Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cardiac dysrhythmias during inhaled anesthesia are well documented and may, in part, involve depression of the fast inward Na+ current (INa) during the action potential upstroke. In this study, we examined the effects of halothane, isoflurane, and sevoflurane at clinically relevant concentrations on INa in single ventricular myocytes isolated enzymatically from adult guinea pig hearts. INa was recorded using standard whole-cell configuration of the patch clamp technique. Halothane at 0.6 mM and 1.2 mM produced significant (P < 0.05) depressions of peak INa of 12.3% +/- 1.8% and 24.4% +/- 4.1% (mean +/- SEM, n = 12), respectively. Isoflurane (0.5 mM, n = 12; 1.0 mM, n = 15) and sevoflurane (0.6 mM, n = 14; 1.2 mM, n = 12) were less potent than halothane, decreasing peak INa by 4.8% +/- 1.1% and 11.4% +/- 1.4% (isoflurane) and 3.0% +/- 0.7% and 10.7% +/- 3.9% (sevoflurane). The depressant effects on INa were reversible in all cases. For all anesthetics tested, the degree of block increased at more depolarizing potentials. Anesthetics induced significant shifts in the steady-state inactivation and activation of the channel toward more hyperpolarizing potentials. The present findings indicate that volatile anesthetics at clinical concentrations decrease the cardiac INa in a dose- and voltage-dependent manner. At approximately equianesthetic concentrations, the decrease of INa caused by halothane was twice that observed with isoflurane or sevoflurane.
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PMID:Voltage-dependent effects of volatile anesthetics on cardiac sodium current. 902 16

1. Inhalational anaesthetics modulate ligand-gated ion channels at clinical concentrations. In this paper we address submolecular mechanisms for gamma-aminobutyric acid (GABA) receptor modulation by isoflurane. 2. Wild-type Drosophila melanogaster homo-oligomeric GABA receptors were characterized and compared with an ion-channel mutant (alanine substituted to a serine in M2) by means of two-electrode voltage-clamp in membrane-invariant Xenopus oocytes. 3. Both channel receptor isoforms generated outwardly rectifying, bicuculline-insensitive currents with reversal potentials characteristic of a chloride current. 4. As previously shown, the point mutation in the M2 domain conferred a profound resistance to the blocking action of 10 microM picrotoxinin (PTX): circa 7 fold reduction at the GABA EC20. 5. Isoflurane, 195-389 microM, enhanced GABA conductance in both receptor variants by significantly increasing the affinity of the agonist for its receptor without changing Hill slope or maximal response. Relative potencies were statistically indistinguishable. 6. Isoflurane concentration-response curves (on circa GABA EC25) demonstrated that enhancement was effected at around 100-195 microM for both receptor subtypes, but a dramatic divergence was evident at concentrations above 400 microM: wild-type receptors exhibited concentration-dependent block, whilst mutant conductances continued to increase over the same concentration range, showing no tendency to saturate (up to 3330 microM). 7. The above divergence was not attributable to differential desensitization: neither wild-type nor mutant conductance desensitized significantly (P > 0.05) in the absence or presence of anaesthetic. 8. This work demonstrates that modulatory sites for anaesthetic are present on a relatively primitive insect ion channel. 9. The depression of GABA response at high isoflurane concentrations, in WT receptors, (typical of a variety of anaesthetic agents) may reflect low affinity channel block via the PTX site. 10. The non-saturable enhancement of chloride conductances, when the PTX site is mutated, is not consistent with topical proposals that inhalational anaesthetics (stereoselectively) occupy a finite number of sites on these membrane spanning proteins.
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PMID:Modulation of a recombinant invertebrate gamma-aminobutyric acid receptor-chloride channel complex by isoflurane: effects of a point mutation in the M2 domain. 937 70

