Pharmacological cardiac preconditioning

Table 1. Volatile anesthetics and opioids withmostly enhancing effects on mitochondrial andsarcolemmal K ATP channels

tential, formation of ROS and energy production.
Toyoda et al. (2000) suggested differential role ofsarcolemmal and mitochondrial K ATP channels inpreconditioning. Reduction of myocardial infarct
size is mediated largely by mitochondrial K ATP
channels, but functional recovery is mediated bysarcolemmal KATP channels. Mitochondrial K ATP
channels also play an important role in the prevention of cardiomyocyte apoptosis (Akao et al.,2001) and in late preconditioning protection (Bolli,2001). Considerable cross-talk was reported between sarcolemmal and mitochondrial KATP channels (Sasaki et al., 2001). A lot of experimental
studies indicate the mitochondrial K ATP channels
as the main end-effector of preconditioning, butrole of sarcolemmal KATP channels cannot be dismissed totally.
Sacrolemmal K AT P channels may modulate myocardial infarct size by reducing Ca 2+
enterance into the myocytes from outside andby attenuating Ca 2+ overload. There are threepossible explanations about reduction of infarct
size by mitochondrial K ATP channels. First, thedecreased mitochondrial Ca 2+ overload during
ischemia (Wang et al., 2001) may prevent openingof the mitochondrial permeability transition poresand guarantee optimal conditions for ATP production (Holmuhamedov et al., 1998). Second,
Garlid and Pancek (2003) proposed that openingof the mitochondrial K ATP channel decreases theischemia-induced swelling of the mitochondrialinterspace, which would preserve functional coupling between adenosine nucleotide translocase
and mitochondrial creatine kinase (preventionof structure/function) (Kowaltowski et al., 2001;
Laclau et al., 2001). This secures the transport of
newly synthesized ATP from the site of production by ATP synthase on the inner mitochondrial
membrane to the cytosol. Thus, high-energy
phosphate substrates are supplied continuously
from the mitochondria to the sites of energy consumption. Third, mitochondrial K ATP channels
may elicit protection in basis of the observation ofincreased formation of ROS (Fobes et al., 2001).
ROS would stimulate the activation of multiple

Anesthetic
agent

K ATP channel
Mitochondrial Sarcolemmal

Isoﬂurane
SevoﬂuraneDesﬂurane
Morphine
Fentanyl
Remifentanil/?
?

, no effect; , increased effect; , decreased effect.
K ATP, ATP-sensitive potassium.

transcriptional factors (NF- B, activator protein-1, protein kinases, protein phosphatase, etc.),
ultimately leading to cardioprotection.

Pharmacogogical preconditioning
Preconditioning can be pharmacologically induced by anesthetics. Volatile anesthetics, opioids
and other anesthetics were found to induce or enhance preconditioning in cardiac tissue.
Volatile anesthetics
Lots of studies have evaluated the cardiac preconditioning effects of isoﬂurane, enfrurane andhalothane (Mattheussen et al., 1993; Warltier etal., 1988). Sevoﬂurane, the most frequently usedvolatile anesthetic in Japan, has also improves
postischemic mechanical and coronary function,and reduces infarct size (Novalija and Stowe,1998; Toller et al., 1999b). Desﬂurane, a volatile
anesthetic used outside of Japan, is suggested the
beneﬁcial cardioprotection (Toller et al., 2000b).
The beneficial effects of volatile anesthetics on
myocardial protection by their pharmacologicalpreconditioning have been evaluated by reduction in infarct size, postischemic contractility
and coronary vasculature. Halothane, isoﬂuraneand sevoflurane reduced the number of neutrophils sequestered in the coronary vasculature49

Y. Inagaki

Fig. 2. Signaling pathways involved in volatile anesthetic- and opioid-induced preconditioning. Multiple signaling cascades prime the sarcolemmal and mitochondrial K ATP channels, allowing rapid opening at the initiation of ischemia.
This ﬁgure is changed slightly from the original ﬁgure quoted from the reference of Zaugg et al., 2003. Abbreviations of
the blockers and signaling components are referred to Table 2 and the legend of Fig. 1.

