A single hydrophobic residue confers barbiturate sensitivity to gamma-aminobutyric acid type C receptor.
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Barbiturate sensitivity was imparted to the human rho1 homooligomeric gamma-aminobutyric acid (GABA) receptor channel by mutation of a tryptophan residue at position 328 (Trp328), which is located within the third transmembrane domain. Substitutions of Trp328 with a spectrum of amino acids revealed that nearly all hydrophobic residues produced receptor channels that were both directly activated and modulated by pentobarbital with similar sensitivities. Previous studies with ligand-gated ion channels (including GABA) have demonstrated that even conservative amino acid substitution within the agonist-dependent activation domain (N-terminal extracellular domain) can markedly impair agonist sensitivity. Thus, the lack of significant variation in pentobarbital sensitivity among the Trp328 mutants attests to an intrinsic difference between pentobarbital- and the GABA-dependent activation domain. Compared with the heterooligomeric alphabetagamma receptor channel, the mode of modulation for homooligomeric Trp328 mutants by pentobarbital was more dependent on the GABA concentration, yielding potentiation only at low concentrations of GABA (fractions of their respective EC50 values), yet causing inhibition at higher concentrations. Agonist-related studies have also demonstrated that residue 328 plays an important role in agonist-dependent activation, suggesting a functional interconnection between the GABA and pentobarbital activation domains. (+info)
Thiopental and propofol impair relaxation produced by ATP-sensitive potassium channel openers in the rat aorta.
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ATP-sensitive potassium channel openers are used as vasodilators in the treatment of cardiovascular disorders. The effects of i.v. anaesthetics on arterial relaxation induced by ATP-sensitive potassium channel openers have not been studied. Therefore, in this study, we have examined if thiopental (thiopentone) and propofol affect the vascular response to the ATP-sensitive potassium channel openers, cromakalim and pinacidil, in the isolated rat aorta. Rings of rat thoracic aortas without endothelium were suspended for isometric force recording. Concentration-response curves were obtained in a cumulative manner. During submaximal contractions with phenylephrine 0.3 mumol litre-1, relaxation after cromakalim 0.1-30 mumol litre-1, pinacidil 0.1-30 mumol litre-1 and papaverine 0.1-300 mumol litre-1 was demonstrated. Thiopental 30-300 mumol litre-1, propofol 10-100 mumol litre-1, 10% Intralipid 45 microliters or glibenclamide 5 mumol litre-1 were applied 15 min before addition of phenylephrine. During contractions with phenylephrine, cromakalim and pinacidil induced concentration-dependent relaxation. A selective ATP-sensitive potassium channel antagonist, glibenclamide 5 mumol litre-1, abolished this relaxation, whereas it did not affect relaxation produced by papaverine. Thiopental concentrations > 30 mumol litre-1 significantly impaired relaxation produced by cromakalim or pinacidil. Propofol concentrations > 10 mumol litre-1 also significantly reduced relaxation produced by cromakalim or pinacidil, whereas Intralipid was ineffective. Thiopental 300 mumol litre-1 and propofol 100 mumol litre-1 did not alter relaxation produced by papaverine. These results suggest that the i.v. anaesthetics, thiopental and propofol, impaired vasodilatation mediated by ATP-sensitive potassium channels in vascular smooth muscle cells. (+info)
Differential inhibitory effects of thiopental, thiamylal and phenobarbital on both voltage-gated calcium channels and NMDA receptors in rat hippocampal slices.
