Effects of Anesthetics on Mitochondrial Signaling and Function

14 Pages·2012·0.25 MB·English

126 Current Drug Safety, 2012, 7, 126-139
Effects of Anesthetics on Mitochondrial Signaling and Function
Enza La Monaca and Vincenzo Fodale*
Department of Neuroscience, Psychiatric and Anesthesiological Sciences, University of Messina, via C. Valeria, 98125
Messina, Italy
Abstract: Mitochondria are considered the powerhouses of the cell playing an important role in energy metabolism.
However, they are highly vulnerable to inhibition or uncoupling of the energy harnessing process and run a high risk of
causing catastrophic damage to the cell. Several anesthetics or drugs commonly given during anesthesia interact with
mitochondria and affect their structure or impair respiratory chain functioning with decreased ATP production.
Mitochondria, in fact, are a potential site of action of general and local anesthetics. The purpose of this review is to update
present knowledge and describe the effects and molecular mechanisms of the action of the most used drugs of anesthesia
on mitochondria.
Keywords: Anesthesia, anesthetics, complications, mitochondria, respiratory chain, toxicity.
1. INTRODUCTION membranes is a phospholipid bilayer with embedded
proteins. The outer membrane is smooth while the inner
Mitochondria are considered the powerhouses of the cell:
membrane has many folds. These folds, the so-called cristae,
they play an important role in energy metabolism through
enhance the "productivity" of cellular respiration by
oxidative phosphorylation with adenosine triphosphate
increasing available surface area. The outer membrane of the
(ATP) production, as well as calcium signaling or reactive
mitochondria contains the protein "porin" that forms an
oxygen species production; other complex processes
aqueous channel through which proteins, up to 10,000
involving mitochondria include cardioprotection and
daltons, can pass into the intermembrane space. Small
apoptosis [1,2]. However, mitochondria are highly
molecules are equilibrated between the outer membrane and
vulnerable to inhibition or uncoupling of the energy
the cytosol. However, most proteins cannot enter the matrix
harnessing process and run a high risk of causing
unless they pass through the inner membrane. The internal
catastrophic damage to the cell [3]. Mitochondrial
space, enclosed by the inner membrane, is the matrix [5].
dysfunctions also play a role in neurodegenerative disorders
such as Parkinson, Huntington and Alzheimer’s diseases, Several thousand mitochondria can be found in cells. The
and mitochondrial diseases [2]. Various drugs, such as number depends on what the cell needs to do. Brain, heart
antiviral immunosuppressant, antitumor, sulfonylureas, muscle, liver, cardiac and skeletal muscles contain the largest
potassium channel openers, along with anesthetics, interact number of mitochondria as they are the more active organs,
with mitochondria, affecting structures and impairing metabolically, and thus are more susceptible to drugs acting on
respiratory chain function with decreased ATP production mitochondria, but also to mitochondria pathologies [2].
[2]. General anesthetics inhibit mitochondrial function as Mitochondria play a central role in energy-generating processes
mitochondria are a potential site of action of general and within the cell. They produce ATP, the main fuel for cellular
local anesthetics. Nevertheless, inhaled and intravenous activities, through cellular respiration. Fatty acid (cid:2)-oxidation,
anesthetics have been reported to affect mitochondrial the urea cycle, and the final common pathway for ATP
functions in different ways, while high lipophilic local production in the respiratory chain occur in mitochondria [2].
anesthetics impair energy metabolism in mitochondria or in ATP is converted from adenosine diphosphate by adding the
the cell and such effects may be associated with certain toxic phosphate group with the high-energy bond. Various reactions
effects of local anesthetics [4]. in the cell either use energy (whereby ATP is converted back to
ADP, releasing the high energy bond) or produce it (whereby
The purpose of this review is to survey available, up-to-
ATP is produced from ADP). Mitochondria also play a role in
date information on the effects and molecular mechanisms of
intermediary metabolism, in the metabolism of steroids, lipids,
the action of drugs administered during anesthesia on
amino acids, cholesterol, nucleotides and in intracellular
mitochondria, and their possible implications.
signaling, and apoptosis [2].
The mitochondrial respiratory chain is a complex system
2. MITOCHONDRIA: STRUCTURE AND FUNCTIONS
that responds to the energy requirements of the cell; it is
Mitochondria are important components of eukaryotic formed by five enzyme complexes localized on the inner
cells. They have a cigar-shaped structure and a subcompart- mitochondrial membrane. Each complex is composed of
ment characterized by a double membrane. Each of these multiple subunits.

The electron transport chain electrons move from an
electron donor (NADH) to a terminal electron acceptor (O) via
*Address correspondence to this author at the Department of Neuroscience, 2
Psychiatric and Anesthesiological Sciences, University of Messina, a series of redox reactions. These reactions are coupled to the
Policlinico Universitario Pad.E, Piano 1, Via C. Valeria, 98125 Messina, creation of a proton gradient across the mitochondrial inner
Italy; Fax: [phone]; E-mail: [email protected] membrane. There are three proton pumps: I, III, and IV. The

