Differential effects of general anesthetics on G protein-coupled inwardly rectifying and other potassium channels.
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BACKGROUND: General anesthetics differentially affect various families of potassium channels, and some potassium channels are suggested to be potential targets for anesthetics and alcohols. METHODS: The voltage-gated (ERG1, ELK1, and KCNQ2/3) and inwardly rectifying (GIRK1/2, GIRK1/4, GIRK2, IRK1, and ROMK1) potassium channels were expressed in Xenopus oocytes. Effects of volatile agents [halothane, isoflurane, enflurane, F3 (1-chloro-1,2,2-trifluorocyclobutane), and the structurally related nonimmobilizer F6 (1,2-dichlorohexafluorocyclobutane)], as well as intravenous (pentobarbital, propofol, etomidate, alphaxalone, ketamine), and gaseous (nitrous oxide) anesthetics and alcohols (ethanol and hexanol) on channel function were studied using a two-electrode voltage clamp. RESULTS: ERG1, ELK1, and KCNQ2/3 channels were either inhibited slightly or unaffected by concentrations corresponding to twice the minimum alveolar concentrations or twice the anesthetic EC50 of volatile and intravenous anesthetics and alcohols. In contrast, G protein-coupled inwardly rectifying potassium (GIRK) channels were inhibited by volatile anesthetics but not by intravenous anesthetics. The neuronal-type GIRK1/2 channels were inhibited by 2 minimum alveolar concentrations of halothane or F3 by 45 and 81%, respectively, whereas the cardiac-type GIRK1/4 channels were inhibited only by F3. Conversely, IRK1 and ROMK1 channels were completely resistant to all anesthetics tested. Current responses of GIRK2 channels activated by mu-opioid receptors were also inhibited by halothane. Nitrous oxide (approximately 0.6 atmosphere) slightly but selectively potentiated GIRK channels. Results of chimeric and multiple amino acid mutations suggest that the region containing the transmembrane domains, but not the pore-forming domain, may be involved in determining differences in anesthetic sensitivity between GIRK and IRK channels. CONCLUSIONS: G protein-coupled inwardly rectifying potassium channels, especially those composed of GIRK2 subunits, were inhibited by clinical concentrations of volatile anesthetics. This action may be related to some side effects of these agents. (+info)
Differential nitric oxide synthase activity, cofactor availability and cGMP accumulation in the central nervous system during anaesthesia.
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We investigated the effects of anaesthesia on dynamic nitric oxide production, concentrations of tetrahydrobiopterin and the accumulation of cyclic GMP (cGMP) in the rat central nervous system (CNS). Rats were assigned to anaesthesia with halothane, isoflurane, pentobarbital, diazepam, ketamine or xenon (n=6 per group). After 30 min, [14C]L-arginine (i.v.) was given and, after a further 60 min of anaesthesia, rats were killed and exposed immediately to focused microwave radiation. After removal of the brain and spinal cord, nitric oxide production from radiolabelled arginine (and hence nitric oxide synthase activity during anaesthesia) was measured as [14C]L-citrulline by scintillation counting. cGMP was determined by enzyme immunoassay and tetrahydrobiopterin by fluorescence HPLC, in brain regions and the spinal cord. Nitric oxide synthase activity was similar in all brain regions but was lower in the spinal cord, and was unaffected by anaesthesia. cGMP was similar in all areas of the CNS and was significantly decreased in rats anaesthetized with halothane. Isoflurane produced similar effects. In contrast, ketamine and xenon anaesthesia increased cGMP in the spinal cord, brainstem and hippocampus. Diazepam and pentobarbital had no effect. Tetrahydrobiopterin concentrations were similar in all areas of the CNS and were increased in the cortex and hippocampus after anaesthesia. We have shown profound differential effects of anaesthesia on the nitric oxide pathway in the rat CNS. (+info)
Psychomotor recovery in very old patients after total intravenous or balanced anaesthesia for cataract surgery.
