Special Contribution

Yonago Acta medica 2007;50:45–55

Cardiac Preconditioning by Anesthetic Agents: Roles ofVolatile Anesthetics and Opioids in Cardioprotection
Yoshimi Inagaki
Division of Anesthesiology and Critical Care Medicine, Department of Surgery, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504 Japan

Cardiac preconditioning is the most potent and consistently reproducible method ofprotecting heart tissue against myocardial ischemia-reperfusion injury. This review
discussed about the signaling and ampliﬁcation cascades from either ischemic preconditioning stimulus or pharmacological preconditioning stimulus, the putative end-effectors
and the mechanisms involved in cellular protection. The pharmacological preconditioning induced by volatile anesthetics and opioids is very similar to the ischemic preconditioning. It includes activation of G-protein-coupled receptors, multiple protein kinases
and ATP-sensitive potassium channels (KATP channels). Volatile anesthetics prime theactivation of the sarcolemmal and mitochondrial K ATP channels, which are the putative
end-effectors of preconditioning, by stimulation of adenosine receptors and subsequent
activation of protein kinase C (PKC) and by increased formation of nitric oxide and freeoxygen radicals. Similarly, opioids activate - and -opioid receptors leading to activation of PKC. The open state of the mitochondrial K ATP channel and sarcolemmal K ATP
channel ultimately induces cytoprotection by decreasing Ca2+ overload in the cytosol andmitochondria.
Key words: ATP-sensitive potassium channel; ischemic preconditioning; pharmacological preconditioning; volatile anesthetic; opioidand opioids in myocardiac protection is likely toshow the strategies of anesthetic management toreduce the incidence of cardiac ischemic eventsin the perioperative period. This short review
reveals the role of volatile anesthetics and opioids
in prevention myocardiac ischemic injury due tocardiac preconditioning.

Anesthesiologists frequently meet perioperative
cardiac ischemic events in the clinical anesthesia and also treat patients with ischemic heartdisease. Myocardiac ischemic events lead tosevere complications and delay the postoperative
recovery, thereby worsening the prognosis of thepatients who underwent surgery. To minimize
the damage or injury of myocardium in the perioperative period is a very important factor to improve outcome of surgery. It has been known wellthat anesthetics have abilities to prevent ischemic
myocarcial injury. Therefore, understanding therole of anesthetics including volatile anesthetics

Ischemic preconditioning
Ischemic precondionig is the concept introduced
by Murry et al. (1986) that four cycles of 5-min

Abbreviations: CABG, coronary artery bypass grafting; DAG, diacylglycerol; Gi, inhibitory G; ICAM-1, intercellular ad-

hesion molecule-1; iNOS, inducible NOS; IP, inositol triphosphate; K ATP , ATP-sensitive potassium; Lcx, left circumﬂex
coronary artery; NF- B, nuclear factor- B; NO, nitric oxide; NOS, NO synthsae; PKC, protein kinase C; ROS, reactive
oxygen species

45Y. Inagaki

malfunctioning endothelium and smooth muscle
cannot dilate when necessary. Moreover, neutrophils/platelets aggregating in the lumen decreaseadequate coronary flow (Opie 1998c; Maxwelland Lip, 1997). Neutrophils release oxygen free
radicals, cytokines and other proinflammatory
substances, which injure the endothelium, vascular smooth muscle and myocardium (Jordan et al.,1999). A pathway for neutrophil sequestrationis the speciﬁc interaction of adhesion molecules
whose expression is promoted by ischemia-reperfusion. Adhesion molecules, for example, intercellular adhesion molecule-1 (ICAM-1), L-selectin
and CD11b/CD18 are expressed on neutrophils
and endothelium. On reperfusion, [H+] outside
the cell is rapidly decreased to normal levels because of wash-out. This results in an increase
in [Ca 2+]i due enhanced Na+ -H+ and Na+ -Ca 2+
exchange (Opie 1998b; Opie 1998c). Reperfusion
also results in a burst of free radical generation
because oxygen abundantly supplied (Opie 1998c;
Maxwell and Lip, 1997). Both increased [Ca2+]and free radicals harm the myocardium during
reperfusion (Opie 1998c; Maxwell and Lip, 1997).
Damage of the vascular system is more prominent during reperfusion than ischemia (Maxwelland Lip, 1997; Jordan et al., 1999). Infarction is
one of the major events of ischemia-reperfusion
injury during anesthesia. Another major event ismyocardial stunning, which is deﬁned as reversible myocardial dysfunction that persists afterreperfusion (Opie 1998c; Bolli and Marban, 1999;
Braunwald and Kloner, 1982).

