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PubMed1998

Barbiturates decrease the expression of vascular endothelial growth factor in hypoxic cultures of porcine brain derived microvascular endothelial cells.

Vascular endothelial growth factor (VEGF) is known to be produced in higher amounts during hypoxia by a variety of cell types and has been shown to increase the permeability of brain derived microvascular endothelial cells (BMEC) during hypoxia by an autocrine mechanism. Because the barbiturates, methohexital (MH) and thiopental (TP), induced a dose-dependent reduction in hypoxia-induced permeability changes of BMEC, the effect of both barbiturates on the VEGF expression during hypoxia was investigated. Both barbiturates decreased the hypoxia-induced expression of VEGF in BMEC in a concentration-dependent manner. This effect is partly caused by the impairment of the hypoxia-induced VEGF mRNA stabilization. VEGF-induced permeability changes during normoxia were unaffected by the barbiturates suggesting that MH and TP are directly reducing hypoxia-induced VEGF synthesis. In conclusion, the inhibiting effect of these barbiturates on the hypoxia-induced VEGF expression results in the decreased permeability of the BMEC monolayer during hypoxia, which may contribute to the described neuroprotective action of barbiturates by reduction of brain edema formation.

Adenosine↗
PubMed1979

Barbiturate protection in tolerant and nontolerant hypoxic mice: comparison with hypothermic protection.

The effects of pentobarbital on survival times of mice exposed to oxygen, 5 per cent, were studied over a large dosage range in normal mice and in mice made tolerant to the effect of barbiturates. Tolerance was induced by pretreatment with phenobarbital, 210 mg/kg, for three days, which increased the median anesthetic dose (AD50) for pentobarbital from 34 to 53 mg/kg. In nontolerant mice there was a dose-related increase in mean survival times for doses between 35 and 60 mg/kg, with a maximum increase to 303 per cent above control. At doses of more than 60 mg/kg survival times progressively decreased toward control. For tolerant mice survival time as a function of pentobarbital dosage was shifted to the right, i.e., protection necessitated higher doses. This shift was not explained by lower brain concentrations of pentobarbital in tolerant animals, but rather parallelled the increased tolerance to the anesthetic effect of the barbiturate. The authors conclude that in this model the protective effect of barbiturate is a function of the anesthetic effect rather than the barbiturate concentration in brain per se. Hypothermia (29 C) resulted in an increase in mean survival time comparable to that in barbiturate-treated animals. This supports the hypothesis that protection is ultimately a function of decreased cerebral metabolism, whether produced by anesthesia or by hypothermia. This model measures only the effect on spontaneous respiration during hypoxia. It is possible that other mechanisms are involved if barbiturates protect in other situations, such as during or after periods of complete ischemia.

Animals↗
PubMed1999

Blockade of glutamate receptors and barbiturate anesthesia: increased sensitivity to pentobarbital-induced anesthesia despite reduced inhibition of AMPA receptors in GluR2 null mutant mice.

BACKGROUND: Barbiturates enhance gamma-aminobutyric acid type A (GABA(A)) receptor function and also inhibit the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype of glutamate receptor. The relative contribution of these actions to the behavioral properties of barbiturates is not certain. Because AMPA receptor complexes that lack the GluR2 subunit are relatively insensitive to pentobarbital inhibition, GluR2 null mutant mice provide a novel tool to investigate the importance of AMPA receptor inhibition to the anesthetic effects of barbiturates. METHODS: GluR2 null allele (-/-), heterozygous (+/-), and wild-type (+/+) mice were injected with pentobarbital (30 and 35 mg/kg intraperitoneally). Sensitivity to anesthetics was assessed by measuring the latency to loss of righting reflex, sleep time, and the loss of corneal, pineal, and toe-pinch withdrawal reflexes. In addition, patch-clamp recordings of acutely dissociated CA1 hippocampal pyramidal neurons from (-/-) and (+/+) mice were undertaken to investigate the effects of barbiturates on kainate-activated AMPA receptors and GABA-activated GABA(A) receptors. RESULTS: Behavioral tests indicate that sensitivity to pentobarbital was increased in (-/-) mice. In contrast, AMPA receptors from (-/-) neurons were less sensitive to inhibition by pentobarbital (concentrations that produced 50% of the maximal inhibition [IC50], 301 vs. 51 microM), thiopental (IC50, 153 vs. 34 microM), and phenobarbital (IC50, 930 vs. 205 microM) compared with wild-type controls, respectively. In addition, the potency of kainate was greater in (-/-) neurons, whereas no differences were observed for the potentiation of GABA(A) receptors by pentobarbital. CONCLUSIONS: The GluR2 null mutant mice were more sensitive to pentobarbital anesthesia despite a reduced sensitivity of GluR2-deficient AMPA receptors to barbiturate blockade. Our results indicate that the inhibition of AMPA receptors does not correlate with the anesthetic effects of barbiturates in this animal model. We postulate that the increase in the sensitivity to anesthetics results from a global suppression of excitatory neurotransmission in GluR2-deficient mice.