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We compared psychomotor recovery after total intravenous anaesthesia (TIVA) with remifentanil/propofol and balanced anaesthesia (BAL) with etomidate/fentanyl/isoflurane in 40 patients, ASA I-III, aged > or =80 yr undergoing elective cataract surgery. Recovery times were recorded and psychomotor recovery was assessed according to simple reaction time, critical flicker fusion frequency (CFF) and short-term memory 30 min, 2 h and 1 day after surgery. Physical characteristics of patients in the two groups (19 in the TIVA group and 21 in the BAL group) were comparable. The TIVA group recovered significantly more quickly. Both groups showed a poorer psychomotor performance 30 min after surgery than at baseline assessment, but simple reaction time and short-term memory were close to baseline values 2 h after surgery. Only performance in the CFF test remained below baseline at this point. No deficits in psychomotor performance were noted on the first day after surgery. We conclude that there is only a minor deficit in psychomotor function in elderly patients 2 h after cataract surgery under general anaesthesia and that psychomotor function recovers completely by 24 h after surgery. (+info)
Comparison of changes in electroencephalographic measures during induction of general anaesthesia: influence of the gamma frequency band and electromyogram signal.
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Recent research has shown that high-frequency, gamma-band electroencephalographic (EEG) oscillations (40-60 Hz) may be an important marker of the conscious state. We compared the ability of the bispectral index (BIS) to distinguish the awake and anaesthetized states during the induction of general anaesthesia with: (i) components of the BIS (BetaRatio, SynchFastSlow); (ii) a new EEG variable--the median frequency of the first time derivative of the EEG signal (SE50d); and (iii) the SE50d derived from an EEG signal that has had the frequencies above 30 Hz removed (SE50d(30Hz)). Two groups of subjects were studied: (i) nine volunteers undergoing a short propofol infusion until loss of response to verbal command, and (ii) 84 patients undergoing routine anaesthesia for a variety of surgical procedures. In the volunteer group, the changes in the BetaRatio and SE50d were comparable with changes in the BIS. The changes in the SE50d(30Hz) were less consistent. In the patient group, the BIS components were equivalent to the BIS in separating the awake from the surgically anaesthetized states (area under receiver operating curve: BIS 0.95, SE50d 0.95, BetaRatio 0.96). Using the submental electromyogram (EMG) signal to estimate the frontalis EMG (30-47 Hz) signal, the changes in EMG signal were, on average, about one-tenth the magnitude of the EEG. We conclude that: (i) there exist simpler derived EEG variables that are similar in accuracy to the BIS; (ii) it is important to avoid filtering out the EEG frequencies above 30 Hz; and (iii) in most patients the confounding effects of the frontalis EMG on the EEG are minimal. (+info)
Changes in plasma creatinine concentration after cardiac anesthesia with isoflurane, propofol, or sevoflurane: a randomized clinical trial.
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BACKGROUND: Renal impairment often follows cardiac surgery. The authors investigated whether sevoflurane produces greater increases in plasma creatinine concentration than isoflurane or propofol after elective coronary artery surgery. METHODS: As part of maintenance anesthesia, including during cardiopulmonary bypass, patients were randomly allocated to receive one of three agents: isoflurane (n = 118), sevoflurane (n = 118), or propofol (n = 118). Fresh gas flows were 3 l/min. The preoperative plasma creatinine concentration was subtracted from the highest creatinine concentration in the first 3 postoperative days. A median maximum increase greater than 44 microM (0.5 mg/dl) was regarded as clinically important. Data were analyzed on an intention-to-treat basis. Subgroup analyses were performed on per-protocol patients and those with preoperative renal impairment (creatinine concentration > 130 microM [1.47 mg/dl] or urea > 7.7 mM [blood urea nitrogen, 21.6 mg/dl]). RESULTS: The differences between the groups were small, clinically unimportant, and not statistically significant for the primary analysis and subgroups. The proportions of patients with creatinine increases greater than 44 microM were 15% in the isoflurane group, 17% in the sevoflurane group, and 11% in the propofol group (P = 0.45). The median increases were 8 microM in the isoflurane group, 4 microM in the sevoflurane group, and 6 microM in the propofol group. The differences between the three median maximum increases were 1-4 microM (P > 0.45). In the subgroup with preoperative renal impairment, the median increases were 10 microM in the isoflurane group, 15 microM in the sevoflurane group, and 5 microM in the propofol group (P = 0.72). CONCLUSIONS: Sevoflurane did not produce greater increases in creatinine than isoflurane or propofol after elective coronary artery surgery. (+info)
Serotonergic receptor antagonists alter responses to general anaesthetics in rats.