We have investigated in rat brain slices the effects of the volatile anaesthetics enflurane, isoflurane and halothane on spontaneous discharge patterns and mean firing rates of cerebellar Purkinje cells. In the absence of these anaesthetics, Purkinje cells fired bursts of action potentials separated by quiescent periods lasting less than 2 s. Mean discharge rates were 10.8 (SEM 0.4) Hz at 23 +/- 1 degrees C and 25.6 (1.2) Hz at 35 +/- 1 degrees C. The agents exhibited qualitatively different effects when applied at concentrations corresponding to 1-3 MAC. Enflurane markedly lengthened burst and inter-burst durations. Isoflurane acted in a similar manner, but effects were less pronounced. In contrast with isoflurane and enflurane, halothane shortened burst durations. At concentrations corresponding to 1-1.5 MAC, halothane, isoflurane and enflurane significantly depressed action potential firing by 15-30% (P < 0.05). Enflurane 1.2 mmol litre-1 (2.0 MAC), isoflurane 0.9 mmol litre-1 (2.8 MAC) and halothane 0.9 mmol litre-1 (3.8 MAC) depressed spontaneous spike rates by 50%. The changes in discharge patterns and the concentration-dependent decrease in the firing rates were similar at 23 +/- 1 degrees C and 35 +/- 1 degrees C. In summary, we observed that neither the anaesthetic-induced alterations in spontaneous discharge patterns nor the EC50 values of the concentration-dependent depression of the mean firing rates were in accordance with the Meyer-Overton rule. However, at clinically relevant concentrations, depression of average spike rates did not differ significantly between the anaesthetics and thus followed the rule. Our results suggest that anaesthetic actions, which are in accordance with the rule, are frequently masked by several side effects.
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PMID:Effects of volatile anaesthetics on spontaneous action potential firing of cerebellar Purkinje cells in vitro do not follow the Meyer-Overton rule. 942 2

1. The effects of the volatile anaesthetic, isoflurane, were investigated on evoked dendritic field excitatory postsynaptic potentials (f.e.p.s.p.) and antidromic and orthodromic population spikes recorded extracellularly in the CA1 cell layer region in the in vitro hippocampal slice taken from young mature (2-3 months) and old (24-27 months) Fisher 344 rats. 2. Isoflurane depressed the f.e.p.s.ps and the orthodromically-evoked population spikes in both old and young hippocampi. However, the magnitude of the anaesthetic-induced depression was greater in slices taken from old rats compared to those taken from young rats during the application of different isoflurane concentrations (0.5-5%). 3. In the presence of the GABA(A) antagonist, bicuculline methiodide (15 microM), isoflurane suppressed the f.e.p.s.ps to the same extent as was observed in the absence of the GABA(A) antagonist. 4. Orthodromically evoked population spikes were suppressed by isoflurane in a manner quantitatively similar to the suppression of the f.e.p.s.ps. However, antidromic population spikes and presynaptic volleys evoked in young and old slices were resistant to anaesthetic action. In addition, paired pulse facilitation ratio of the evoked dendritic f.e.p.s.ps was not affected in both young and old slices during the application of isoflurane. 5. When slices were exposed to low Ca2+/high Mg2+ solution, isoflurane (1 and 3%) depressed the f.e.p.s.ps in aged slices to the same extent as in young slices. 6. The augmented anaesthetic depression of f.e.p.s.ps in old compared to young hippocampi in the absence and presence of bicuculline, and the lack of anaesthetic effects on antidromic population spikes and presynaptic volleys in old and young slices, suggest that the increased sensitivity of anaesthetic actions in old hippocampi is due to age-induced attenuation of synaptic excitation rather than potentiation of synaptic inhibition. Furthermore, elimination of the increased sensitivity of old slices to anaesthetic actions when the slices were perfused with low Ca2+/high Mg2+ medium, which presumably would decrease intracellular [Ca2+], suggests that the enhanced anaesthetic effects in aged neurones might be related to increased intraneuronal [Ca2+] in the synaptic terminal.
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PMID:Enhanced isoflurane suppression of excitatory synaptic transmission in the aged rat hippocampus. 972 Jul 76

Inhaled and other anesthetics profoundly affect the central nervous system, causing amnesia, immobility in the face of noxious stimulation, and depression of thermoregulation. Nonimmobilizers, inhaled compounds whose lipophilicity suggests that they should be anesthetics, do not produce immobility, but they do cause amnesia. Their effects on thermoregulation were the subject of the present study. We gave eight rats isoflurane on one occasion and the nonimmobilizer 2N (1,2-dichlorolhexafluorocyclobutane) on another. We measured the effect of various concentrations of each compound on thermoregulation provoked by body cooling. The specific outcome was increased metabolism, as reflected in increased output of carbon dioxide. Isoflurane decreased the temperature threshold for such increases and the maximum response intensity, doing so in a concentration-dependent manner, whereas 2N had a minimal or no effect at any concentration up to 0.9 minimum alveolar concentration (estimated from its lipophilicity). Thus, 2N may be a useful tool for studies of the mechanisms mediating the thermoregulatory depression produced by anesthetics: 2N should not affect such a mechanism.
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PMID:The nonimmobilizer 1,2-dichlorohexafluorocyclobutane does not affect thermoregulation in the rat. 1100 66