involve activation of A1 adenosine receptors, PKC
and K ATP channels. Ischemic preconditioning
and anesthetic preconditioning similarly reduce
Ca2+ loading, augment post-ischemic contractile
responsiveness to Ca2+ and decrease infarct size
(An et al., 2001). Whether volatile anesthetics induce late preconditioning is still unknown.
Key signaling components involved in preconditioning elicited by volatile anesthetics were
unraveled recently by means of speciﬁc blockers
for signaling steps (Fig. 2) and the speciﬁc openers and blockers for signaling steps are shown in
Table 2. The main routes of activation by volatile anesthetics involve the Gai protein-coupledadenosine receptor and the production of NO,
probably by modulation of NOS activity (Zaugg
et al., 2002). These two signaling pathways converged at the level of PKC, although alternativeroutes for NO could be operative as well. Finallyafter ischemia (Kowalski et al., 1997; Heindl etal., 1999a). A similar effect was also shown forplatelets (Heindl et al., 1998; Heindl et al., 1999b).
Reduced neutrophils/platelet entrapment by anesthetics was accompanied by enhancement of
postischemic mechanical function (Heindl et al.,1999a; Heindl et al., 1999b). Novalija et al. (1999)
measured coronary flow changes in response toendotherial-dependent and independent vasodilators. Sevoﬂurane preserved the reaction elicitedby both types of vasodilators during the reperfusion period better than no treatment.
The favorable oxygen supply/demand ratio
provided by volatile anesthetics is not requiredfor preconditioning because volatile anesthetic-induced protection occurs under cardioplegic arrest(Lochner et al., 1994). Many characteristics ofpreconditioning by volatile anesthetics are similar to those of ischemic preconditioning. These50

Pharmacological cardiac preconditioning

Table 2. Speciﬁc openers and blockers for signaling steps of pharmacological preconditioning
Selectivity

Opener

References

Blocker

Adenosine receptors
PKC
Gi-proteins
Mitochondtrial K ATP channel
Nicorandil
DIAZO

Piriou et al., 1997
Sato et al., 2000

Sarcolemmal K ATP channel
NOS
NO
S-nitroso-N-acetylDL-penicillamine
ROS-adrenergic receptor-adrenergic receptor-opioid
DADLE
McPherson and Yao, 2001
TAN-67
Fryer et al., 1999
1-selective

References

SPT
DPCPX
CHE
Bicindolylmaleimide
PTX

Cope et al., 1997
Kersten et al., 1997
Toller et al., 1999aToller et al., 1999aToller et al., 1999a

5HD

Toller et al., 1999a;
Piriou et al., 1997;
Hanouz et al., 2002;
Zaugg et al., 2002;
Shimizu et al., 2001
Hanouz et al., 2002
Müllenheim et al., 2002

HMR-1098
L-NIL, L-NAME
PTIO
MnTBAP, MPG
Phentramine, Prazosin
Propranolol
Naloxone

Müllenheim et al., 2002
Hanouz et al., 2000
Hanouz et al., 2000
Tomai et al., 1999b

CHE, chelerythrine; DADLE, D-Ala2-D-Leu5-enkephalin; DIAZO, diazoxide; DPCPX, 8-cyclophenyl-1,3-dipropylxanthine; 5HD, 5-hydroxydecanoate; Gi, inhibitory G; L-NIL, L-N6-(l-iminoethyl)lysine; L-NAME, N G -nitro-L-arginine
methyl ester; MnTBAP, Mn(III)tetrakis(4-benzoic acid)porphyrine chloride; MPG, N-(2-mercaptopropionyl)glycine; NO,nitric oxide; NOS, NO synthase; PKC, protein kinase C; PTIO, 2-(4-carboxyphenyl)-4,4’,5,5’-tetramethylimidazole-l-oxyl3-oxide; PTX, pertussis toxin; ROS, reactive oxygen species; SPT, 8-sulfophenyl theophylline.

the other hand, volatile anesthetics mediate theirprotection by selectively enhancing mitochondrial
KATP channels through the triggering of multiple
PKC-coupled signaling pathways, namely NO
and adenosine/Gi signaling pathways (Zaugg etal., 2002). Biosynthesis of NO plays a pivotal
role in reducing ischemic damage in heart tissue.
Moreover, NO and cGMP may be major players
in volatile anesthetic-induced cardioprotection.
Both NO/cGMP signaling and basal NOS activity play a fundamental role in pacing associatedpreconditioning. Volatile anesthetics may differentially modulate the activity of the various
isoenzymes of NOS (nNOS, eNOS, iNOS), which
are ubiquitous but heterogeneously distributed
in myocytes. The observation that isoﬂurane-induced preconditioning is inhibited by free radical
scavengers supports the concept that generation ofradicals, either by means of altered NO synthesis

volatile anesthetics activate mitochondrial andsarcolemmal K ATP channels, thereby providing
cardioprotection. There is a question of whether
the sarcolemmal K ATP channel or mitochondrial
K ATP channel is more important in mediating
volatile anesthetic-induced preconditioning.
Although several experimental studies have addressed this question (Toller et al., 2000; Zaugg
et al., 2002; Hara et al., 2001), it is important tonote that considerable cross-talk is documented
between sarcolemmal and mitochondrial K ATP
channels (Sasaki et al., 2001) and the importanceof the individual K ATP channels may vary amongexperimental approaches and species differences. Sato et al. (2000) proposed the concept ofchannel priming (including the sarcolemmal andmitochondrial K ATP channels) by volatile anesthetics. The primed channel state allows easy andrapid opening at the initiation of ischemia. On
51