1574-8863/12 $58.00+.00 © 2012 Bentham Science Publishers
Anesthesia and Mitochondria Current Drug Safety, 2012, Vol. 7, No. 2 127
resulting transmembrane proton gradient is used to produce effect from local anesthetics [1]. Nevertheless, during
ATP via ATP synthase [6,7]. general anesthetic procedures there is extensive inhibition of
substrate oxidation in human muscle mitochondria not
The reactions catalyzed by Complex I and Complex III
related to a direct effect on mitochondrial respiratory chain
work roughly in equilibrium. This means that these reactions are
complexes or via uncoupling oxidative phosphorylation [21].
readily reversible by increasing the concentration of the
The effects of the different drugs administered during
products relative to the concentration of the reactants. ATP
anesthesia on mitochondria and their molecular mechanisms
synthase is also readily reversible. Thus ATP can be used to
are described below.
build a proton gradient, which in turn can be used to produce
NADH [6-8].
4. VOLATILE ANESTHETICS
The mitochondrial ATP-sensitive potassium channel is an
important component of the mitochondria. It is localized in the The interaction of volatile anesthetics with mitochondrial
inner membrane, but the structure is not well understood [9]. metabolism consists essentially in preconditioning, inhibition
Most information regards the sarcolemma K ATP channel. The of complex I, as seen in isolated cardiomyocytes or in
first purification of mitoK was realized in 1990 [9]. This humans with mitochondrial disease [1-2]. In particular, all
ATP
structure is found in various tissues such as brain, liver, kidney inhaled anesthetics studied cause a dose-dependent increase
and heart [1]. The channel is formed by two types of subunits: in NADH fluorescence, and deterioration in myocardial
mitoK of 55 kDa and mito SUR of 63 kDa [10]. The subunit oxidation-reduction status may be due to inhibition of the
IR
mitoK is a “K channel protein”, whereas mito SUR is a electron transport chain in mitochondria [22]. The first report
IR
sulfonylurea receptor. When the channel is open, K+ ions enter concerning volatile anesthetic-induced myocardial protection
the mitochondrial matrix with a reduction of membrane concerned enhancement of recovery in contractile function
potential and swelling of the matrix caused by water binding to of stunned myocardium by halothane or isoflurane [23].
K+ iones [1]. Volatile anesthetics have cardioprotective effects that mimic
ischemic preconditioning, including the involvement of
In vitro activity of mitoK is regulated by ATP, ADP, Mg,
ATP mitoK channels. However, evidence of a direct effect of
and acyl-CoA that inhibit the channel, while GPT and GDP ATP
volatile anesthetics on the mitoK channel is limited,
cause opening of the channel [11]. In vivo, channel opening is ATP
although indirect evidence has been provided in dogs [24].
caused by calcium signal or by brief episodes of ischemia and
reperfusion [1]. Anesthetic-induced preconditioning and ischemic
preconditioning is mediated by activation of G-protein-
Recent evidence suggests that mitoK channels are
ATP coupled receptors, multiple protein kinases and by increased
important in cardiac preconditioning. Ischemic preconditio-ning
formation of nitric oxide, free oxygen radicals and mitoK
is a phenomenon whereby exposure of the myocardium to a ATP
channels, the end-effectors of preconditioning. The opening
brief episode of ischemia and reperfusion markedly reduces
of mitoK channels ultimately elicits cytoprotection by
tissue necrosis induced by subsequent prolonged ischemia. A ATP
decreasing cytosolic and mitochondrial Ca(2+) overload
variety of intracellular signaling pathways have been implicated
[25]. Flavoprotein oxidation through opening of the
in the protective mechanism. It would seem that mitoK
ATP mitoK channel is another mechanism contributing to
channels serve as one of the effectors of cardioprotection and ATP
inhaled anesthetic-induced preconditioning. Administration
that adenosine receptor activation primes the opening of
of isoflurane and sevoflurane produced an increase in
mitoK channels in a protein kinase C (PKC)-dependent
ATP flavoprotein oxidation through mitoK opening while the
manner [12,13]. ATP
intravenous anesthetics propofol and pentobarbital had no
How the opening of mitoK channels might protect direct effect on mitoK opening, although they did inhibit
ATP ATP
against ischemic damage still remains unclear. Mitochondrial isoflurane-induced flavoprotein oxidation; thus, intravenous
depolarization accelerates respiration, slows ATP production, agents may block volatile anesthetic protection [26]. Long-
releases accumulated Ca2+, produces swelling, and stimulates chain acylCoA appears to play a relevant role in anesthetic-
the efflux of intermembrane proteins [14]. However, other induced mitochondrial injuries, where levels are markedly
authors have reported that the opening of mitoK channels has increased in mitochondria incubated in the presence of
ATP
little effect on respiration, membrane potential, or Ca2+ uptake halogenated anesthetics. In addition, the amount of
but does have an important effect on matrix and intermembrane intramitochondrial calcium may also influence the severity
space volume [15]. Those authors also demonstrated that of these injuries [27]. Studies have suggested that volatile
uncoupling and depolarization secondary to opening mitoK anesthetics administered upon early reperfusion or
ATP
channels in vivo are too small to cause significant direct effects "anesthetic postconditioning" could protect post-ischemic
on mitochondrial energetics. Another possibility is that hearts against myocardial ischemia reperfusion injury.
mitochondrial depolarization secondary to opening mitoK However, the mechanism responsible for such protection
ATP
channels protects the heart by reducing mitochondrial Ca2+ was not well elucidated [28].
uptake. Inhibition of the mitochondrial Ca2+ uniporter by
There is data on mitochondrial-mediated apoptosis for
ruthenium red protects the hearts against ischemia and
most anesthetics; for example, inhalational anesthetics may
reperfusion injury [16,17].
induce cell apoptosis by causing abnormal calcium release
from the endoplasmic reticulum via excessive activation of
3. ANESTHETICS DRUGS AND MITOCHONDRIA
IP receptors [29-31]. In particular, isoflurane has greater
3
The effects of general anesthetics on mitochondria have potency than sevoflurane or desflurane to cause calcium
been previously investigated [18-20], resulting mostly in a release from the endoplasmic reticulum and to induce cell
cardioprotector effect from volatile anesthetics, or a toxic damage [29-32]. In addition, these anesthetics induce
128 Current Drug Safety, 2012, Vol. 7, No. 2 La Monaca and Fodale
apoptosis in T lymphocytes via increased mitochondrial In the last few years, some authors have shown that
membrane permeability and caspase-3 activation, but isoflurane reduces myocardial damage when administered
independently of death receptor signaling, in a dose- during the early phase of reperfusion (isoflurane
dependent manner. By contrast, desflurane did not exert any postconditioning), however, the exact mechanism is
proapoptotic effects [33]. unknown as cardioprotection is modified by genetic factors,
such as deficiency of nitric oxide synthase (NOS) [48-50].
Growing evidence suggests that among potential candidates,
4.1. Halothane
the mitochondrial permeability transition (MPT) pore is a
Halothane inhibits the electron transport chain at key target for nitric oxide-induced protection against
complex I (NADH: ubiquinone oxidoreductase) in a dose- ischemia/reperfusion injury [51-54]. Isoflurane
dependent manner [34-36]. In the presence of halothane, at postconditioning protects mouse hearts from reperfusion
concentrations of two MAC, the activity of complex I was injury by preventing MPT pore opening in an eNOS-
reduced by about 20%. These inhibitory effects at usual dependent manner. Nitric oxide functions as both a trigger
clinical concentrations are unlikely to compromise cardiac and a mediator of cardioprotection [55].