The role of presynaptic mechanisms in general anesthetic depression of excitatory glutamatergic neurotransmission and facilitation of GABA-mediated inhibitory neurotransmission is unclear. A dual isotope method allowed simultaneous comparisons of the effects of a representative volatile (isoflurane) and intravenous (propofol) anesthetic on the release of glutamate and GABA from isolated rat cerebrocortical nerve terminals (synaptosomes). Synaptosomes were prelabeled with L-[(3)H]glutamate and [(14)C]GABA, and release was determined by superfusion with pulses of 30 mM K(+) or 1 mM 4-aminopyridine (4AP) in the absence or presence of 1.9 mM free Ca(2+). Isoflurane maximally inhibited Ca(2+)-dependent 4AP-evoked L-[(3)H]glutamate release (99 +/- 8% inhibition) to a greater extent than [(14)C]GABA release (74 +/- 6% inhibition; P = 0.023). Greater inhibition of L-[(3)H]glutamate versus [(14)C]GABA release was also observed for the Na(+) channel antagonists tetrodotoxin (99 +/- 4 versus 63 +/- 5% inhibition; P < 0.001) and riluzole (84 +/- 5 versus 52 +/- 12% inhibition; P = 0.041). Propofol did not differ in its maximum inhibition of Ca(2+)-dependent 4AP-evoked L-[(3)H]glutamate release (76 +/- 12% inhibition) compared with [(14)C]GABA (84 +/- 31% inhibition; P = 0.99) release. Neither isoflurane (1 mM) nor propofol (15 microM) affected K(+)-evoked release, consistent with a molecular target upstream of the synaptic vesicle exocytotic machinery or voltage-gated Ca(2+) channels coupled to transmitter release. These findings support selective presynaptic depression of excitatory versus inhibitory neurotransmission by clinical concentrations of isoflurane, probably as a result of Na(+) channel blockade.
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PMID:Selective depression by general anesthetics of glutamate versus GABA release from isolated cortical nerve terminals. 1260 96

Windup is a progressive increase in responses of nociceptive spinal cord neurons to repeated electrical C fiber stimulation. We hypothesized that isoflurane would depress windup at approximately the minimum alveolar anesthetic concentration (MAC) required to suppress purposeful movement in response to noxious stimulation. We recorded windup responses in single lumbar spinal neurons (n = 17) to a series of 15 repetitive electrical stimuli delivered at 1 Hz to the hindpaw at C fiber strength; hindpaw withdrawal force was simultaneously recorded. The total number of action potentials per 15 stimuli (mean +/- sem as a percentage of each neuron's maximal response) was 83% +/- 5%, 84% +/- 5%, 67% +/- 7%, and 57% +/- 8% at 0.7, 0.9, 1.1, and 1.4 MAC, respectively. The 0.9 and 1.1 MAC values differed significantly from each other, whereas the 0.7 and 0.9 MAC values differed from the 1.4 MAC value (P < 0.05). The reduced firing was attributed to a depression of the initial C fiber-evoked responses in most units, and a reduction in windup slope over the initial 5 stimuli in 6 units. Muscle force was 67%, 11%, and 4% of the 0.7 MAC value at 0.9, 1.1, and 1.4 MAC, respectively. Isoflurane depressed excitability and variably affected windup of lumbar spinal cord neurons, while uniformly depressing windup of limb withdrawals in a concentration-dependent manner.
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PMID:Isoflurane depresses windup of C fiber-evoked limb withdrawal with variable effects on nociceptive lumbar spinal neurons in rats. 1550 40

