Volatile anaesthetics depolarize neural mitochondria by inhibiton of the electron transport chain

Bains, R.; Moe, Morten C.; Larsen, Geir Arne; Berg-Johnsen, Jon; Vinje, Morten Larsen

doi:10.1111/j.1399-6576.2006.00988.x

Cited by 48 publications

(36 citation statements)

References 50 publications

(60 reference statements)

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“…H 2 S is thought to specifically inhibit complex IV in the respiratory chain, whereas isoflurane has been shown to be more specific for complexes I and V (Hanley et al, 2002;Bains et al, 2006). It is possible that the different sites of inhibition within the complex array of interacting subunits might actually oppose each other's actions via allosteric communication.…”

mentioning

confidence: 99%

“…Halothane, isoflurane, and sevoflurane all inhibit complex I activity in cardiac mitochondria, whereas sevoflurane and isoflurane also inhibit complex V to some extent (Hanley et al, 2002;Bains et al, 2006). Volatile anesthetics bind specifically to many mitochondrial proteins and preferentially accumulate in mitochondria (Eckenhoff and Shuman, 1990).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Is Hydrogen Sulfide-Induced Suspended Animation General Anesthesia?

McKinstry²,

Moore³

et al. 2012

J Pharmacol Exp Ther

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Hydrogen sulfide (H 2 S) depresses mitochondrial function and thereby metabolic rates in mice, purportedly resulting in a state of "suspended animation." Volatile anesthetics also depress mitochondrial function, an effect that may contribute to their anesthetic properties. In this study, we ask whether H 2 S has general anesthetic properties, and by extension, whether mitochondrial effects underlie the state of anesthesia. We compared loss of righting reflex, electroencephalography, and electromyography in mice exposed to metabolically equipotent concentrations of halothane, isoflurane, sevoflurane, and H 2 S. We also studied combinations of H 2 S and anesthetics to assess additivity. Finally, the long-term effects of H 2 S were assessed by using the Morris water maze behavioral testing 2 to 3 weeks after exposures. Exposure to H 2 S decreases O 2 consumption, CO 2 production, and body temperature similarly to that of the general anesthetics, but fails to produce a loss of righting reflex or muscle atonia at metabolically equivalent concentrations. When combined, H 2 S antagonizes the metabolic effects of isoflurane, but potentiates the isoflurane-induced loss of righting reflex. We found no effect of prior H 2 S exposure on memory or learning. H 2 S (250 ppm), not itself lethal, produced delayed lethality when combined with subanesthetic concentrations of isoflurane. H 2 S cannot be considered a general anesthetic, despite similar metabolic suppression. Metabolic suppression, presumably via mitochondrial actions, is not sufficient to account for the hypnotic or immobilizing components of the anesthetic state. Combinations of H 2 S and isoflurane can be lethal, suggesting extreme care in the combination of these gases in clinical situations.

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mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Is Hydrogen Sulfide-Induced Suspended Animation General Anesthesia?

McKinstry²,

Moore³

et al. 2012

J Pharmacol Exp Ther

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“…Anesthetic-induced inhibition of mitochondrial electron transport could lead to increased O 2 -levels and downstream reactions, which could trigger APC [9]. Moreover, isoflurane and sevoflurane both inhibit mitochondrial electron transport [12], whereas N 2 O does not inhibit mitochondrial electron transport or ATP formation [13,14]. Many investigators have shown that protein kinase C (PKC), ATP-sensitive mitochondrial and sarcolemmal potassium (mitoK ATP ?…”