performance, but may contribute to the mechanism by which
Furthermore, isoflurane postconditioning, at reperfusion,
volatile anesthetics induce pharmacological preconditioning
inhibited mitochondrial respiration, depolarized
[37]. An increase in NADH fluorescence, evoked by
mitochondria and acidified pH. These events may lead to
halothane, and similarly to isoflurane, has been observed
inhibition of mPTP opening and, consequently, ATP
also in isolated ventricular trabeculae [38] and isolated,
synthesis. This reduces intracellular Ca(2+) overload and cell
perfused hearts [22]. However, halothane was found to
death [56].
inhibit also succinate dehydrogenase, the catalytic
component of complex II [39]. Halothane decreases cell
viability, impairs DNA integrity and provokes stress-induced 4.3. Sevoflurane
apoptosis in A549 cells in the lung when applied at clinically
Sevoflurane inhibits complex I and does not affect
relevant concentrations. In vitro effects of halothane on lung
succinate oxidation. At concentrations of 2 MAC, the
cells involved alteration in the expression of proteins of the
activity of NADH: ubiquinone oxidoreductase is reduced by
mitochondrial apoptotic pathway [40].
about 10% [37,38]. Reduction of complex I is mediated by
reactive oxygen species, whereas attenuation of other
4.2. Isoflurane respiratory complexes is mediated by a different mechanism.
Opening of mitoK channels by sevoflurane does not seem
Isoflurane inhibits complex I of the mitochondrial ATP
to be involved in this effect. Thus, reactive oxygen species
electron transport chain [37] and increases NADH
formation may not only result from attenuated electron
fluorescence in isolated ventricular trabeculae [38] and
transport by sevoflurane, but may also contribute to complex
isolated, perfused hearts [39]. Succinate oxidation is not
I reduction, possibly leading to a positive feedback and
affected by isoflurane or sevoflurane, suggesting that
amplification of sevoflurane-induced reactive oxygen species
complexes II, III and IV are not inhibited [38].
formation in triggering anesthetic preconditioning [57].
This volatile anesthetic has a cardioprotective effect that Thus, reactive oxygen species are implicated in triggering
mimics the ischemic preconditioning phenomenon mediated anesthetic preconditioning. Sevoflurane directly increased
by the opening of the sarcolemma mitoKATP channel not due ROS superoxide (O2(cid:2)-) but led to attenuated O2(cid:2)- formation
to direct interaction with the mitoKATP channel protein, but during ischemia [58,59]. A cardioprotective effect of
to an intracellular component, probably including the sevoflurane was demonstrated in ischemic canine hearts, by
translocation of specific protein kinase C isoforms [41]. activation of mitoK channels, but not sarcolemmal K
ATP ATP
In another study in rabbits and dog, the cardioprotective channels, reducing myocardial infarct size and decreasing
effect of isoflurane was mediated through adenosine the time threshold for ischemic preconditioning [24,60].
receptors and KATP channels [42,43]. It would appear that This effect of sevoflurane is independent of effects on
isoflurane activates mitoKATP channels, but not through blood pressure and coronary blood flow [60]. It mimics
pathways involving adenosine, protein kinase C, tyrosine ischemic preconditioning to improve postischemic
kinase, or p38 mitogen-activated protein kinase. Protective contractility and coronary flow in isolated guinea pig hearts
effects of isoflurane are abolished by KATP channel blockers [61]. The cardioprotective effect of sevoflurane depends on
5-HD (hydroxydecanoate, a specific inhibitor of the PKC activation, the opening of mitoK channels, and the
ATP
mitoKATP channel) and glyburide [17,43-45]. Concentrations endogenous production of ROS. These results suggest that
of isoflurane as low as 0.25 MAC are sufficient to all three of these signaling events are active within the
precondition myocardium against infarction. High common intracellular signaling cascade of sevo-induced
concentrations of isoflurane may have greater efficacy in cardioprotection [62]. A recent study has demonstrated that
protecting the myocardium during conditions of low phosphatidylinositol-3-kinase (PI3K), extracellular signal-
coronary collateral blood flow [46]. Anesthetic regulated kinase 1 and 2 (ERK 1/2), mitoK channels and
ATP
preconditioning with volatile anesthetics improves recovery the MPT pore are key players in sevoflurane
of contractile function and reduces calcium overload after postconditioning induced cardioprotective mechanisms in
ischemia/reperfusion. Ischemia/reperfusion is associated also isolated rat hearts subjected to myocardial ischemia
with a down-regulation of the major sarcoplasmic reticulum reperfusion injury [63]. Sevoflurane-induced cardioprotect-
Ca2+-cycling proteins and this effect is independent of its ion has also been demonstrated by activation of PKB/Akt
activation of mitoK channels [47].
ATP
Anesthesia and Mitochondria Current Drug Safety, 2012, Vol. 7, No. 2 129
(protein kinase B) and GSK3 beta (glycogen sinthase kinase In in vivo rodent studies, in addition to causing widespread
3 beta) in isolated perfused rat hearts [64]. apoptotic neurodegeneration in vulnerable brain regions,
exposure to general anesthesia at the peak of synaptogenesis
causes learning and memory deficiencies later in life, and this
4.4. Desflurane
disturbance in mitochondrial integrity and function could be the
In vitro, desflurane preconditions human myocardium earliest triggering event [80]. This anesthesia, administered at
against simulated ischemia through activation of mitoKATP the peak of synaptogenesis, causes significant enlargement of
channels, adenosine A1 receptor, and alpha and beta mitochondria, impairment of structural integrity, increase in
adrenoceptors [65]. Desflurane, when compared with complex IV activity and a twofold decrease in regional
halothane, shows better preservation of mitochondrial distribution in presynaptic neuronal profiles, heightened
function at 4 h after cerebral ischemia reperfusion injury in autophagic activity, decrease in mitochondrial density and long-
terms of mitochondrial swelling inhibition, increase in lasting disturbances in inhibitory synaptic neurotransmission
membrane potential and improvement of functions of [79].
mitochondria respiratory complexes I + III and IV [66].
Moreover, desflurane improves resistance of the 7. INTRAVENOUS ANESTHETICS
transition pore to calcium-induced opening. This effect is
7.1. Benzodizepines
inhibited by 5 hydroxydecanoate, suggesting a link between
mitochondrial adenosine triphosphate-sensitive potassium Benzodizepines are popular drugs prescribed for relieving
and mitochondrial permeability transition [67]. Some data anxiety, and as anticonvulsants, muscle relaxants, or hypnotics.
suggest that desflurane-induced anesthetic preconditioning is These effects are mediated in the central nervous system
mediated in part by activation of mitochondrial large- through postsynaptic plasma membrane GABA A receptors that
conductance K(Ca) channels mediated by PKA [68]. In an in are (cid:2)-aminobutyric acid-gated chloride channels. Another
vivo dog model, both desflurane and isoflurane improve benzodiazepine receptor has also been identified in peripheral
postischemic contractile performance [59], and reduce tissue, peripheral benzodiazepine receptor (PBR), and has
myocardial infarct size, suggesting that sarcolemmal and already been proposed as playing a role in mitochondrial
mitoKATP channels could be involved [24]. regulation. PBRs are localized in peripheral tissues, such as
adrenal glands testis, uterus, kidney, heart, brain and platelets
5. XENON [81,82]. They have been localized in mitochondrial membranes
in contact sites between the outer and inner mitochondrial
Xenon appears to exert an action on cardiac and neural membranes, but also non mitochondrial localizations have been
signal transduction similar to volatile anesthetics; therefore,
observed in heart, liver, and testis. Furthermore, PBRs have
the reductions in infarct size observed with administration of
