Netherlands Journal

netherlands journal of critical care
periods remarkably well and Verdouw et al. (1979) show that repeated
brief ischaemic periods favourably alter myocardial energy metabolism
[22], whereas Basuk et al. (1986) suggest the possible cardioprotective
effect of repeated brief ischaemic periods [23].
The phenomenon of ischaemic preconditioning (IPC) was introduced
by Murry et al. (1986) who showed that four five-minute cycles
of ischaemia reduced the infarct size after prolonged I/R-injury [24].
The cardioprotective effect of the preconditioning stimulus lasted
for about 2 to 4 hours but thereafter protection was reduced [25].
Interestingly, 24 hours after the initial preconditioning stimulus the
heart again developed an increased resistance to I/R-injury [26]. The
delayed preconditioning response lasts for about 72 hours and this
phenomenon is referred to as the ‘second window of protection’.
These observations clearly suggest that the myocardium possesses
endogenous protective mechanisms, which have been demonstrated
in a variety of experimental studies. Due to the potential benefit of
an effective clinical cardioprotective strategy, the underlying cellular
mechanisms of cardioprotection have been extensively studied and
the subject of many reviews [27,28]. Inhibitory G-protein coupled
receptor agonists, like adenosine, bradykinin, norepinephrin, opioids,
angiotensin and endothelin, can trigger preconditioning of the
myocardium. In addition, ROS, NO and Ca 2+ are also able to trigger
cardioprotection.
Several protein kinases are recognised as important mediators
of the protective response: these include protein kinase C (PKC), tyrosine
kinases (TK), mitogen-activated protein kinases (MAPK) and
phosphatidylinositol 3-kinase (PI3-kinase). The contribution of the
mitoK + ATP channels to preconditioning is complex, as opening of
the mitoK + ATP channels is involved as a trigger and mediator in the
cardioprotective signalling cascade. In addition, of the possible endeffectors,
it has been suggested that the mitoK + ATP channels might
be involved in the preservation of mitochondrial function [29]. However,
the interaction of the various intracellular signalling pathways
during cardioprotection is complex and the exact mechanism and
definition of end-effector proteins remain to be elucidated
Anaesthetic-induced preconditioning
As long ago as 1976, Bland and Lowenstein described the beneficial
effects of halothane on the severity of the ischaemic injury [30]. Subsequently,
Davis et al. (1983) reported that halothane pretreatment
reduced infarct size after I/R-injury [31]. Following the introduction
of the concept of ischaemic preconditioning by Murry et al. in1986,
[24], further extensive research on the mechanism of anaesthetic-induced
protective signalling was carried out and has been summarised
in several recent reviews [1,32,33].
In a number of experimental studies halothane, enflurane, isoflurane
and sevoflurane were shown to reduce infarct size after I/R
[34,35,36]. In addition to a reduction of cardiomyocyte cell death,
several studies show that volatile anaesthetics also improve postischaemic
contractile function [2,37]. Like ischaemic preconditioning,
volatile anaesthetics also induce a second window of cardioprotection
[38]. Finally, in several experimental studies, the application
of volatile anaesthetics solely during reperfusion was also shown to
reduce infarct size [39]. Only two minutes of sevoflurane exposure
during reperfusion maximally protected the myocardium [40], and
therefore mimics the recently reported phenomenon of postconditioning
by brief ischaemic periods during reperfusion [41].
The exact mechanism of cardioprotection afforded by volatile anaesthetics
remains unresolved, however the protective effect seems
to rely on the same intracellular signalling pathways involved in
ischaemic preconditioning, including protein kinase C (PKC), ROS
and mitoK + ATP channels. Figure 2 shows the cardioprotective signalling
pathways involved in anaesthetic-induced cardioprotection.
In addition to ROS, PKC and mitoK + ATP channels, volatile anaesthetic-induced
cardioprotective signalling seems to rely on a variety
of other signalling molecules. These include G-protein-coupled receptors
(adenosine receptor [42], opioids receptor [43] and α- and
β-adrenoreceptors [44]), G-proteins [45] in addition to other kinasedependent
pathways like the phosphatidylinositol-3-kinase (PI3kinase)/protein
kinase B (PKB) signalling pathway [46], nitric oxide
(NO) synthase/NO/cyclic guanine monophosphate (cGMP)/protein
kinase G (PKG)-pathway [45] and protein tyrosine kinase signalling
pathway [47]. Currently, the exact interaction between the different
protective signalling pathways remains unclear.
Mechanisms of protection: end-effector proteins
The end-effector mechanisms that indeed result in cardioprotective
activity induced by volatile anaesthetics remain unknown and the
subject of speculation. However, reduction of cellular Ca 2+ overload,
ROS production and preservation of mitochondrial function have
been associated with improved contractility, improved metabolic
function and a reduction of infarct size, and may form the main endeffector
targets for cardioprotective signalling pathways. Reduced
cellular Ca 2+ loading due to volatile anaesthetics has been attributed
to the depressant effects on the various elements of the myocardial
Ca 2+ homeostasis (see: “effect of anaesthetics on excitation-contraction coupling”).
In contrast to elevation of ROS during anaesthetic preconditioning,
ROS production during and after I/R has been demonstrated
to be reduced in preconditioned hearts and may contribute to anaesthetic-induced
cardioprotection [48]. During ischaemia and reperfusion
the mitochondria were demonstrated to be the major source of
ROS [49], and therefore preservation of mitochondrial bioenergetics
is the suggested underlying mechanism for reduced production of
ROS in preconditioned hearts.
Finally, several other mechanisms which may provide cardioprotection
have been proposed. These include reduced membrane damage,
reduced cytoskeletal fragility, reduced Ca 2+ sensitivity (thereby
preventing hypercontracture), preservation of cardiac (SR) Ca 2+
handling and a reduced activation of pro-apoptotic signalling pathways
[27,50,51,52].
Clinical implications
Despite the interesting progress on the mechanism of cardioprotective
signalling in experimental animal studies, the most important
question is whether the phenomenon of preconditioning can be
used in the development of clinical cardioprotective strategies. The
phenomenon of ischaemic preconditioning in patients was reported
soon after its introduction in animal studies, however, the choice of
anaesthetic agent during surgery was generally believed not to influence
the occurrence of ischaemic episodes [53].
Nevertheless, in vitro experiments in isolated human atrial trabeculae
showed enhanced contractile recovery due to pretreatment
with volatile anaesthetics [54]. Interestingly, the cardioprotective
signalling cascade seems to rely on similar signal transduction elements
as does ischaemic preconditioning such as PKC, ROS as well
as mitoK + ATP channels [55,56]. Several clinical studies that focus on
the cardioprotective effect of volatile anaesthetics were performed
on patients scheduled for coronary artery surgery. As part of their
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