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Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286


Editorial (Thematic Issue: Novel Insights into the Role of Anesthetics and Opioids in Organ or Tissue Protection)

Author(s): Hiroyuki Kinoshita

Volume 20, Issue 36, 2014

Page: [5671 - 5672] Pages: 2

DOI: 10.2174/138161282036140912105849


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.

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