been found in mature erythrocytes, which lack mitochondria.
xenon were initially assumed to be related, at least in part, to
The PBR subunit composition roughly coincides with that of the
its anesthetic action [69,70]. There is evidence suggesting MPT pore [83-85] that opens under specific conditions and
that brief exposure to the noble gas xenon before prolonged enables unselective passage of molecules of up to 1.5 kDa
coronary artery occlusion and reperfusion protects between the mitochondrial matrix and the cytoplasm [86,87].
myocardium against infarction [71,72]: the mechanisms by
This pore, also called the "mitochondrial megachannel", may
which xenon produces these beneficial effects are similar to
have a role in events leading to programmed cell death
volatile anesthetic-induced preconditioning [73]. A mitoK
ATP (apoptosis) in multicellular organisms [88-90]. PBRs have been
channel-dependence of xenon preconditioning has recently implicated in several mitochondrial functions, but their exact
been reported [74,75]. physiological role is still unclear. In vitro studies using isolated
cells, mitochondria, and submitochondrial fractions
6. NITROUS OXIDE demonstrated that PBRs are present in steroid-synthesizing cells
and are involved in this kind of cell in the regulation of
Nitrous oxide has been found to inhibit cellular
cholesterol transport from the outer to the inner mitochondrial
respiration, and, at physiological concentrations, reversibly
membrane, known to be the rate-determining step in steroid
inhibits cytochrome-c-oxidase (COX) by two alternative
biosynthesis [91]. It has been demonstrated that PBRs play a
reaction pathways, yielding either a nitrosyl- or a nitrite-
major role in the regulation of cardiac ischemia-reperfusion
heme a3 derivative [76,77]. In fact, it has been shown that
injury [92].
nitrous oxide causes inhibition of tissue respiration in the
myocardium and liver and alters the rate of phosphorylation, Midazolam, a benzodiazepine used as a pre-anesthetic and
though this is not accompanied by a decrease in hypnotic drug, is a mitochondrial electron transport inhibitor. It
phosphorylation efficacy, which is indicative of great decreases complex I and III activities and also inhibits complex
reserves of the mitochondrial oxidation chain and the II activity. These effects, not necessarily related to pre-
reversibility of the occurring shifts. The absence of shifts in anesthetic and hypnotic action, are probably mediated via
the cytochrome system in response to the inhibition of mitochondrial benzodiazepine receptors [93]. Midazolam did
mitochondrial oxidation in different conditions demonstrates not affect mitoK channel activity in live cells [94].
ATP
that the metabolic effect of N2O is manifested in NAD-
dependent regions of the respiratory chain [78]. 7.2. Barbiturates
Nitrous oxide, in combination with other general anesthetics
Barbiturates are anesthetics and anticonvulsants drugs
such as isoflurane and midazolam, is damaging to the with neuroprotective effects [95]. It has been previously
developing mammalian brain [79]. demonstrated that barbiturates can block complex I activity
130 Current Drug Safety, 2012, Vol. 7, No. 2 La Monaca and Fodale
in isolated liver mitochondria at submillimolar concentrat- be an imbalance between energy demand and utilization with
ions, inhibiting mitochondrial respiration, whereas compromising cardiac and peripheral muscle cell function
mitochondrial inhibitors are known to potentiate NMDA [109]. Propofol impairs oxygen utilization and inhibits
receptor-mediated neurotoxicity. Oligomycin, an ATP electron flow along the mitochondrial electron transport
synthase inhibitor, increases barbiturate-induced mitochon- chain in cardiomyocytes. Activity of malonyl CoA, which in
drial depolarization. In this way, barbiturates inhibit electron turn inhibits carnitine palmitoyl transferase I, which
transport sufficiently to cause ATP synthase reversal [95]. transports long-chain free fatty acids into the mitochondria,
The NMDA effects on cytoplasmic free calcium concentrat- is increased, causing myocytolysis. Propofol also uncouples
ions are also amplified by barbiturates. Only N-glucoside b-oxidation and the respiratory electron transport chain II;
amobarbital (a cell-impermeant barbiturate) does not neither medium- nor short- free fatty acids, which freely
influence mitochondrial potential or potentiate NMDA cross the mitochondria membranes, can be utilized and low
neurotoxicity or calcium responses, whereas secobarbital and energy production can lead to cardiac and peripheral muscle
thiobarbital increase NMDA neurotoxicity [95]. necrosis during exercise. The patient may have arrhythmias
with the accumulation of unutilized free fatty acids, probably
Thiopental: High concentrations of pentobarbital sodium
related to Ca2+ overload in myocardial cells [109]. Propofol
inhibit myocardial contractility, mitochondrial electron
did not affect mitoK channel activity in live cardiomyo-
transport and energy transfer: however, in the isolated ATP
cytes cells [94].
myocardial mitochondria of rat heart, respiratory function is
not suppressed after high-dose pentobarbital anesthesia [96]. The effects on mitochondria of propofol infusion in
In the past, analyzed key enzymes in the glycolytic pathway humans have been indicated as a possible cause of the so-
showed competitive inhibition of phosphofrucktokinase called propofol infusion syndrome (PRIS). This rare, but
activity by thiopental, but no inhibition of hexokinase and frequently fatal complication, is characterized by metabolic
pyruvate-kinase activity [97]. No inhibition of hexokinase acidosis, rhabdomyolysis of both skeletal and cardiac
was found in either the total brain extract, nor in the soluble muscle, arrhythmias (bradycardia, atrial fibrillation,
or particulate fraction. The results suggest that ventricular and supraventricular tachycardia, bundle branch
phosphorylation of glucose in the brain may be suppressed in block and asystole), myocardial failure, renal failure,
anesthesia by shifting hexokinase activity from a more active hepatomegaly and death [109].
mitochondrial form to its less active soluble form. This effect
The antioxidant activity of propofol (2,6-
seems to be caused by a direct action of thiopental and is
diisopropylphenol), together with the stimulating effect of
obviously correlated with anesthesia [98].
protein kinase C, suggests that propofol might have the
potential to modulate apoptosis. Propofol may induce
7.3. Ketamine apoptosis, which is dependent on the mechanism that
activates both the cell surface death receptor pathway and the
In rats, injections of ketamine show no modifications of
mitochondrial pathway [110].
phosphorylation efficacy coefficient but only a reduction of
breathing control in palmitoylcarnitine oxidation. Moreover,
mitochondrial matrix induration and insignificant focal 7.5. Etomidate
disturbances of cardiac myofibril contractility has been
It has been shown that etomidate, a general anesthetic,
demonstrated. During ketamine anesthesia, a reduction in
has effects on oxidative phosphorylation in isolated rat liver
breathing control and phosphorylation efficacy coefficient by
mitochondria; it causes inhibition of complex I and also, but
myocardial mitochondria has been noted, by stimulating the
to a lesser extent, complex III. Etomidate decreases oxidative
heart with novodrine (beta-adrenergic agent) [99]. Ketamine
phosphorylation rate without changing yield. The H(+) leak
did not affect mitoK channel activity in live cells [94].
ATP which appears under non-phosphorylating conditions
Studies indicate that activation of NMDA receptors becomes negligible in physiological conditions [111].
causes apoptosis and necrosis [100-104]. Data from both
Etomidate, at 0.4 microg/mL, has no significant effect on
rodents and nonhuman primates have demonstrated the
isolated rat liver mitochondria, but at 4 microg/mL it can
neurotoxic effects of ketamine on the developing brain in a
lead to disruption of mitochondrial energy metabolism [112];
dose and exposure duration dependent manner [100,101,105-
however, it did not affect mitoK channel activity in
