinal cord was also significantly increased in Ca-free medium. In contrast, the release of cortical [(3)H]-noradrenaline and [(14)C]-acetylcholine caused by the alkaloid was greatly diminished in Ca-free medium.5 The veratridine but not the K-evoked release of [(3)H]-GABA was abolished when the external Na concentration [Na](o) was reduced to zero and by tetrodotoxin (TTX) (0.2 muM). Cl-free medium did not affect the veratridine-evoked release of [(3)H]-GABA or its potentiation by Ca-free medium.6 Exposure of the tissue to depolarizing concentrations of external K ([K](o) = 120 mM) did not abolish the veratridine evoked release of [(3)H]-GABA or its potentiation by Ca-free medium.7 Pre-incubation of cortical slices with L-2,4, diaminobutyric acid (DABA), or substitution of Na in the superfusion medium with Li, did not affect the veratridine-evoked release of [(3)H]-GABA, indicating that the alkaloid does not stimulate GABA efflux by a carrier-mediated transport process.8 Exposure of the tissue to ruthenium red (10 muM) increased the veratridine evoked release of [(3)H]-GABA in both normal and in Ca-free medium but almost abolished the K-evoked release.9 It is suggested that veratridine causes GABA release by increasing the permeability of the nerve terminals to Na. In normal medium, the resulting influx of Ca(2+) ions through voltage-dependent Ca(2+) channels may be involved in triggering the release of GABA. However, a major part of the GABA efflux appears to be triggered by the release of Ca(2+) ions from intraterminal mitochondria, which results from the increase in[Na](i). Since Ca(2+) ions antagonize the action of veratridine, the potentiation of the drug-evoked release of GABA that occurs in Ca-free medium, might be due to the absence of the antagonistic Ca(2+) ions. The resulting greater increase in Na entry and [Ca](i) caused by Ca release from intracellular stores, must presumably more than balance the contribution normally made by any influx of extracellular Ca(2+).
Acetylcholine↗
Effect of tetanus toxin on transmitter release from substantia nigra and striatum in vitro.
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Acetylcholine↗
The uptake and radioautographical localization in the frog retina of [3H](+/-)-aminocyclohexane carboxylic acid, a selective inhibitor of neuronal GABA transport.
The accumulation of [3H](+/-)-cis-3-aminocyclohexane carboxylic acid ([3H] ACHC) in frog retinae in vitro was highly localized in horizontal cells and their processes. [3H]GABA was also mainly accumulated within horizontal cells, but [3H]L-2,4-diaminobutyric acid ([3H]DABA) was taken up predominantly by the neuroglial Müller cells, whilst [3H]beta-alanine was localised largely within the photoreceptors. The uptake of [3H]ACHC (4.2 microM) was almost linear for 30 min and after 60 min a tissue/medium ratio of 5.25 was achieved. The uptake process was temperature sensitive highly dependent on sodium ions, and appeared to be mediated by a saturable transport process with an IC50 value of 0.83 mM. The accumulation of [3H]ACHC was inhibited by GABA and DABA (IC50 = 0.32 mM and 0.23 mM, respectively) whilst beta-alanine was a relatively weak inhibitor (IC50 = 9 mM) of ACHC uptake. In agreement with these results, the efflux of [3H]ACHC from the retina was increased by exposure to ACHC, GABA and DABA but not beta-alanine. In contrast, the efflux of [3H]DABA from the retina was not increased by GABA or ACHC, although DABA itself and potassium depolarization stimulated the release of [3H]DABA. These results strongly suggest that ACHC is accumulated in the frog retina by the same neuronal transport process as GABA. In contrast, the high affinity sites for DABA are localized mainly in glia, although inhibitor and release studies suggest that, at high concentration, DABA also interacts with the neuronal GABA (ACHC) transport process.
Alanine↗
Differential effects of veratridine and potassium depolarization on neuronal and glial GABA release.
The effect of veratridine and potassium depolarization on the release of [3H]GABA from neural tissues in which GABA uptake is neuronal (cerebrocortical slices and frog retina) or glial (rat retina, spinal and sympathetic ganglia) was studied. The 'neuronal' but not the 'glial' release of [3H]GABA was greatly increased by KC1 (25 mM) and veratridine (10 microM). The 'neuronal' release of [3H]GABA evoked with KC1 was calcium dependent but the small potassium induced increase in 'glial' release were not reduced in the absence of calcium ions even when additional Mg2+ was included in the medium. Surprisingly, the veratridine induced release of [3H]GABA from cortical slices was greatly potentiated in calcium free medium although the release of [3H]noradrenaline produced by veratridine was calcium dependent. Because of the insensitivity of the glial GABA release mechanism to potassium depolarization, it is concluded that release of endogenous GABA from glial pools in response to physiological increases in extracellular potassium is unlikely to be important.
Animals↗
Inhibition of aspartate release from the retina of the anaesthetised rabbit by stimulation with light flashes.
Rabbits were anaesthetised and the cornea, iris, lens and vitreous were removed from eyes to form an eye-cup which was filled with Krebs-bicarbonate Ringer. The medium in the eye-cup was replaced at 10-min intervals and the amino acids in each resulting sample were assayed. Exposure of the dark-adapted retina to flashes of light (3 Hz) did not alter the efflux of glutamate glutamine, alanine, glycine or GABA. The efflux of taurine and ACh was greatly increased by light flashes, but in contrast, the release of aspartate was reduced by more than 50%, a result consistent with the suggestion that aspartate may be a photoreceptor transmitter substance.
Anesthesia, General↗
The light evoked release of acetylcholine from the rabbit retina iN vivo and its inhibition by gamma-aminobutyric acid.
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Acetylcholine↗
Release of [3H]-acetylcholine from the isolated retina of the rat by potassium depolarization: dependence on high affinity choline uptake.
1. The effect of potassium depolarization on the release of [3H]-acetylcholine ([3H]-ACh) from the isolated retina of the rat was studied. 2. Exposure of retinae to medium containing KCl (50 mM) evoked a large increase in the efflux of [3H]-ACh with only a small concurrent increase in the efflux of [3H]-choline. The KCl-evoked release of [3H]-ACh was almost abolished in calcium-free medium. 3. Incubation of retinae with [3H]-choline in sodium-free medium, or medium containing hemicholinum-3 (HC-3), procedures that are believed to inhibit selectively the high affinity choline transport system, reduced the retinal uptake of [3H]-choline by approximately 50% and the synthesis of [3H]-ACh by about 97%. 4. The potassium-evoked release of [3H]-ACh was almost abolished in retinae that had been loaded with [3H]-choline in sodium-free medium or medium containing HC-3, and subsequently superfused in normal medium. 5. It is suggested that as in other areas of the nervous system, a sodium-dependent, high affinity uptake system for choline is important in retinal cholinergic nerve terminals.
Acetylcholine↗
Effect of tetanus toxin on uptake and potassium-evoked release of radio-labelled transmitters from the substantia nigra and striatum of the rat [proceedings].
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Animals↗