In vitro and in vivo GABAA Receptor Interaction of the Propanidid Metabolite 4-(2-[Diethylamino]-2-Oxoethoxy)-3-Methoxy-Benzeneacetic Acid.

BACKGROUND: Propanidid is a γ-aminobutyric acid type A (GABAA) receptor agonist general anesthetic and its primary metabolite is 4-(2-[diethylamino]-2-oxoethoxy)-3-methoxy-benzeneacetic acid (DOMBA). Despite having a high water solubility at physiologic pH that might predict low-affinity GABAA receptor interactions, DOMBA is reported to have no effect on GABAA receptor currents, possibly because the DOMBA concentrations studied were simply insufficient to modulate GABAA receptors. Our objectives were to measure the propanidid and DOMBA concentration responses on -GABAA receptors and to measure the behavioral responses of DOMBA in mice at concentrations that affect GABAA receptor currents in vitro. METHODS: GABAA receptors were expressed in oocytes using clones for the human GABAA α1, ß2 and γ2s subunits. The effects of DOMBA (0.2-10 mmol/L) and propanidid (0.001-1 mmol/L) on oocyte GABAA currents were studied using standard 2-electrode voltage clamp techniques. Based on in vitro results, 6 mice received -DOMBA 32 mg intraperitoneal and were observed for occurrence of neurologic effects and DOMBA plasma concentration was measured by liquid chromatography tandem mass spectrometry. RESULTS: DOMBA both directly activates GABAA receptors and antagonizes its GABA-mediated opening in a concentration-dependent manner at concentrations between 5-10 and 0.5-10 mmol/L respectively. In vivo, DOMBA produced rapid onset sedation at plasma concentrations that correlate with direct GABAA receptor activation. CONCLUSION: DOMBA modulation of GABAA receptors is associated with sedation in mice. Metabolites of propanidid analogues currently in development may similarly modulate GABAA, and impaired elimination of these metabolites could produce clinically relevant neurophysiologic effects.

[Readaptation after total intravenous anesthesia in one-day surgery]. / Readaptatsiia posle total'noi vnutrivennoi anestezii v khirurgii odnogo dnia.

The authors analyze the stages of readaptation and recovery of clear consciousness in the immediate postoperative period in 200 patients administered one of the four variants of intravenous anesthesia in a one-day surgical hospital. The purpose of this work was to optimize the anesthetic care and the readaptation period. The stages of readaptation were assessed by psychophysiological testing. This process coursed most smoothly after propofol-phentanyl and hypnomidate-phentanyl anesthesia. Readaptation after sombrevin-phentanyl coursed reliably slower. The longest recovery was observed after calipsol-diazepam anesthesia, despite drug stimulation. This type of narcosis is irrational for one-day surgery, for it requires prolonged postoperative monitoring and thus makes the hospital stay longer.

[Transcranial Doppler sonographic study of the effect of electroconvulsive therapy on the circulation in the median cerebral artery]. / Az electroconvulsiv kezelés transcranialis Doppler sonographiás módszerrel megfigyelt hatása az arteria cerebri media keringésére.

The authors monitored the circulation of middle cerebral artery in subdominant hemisphere using the transcranial Doppler sonographic method during electroconvulsive treatment. They intravenously administered the patient 500 mg propanididum to put him/her to sleep and 150 mg of suxamethonium for muscle relaxation. The phasis of narcosis and awakening were continuously recorded under the treatment. After the administration of propanididum a sudden brief rise in flow velocity was measured with transient bradycardia followed by tachycardia. After the muscle relaxation the peak flow velocity diminished long lasting and the mean flow velocity fell from 60 cm per second to 30 cm per second average. At the beginning of the electroconvulsive treatment the velocity suddenly rose. The flow velocity increased significantly during the clonic phase of convulsive jerks with the pulsatility indices falling rapidly. Very low pulsatility indices lasted for long period of time during and following clonic convulsions.

[Intravenous anesthesia for cesarean section. Comparison of propanidid and methohexital]. / Anesthésie intraveineuse pour césarienne. Comparaison du propanidide et du métohexital.

Propanidid and methohexital were compared retrospectively to assess the possible neonatal depression following general anesthesia for caesarean section: both have rapid onset and short duration of action and their transplacental passages are similar. Anesthesia was induced with equivalent doses of the two agents in 90 women (45 in each group). For each anesthetic agent, three subgroups were defined according to the indications, depending on emergency criteria and fetal state. There was no significant statistical difference (Student test) regarding clinical and biochemical criteria except for the fetal arterial pH which was more acidic in the propanidid group. In both groups, Apgar scores, arterial and venous pH were significantly more altered when caesarean section was performed for acute fetal depression.

[The dynamics of the orientation adjustment of the neurons in the cat visual cortex under the action of sombrevin]. / Dinamika orientatsionnoi nastroiki neironov zritel'noi kory koshki pri deistvii sombrevina.