107]. ATP
cardiomyocytes cells [94].
Plasma and brain tissue ketamine levels do not correlate
in time with the occurrence of cell death, which occurs after,
8. LOCAL ANESTHETICS
when ketamine levels are quite low. Ketamine administration
stimulates the up-regulation of NMDA receptor subunits Effects of local anesthetics (LA) on mitochondria have been
which may further activate pro-apoptotic genes through observed since the 1960s [113-115]: these observations concern
various pathways and trigger apoptosis [108]. mitochondrial ion transport including adenine nucleotide
translocase [116]. LA have different effects on mitochondria.
They are mostly tertiary amines with pKa values ranging from 7
7.4. Propofol
to 9, and, probably due to these and their lipophilic properties,
Use of propofol causes impaired oxidation of fatty acid they uncouple oxidative phosphorylation [19,117-119].
chains and inhibits oxidative phosphorylation in the Depending on their chemical structure, they inhibit
mitochondria, determining decreased ventricular perfor- mitochondrial ATPase, stimulate or inhibit electron transport
mance in the isolated, perfused heart. Therefore, there may
Anesthesia and Mitochondria Current Drug Safety, 2012, Vol. 7, No. 2 131
and F1-ATPase, affect transport of ions such as Ca2+ and attenuate lipopolysaccharide-induced cell injury in
uncouple oxidative phosphorylation [120-122]. endothelial cells. Nevertheless, they attenuate cell injury
induced by ischemic-reperfusion and inflammation mediated
These effects of LA are also secondary to their basic site of
through activation of mitoK channels. In rat liver
action (i.e., the plasma membrane of nerve cells) but are ATP
probably responsible for the primary toxic effects observed mitochondria, procaine, like lidocaine, tetracaine and
dibucaine, brought about stimulation of the basal state
during analgesia [113-115]. In some instances, there are
(respiration before ADP addition) in a concentration-
conflicting reports concerning the existence of these effects.
dependent manner, but when concentration was higher this
However, it has been reported that anions are not always
effect was reduced. Procaine, like other drugs, had a biphasic
necessary for the uncoupling actions of LA. Furthermore, it has
effect: slight stimulation of state 3 at low and moderate
been demonstrated that hydrophobic amines with local
concentrations, and inhibition at higher concentrations [129].
anesthetic properties can mimic weak acid uncouplers in both
respiring and non-respiring mitochondria, and that this drug
effect necessarily requires a lipophilic anion. Another study has 8.2. Lidocaine
demonstrated that the uncoupling effect of LA depends on their
Lidocaine has been reported to attenuate ischemic-
liposolubility and thus the anesthetic action of LA depends reperfusion injury and ischemic-reperfusion induced
greatly on liposolubility and the natural presence of lipophilic
inflammatory response in endothelial and vascular smooth
anions. It involves different types of mechanisms: direct muscle cells. Mechanisms underlying LA induced protection
uncoupling by electrophoretic entry of the cationic form of the
against injury are not completely understood. This recovery
amine, protonophoric effects and the inhibition of mitochondrial of cardiac function has been related to a decrease in calcium
membrane activities, including respiratory chain components. It
and sodium overload. Thus, regulation of calcium
is thought that liposoluble LA may cross the cytoplasmic homeostasis by inducing the activation of mitoK channels
ATP
membrane and accumulate in mitochondria as a result of high may be a protective mechanism of LA. Lidocaine has been
transmembrane potential, leading to the uncoupling of oxidative reported to inhibit activation of myocardial mitoK
phosphorylation in vivo and a decrease in mitochondrial ATP
channels induced by diazoxide. Lidocaine-induced
metabolism [123]. Membrane-mediated effects of local protection is abolished by the selective mitoK channel
anesthetics on mitochondrial metabolism, such as uncoupling of ATP
antagonist, 5-hydroxydecaonate [128].
oxidative phosphorylation, would appear mainly to depend on
the lipid solubility molecule. However, LA isomers could have Lidocaine reduces flavoprotein fluorescence induced by
different direct effects on the enzymatic complexes of the diazoxide in rat ventricular myocytes, indicating that these
respiratory chain [124]. LA also decrease complex I activity in antiarrhythmic drugs may produce impairment of
living cells, and NADH ubiquinone reductase shows a high mitochondrial oxidation mediated by mitoKATP channels
sensitivity to structurally different molecules [124]. [130]. It may be neurotoxic and some data indicate that
neurotoxicity involves mitochondrial dysfunction with
The effects of LA on mitochondria could be associated with
activation of apoptotic pathways [131].
certain toxic effects of local anesthetics as cardiotoxicity may be
the result of interference with mitochondrial energy Lidocaine can also lead to persistent cauda equina syndrome
transduction. Two mechanisms have been described for the after spinal anesthesia, and this drug has been reported to trigger
interaction of local anesthetics with mitochondrial metabolism: apoptosis, although the underlying mechanisms remain
(1) an uncoupling effect between oxygen consumption and ATP unknown. Probably, apoptosis is triggered by concentrations of
synthesis by increasing proton membrane permeability, thus lidocaine occurring intrathecally after spinal anesthesia, whereas
dissipating the proton gradient; and (2) a direct inhibitory effect higher concentrations induce necrosis. Lidocaine induces
of LA (at higher concentrations) on mitochondrial enzyme apoptosis via the mitochondrial pathway independently of death
complexes with a reduction in enzyme activities of the different receptor signaling [132]. In another study it is also reported to
respiratory chain complexes of the mitochondrial inner have suppressed neutrophil function, inhibited ATP synthesis,
membrane. All these effects lead to a decrease in ATP synthesis reduced mitochondrial membrane potential, and induced
and a depletion in ATP content of the cell [125]. apoptosis [133].
The decrease in ATP synthase activity may be explained by
8.3. Bupivacaine
direct inhibition of mitochondrial F0F1-ATPase or by global
decline in cellular protein synthesis with a decrease in In vitro, bupivacaine myotoxicity is mediated by
mitochondrial proteins as a consequence. Mitochondrial local mitochondria [125,134]. However, the bupivacaine
anesthetics myotoxicity may be caused by the inhibition of uncoupling effect depends on the mitochondrial respiration
carnitine transport, which has been demonstrated for heart state. In state 4 respiration (no ADP phosphorylation),
mitochondria [126]. bupivacaine acts as a true protonophoric uncoupler. In
contrast, in state 3 respiration (ADP phosphorylation), the
Lidocaine, bupivacaine, and ropivacaine cause delayed
anesthetic induces a change in proton pump stoichiometry.
mitochondrial dysfunction and apoptosis in cultured human
Moreover, at high concentration, bupivacaine inhibits the
chondrocytes [127].
respiratory chain. Both bupivacaine enantiomers tested on rat
heart mitochondria appeared to equally inhibit the activity of
8.1. Tetracaine and Procaine
complex I of the respiratory chain and to uncouple oxidative
Tetracaine and procaine inhibited activation of mitoK phosphorylation [124]. Bupivacaine also inhibits
ATP
channels [128]. They had no protective effects unlike acylcarnitine exchange in cardiac mitochondria [135]
lidocaine, ropivacaine, bupivacaine and amide analog, which inducing decreased fatty acids transport into mitochondria by
132 Current Drug Safety, 2012, Vol. 7, No. 2 La Monaca and Fodale
inhibiting the carnitine-acylcarnitine translocase. This effect The mechanism for lower toxicity of ropivacaine in vivo
could contribute to bupivacaine cardiotoxicity, and a has been ascribed to low lipid solubility leading to reduced
difference between the enantiomers of bupivacaine is access to the mitochondrial membrane [147,148].