left circumﬂex coronary artery (Lcx) occlusion, in
advance of 40-min Lcx occlusion, reduced infarct
size by 75% in a canine model. Thereafter, there
have been many reviews on ischemic preconditioning (Okubo et al., 1999; Nakano et al., 2000;
Rubino and Yellon, 2000). Ischemic preconditioning can be observed from isolated cardiomyocytes and vascular endothelial cells to hearts insitu in various species (Okubo et al., 1999; Tomaiet al., 1999a; Nakano et al., 2000; Rubino andYellon, 2000). In humans, ischemic preconditioning enhanced postischemic contraction in ventricular trabeculae muscle and improved survival rateof isolated cardiomyocites (Tomai et al., 1999a).
Moreover, in clinical application, ischemic preconditioning elicited by two periods of 3-min aortic cross clamping before cardiopulmonary bypass
for valve replacement reduced myocardial enzyme
leakage, free radical production and histological degeneration and increased contractility after
cardiopulmonary bypass (Lu et al., 1998; Li et al.,1999). Szmagala et al. (1998) applied 4-min aortic cross clamping and 6-min reperfusion prior tocoronary artery bypass grafting (CABG), thereby
reducing troponin from blood samples. The present author addresses the mechanisms of ischemiareperfusion injury before showing the possible
mechanisms of ischemic preconditioning.
Ischemia precludes adequate oxygen supply,
which rapidly results in depletion of ATP. This
inhibits ATP-driven Na+ -K+ pumps, increasing[Na+]i. [H+]i is increased due to poor washoutof metabolites and inhibition of mitochondrial
oxidation of NADH2. Increased [H+]i enhances
Na+ -H+ exchange to retain normal pHi, leading
to increased [Na+]i. Accordingly, [Ca2+]i is augumented via Na+ -Ca2+ exchange (Opie, 1998a,1998b). High [Ca2+]i degrades proteins and phospholipids (Opie 1998c; Maxwell and Lip, 1997).
Onset of ischemia increased the production offree radicals derived mainly from neutrophils
and mitochondria (Opie 1998a; Maxwell and Lip,1997). When coronary arteries are damaged,
ischemia-related injury prevents swift gas exchange by swollen endothelial cells. Vessels with

Mechanisms of early preconditioning
Preconditioning is a treatment before an ischemic
event while ischemia-reperfusion injury is developed during and after an ischemic period. The
signals were generated by short period of ischemia in ischemic preconditioning. Ischemic preconditioning is mediated via several sacrolemmal
receptors, which are mostly linked to inhibitory
G (Gi)-protein (Ninomiya et al., 2002), namely46

Pharmacological cardiac preconditioning

Fig. 1. Signaling for cardiac preconditioning. The left of dashed line represents mechanisms of early preconditioning
and the right represents those of late (delayed) preconditioning. This ﬁgure is quoted from the reference of Zaugg et al.,2003. dym, inner mitochondrial membrane potential; AlRed, aldose reductase; Bcl-2, anti-apoptotic protein; Ca, sarcolemmal voltage-dependent Ca2+ channels; COX-2, cyclooxygenase type 2; DAG, diacylglycerol; eNOS, endotherial NO
synthase; HSP, heat shock proteins; iNOS, inducible NO synthase; IP3, inositol triphosphate; IP3R, inositol triphosphate
receptor; K, sarcolemmal and mitochondrial K ATP channels; MnSOD, manganese superoxide dismutase; NF- B, nuclear
factor- B; NO, nitric oxide; PIP2, phosphatidylinositol bisphosphate; PKC, protein kinase C; PLC/PLD, phospholipases
C and D; ROS, reactive oxygen species; RYR, ryanodine Ca2+ -release channel; SERCA2, Ca2+ pump of the SR; SR, sarcoplasmic reticulum.