Alleles↗
PubMed1991

Paradoxical Modulation of Nociception in Mice by Barbiturate Agonism and Antagonism: Is a GABA Site Involved in Nociception?

In a battery of four acute and chronic nociceptive tests, the GABA antagonist picrotoxin produces a uniform and sustained analgesia in mice. By contrast, barbiturates which have been presumed to act at the same receptor produce mixed and paradoxical actions. At a standard time of 10 min after drug administration a convulsant barbiturate [5-ethyl-5-(3'-methyl-but-2'-enyl)-barbituric acid] produced analgesia in three tests but had no effect in the fourth; a pure hypnotic barbiturate (amylobarbitone) produced hyperalgesia in three tests but analgesia in the fourth; while the mixed hypnotic-convulsant pentobarbitone produced hyperalgesia in two of the tests and was without any effect in the other two. There was no pattern in these results with respect to acute or chronic nociceptive tests. Surprisingly, with extended observation using the tail-flick test both pentobarbitone and the pure hypnotic (amylobarbitone) gave early hyperalgesia followed by analgesia; the convulsant barbiturate gave only analgesia. The results suggest a role for GABAA receptors in the transmission of nociceptive information; they also suggest that barbiturates act at quite a different receptor.

Journal Article↗
PubMed1978

Reversal of the action of amino acid antagonists by barbiturates and other hypnotic drugs.

1 The effects of pentobarbitone (PB) and other sedative/hypnotic drugs have been examined in relation to gamma-aminobutyric acid (GABA) in vitro on the superfused isolated superior cervical ganglion of the rat and in vivo on single units in the brain stem of the anaesthetized rat.2 PB, and other barbiturates, depolarized the ganglion in a dose-dependent manner (threshold concentration 100-300 muM, cf. GABA depolarization threshold 1 muM). The depolarization was reduced in the presence of the selective GABA antagonist (+)-bicuculline methochloride (Bic). Other non-barbiturate sedatives e.g. chlordiazepoxide, amitriptyline, promethazine at concentrations up to 2mM produced no depolarization.3 PB, tested at concentrations up to 80 muM, produced variable effects on the dose-response curve to GABA. On most occasions a slight potentiation occurred in responses to low concentrations of GABA (below 10 muM) coupled with a depression in the responses to concentrations of GABA greater than 10 muM.4 Superfusion with PB in the presence of Bic reversed the depression in the response to GABA produced by Bic. This reversal phenomenon occurred at concentrations of PB too low to depolarize the ganglion and was dependent not only on the concentration of PB but also on that of Bic.5 The reversal potency within an homologous series of barbiturates increased with the size of the alkyl substituent (R2) at C5 on the barbiturate ring. The most potent occurred when the substituent contained 5 carbon atoms (pentobarbitone and amylobarbitone); above this, activity decreased.6 PB reversed the effects of the other GABA antagonists, tetramethylenedisulphotetramine and isopropyl bicyclophosphate and also the non-selective antagonism produced by strychnine. A concomitant reduction by strychnine of responses to the cholinomimetic, carbachol, was not reversed by PB.7 Non-barbiturate sedative/hypnotics also reversed the GABA antagonism produced by Bic. The benzodiazepines were effective at lower concentrations than PB (chlordiazepoxide threshold concentration 0.5 muM, cf. PB 5 muM), however, they only produced a partial reversal even at concentrations much higher than the maximally effective concentration of PB.8 The Bic reversal effect of chloridazepoxide (and other benzodiazepines) lasted many hours after removal from the superfusion solution. By contrast the effect of PB lasted only 15-30 min after its removal.9 Chlordiazepoxide (30 muM) applied in the absence of Bic did not affect the response to GABA but did reduce the depression produced by the subsequent application of Bic even though the chlordiazepoxide had been removed 40 min earlier.10 In the rat brain stem in vivo PB, applied iontophoretically in amounts which neither decreased the spontaneous neuronal firing rate nor affected the response to GABA or glycine, reversed the GABA antagonism induced by iontophoretic application of Bic (in all 23 neurones tested). PB also reversed the antagonism produced by strychnine of responses to glycine although this was less readily observed (5 out of 14 neurones tested).11 Iontophoretic application of other barbiturates and chlordiazepoxide also reversed the effect of Bic. Chlordiazepoxide only produced a partial reversal, as in the isolated ganglion, and no reversal could be demonstrated with flurazepam.12 Intravenous administration of thiopentone (1.3 mg/kg) pentobarbitone (0.4-5.5 mg/kg) hexobarbitone (0.4-0.8 mg/kg) and clonazepam (0.1-0.2 mg/kg) also reversed the effect of iontophoretically applied Bic. The reversal by clonazepam was of much longer duration than that produced by the barbiturates.13 It is suggested that the reversal exhibited by PB and the other hypnotics may be explained by assuming that the amino acids and their antagonists bind to the membrane at separate sites. If the reversal agent has particular affinity only for the antagonist binding site then it may displace the antagonist without affecting the receptor.