possible at this level [124].
The mechanism of bupivacaine uncoupling has been 8.5. Levobupivacaine
extensively investigated [124]. The uncoupling effect of LA
Levobupivacaine, like bupivacaine and ropivacaine,
corresponds to the dissipation of the transmembrane proton
alters mitochondrial energy metabolism in the same way,
gradient that reduces the efficiency of ATP synthesis, with a
despite stereo selectivity or liposolubility of the molecule
large decrease in the ATP-to-oxygen ratio.
[149].
On rat skeletal muscle mitochondria and isolated
myofibers from soleus, bupivacaine causes mitochondrial 9. OPIOIDS
membrane depolarization with an opening of the
Opioids, similarly to volatile anesthetics, produce
permeability transition pore, which plays a key role in many
protection against myocardial infarction by means of an
forms of cell death [134]. In vivo, when continuous femoral
adenosine triphosphate-regulated potassium channel
nerve blocks were performed in porcine models using
equipotent doses of injected ropivacaine or bupivacaine, mechanism. In addition, they activate delta- and kappa -
acute effects were seen, with severe tissue damage [136]. opioid receptors, and this also leads to PKC activation that
Clinically relevant concentrations of bupivacaine, acts as an amplifier of the preconditioning stimulus and
stabilizes the open state of the mitoK channel and the
levobupivacaine and ropivacaine in vivo produced similar ATP
sarcolemmal K(ATP) channel, through phosphorylation.
changes in mitochondrial energy metabolism with a
Opening of K(ATP) channels ultimately elicits
significant decrease in ATP synthesis and a global reduction
in enzyme activities of the respiratory chain. On the other cytoprotection by decreasing cytosolic and mitochondrial
hand, only levobupivacaine had deleterious effects on Ca(2+) overload [150]. Stimulation of mu, delta, and kappa
calcium homeostasis in rat psoas muscle. Although skeletal opiate receptors also increases myocardial tolerance to the
arrhythmogenic effect of ischemia and reperfusion through
muscle damage induced by long-acting LA has been
activation of KATP channels [151].
described for a few decades, the pathogenesis of bupivacaine
myotoxicity in vivo is still unclear [137-141]. In rabbits, the non selective opioid receptor antagonist
In promyelocytic leukemia cells HL-60, bupivacaine naloxone abolishes the protective effect of preconditioning
induces apoptosis and DNA fragmentation in a time- and [152]. Combined administration of isoflurane and morphine
enhances protection against myocardial infarction to a
dose-dependent manner [142]. Caspase-3, -8 and -9, which
greater extent than either drug alone. This beneficial effect is
play a pivotal role in the initiation and execution of receptor-
mediated by mitochondrial adenosine triphosphate-regulated
or mitochondria-mediated apoptosis, were all clearly
activated by this anesthetic in good correlation with the potassium channels and opioid receptors in vivo [153].
degree of DNA fragmentation. Even if indirect action of
bupivacaine on mitochondria occurs and other mechanisms 9.1. Morphine
may be involved, it induced neither mitochondrial
In cultured glioma cells, morphine-induced NO release
permeability transition (PT) nor release of cytochrome c in
decreases mitochondrial membrane potential, as one might
experiments with isolated mitochondria [142].
expect based on the rapid inhibition of the respiratory chain
by NO [154].
8.4. Ropivacaine
Morphine mimics preconditioning via direct stimulation
Low concentrations of ropivacaine decrease the rate of of opioid (cid:2)1 receptors and activation of mitoK channels
oxygen uptake due to inhibition of electron transport in and an increase in free radical signals in anesAthTPetized rats
complexes I and II of the respiratory chain. Inhibition of and rabbits [152,155]. However, whether morphine protects
respiration, decrease of ATP content, and depolarization of via direct effects on myocardial opioid receptors or by
mitochondrial membrane caused by this anesthetic have also affecting the opioid receptors of other systems is less clear.
been observed [143-145]. Inhibition of lipid substrate Morphine protects against ischemia-reperfusion injury in
oxidation may be responsible for the cardiotoxicity induced cardiomyocytes. Functional opioid receptors exist in
by bupivacaine and ropivacaine [146]. ventricular myocytes [156,157]. The mechanism by which
Furthermore, ropivacaine is less cardiotoxic in both direct stimulation of cardiomyocyte opioid receptors mimics
isolated mitochondria and permeabilized heart fibers than preconditioning is unknown. Free radicals are intracellular
signaling components in hypoxia, ischemia, and
bupivacaine. A lower lipid solubility of ropivacaine may be
responsible for weaker dose-dependent effects on acetylcholine mediated preconditioning [158-160]. In
mitochondrial bioenergetics [125]. Under these conditions addition, increased free radical signals are abolished by
and low drug concentrations, state 4 respiration was naloxone [156-158]. Although the mechanism by which
stimulated and mitochondrial membrane potential collapsed stimulation of opioid receptors increases free radical signals
is not fully understood, some data indicate that K channel
[147]. Ropivacaine did not alter ADP-stimulated respiration ATP
and did not substantially affect resting respiration, and data activation is an important intermediate step after opioid
receptor stimulation, so K channel activation mediates the
findings suggest that in rat liver mitochondria ropivacaine is ATP
less toxic than bupivacaine [148]. cardioprotection of morphine and the benefit of morphine is
abolished by 5-HD or glibenclamide [156,157].
Anesthesia and Mitochondria Current Drug Safety, 2012, Vol. 7, No. 2 133
MitoK channel activation contributes to the increased Fentanyl, at high concentrations, interferes with
ATP
signal of free radicals that amplifies activation of the channel. mitochondrial electron chain (complexes III, IV) and
Free radicals with morphine also activate protein kinase C [161] mitochondrial phosphorylation unit (complex V).
which is a component of the intracellular signaling pathway in Mitochondrial permeability transition pore was not induced
opioid-mediated preconditioning in intact rabbit hearts [162]. by fentanyl. It showed a stronger inhibitory effect on
Opioid (cid:2)1 receptor stimulation increases intracellular free mitochondrial bioenergetics than remifentanil [165].
radical signals through activation of mitoK channels, which
ATP A study has demonstrated how pretreatment with
are important intracellular signaling components of morphine-
fentanyl and propofol attenuates myocardial injury in rabbits
induced preconditioning [163].
with acute hemorrhagic shock, promoting the recovery of
The cardioprotective effect is the result of (cid:2)1 opioid receptor hemodynamics with less pronounced alterations of
activation and is elicited through a G protein-mediated myocardial structure and mitochondria [166].
mechanism and subsequent opening of the K channel [164].
ATP Fentanyl may induce a time-dependent apoptosis of
peripheral blood lymphocytes by altering mitochondrial redox
9.2. Fentanyl
metabolism [167]. Studies in human surgical neonates have
Fentanyl, in clinical concentrations, does not interfere shown that intraoperative fentanyl analgesia results in a greater
with rat brain isolated mitochondria, while at concentrations fall in perioperative body core temperature compared with
>4 microg/mL it alters mitochondrial metabolism, inducing morphine analgesia. This study demonstrates that therapeutic
an impairment of the respiratory chain with a decrease in doses of two commonly used analgesic drugs impair neonatal
respiratory control ratio, state 3 and uncoupled respiration. hepatic oxidative metabolism. Fentanyl exerts a greater effect
Also, it has been seen to cause membrane potential collapses than morphine by diminishing liver oxygen consumption by up
with ADP/O ratio reduced [165]. to 40%. The inhibitory effect of fentanyl occurs directly on the
Table 1. Effects of Anesthetic Drugs on Mitochondria