The dynamics of orientation tuning of 59 neurons in the primary visual cortex of cat was studied by the method of temporal slices before and after narcotization by sombrevine. It was found that in 2/3 of neurons a dynamic shift of the preferred orientation (from 22 up to 157 degrees) was observed during their response. After injection of sombrevine this shift reliably diminished in 45% of neurons, in some cases up to its complete disappearance, while in 30% of cases this shift increased. Differences in dynamics of orientation tuning under narcosis in two groups of units, as well as the mechanisms of the effect are discussed.

An electrophysiological investigation of the characteristics and function of GABAA receptors on bovine adrenomedullary chromaffin cells.

The characteristics and function of gamma-aminobutyric acidA (GABAA) receptors expressed on bovine chromaffin cells in culture have been investigated using patch-clamp techniques. In voltage-clamped whole-cells, locally applied GABA (100 microM) evoked a transmembrane chloride current which demonstrated outward rectification. The amplitude of such currents was reversibly suppressed by the GABAA receptor antagonists bicuculline, picrotoxin and RU5135, and enhanced by the general anaesthetic propanidid. Glycine (100 microM) and baclofen (100 microM) were ineffective as agonists. In support of a physiological role for GABA in the adrenal medulla, the co-existence of GABAA and nicotinic acetylcholine (ACh) receptors was demonstrated on whole cells and outside-out membrane patches. Ionophoretically applied GABA reduced the amplitude of depolarization and action potential discharge occurring in response to locally applied ACh (100 microM), but had no effect upon the underlying ACh-induced current. In addition, an excitatory action of GABA was demonstrated by recording action potential waveforms in cell-attached patches. The results are discussed in the context of a GABA-ergic regulation of catecholamine secretion.

[The effect of sombrevin on the orientation adjustment of the visual cortex neurons in the cat]. / Vliianie sombrevina na orientatsionnuiu nastroiku neironov zritel'noi kory koshki.

Change in the orientation tuning of 58 visual cortex neurons, evoked by light sombrevine anaesthesia were studied in acute experiments on immobilized cats. After the sombrevine injection a reliable change of the preferable orientation by 47.6 +/- 5.6 degrees took place in 60% of cells, while in the remaining cells it was stable in all stages of anaesthesia. Stable neurons preferred the horizontal and vertical orientations, in the unstable ones this preference was less expressed. The stable neurons possessed higher qualities of orientation detection than the unstable ones. The width of the orientation tuning changed reliably by 65.2 +/- 6.7 degrees on the average in 55% of neurons, while in 31% of neurons the tuning acuteness was worse, but in 24% it was sharper. The frequency of background discharges under anaesthesia in 2/3 of investigated neurons was reduced by 58% and that of the evoked discharges by 35%. The preferable orientation, the width of the tuning and the frequency of the neuron discharge as a rule recovered in 30 min after the beginning of the anaesthesia.

Isolation of mast cells from rabbit lung and liver: comparison of histamine release induced by the hypnotics Althesin and propanidid.

The enzyme collagenase was used to disperse rabbit lung and liver into their component cells. The resulting cell suspensions contained ca. 6.9% (lung) or 6.5% (liver) mast cells and were used in studies of histamine release without further purification. Both cell suspensions exhibited a low spontaneous release of histamine (ca. 6.6% lung, ca. 7.2% liver). Both cell types responded to challenge with anti-rabbit serum with a maximum release of the amine of ca. 22% (lung) and ca. 45% (liver). Concanavalin A challenge generally resulted in bell-shaped dose response curves, however some lung preparations did not respond. The rabbit cells were refractory to stimulation by Compound 48/80 and dextran. However a dose-dependent release of histamine was elicited after challenge with the detergents cremophor El, TN (12-hydroxystearic acid polymerized with ethylene oxide, degree of polymerization 15) and the hypnotics Althesin and propanidid. The maximum release observed depended on which cell preparation had been used. These results further emphasize the functional heterogeneity of mast cells from both different species and from different organs within the same species.

[The spectrum of analgesic activity of baclofen and tolibut]. / Spektr boleutoliaiushchei aktivnosti baklofena i tolibuta.

Spectrum of the analgetic activity of GABA derivatives baclofen (2.5-10.0 mg/kg) and tolibut (12.5-100.0 mg/kg) was studied in experiments on albino mice and rats. Baclofen and especially tolibut showed a dose-dependent inhibition of perceptive, emotional and autonomic manifestations of nociceptive reactions at the tail's thermal and electrical stimulation and enhancement of the analgetic effect of promedol. The regressive analysis made it possible to show dependence of the analgetic effect on the level of pain sensitivity and emotional reactivity of the animals. Tolibut deepens and prolongs sombrevin anesthesia, baclofen fails to alter it.

The gamma-aminobutyrate/benzodiazepine receptor from pig brain. Enhancement of gamma-aminobutyrate-receptor binding by the anaesthetic propanidid.