Aminobutyrates↗
PubMed1978

[Hemodynamic and metabolic effects of barbiturates on the human central nervous system].

Anoxic cerebral ischemia results in an almost instantaneous stoppage of the EEG, and a depletion of the cerebral energy reserves with anaerobic orientation. The experimental work, especially of Safar and Michenfelder, have proven the significant cerebral protection under barbituric hypometabolism. The cerebral impacts of barbiturates in the animal, in vitro and in vivo, are multiple: decrease in glycolysis, energetic stabilisation, a blocking of the adenylcyclase activity, membrane stabilisation by trapping of the free radicals or by an increase of the cerebral osmolarity, ect... In man, the metabolic and the hemodynamic data, of which there is little, have only confirmed the reports of metabolic and circulatory depression made by Himwich as early as 1947. The use of barbiturates in postischemic protection poses a problem of their specificity. For an equivalent cerebral metabolic depression a protective effect could not be proven with the tilisation of halogens nor with the morphines... Other narcotics (Alfatésine, Gamma OE) also depress the CNS, but their protective effects are unknown. MICHENFELDER attributes the barbituric protection to the "functional neuron" block without interference at the metabolic level of cellular life. The specificity of barbiturates in this block has yet to be proven. In the post-ischemic resuscitation, Safar insists, and rightly so, on the urgency to correct the cerebral hypoperfusion with a parallel barbituric induction. If there is no "specificity" in the narcotic hypometabolism, it would be logically imperative to use that which provides the best protection, in the shortest, delay, and with the least systemic depression.

Adenine Nucleotides↗
PubMed1976

Permethylation of barbiturates: variation in product ratios with varying methylsulfinylmethide carbanion.

Permethylation of a barbiturate with the methylsulfinylmethide carbanion and methyl iodide gave three products clearly separable by GLC. Alteration of the reaction conditions by varying the barbiturate to carbanion ratio or the barbiturate to carbanion exposure time resulted in a single product for only one examined barbiturate, secobarbital. This derivatization technique is useful for the GLC analysis of polar barbiturate metabolites, such as glucuronides, in biological fluids but is of limited value for the analysis of the parent compounds.

Barbiturates↗
PubMed1981

Solubility behavior of barbituric acids in aqueous solution of sodium alkyl sulfonate as a function of concentration and temperature.

The solubility of 13 barbituric acids was determined in aqueous solutions of sodium alkyl sulfonate. The effects of concentration and temperature were investigated, and the thermodynamic functions of the solubilization process were calculated. An analysis of the location of a solubilized species within a micelle is suggested in terms of the sign and amplitude of the standard entropy of solubilization, which is strongly positive for micelle penetration and negative for adsorption. A solubilization mechanism through adsorption onto the micellar surface is suggested for most of the barbituric acids studied. The enthalpy/entropy compensation phenomenon was identical for barbituric acids in ionic and nonionic (polyoxyethylene lauryl ether )surfactant solutions with a compensation temperature of 270 degrees K, indicating common behavior of these compounds with respect to micellar solubilization. The concept of molecular surface area was used to correlate the free energy of solubilization of the solutes to their size and structure. A linear relationship was found with an excellent correlation factor for the alkane derivatives of the 5-ethyl-barbituric acids. The specific behavior of some of the barbituric acids investigated is discussed.