Complex I Complex II Complex III Complex IV Complex V mitoK (ATP) M(PTP) PBR
Volatile Anesthetics
HALOTHANE [34-36,39]. - - n.e. n.e. n.e. n.e. n.e. n.e.
ISOFLURANE [37,38,55]. - + + + n.e. + - n.e.
SEVOFLURANE [28,37,38,60]. - n.e. n.e. n.e. n.e. + + n.e.
DESFLURANE [46,65,66]. + n.e. + + n.e. + - n.e.
XENON [74,75]. NA NA NA NA NA + NA n.e.
Intravenous Anesthetics
Benzodiazepines MIDAZOLAM [93,94]. - - - n.e. n.e. + n.e. +
BARBITURES [95]. - n.e. n.e. n.e. n.e. n.e. n.e. n.e.
PROPOFOL [94,109]. n.e. - n.e. n.e. n.e. n.e. n.e. n.e.
KETAMINE [94]. n.e. n.e. n.e. n.e. n.e. n.e. n.e. n.e.
ETOMIDATE [94,111] - n.e. - n.e. n.e. n.e. n.e. n.e.
Local Anesthetics
TETRACAINE AND PROCAINE [117] n.e. n.e. n.e. n.e. n.e. - n.e. n.e.
LIDOCAINE [117] n.e. n.e. n.e. n.e. n.e. + n.e. n.e.
BUPIVACAINE [113,123] + n.e. n.e. n.e. n.e. n.e. + n.e.
ROPIVACAINE
- - n.e. n.e. n.e. n.e. n.e. n.e.
[131-133]
LEVOBUPIVACAINE [137] - - n.e. n.e. n.e. n.e. n.e. n.e.
Opioids
MORPHINE [142,145] n.e. n.e. n.e. n.e. n.e. + n.e. n.e.
FENTANYL [140,154] n.e. n.e. + + + + n.e. n.e.
REMIFENTANIL [140,154] n.e. n.e. + + + + n.e. n.e.
COMPLEX I : also called NADH: ubiquinone oxidoreductase; COMPLEX II : succinate dehydrogenase; COMPLEX -III ubiquinone-cytochrome c oxido-reductase; COMPLEX
IV:citochrome c oxidase; COMPLEX V: ATP synthase; mitoK(ATP): mitochondrial K channels; M(PTP): mitochondrial permeability transition pore; PBR: tissue peripheral
benzodiazepine receptor also called the mitochondrial megachannel.
- : INHIBITH; + ACTIVE; NA: data not available; n.e. no effect.
134 Current Drug Safety, 2012, Vol. 7, No. 2 La Monaca and Fodale
mitochondrial respiratory chain, either on substrate oxidation or within the organelle are represented in the Fig. (1). However,
on the thermogenic proton leak [168]. Stimulation of in spite of the attempt to identify the complex actions of
endogenous opioid receptors has been shown to increase these agents, the underlying mechanisms, functional
survival in mice after hypoxia [168-170]. consequences, and overall, in vivo relevance of these
findings, remain largely to be determined.
9.3. Remifentanil Opposite results also exist, making the translation of
these findings from bench to bedside and back very difficult,
Remifentanil at clinical concentrations does not interfere
as in the case, for instance, of comparing the effects of
with rat brain isolated mitochondria and has the same profile of
general and local anesthesia in clinical conditions associated
fentanyl, but, at higher concentrations (>10 microg/mL), it
to alterations of mitochondrial metabolism. This is
impairs mitochondrial complexes III, IV and complex V [165].
particularly true, especially after recent studies have outlined
that local anesthesia revealed the possible occurrence of
10. CONCLUSION
myopathies induced by local anesthetics by means of
Mitochondria play a crucial role in both physiological mitochondria impairment, depending on LA concentration,
and pathological conditions. As a consequence, there is an volume and duration of analgesia [171]. Such iatrogenic
increasing interest in studying mitochondrial functions and effects should encourage anesthesiologists to study the
dysfunctions, as well as in finding new methods and toxicity of local anesthetics and reevaluate their protocols in
techniques of research. order to reduce muscle pain and dysfunction [171].
In the present review, various classes of anesthetic drugs Nevertheless, ongoing studies on mitochondria open
commonly used in clinical anesthesia, and their interaction perspectives of further research and new insights for
with mitochondrial enzymes and metabolic pathways, have clinicians. Special mention must be made to the recent
been presented. The different effects of anesthetic drugs on acquisition that mitochondrial dysfunction is a component of
mitochondria have been summarized in Table 1. Site of many neurodegenerative conditions. In particular, extensive
action of various drugs of anesthesia and molecular targets evidence implicates mitochondrial dysfunction and