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Although it is known that there are some pharmacological differences between the structurally similar barbiturates, the underlying mechanism of action remains unclear. We have compared the effects of thiopental, thiamylal and phenobarbital on both voltage-gated calcium channels (VGCC) and N-methyl-D-aspartate (NMDA) receptors in rat hippocampal slices by determining changes in intracellular calcium ([Ca2+]i). Experiments were performed in adult rat hippocampal slices perfused with Krebs solution (37 degrees C). Concentrations of [Ca2+]i in the pyramidal cell layer of the CA1 region were measured using a calcium indicator dye, fura-2. To activate VGCC and NMDA receptors, slices were exposed to K+ 60 mmol litre-1 (< or = 60 s) and NMDA 100 mumol litre-1 (30 s), respectively. Thiopental, thiamylal and phenobarbital were present 5 min before, during and 1 min after high K+ or NMDA application. Both thiamylal and thiopental (50-600 mumol litre-1) attenuated the increases in [Ca2+]i produced by high K+ or NMDA in a concentration-dependent manner, while phenobarbital 50-1000 mumol litre-1 only slightly attenuated the [Ca2+]i increase produced by high K+ at concentrations of more than 200 mumol litre-1 and was ineffective on the [Ca2+]i response produced by NMDA. Although the increases in [Ca2+]i caused by membrane depolarization with high K+ were reduced equally with thiamylal and thiopental, thiamylal was more effective in attenuating the increase in [Ca2+]i produced by NMDA receptor activation than thiopental. We conclude that the depressant effects of barbiturates on both VGCC and NMDA receptors varied between agents. Differential inhibition of both VGCC and NMDA receptors may determine the pharmacological properties of barbiturates and their ability to protect neurones against ischaemia. (+info)
Recovery after halothane anaesthesia induced with thiopental, propofol-alfentanil or halothane for day-case adenoidectomy in small children.
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We studied recovery from halothane anaesthesia in 93 children, aged 1-3 yr, undergoing day-case adenoidectomy. Children were allocated randomly to receive thiopental 5 mg kg-1 (group TH), alfentanil 10 micrograms kg-1 and propofol 3 mg kg-1 (group PAH) or 5% halothane (group HH) for induction of anaesthesia. In group TH, tracheal intubation was facilitated with succinylcholine (suxamethonium) 1.5 mg kg-1. In groups PAH and HH, tracheal intubation was performed without neuromuscular block, and succinylcholine was used only if required. Anaesthesia was maintained with 1-3% halothane during spontaneous respiration. Times to achieving predetermined recovery end-points were recorded. Quality of recovery was assessed using a score of 1-9 (best to worst) for sedation, crying, restlessness and agitation. A postoperative questionnaire was used to determine the well-being of the child at home, 24 h after operation. Emergence from anaesthesia (response to non-painful stimuli) occurred earlier in group HH (mean 9 (SD 6) min) than in groups PAH (13 (6) min, P < 0.01) and TH (18 (14) min, P < 0.01). Sitting up, walking and home readiness were achieved earlier in groups PAH and HH than in group TH (P < 0.05 for each variable). Children in group TH were more sedated during the first 30 min after anaesthesia than those in the two other groups (P < 0.05) while emergence-related delirium was more common in group HH than in group TH (P < 0.01). Well-being at home was similar in all groups. We conclude that induction of halothane anaesthesia with propofol-alfentanil or halothane provided more rapid recovery and earlier discharge than that with thiopental. (+info)
Comparison of the effects of convulsant and depressant barbiturate stereoisomers on AMPA-type glutamate receptors.
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BACKGROUND: Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors mediate fast excitatory synaptic transmission in the central nervous system. Although barbiturates have been shown to suppress the AMPA receptor-mediated responses, it is unclear whether this effect contributes to the anesthetic action of barbiturates. The authors compared the effects of depressant [R(-)] and convulsant [S(+)] stereoisomers of 1-methyl-5-phenyl-5-propyl barbituric acid (MPPB) on the AMPA and gamma-aminobutyric acid type A (GABA(A)) receptor-mediated currents to determine if the inhibitory effects on AMPA receptors correlate to the in vivo effects of the isomers. METHOD: The authors measured whole-cell currents in the rat cultured cortical neuron at holding potential of -60 mV. Kainate 500 microM was applied as the agonist for AMPA receptors. Thiopental (3-300 microM), R(-)-MPPB or S(+)-MPPB (100-1,000 microM) was coapplied with kainate under the condition in which the GABA(A) receptor-mediated current was blocked. Effects of MPPB isomers on the current elicited by GABA 1 microM were studied in the separate experiments. RESULTS: Thiopental inhibited the kainate-induced current reversibly and in a dose-dependent manner, with a concentration for 50% inhibition of 49.3 microM. Both R(-)-MPPB and S(+)-MPPB inhibited the kainate-induced current with a little stereoselectivity. R(-)-MPPB was slightly but significantly more potent than S(+)-MPPB. In contrast, R(-)-MPPB enhanced but S(+)-MPPB reduced the GABA-induced current. CONCLUSIONS: Both convulsant and depressant stereoisomers of the barbiturate inhibited the AMPA receptor-mediated current despite of their opposite effects on the central nervous system in vivo. Although thiopental exhibited a considerable inhibition of AMPA receptors, the results suggest that the inhibition of AMPA receptors contributes little to the hypnotic action of the barbiturates. (+info)
Effect of propofol on the electrocorticogram in epileptic patients undergoing cortical resection.