Y. Inagaki

ditioning in in vivo models (Chien et al., 1999).
These ﬁndings suggest that it is in the heart itself
that opioid receptors play a role in protection byischemic preconditioning.
Morphine and fentanyl are capable of binding to - and -receptors although they bind dominantly with -receptors (Jaffe and Martin, 1990).
Selective - (McPherson and Yao, 2001) and 1(Huh et al., 2001) agonists induce cardioprotection. Conversely protection by morphine andfentanyl is abolished by -antagonists (McPherson
and Yao, 2001). The role of -receptors remains
controversial. Activation of opioid receptors results in a potent cardioprotection effect similar toclassical and late preconditioning. Currently, it
is considered that selective activation of 1 opioid
agonists exert this protection through an interaction with Gi-proteins and activation PKC, tyrosine kinases (and possibly other kinases, such as
MAPK), and ultimately K ATP channels, especially
mitochondrial KATP channels (Fryer et al., 1999).
Morphine 1 mM induced the same protection as
preconditioning with 5 min of ischemia and that
protection were abolished by 5-hydroxydecanoate(a speciﬁc mitochondrial K ATP channel blocker),which emphasizes the dominant role of mitochondrial K ATP channels in preconditioning (Liangand Gross, 1999).
Remifentanil, a new comer of fentanyl family, induces also the pharmacological preconditioning effect as well as morphine and fentanyl
through the same mechanism (Zang et al., 2004,
2005).

or by enhanced formation of ROS/NO (possiblyby opening mitochondrial KATP channels), is important (Müllenheim et al., 2002). These results
show that the preconditioning effects of volatile
anesthetics are triggered by multiple signalingcascades and mediated mainly by mitochondrial
K ATP channels, but sarcolemmal K ATP channels
may also contribute to the protection induced byvolatile anesthetics.
Volatile anesthetics can elicit coronary protection through an ischemic (pharmacological)
preconditioning-like effect. Ischemic preconditioning is known to reduce ICAM-1 production
and neutrophil entrapment, and to preserve theresponse to vasodilators (Rubino and Yellon.,
2000). Treatment with volatile anesthetics decreased neutrophil adhesion on the endothelium
and expression of CD11b, which forms an integrin
with CD18, while the anesthetic did not affectendothelial cell actibation vis-à-vis neutrophils(Mobert et al., 1999). These findings supportsthat administration of volatile anesthetics prior toreperfusion maintains coronary vasculature.
Opioids
The involvement of opioid receptors in ischemic
preconditioning has been demonstrated in various animal species (Schultz and Gross 2001) andhumans (Bell et al., 2000). Among opioid receptor subtypes, -opioid receptors are responsiblefor ischemic preconditioning in rats and humans.
Although opioid receptors are located more abundant in the central nervous system, they are also
located in the heart (Bell et al., 2000). Opioid
receptor subtype distribution in heart is considered to differ between species; - and -, but not-opioid receptors are expressed in the rat heart(Schultz and Gross, 2001), - and -opioid receptors are dominant compared with -opioid receptors in human atrium (Schultz and Gross, 2001).
Naloxone blocked the effect of ischemic preconditioning in isolated hearts, and quaternary naloxone, which does not cross the blood-brain barrier,eliminated the protection by ischemic precon-

Conclusions: This review summarizes recent
knowledge about the key cellular events involved
in ischemic and pharmacological preconditioning. Many characteristics of anesthetic-induced
preconditioning are similar to ischemic preconditioning. However, there may be fundamental
differences in terms of signal intensity and thepotential to concomitantly injured cardiac tissue. Of many anesthetics, volatile anesthetics arearguably the most promising agents as cardiopro52

Pharmacological cardiac preconditioning

tectors. They demonstrated the beneﬁcial effectagainst ischemic-reperfusion injury better thanany other anesthetic. Volatile anesthetics provide
cardioprotection at clinically relevant concentrations and morphine has also been to be protectiveat clinical concentrations. Therefore, volatile anesthetic and morphine might be good choice forthe patients at risk of myocardial ischemia.

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Received September 3, 2007; accepted September 6, 2007
Corresponding author: Yoshimi Inagaki, MD, PhD

55