+(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:2)
Desflurane(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)Tetracaine(cid:3)
Isoflurane(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)Procaine(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)
Sevoflurane(cid:3)

Midazolam(cid:3)
Xenon(cid:3)

Morphine(cid:3)
Remifentanil(cid:3)

Fentanyl(cid:3)

(cid:2)
PTP

(cid:2)
PBR

+(cid:3)
Sevoflurane(cid:3)

Bupivacaine(cid:3) +(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:2)(cid:3)(cid:3)(cid:3)
(cid:3)
Midazolam(cid:3)
(cid:2)(cid:3)
Isoflurane(cid:3)

Desflurane(cid:3)

(cid:2)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)+(cid:3) (cid:2)

Halothane(cid:3)(cid:3)(cid:3)(cid:3)Desflurane(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)
Isoflurane(cid:3)

Sevoflurane(cid:3)
Midazolam(cid:3) (cid:2)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)+
(cid:2)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)+(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3) (cid:2)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)+(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)
Barbiturates(cid:3) Halothane(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)
(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)Isoflurane(cid:3) (cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)Remifentanil(cid:3)
Etomidate(cid:3) Isoflurane(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)
(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)Remifentanil(cid:3) (cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)Fentanyl(cid:3)
Ropivacaine(cid:3)(cid:3)(cid:3) Midazolam(cid:3)
(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)Fentanyl(cid:3)
Levobupivacaine(cid:3) Propofol(cid:3) (cid:2)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)+(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)Desflurane(cid:3)
Ropivacaine(cid:3)(cid:3)(cid:3) Midazolam(cid:3)(cid:3)(cid:3)(cid:3)Isoflurane(cid:3)
Levobupivacaine(cid:3) Etomidate(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)Remifentanil(cid:3)
(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)Fentanyl(cid:3)
(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)Desflurane(cid:3)

Fig. (1). Site of action of various drugs of anesthesia and molecular targets within the organelle.
Anesthesia and Mitochondria Current Drug Safety, 2012, Vol. 7, No. 2 135
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