Memory phase of sevoflurane preconditioning

Ouska et al.
European Joural of Anaesthesiology

Special Author Introduction
Since the first report by Murry et al. [1], ischaemic preconditioning has been shown to exert a cardioprotective effect against cardiac ischaemia-reperfusion injury. Volatile anaesthetics such as isoflurane, sevoflurane and desflurane induce cardioprotection mimicking ischaemic preconditioning. There are three important periods in preconditioning, that is, the time of preconditioning stimulus, the acute memory phase and sustained ischaemia. It has been demonstrated that if one of these periods is too short or long, preconditioning cardioprotection may not occur. The acute memory phase is the interval between brief exposure of a volatile anaesthetic to the heart and sustained ischaemia, that is, the washout time. This washout time allows intracellular signaling mediating this cardioprotection to transpire. It has not been determined how long the washout time can be extended and still exerts a cardioprotective effect in sevoflurane preconditioning. The first purpose of our study was to define the critical limits of efficacy of sevoflurane preconditioning by varying the duration of washout time.

Intramyocyte translocation of protein kinase C (PKC) during the acute memory phase is known to be a key mediator in volatile anaesthetic preconditioning, as well as ischaemic and ethanol-induced preconditioning [2-4]. PKC-α, δ, ε, η have been shown to play a role in ischaemic preconditioning [5,6]. We first discovered that regular ethanol consumption induced chronic preconditioning which was associated with sustained intramyocyte translocation of PKC-ε, but not PKC-α or δ, in guinea pig [3]. It has not been elucidated which isoforms of PKC is involved in activating and maintaining the acute memory phase in sevoflurane preconditioning. The second objective of our study was to examine the relationship between the time frame of the acute memory phase of sevoflurane preconditioning and intramyocyte translocation of PKC isoforms.

Upon activation, PKC isoforms translocate to the particulate fraction of the myocytes, binding to anchoring molecules (receptors for activated C kinase or RACKs) and phosphorylating protein substrates. Recent studies have shown that some isoforms of PKC translocate to mitochondria during the acute memory phase [7] and the cardioprotective signaling of volatile anaesthetic preconditioning converges on mitochondria. Opening of mitochondrial adenosine triphosphate-sensitive potassium (mK_ATP) channels and inhibition of permeability transition pore (mPTP) opening have been implicated in the mechanism of volatile anaesthetic preconditioning [8]. A recent study demonstrated that nitric oxide opens mK_ATP channels in a PKC-ε dependent mechanism in isolated mitochondria [9]. Interestingly, we recently found that sevoflurane enhances ethanol preconditioning through modulation of nitric oxide synthase and PKC [10], and increases nitric oxide production after ischaemia-reperfusion [11]. Future research will need to determine how different isoforms of PKC interact with mK_ATP channels and mPTP.

Numerous investigations have been conducted in the past two decades to elucidate the intracellular mechanisms producing the cardioprotection of preconditioning. No therapy is yet available to reproduce the benefits of preconditioning in patients at risk for myocardial infarction. A short period of ischaemia immediately prior to coronary artery bypass surgery has shown promise [12]. Understanding the time frame of the acute memory phase of sevoflurane preconditioning may add to preconditioning cardioprotection prior to surgery.

Masami Miyamae, MD, PhD
Chika Okusa, DDS, PhD
Vincent M. Figueredo, MD

References:
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