The binding of [3H]muscimol, a gamma-aminobutyrate (GABA) receptor agonist, to a membrane preparation from pig cerebral cortex was enhanced by the anaesthetic propanidid in a concentration-dependent manner. At 0 degrees C, binding was stimulated to 220% of control values, with 50% stimulation at 60 microM-propanidid. At 37 degrees C, propanidid caused a more powerful stimulation of [3H]muscimol binding (340% of control values). Propanidid (1 mM) exerted little effect on the affinity of muscimol binding (KD approx. 10 nM), but increased the apparent number of high-affinity binding sites in the membrane by 2-fold. Enhancement of [3H]muscimol binding was observed only in the presence of Cl- ions, half-maximal activation being achieved at approx. 40 mM-Cl-. Picrotoxinin inhibited the stimulation of [3H]muscimol binding by propanidid with an IC50 (concentration causing 50% inhibition) value of approx. 25 microM. The enhancement of [3H]muscimol binding by propanidid was not additive with the enhancement produced by secobarbital. Phenobarbital inhibited the effect of propanidid and secobarbital. The GABA receptor was solubilized with Triton X-100 or with Chaps [3-[(3-cholamidopropyl)dimethylammonio]propanesulphonate]. Propanidid and secobarbital did not stimulate the binding of [3H]muscimol after solubilization with Triton X-100. However, the receptor could be solubilized by 5 mM-Chaps with retention of the stimulatory effects of propanidid and secobarbital. Unlike barbiturates, propanidid did not stimulate the binding of [3H]flunitrazepam to membranes. It is suggested that the ability to modulate the [3H]muscimol site of the GABA-receptor complex may be a common and perhaps functional characteristic of general anaesthetics.

Mixtures of inhalation and i.v. anaesthetics at high pressure. A test of the multi-site hypothesis of general anaesthesia.

We have tested the hypothesis that anaesthetics having different pressure reversal characteristics act at different molecular sites with finite capacities and, therefore, do not necessarily have additive potencies when used in mixtures of varying composition. The additivity of the anaesthetic potencies has been tested at normal pressures and at pressures up to 100 ATA for eight combinations of the following mixtures: Althesin plus nitrous oxide; methohexitone plus nitrous oxide; thiopentone plus nitrous oxide; thiopentone plus propanidid. The anaesthetic potencies of the first two mixtures were not additive at increased pressures, whereas those of the latter two mixtures were additive. These data support the multi-site hypothesis of general anaesthesia.

The action of intravenous anaesthetic and central depressant drugs on the contractures elicited by tetraethylammonium in the chick biventer cervicis muscle.

A group of intravenous anaesthetic drugs was compared with methohexitone sodium for their ability to potentiate tetraethylammonium induced contractures of the chick biventer cervicis muscle (TEA test). The equipotent concentrations in the TEA test were: methohexitone 8.8 X 10(-5) M, propanidid 1.78 X 10(-4) M, althesin 3.58 X 10(-5) M (in terms of alphaxalone), etomidate 1.6 X 10(-4) M, thiopentone 2.13 X 10(-5) M and valium 4.95 X 10(-5) M. There was no relation between activity in the TEA test and excitatory muscular activity reported clinically. The central depressant drugs ethyl alcohol and urethane also potentiated TEA but they were only active in high concentrations (10(-1) - 10(-2) M). alpha-Chloralose was inactive but paraldehyde (3.8 X 10(-3) M) actually reduced TEA induced contractures. Lipophilicity is only one factor in determining activity in the TEA test, the ability to block Ca2+ reuptake may also be important.

Comparative study of intravenous anaesthetic techniques administered during short-term gynecological operations.

The effects of nine intravenous anaesthetic techniques on serum cortisol level and circulatory parameters were studied in healthy patients undergoing termination of pregnancy. Considering the increased pre-operation values and those of the pregnant control group as well as diurnal variations, it was found that the serum cortisol value changed during and after the procedure depending on the type of anaesthesia used. This might mean that the optimal type of anaesthesia for interruption could be designed by measuring the serum cortisol level, assuming that this parameter was one of the indicators of stress. The rating the different types of anaesthetics, the circulatory parameters were also considered. According to these criteria the best results were observed using methohexital in combination with fentanyl or diazepam.

Reliability of the vestibulo-ocular reflex as an index of the effects of hypnotic drugs on the central nervous system.

The vestibulo-ocular reflex was tested after the administration of step doses of thiopentone or propanidid in 171 unpremedicated patients. The dose of thiopentone (3 mg kg-1) required to induce loss of nystagmus also abolished the response to verbal command. The dose required to inhibit the reflex in 95% of patients was 7.22 mg kg-1 and prevented adrenergic responses to nociceptive stimulation. The dose of propanidid required to induce loss of nystagmus was greater than that necessary to abolish response to verbal command. The reflex inhibition rate increased proportionally to the dose up to 8 mg kg-1; larger doses exerted a facilitatory effect and reduced the reflex inhibition rate. The vestibulo-ocular reflex is a reliable and sensitive means of demonstrating the different effects exerted by step doses of hypnotic drugs.