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We have compared the effect of clinical doses of propofol with thiopental on epileptiform activity in the electrocorticograms (ECoG) of 20 epileptic patients undergoing temporal lobe resection. After baseline ECoG had been obtained, with inspired concentrations of 0.5-1% isoflurane and 70% nitrous oxide to provide background anaesthesia, subjects were allocated randomly to receive boluses of either thiopental 25 mg or propofol 20 mg i.v. every 30 s to a maximum of 5 mg kg-1 or until burst suppression was seen. The ECoG was recorded throughout administration and for 10 min thereafter. After return of baseline ECoG tracings, the alternate agent was administered. The amount of epileptiform activity was recorded on an ordinal rating scale, an increase being indicated by either a rise of at least one category on the scale or discharges occurring at a minimum of one new site. Activation occurred more frequently with thiopental but the difference was not significant. This study suggests that propofol has no greater proconvulsive effect than thiopental, a drug commonly used in managing status epilepticus. (+info)
Bolus dose remifentanil for control of haemodynamic response to tracheal intubation during rapid sequence induction of anaesthesia.
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The effect of three bolus doses of remifentanil on the pressor response to laryngoscopy and tracheal intubation during rapid sequence induction of anaesthesia was assessed in a randomized, double-blind, placebo-controlled study in four groups of 20 patients each. After preoxygenation, anaesthesia was induced with thiopental 5-7 mg kg-1 followed immediately by saline (placebo) or remifentanil 0.5, 1.0 or 1.25 micrograms kg-1 given as a bolus over 30 s. Cricoid pressure was applied just after loss of consciousness. Succinylcholine 1 mg kg-1 was given for neuromuscular block. Laryngoscopy and tracheal intubation were performed 1 min later. Arterial pressure and heart rate were recorded at intervals until 5 min after intubation. Remifentanil 0.5 microgram kg-1 was ineffective in controlling the increase in heart rate and arterial pressure after intubation but the 1.0 and 1.25 micrograms kg-1 doses were effective in controlling the response. The use of the 1.25 micrograms kg-1 dose was however, associated with a decrease in systolic arterial pressure to less than 90 mm Hg in seven of 20 patients. (+info)
Drug blockade of open end-plate channels.
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1. The actions of amylobarbitone, thiopentone, methohexitone and methyprylone at voltage-clamped frog end-plates were studied. 2. In the presence of barbiturates the conductance change evoked by an iontophoretic carbachol application was reduced by a prepulse of carbachol. The extra inhibition evoked by a prepulse disappeared exponentially with a time constant of 150-200 ms. 3. Barbiturates produce an increased rate of decay of nerve evoked endplate currents. Tne concentration and voltage dependence of the barbtiruate e.p.c. decay rates tally with the hypothesis that the increased rate of decay is due to block of active receptor-channel complexes by barbiturates with a rate constant of 10(6) M-1S-1. 4. Conductance changes produced by bath applied agonists were depressed by thiopentone, the effect becoming greater the higher the agonist concentration. This effect, and also the observation that the concentration of thiopentone required to depress the bath agonist response is much greater than the apparent dissociation constant for binding to active receptor-channel complexes calculated from kinetic measurements, suggest that the selectivity for binding to open receptor-channel complexes is very high. 5. Methyprylone, which is structurally similar to the barbiturates, is only a weak antagonist and shows no interpulse interaction. It was predicted that methyprylone should produce fast and slow components in the e.p.c. decay, and this prediction was verified. 6. In the presence of barbiturates large iontophoretic carbachol applications produce conductance changes which show fast and slow components. Under these conditions the effects of carbachol prepulses become complex. However the effects are qualitatively consistent with the notion that different components of the response are contributed by channels located at various distances from the iontophoretic pipette tip. 7. All the data agree with a model in which the channel has three stages: closed, open and blocked. Only open channels can block, and blocked channels can only open. (+info)