Alkanesulfonates↗
PubMed1985

Quantitative structure-stability relationships among inclusion complexes of cyclodextrins. I: Barbituric acid derivatives.

Quantitative structure-stability relationships (QSSRs) are formulated for the inclusion complexation of 17 barbituric acid derivatives with alpha- and beta-cyclodextrin. The variation in the complex stability constants K alpha and K beta is found to be partly accounted for by the molar refractivity or the hydrophobicity of the substituent R1 at position 5 of the barbiturate ring. In addition, K alpha also depends upon whether or not R1 is branching or cyclic, and K beta also depends upon whether the guest molecule is a barbiturate or a thiobarbiturate. The results suggest that in alpha-cyclodextrin-barbiturate complexes the cyclodextrin cavity includes only R1, while in beta-cyclodextrin complexes both R1 and (part of) the barbiturate ring are included. This complexation model is compared with those proposed by other authors.

Barbiturates↗
PubMed1984

[Postmortem evaluation of barbiturate poisonings].

The evaluation of barbiturate intoxication as the cause of death is often difficult when the concentration in body fluids and organs is not extremely high. The problem arises because of the great capacity of barbiturates to produce tolerance after chronic use, a property that is often unknown. Therefore, the most abused barbiturates were studied to assess whether chronic intake causes morphological liver changes or not. It was found that the chronic abuse of drugs containing seco-, cyclo-, brallo-, and/or pentobarbital produces hypertrophy of the smooth endoplasmic reticulum of hepatocytes corresponding to that of phenobarbital. Neither acute barbiturate overdose (without a history of abuse) nor chronic abuse of opiates causes similar liver changes. In conclusion, barbiturate tolerance can be evaluated postmortem by light microscopic examination of the liver.

Animals↗
PubMed1975

Effects of barbiturates on ultrastructure and polymerization of microtubules in vitro.

Barbiturates were examined for in vitro effects on ultrastructure of the frog sciatic system and polymerization of microtubules (MT) in a brain supernatant. Exposure for 5-17 h to 2.0 mM barbiturates caused a considerable loss of MT in ganglionic cell bodies and sciatic axons. This was mostly followed by a proliferation of 10 nm filaments. Under similar conditions treatment with 1 mM NaCN or 0.1 mM 2,4-DNP did not change the number or ultrastructure of MT and filaments. Eight barbiturates, varying in binding ratios to serum albumin and partition coefficients, were tested for effects on polymerization of MT using viscometry. Inhibitory effects were found which correlated with their reported ability to bind to albumin and brain fractions. Dimethylsulphoxide and ethanol were used as solvents for some of the barbiturates. These solvents at 1% had stabilizing effects on MT. The present results are discussed in relation to previous findings of inhibition of rapid axonal transport in vitro in the frog sciatic system by barbiturates.

Animals↗
PubMed1976

The comparative effects of barbituric acid phenobarbital on blood glucose and insulin secretion in mice.

The effects of barbituric acid and phenobarbital upon carbohydrate metabolism in mice were compared. An intraperitoneal dose of 100 mg/kg of barbituric acid increased blood glucose concentrations during an intravenous glucose tolerance test, but did not alter the rate of glucose disappearance from the blood. Barbituric acid also antagonized the hypoglycemic effect of intravenously administered tolbutamide. The same dose of phenobarbital had no effect. An in vitro concentration of 100 mug/ml of barbituric acid decreased the responsiveness of isolated mouse pancreatic islets to glucose stimulation (3.0 mg/ml D-glucose). Again phenobarbital, 100 mug/ml, was without effect. The structural similarities between barbituric acid, tolbutamide and alloxan suggest that the effects observed in these experiments might reflect a competition for binding to reactive sites on or within the pancreatic B-cell.

Animals↗
PubMed1989

Measurements of CO2 reactivity and barbiturate reactivity in patients with severe head injury.