Section: Discussionmentioning

confidence: 99%

Sevoflurane and nitrous oxide exert cardioprotective effects against hypoxia-reoxygenation injury in the isolated rat heart

et al. 2009

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It is unclear whether nitrous oxide (N(2)O) has a protective effect on cardiac function in vitro. In addition, little is known about the cardioprotective effect of anesthesia administered during hypoxia or ischemia. We therefore studied the cardioprotective effects of N(2)O and sevoflurane administered before or during hypoxia in isolated rat hearts. Rat hearts were excised and perfused using the Langendorff technique. For hypoxia-reoxygenation, hearts were made hypoxic (95% N(2), 5% CO(2)) for 45 min and then reoxygenated (95% O(2), 5% CO(2)) for 40 min (control: CT group). Preconditioning was achieved through three cycles of application of 4% sevoflurane (sevo-pre group) or 50% N(2)O (N(2)O-pre group) for 5 min with 5-min washouts in between. Hypoxic conditions were achieved by administering the 4% sevoflurane (sevo-hypo group) or 50% N(2)O (N(2)O-hypo group) during the 45-min hypoxic period. L-type calcium channel currents (I(Ca,L)) were recorded on rabbit myocytes. (1) Both 4% sevoflurane and 50% N(2)O significantly reduced left ventricular developed pressure (LVDP). Sevoflurane also increased left ventricular end-diastolic pressure, though N(2)O did not. (2) The recoveries of LVDP and pressure-rate product (PRP) after hypoxia-reoxygenation were better in the sevo-pre group than in the CT or N(2)O-pre group. (3) Application of either sevoflurane or N(2)O during hypoxia improved recovery of LVDP and PRP, and GOT release was significantly lower than in the CT group. (4) Sevoflurane and N(2)O reduced I(Ca,L) to similar extents. Although sevoflurane administered before or during hypoxia exerts a cardioprotective effect, while N(2)O shows a cardioprotective effect only when administered during hypoxia.

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“…In pig heart studies, the volatile anesthetics halothane, isoflurane, and sevoflurane inhibit complex I activity (NADH:ubiquinone oxidoreductase) [Hanley et al, 2002]. In rat brain, the inhaled anesthetics isoflurane and sevoflurane inhibit complexes I, IV, and V as well as DC under different conditions [Bains et al, 2006]. These effects may not all be deleterious, as depolarization may prevent ischemic injury by activation of signaling pathways through mechanism previously described [Moe et al, 2004].…”

Section: Anesthetics As a Model Of Mitochondrial Toxicitymentioning

confidence: 96%

Pharmacologic effects on mitochondrial function

Cohen

2010

Dev Disabil Res Revs

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The vast majority of energy necessary for cellular function is produced in mitochondria. Free-radical production and apoptosis are other critical mitochondrial functions. The complex structure, electrochemical properties of the inner mitochondrial membrane (IMM), and genetic control from both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) are some of the unique features that explain why the mitochondria are vulnerable to environmental injury. Because of similarity to bacterial translational machinery, mtDNA translation is likewise vulnerable to inhibition by some antibiotics. The mechanism of mtDNA replication, which is required for normal mitochondrial maintenance and duplication, is inhibited by a relatively new class of drugs used to treat AIDS. The electrochemical gradient maintained by the IMM is vulnerable to many drugs that are weak organic acids at physiological pH, resulting in excessive free-radical generation and uncoupling of oxidative phosphorylation. Many of these drugs can cause clinical injury in otherwise healthy people, but there are also examples where particular gene mutations may predispose to increased drug toxicity. The spectrum of drug-induced mitochondrial dysfunction extends across many drug classes. It is hoped that preclinical pharmacogenetic and functional studies of mitochondrial toxicity, along with personalized genomic medicine, will improve both our understanding of mitochondrial drug toxicity and patient safety.

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Volatile anaesthetics depolarize neural mitochondria by inhibiton of the electron transport chain

Cited by 48 publications

References 50 publications

Is Hydrogen Sulfide-Induced Suspended Animation General Anesthesia?

Is Hydrogen Sulfide-Induced Suspended Animation General Anesthesia?

Sevoflurane and nitrous oxide exert cardioprotective effects against hypoxia-reoxygenation injury in the isolated rat heart

Pharmacologic effects on mitochondrial function

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