Title:Editorial (Thematic Issue: Novel Insights into the Role of Anesthetics and Opioids in Organ or Tissue Protection)
VOLUME: 20 ISSUE: 36
Author(s):Hiroyuki Kinoshita
Affiliation:Department of Anesthesiology Aichi Medical University School of Medicine 1-1 Yazako Karimata, Nagakute, 480-1195, Japan.
Abstract:Evidence is accumulating that anesthetics as well as opioids demonstrate some protective effects toward several organs including the heart
and brain. However, in the field of anesthesiology, a wide range of reviews regarding such topics is scarce. Therefore, it has been difficult for
clinicians as well as scientists to obtain crucial information about anesthetics and opioids from one issue of a journal. In this context, a series
of reviews covering protective effects of anesthetics and opioids from both basic and clinical aspects were conducted in this issue of the Current
Pharmaceutical Design “Novel insights into the role of anesthetics and opioids in organ or tissue protection.”
Kitahata et al. [1] discussed the role of mitochondria in anesthetic pre- and post-conditioning based on the results from basic experiments.
During pre-conditioning, low levels of reactive oxygen species, which are produced by anesthetics in the mitochondria, act as a trigger to
prevent cardiomyocyte death. During post-conditioning, decreased mitochondrial matrix pH, which was caused by anesthetics, triggers the
onset of a rapid protective effect. The mitochondrial membranes have several ion channels that act as major determinants of cellular life and
death under pathophysiological conditions. Mitochondrial permeability transition pores are end effectors, which contribute to myocardial preand
post-conditioning. Mitochondria have been shown to play a role in the myocardial protective mechanisms by anesthetics, and they are
both triggers and targets of cardioprotection in response to ischemia/reperfusion injury.
Roth et al. [2] outlined a general overview of caveolae and caveolins and their role in protective signaling with a focus on the effects of volatile
anesthetics. Caveolae are flask-like invaginations of the cell surface that have been identified as signaling epicenters. Within these microdomains,
caveolins are structural proteins of caveolae, which are able to interact with numerous signaling molecules affecting temporal and
spatial dimensions required in cardiac protection. This complex moiety is essential to the mechanisms of organ protection related to volatile
anesthetics.
Bonney et al. [3] focused on adenosine signaling in the context of anesthetic cardioprotection where they highlight new discoveries that could
lead to new therapeutic concepts to treat myocardial ischemia using anesthetic pre-conditioning. Although the mechanism through which
anesthetics can mimic ischemic pre- or post-conditioning is still unknown, adenosine generation and signaling are the most redundant triggers
in ischemic pre- and post-conditioning. In fact, adenosine signaling has been implicated in isoflurane-mediated cardioprotection. Cardioprotection
has been associated with all subtypes of adenosine receptors, although the role of each remains controversial. Recently, more specific
receptor agonists and new genetic animal models have become available to pave way towards new discoveries. As such, the adenosine A2b
receptor was shown to be one of the adenosine receptors whose cardiac expression is induced by ischemia in both mice and humans and
whose function is implicated in ischemic pre- and post-conditioning.
Riess et al. [4] provided an overview of mechanisms of opioid-induced protection against myocardial ischemia/reperfusion injury, as observed
in cells, tissues and whole organs and in different species including humans, and provide an outlook on future directions and drug development.
δ- and/or δ-opioid receptor activation is involved in direct myocardial protection, while the role of μ-opioid receptors seems less
clear. In addition, differential affinities to the three opioid-receptor subtypes by various agonists and cross-talk among different G-protein
coupled receptors render conclusions regarding opioid-mediated cardioprotection challenging.
Zaugg et al. [5] showed growing evidence that volatile anesthetics and opioids provide cardioprotection in cardiac and noncardiac surgical
patients. However, it is crucial to note that age, diabetes and myocardial remodeling diminish the cardioprotective benefits of these agents.
They also emphasized that in patients at risk for perioperative cardiovascular complications, it is not recommended to use “anti-conditioning”
drugs, including sulfonylureas and cyclooxygenase-2 inhibitors, and to avoid interference in cardioprotection between sevoflurane and propofol.