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Serotonergic neurotransmission is involved in controlling arousal levels in humans and other animals. Here, the effects of serotonergic receptor antagonists on the induction and depth of anaesthesia produced by three different general anaesthetics were investigated. Rats were pretreated (i.p.) with either methiothepin (1.5 mg kg(-1)), mianserin (5 mg kg(-1)), ketanserin (7 mg kg(-1)) or saline. Subsequently, successive, cumulative doses (i.p.) of either ketamine (final, cumulative dose of 350 mg kg(-1)), sodium pentobarbital (final dose 77 mg kg(-1)), or chloral hydrate (final dose 600 mg kg(-1)) were administered. The response to the anaesthetics was measured using a behavioural test battery assessing nocifensive reflexes and hypnotic state. Pre-treatment with methiothepin enhanced responses to all three anaesthetics; mianserin enhanced responses to chloral hydrate. These results show that some serotonergic receptor antagonists change anaesthetic requirements, resulting in enhanced anaesthesia to hypnotics with different mechanisms of action. (+info)
Methionine 286 in transmembrane domain 3 of the GABAA receptor beta subunit controls a binding cavity for propofol and other alkylphenol general anesthetics.
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gamma-Aminobutyric acid type A (GABA(A)) receptors are an important target for general anesthetics in the central nervous system. Site-directed mutagenesis techniques have identified amino acid residues that are important for the positive modulation of GABA(A) receptors by general anesthetics. In the present study, we investigate the role of an amino acid residue in transmembrane (TM) domain 3 of the GABA(A) receptor beta(2) subunit for modulation by the general anesthetic 2,6-diisopropylphenol (propofol). Mutation of methionine 286 to tryptophan (M286W) in the beta(2) subunit abolished potentiation of GABA responses by propofol but did not affect direct receptor activation by propofol in the absence of GABA. In contrast, substitution of methionine 286 by alanine, cysteine, glutamate, lysine, phenylalanine, serine, or tyrosine was permissive for potentiation of GABA responses and direct activation by propofol. Using propofol analogs of varying molecular size, we show that the beta(2)(M286W) mutation resulted in a decrease in the 'cut-off' volume for propofol analog molecules to enhance GABA responses at GABA(A) alpha(1)beta(2)gamma(2s) receptors. This suggests that mutation of M286 in the GABA(A) beta(2) subunit alters the dimensions of a 'binding pocket' for propofol and related alkylphenol general anesthetics. (+info)
The septohippocampal system participates in general anesthesia.
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How the brain mediates general anesthesia is not known. We report that two interconnected structures in the forebrain, the medial septum and the hippocampus, participate in maintaining awareness and movements during general anesthesia. In the awake, freely behaving rat, inactivation of the medial septum or the hippocampus by local injection of a GABA(A) receptor agonist, muscimol, decreased the dose of a general anesthetic needed to induce a loss of the tail-pinch response or a loss of righting reflex. Septohippocampal inactivation also suppressed the behavioral hyperactivity or the delirium stage associated with general anesthesia. An increase and decrease of 30-50 Hz (gamma) waves in the hippocampus correlated with an increase and decrease in behavioral activity, respectively. Similar results were found for both volatile (halothane and isoflurane) and nonvolatile (propofol and pentobarbital) anesthetics. We conclude that the behavioral hyperactivity induced by a general anesthetic is mediated in part by the septohippocampal system, and that depression of the septohippocampal system increases the potency of a general anesthetic. It is suggested that more potent general anesthetics or adjuvants may be developed by maximizing the pharmacological depression of the septohippocampal system. (+info)