In nine patients with severe head injury subjected to continuous hyperventilation and barbiturate coma treatment with pentobarbitone, the regional cerebral blood flow was measured as initial slope index (ISI) with a 32 channel Cerebrograph, and cerebral metabolic rate of oxygen (CMRO2) was calculated as the product of mean global CBF and the arterio-venous oxygen content difference. CBF was measured at strategic intervals either to follow the treatment (hyperventilation and/or pentobarbitone), or to determine whether these principles of treatment should be intensified or reduced. During the flow measurements the CO2 reactivity and the reactivity to a bolus injection of thiopentone 5 mg/kg were calculated globally and regionally. The global CO2 reactivity was calculated as relative (%change CBF/delta PaCO2 mmHg) and absolute (deltaCBF/deltaPaCO2 mmHg), and the reactivity to barbiturate was calculated globally as delta CMRO2, and regionally as %change rCBF. The absolute and relative global CO2 reactivities correlated positively with the mean CBF values before hyperventilation, and the global barbiturate reactivity was dependent on the CMRO2 value obtained before hyperventilation. However, at low levels of CMRO2 ranging between 1.0 and 1.1 ml O2 the barbiturate reactivity was abolished. The regional studies of CBF, CMRO2, CO2 reactivity and barbiturate reactivity gave important information, when decisions concerning therapeutic regimes with special reference to hyperventilation and sedation with pentobarbitone were necessary.

Adolescent↗
PubMedDate not supplied

Dose-dependent rate of nosocomial pulmonary infection in mechanically ventilated patients with brain oedema receiving barbiturates: a prospective case study.

In a prospective case study we investigated whether the application of barbiturates in artificially ventilated patients with brain oedema has dose-dependent effects on the rate of nosocomial pneumonia. Pneumonia developed within the first seven days of controlled ventilation in patients receiving barbiturates; furthermore, the rate of nosocomial pneumonia was significantly higher in patients receiving barbiturates than in the control group without barbiturates (7.7%; p less than 0.0181); thus a clear dose dependency was shown (high-dose group: 43.8%, low-dose group: 21.4%). In all patients with pneumonia, colonization of the respiratory tract with pathogenic organisms preceded the pulmonary infection by four days. Under barbiturate therapy colonization of the respiratory tract occurred in all patients and one or two days earlier than in the control group, in which only 70% of the patients were colonized. These differences were significant for each of the first six days after hospitalization (p less than 0.0001-0.013). While in the high-dose group both colonization and pneumonia were caused mainly by gram-positive pathogens, mixed gram-positive and gram-negative pathogens were isolated in groups 2 and 3. Thus the higher rate of pneumonia of 43.8% in the high-dose group suggests a need for regular and semiquantitative monitoring of the causative agents and their antibiogram. Such measures could lead to early recognition with high predictability of the development of nosocomial pneumonia in colonized patients, allowing for timely application of the most appropriate antibiotics.

Adolescent↗
PubMed1983

Optimization of a novel two-phase potentiometric titration method of barbiturates with mercury (II). Part II: Experimental evaluation.

A two-phase potentiometric titration procedure of barbiturates with mercury(II) was developed. The composition of the formed mercury-barbiturate complexes was elucidated by infrared spectrometry. In the new titration procedure the barbituric acid derivative is dissolved in an aqueous borate buffer. An organic phase consisting of chloroform and benzyl alcohol is added, and the vigorously stirred contents of the titration vessel are titrated by a mercury(II) nitrate solution. In the potentiometric determination of the end-point a rotating mercury electrode is used as an indicator electrode that also serves as an efficient stirrer. The two-phase procedure was compared with a one-phase mercurimetric potentiometric titration in borate buffer and with the potentiometric titration by sodium hydroxide in an ethanol-water solution. The proposed two-phase procedure is superior to both methods because lower concentrations of barbiturates (10(-3) - 10(-4) M) can be determined successfully. The one-phase procedure suffers from systematic errors, while the titration with sodium hydroxide is less precise at concentration levels of the barbiturates prevailing in content uniformity studies. By the two-phase procedure the direct titration of phenobarbital and mephobarbital in a dry mix of tablet excipients was possible with a relative standard deviation smaller than 1.5 percent.

Barbital↗
PubMed1989

Improved maintenance of adult rat hepatocytes in a new serum-free medium in the presence or absence of barbiturates.