Kawahito et al. [6] described the physiological and pathological roles of ATP-sensitive K+ channels in vascular smooth muscle and the effects
of anesthetics toward these channels. Metabolic stresses including ischemia, hypoxia, hypercapnea and acidosis activate these channels, resulting
in maintenance of the blood flow in vital organs including the heart and brain. Volatile anesthetics mostly enhance vasodilator effects
mediated by these channels, whereas intravenous and local anesthetics reduce them. Although accumulated experimental evidence suggests
that many anesthetics can modify the K+ channel function, further studies in clinical settings are certainly needed to improve the anesthetic
management.
Ishikawa et al. [7] described basic concepts of pathology following spinal cord injury and how anesthetics contribute to spinal protection.
They mentioned possible neuroprotection mediated by anesthetics and/or analgesics in the perioperative period. In this regard, Ishikawa et al.
recommend employing isoflurane but not barbiturates for this particular purpose. They also introduced recent advances of understanding stem
cell biology, which may lead us to successful recovery of spinal cord function after the insult.
Kakinohana [8] described that some anesthetics, especially inhalational anesthetics, may clinically provide neuroprotective effects against the
spinal cord ischemia, but the administration of neuraxial opioid after spinal cord ischemia might exacerbate neurological dysfunction. Indeed,
isoflurane as well as sevoflurane probably provides neuroprotective effects against spinal ischemia via activation of TWIK-related K channels-
1 or the ATP sensitive K+ channels. In addition, nitric oxide inhalation might be a tool to protect the spinal cord from intraoperative
ischemia in patients undergoing aortic cross-clamp during surgery. In contrast, clinical cases and experimental studies have indicated that
neuraxial opioids are capable of exacerbating neurological deficits even after a non-injurious interval of spinal ischemia.
Ishida et al. [9] examined the history of anesthetic neuroprotection research, and then systematically reviewed major clinical trials of anesthetic
neuroprotection. They found overall poor quality of both preclinical efficacy analysis portfolios and clinical trial designs and conduct.
As a result, they concluded that anesthetics appear not to have efficacy for neuroprotection in humans. They state that the quality of science
conducted to date can be markedly improved upon to allow more rational clinical trial design and better opportunity to provide a convincing
answer to this question.
Hatakeyama et al. [10], showed that organ injury accompanied by an inflammatory condition including systemic inflammatory response syndrome
and sepsis mainly involves activation of nuclear factor-δB at an early stage and activator protein-1 at an advanced stage. They emphasized
that the pathological condition induces apoptosis and cell death via the inflammatory activation of alert cells. Volatile and local anesthetics
seem to have anti-inflammatory effects, and both experimental and clinical studies have shown the beneficial effects of these drugs in
various settings of inflammatory conditions. In contrast, intravenous anesthetics lack confirmatory evidence that they are organ-protective in Azma et al. [11] documented clinical evidence indicating beneficial roles of neuraxial anesthesia/analgesia in the prevention of venous
thromboembolism in surgical patients. Clinical as well as experimental findings point to the involvement of immune cells in red thrombus
generation and to the interaction of anesthetics with these cells. Of these, the adhesion molecule associated with the formation of monocyte
platelet aggregation as well as the substance P-neurokinin-1 receptor pathway should be emphasized. Local anesthetics and neurokinin-1
receptor antagonists may possess prevention of venous thrombotic disorders in perioperative settings.
Ishii [12] summarized recent clinical trials on the effects of opioids on ischemic heart disease and discussed the barriers to the use of opioids
for cardioprotection. In vitro and in vivo studies have demonstrated that the opioid system plays an important role in maintaining cardiac
function. In support of these research findings, there is clinical evidence that opioids, especially acting on κ, σ μ3 opioid receptors, might
be effective as cardioprotective drugs. Although opioids are administered to many patients undergoing surgery or management in the intensive
care unit, no recommendations about their use for the preconditioning/management of myocardial ischemia have been included in recent
clinical guidelines due to the weak clinical evidence about their effects. To establish reproducible cardioprotective opioid-based treatments,
we must clarify the patient factors that influence the cardiac response to opioids.
In summary, this issue contains a broad range of findings regarding protective effects of anesthetics and opioids, which are currently used in
clinical anesthesia, on a variety of organs and tissues including those in some pathological conditions. However, many questions remain, and
will have to be further examined to improve the quality of clinical anesthesia.