tion of cellular metabolism and activation of ATPsensitive potassium channels (K ATP channels), theputative main end-effectors of preconditioning.
Activation of phospholipase C and D introduces
formation of inositol triphosphate (IP3) for therelease of Ca2+ from the sarcoplasmic reticulum
via the IP3 receptor, and production of diacylglycerol (DAG). DAG activates different isoforms
of protein kinase C (PKC). PKC is activated bya large number of phosphorylating enzymes, including G-proteins, phosphlipids, DAG, increased
intracellular Ca2+, and nitric oxide (NO), which
is derived from intracellular constitutively active
NO synthsae (NOS) or from extracellular sources.
PKC can be activated by reactive oxygen species

adenosine (A-1, A-3), purinoceptors (P2Y), endothelin (ET1), acetylcholine (M2), 1- and -adrenergic, angiotensin II (AT1), bradykinin (B2) andopioid ( 1, ) receptors, which couple to a highly
complex network of kinases. The involvement ofmany receptors or triggers in mediating preconditioning reﬂects the biological redundancy in thislife-saving signal transduction pathway. Figure 1
shows the main signaling steps and componentsof early and delayed preconditioning (Zaugg etal., 2003).
G-proteins link the initial stimulus from theindividual receptors to phospholipase C and D.
They have several additional functions such as
inhibition of Ca2+ inﬂux during ischemia, regula47

Y. Inagaki

early preconditioning effect, that is, NO is sufﬁcient but no necessary for early preconditioning(Bolli, 2001). Conversely, NO has an obligatoryrole in late preconditioning (Guo et al., 1999).

(ROS) derived from mitochondria either during
the short ischemic or the subsequent repetitive
reperfusion episodes. Activation of this key enzyme leads to isoform-speciﬁc and cytoskeletonmediated translocation of cytosolic PKC, inducing phosphorylation and thus activation of thesacrolemnal and mitochondrial K ATP channels(Light et al., 2000). After only 10 min of ischemic
preconditioning, PKC activity in the cytosol reduces, whereas PKC in the particulate fraction (i.e.,nuclei, mitochondria and membranes) increases(Strasser et al., 1992). PKC- translocation seems
to be responsible for activating mitochondrial
KATP channels and PKC- translocation for the establishment of late preconditioning by phosphorylating nuclear targets (Kawamura et al., 1998).
However, the observation that PKC inhibition may
not completely block the preconditioning stimulus(Vahlhaus et al., 1996) supports the concept that
additional intracellular kinases downstream, upstream or in parallel to PKC signaling contributeto the ampliﬁcation and establishment of the preconditioned state. Recent studies suggested thatmitochondrial K ATP channels play a greater role
than sacrolemmal K ATP channels (Nakano et al.,
2000; Rubino and Yellon, 2003).
ROS, important intracellular signaling molecules derived from mitochondria, are increased
during sublethal oxidative stress (preconditioning stimulus) and play a pivotal role in triggering early and delayed cardioprotection (Cohenet al., 2001). ROS activate phospholipase C andPKC, which, in turn, amplify the preconditioning
stimulus. Generation of ROS during the initiationof preconditioning represents an essential trigger for early and delayed cardioprotection. NO
can induce a cardioprotective effect against myocardial stunning and infarction. Recent studies
revealed direct evidence of enhanced biosynthesis
of NO in the myocardium subjected to brief episodes of ischemia and reperfusion, probably via
increased NOS activity (Bolli, 2001). Although
NO is not necessary for ischemia-induced earlypreconditioning, exogenous or pharmacologicallyincreased endogenous NO production elicits anMechanisms of late preconditioning
Late preconditioning requires NO formation andincreased synthesis of protective proteins (Bolli,2001). PKC and multiple kinases are involvedin the signaling cascade, leading to activationof several transcription factors, such as nuclear
factor- B (NF- B), which leads to the sustained
expression of a number of proteins considered tobe responsible for the delayed protection phase.
Disruption of the inducible NOS (iNOS) genecompletely abolished the delayed infarct-sparing
effect, which indicates the obligatory role of iNOS
in the cardioprotection afforded by delayed preconditioning (Guo et al., 1999). The most likely
cardioprotective effects of NO in late preconditioning are: i) inhibition of Ca2+ inﬂux; ii) antagonism of -adrenergic stimulation; iii) reduced contractility and myocardial oxygen consumption; iv)
opening of K ATP channels; v) antioxidant actions;and vi) activation of COX-2 with the synthesis ofprostanoids. Activation of K ATP channels also
plays a role in delayed protection (Bernardo et al.,1999).

Sarcolemmal andmitochondrial K ATP channels
Cardiomyocytes have two distinct types of K ATPchannels, one located in the surface membrane(sacrolemmal K ATP channels) and another in theinner mitochondrial membrane (mitochondrial
KATP channels). Sarcolemmal K ATP channels are
physically bound with the creatine phosphatecreatine kinase system and provided a direct link
between metabolic state and cellular excitability.
Mitochondrial K ATP channels regulate mitochondrial volume state, mitochondrial membrane po48