For serum-free primary culture of adult rat hepatocytes, a synthetic medium DM-160 and rat-tail collagen were selected for the basal medium and for the culture substratum, respectively. Barbiturates, such as phenobarbital and 1-ethyl-5-isobutylbarbiturate, efficiently supported survival of hepatocytes and maintained their morphologic features at lower concentrations under the serum-free conditions than under the serum-supplemented conditions. However, the hepatocyte survival rates under the serum-free conditions were lower than those under the serum-supplemented conditions in the presence or absence of barbiturates. Supplementation of the basal medium with a combination of five groups of factors (5Fs), such as eight amino acids (Ala, Arg, Gly, Ile, Met, Phe, Pro, and Trp), two unsaturated fatty acids (linoleate and oleate), a protease inhibitor (aprotinin), three vitamins (A, C, and E), and five trace elements (Mn, Fe, Cu, Zn, and Se), improved the hepatocyte survival under the serum-free conditions in the presence or absence of barbiturates. In other words, the serum could be completely substituted by the 5Fs. Hepatocyte cultures maintained in the 5Fs-supplemented basal medium showed excellent induction of tyrosine aminotransferase activity in response to dexamethasone in the presence or absence of barbiturates. The efficiency of the 5Fs-supplemented basal medium for maintaining hepatocytes was not inferior to those of other media in common use with hepatocytes, such as Williams' medium E and Waymouth's medium MB-752/1. In conclusion, maintenance of functional hepatocytes in serum-free primary culture could be improved by use of the new medium preparation (the 5Fs-supplemented DM-160) in the presence of barbiturates.

Animals↗
PubMed1984

Barbiturates allosterically inhibit GABA antagonist and benzodiazepine inverse agonist binding.

Barbiturates and the related depressant drugs, etazolate and etomidate, inhibited both the binding of [3H]bicuculline methochloride (BMC) to gamma-aminobutyric acid (GABA) receptor sites and the binding of [3H] beta-carboline-3-carboxylic acid methyl ester (beta CCM) to benzodiazepine receptor sites in mammalian brain. These concentration-dependent effects were chemically specific and stereospecific in a manner correlating with the activity of barbiturates to enhance GABA responses in neurons and to enhance GABA and benzodiazepine receptor agonist binding in vitro. The barbiturate inhibition of [3H]BMC binding involved a decrease in affinity which at high concentrations of barbiturates results in an effective complete loss of detectable binding. The maximal inhibition of [3H] beta CCM binding involved a more modest decrease in affinity (increase in KD from 1.35 to 1.85 nM). The barbiturate inhibitions of both ligands could be reversed by picrotoxin, suggesting an indirect action at previously defined picrotoxin/barbiturate modulatory sites on the GABA-benzodiazepine receptor/chloride ion channel complex.

Allosteric Regulation↗
PubMed1983

Increased release of [3H]acetylcholine in vitro from the mouse hippocampus by a convulsant barbiturate.

The effects of the convulsant barbiturate, 5-(2-cyclohexylidene-ethyl)-5-ethyl barbituric acid (CHEB), on the spontaneous release of [3H]acetylcholine (ACh) from mouse hippocampal slices in an in vitro superfusion system have been evaluated. The pattern of the release of [3H]ACh by a single treatment with CHEB or an elevated potassium concentration was similar, with the peak release occurring in the same fraction. A maximally effective concentration of CHEB (500 microM) caused a 177% stimulation of spontaneous release of [3H]ACh, while 50 mM KCl increased the release by 2100% above the baseline. The stimulation of the spontaneous release of [3H]ACh by CHEB was concentration-dependent with an EC50 of 180 microM. The pattern of release of [3H]ACh induced by multiple treatment with CHEB and elevated potassium appeared to differ, suggesting that different pools of [3H]ACh in the cholinergic neurons might be affected by these treatments. The action of CHEB on the spontaneous release of [3H]ACh was unique among some other convulsant drugs that were studied. Another convulsant barbiturate, S(+)-1-methyl-5-phenyl-5-propyl barbituric acid [S(+)-MPPB], pentylenetetrazol and a convulsant benzodiazepine 1,3-dihydro-5-methyl-2H-1,4-benzodiazepine-2-one (Ro-5-3663) did not affect the spontaneous release of [3H]ACh. The relationship between the stimulation of release of ACh and the convulsant action of the barbiturates is discussed.

Acetylcholine↗