General anesthetics have marked effects on synaptic transmission, but the mechanisms of their presynaptic actions are unclear. We used quantitative laser-scanning fluorescence microscopy to analyze the effects of the volatile anesthetic isoflurane on synaptic vesicle cycling in cultured neonatal rat hippocampal neurons monitored using either transfection of a pH-sensitive form of green fluorescent protein fused to the luminal domain of VAMP (vesicle-associated membrane protein), (synapto-pHluorin) or vesicle loading with the fluorescent dye FM 1-43. Isoflurane reversibly inhibited action potential-evoked exocytosis over a range of concentrations, with little effect on vesicle pool size. In contrast, exocytosis evoked by depolarization in response to an elevated extracellular concentration of KCl, which is insensitive to the selective Na+ channel blocker tetrodotoxin, was relatively insensitive to isoflurane. Inhibition of exocytosis by isoflurane was resistant to bicuculline, indicating that this presynaptic effect is not caused by the well known GABA(A) receptor modulation by volatile anesthetics. Depression of exocytosis was mimicked by a reduction in stimulus frequency, suggesting a reduction in action potential initiation, conduction, or coupling to Ca2+ channel activation. There was no evidence for a direct effect on endocytosis. The effects of isoflurane on synaptic transmission are thus caused primarily by inhibition of action potential-evoked synaptic vesicle exocytosis at a site upstream of Ca2+ entry and exocytosis, possibly as a result of Na+ channel blockade and/or K+ channel activation, with the possibility of lesser contributions from Ca2+ channel blockade and/or soluble N-ethylmaleimide-sensitive factor attachment protein receptor-mediated vesicle fusion.
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PMID:The general anesthetic isoflurane depresses synaptic vesicle exocytosis. 1572 62

Isoflurane and halothane cause electroencephalographic (EEG) depression and neuronal depression in the reticular formation, a site critical to consciousness. We hypothesized that isoflurane, more than halothane, would depress EEG activation elicited by electrical microstimulation of the reticular formation. Rats were anesthetized with either halothane or isoflurane and stimulating electrodes were positioned in the reticular formation. In a crossover design, anesthetic concentration was adjusted to 0.8 and 1.2 minimum alveolar concentration (MAC) of halothane or isoflurane and electrical microstimulation was performed and the EEG responses were recorded. Microstimulation increased the spectral edge and median edge frequencies 2-2.5 Hz at 0.8 MAC for halothane and isoflurane and 1.2 MAC halothane. At 1.2 MAC isoflurane, burst suppression occurred and microstimulation decreased the period of isoelectricity (24% +/- 19% to 8% +/- 7%; P < 0.05), whereas the spectral edge and median edge frequencies were unchanged. At anesthetic concentrations required to produce immobility, the cortex remains responsive to electrical microstimulation of the reticular formation, although the EEG response is depressed in the transition from 0.8 to 1.2 MAC. These data indicate that cortical neurons remain responsive to synaptic input during isoflurane and halothane anesthesia.
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PMID:The differential effects of halothane and isoflurane on electroencephalographic responses to electrical microstimulation of the reticular formation. 1671 14

The serotonergic system may play a role during general anesthesia. Furthermore, alterations in serotonergic neurotransmission in the hippocampus have been linked to depression and anxiety as well as to changes in arousal and cognition. Little is known about the effects of volatile anesthetics on hippocampal serotonin (5-HT) levels. In this study we examined the effects of isoflurane on hippocampal 5-HT levels in mice. Adult male 129/SvEv mice were exposed to either isoflurane 1 or 1.5 minimum alveolar concentration (MAC) both in 40% O2 in air or to 40% O2 in air alone (control) for a period of 80 min, and hippocampal 5-HT levels were measured by microdialysis coupled with high performance liquid chromatography. Within 20-40 min of administration, both doses of isoflurane similarly produced a significant decrease in hippocampal 5-HT to 41.5% +/- 11.0% and 36.4% +/- 13.9% of the baseline level in the isoflurane 1 MAC and 1.5 MAC groups, respectively. Furthermore, when additional dialysates were obtained on termination of anesthesia in the isoflurane 1.5 MAC group, the decrease in extracellular 5-HT levels persisted for several hours. To determine if isoflurane-induced changes in extracellular 5-HT involve the serotonin transporter (SERT), similar microdialysis studies were performed in C57BL/6 wild-type (SERT +/+) and homozygous SERT knockout (SERT -/-) mice exposed to either 1 MAC isoflurane in 40% O2 in air or to 40% O2 in air alone for a period of 80 min. Isoflurane produced a significant decrease in hippocampal 5-HT in SERT +/+ and SERT -/-, and this decrease was larger in SERT -/- compared with SERT +/+: to 22.4% +/- 8.5% versus 50.2% +/- 17.4% of the baseline 5-HT level, respectively. These data suggest that isoflurane produces a decrease in hippocampal 5-HT, independent of SERT function.
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PMID:Isoflurane decreases extracellular serotonin in the mouse hippocampus. 1679 Jun 33


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