Current Pharmaceutical Design - Volume 20, Issue 36, 2014

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. κ- 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-κB 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.

Anesthetic pre- and postconditioning pharmacologically reduces ischemia/reperfusion injury. Mitochondria play a central role in these myocardial protective salvage effects. In the preconditioning, low levels of reactive oxygen species, which are produced by anesthetics in the mitochondria, act as a trigger to prevent cardiomyocytes death and modify intracellular signaling mechanisms. In the postconditioning, 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 determining factors of cellular life and death under pathophysiological conditions. In these channels, the mitochondrial adenosine triphosphate-sensitive K+ channels, the mitochondrial Ca2+-activated K+ channels and mitochondrial permeability transition pores play critical roles in cardioprotection against ischemia/reperfusion injury. Mitochondrial permeability transition pores are end effectors, which contribute to myocardial preconditioning and postconditioning. Activation of intracellular signaling and acidification of mitochondrial matrix pH prevent the mitochondrial permeability transition pore opening, and therefore, preserve the mitochondrial function to supply adenosine triphosphate, resulting in myocardial protection due to the maintenance of intracellular homeostasis.

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 involved in volatile anesthetics. In this review we will outline a general overview of caveolae and caveolins and their role in protective signaling with a focus on the effects of volatile anesthetics. These recent developments have allowed us to better understand the mechanistic effect of volatile anesthetics and their potential in cardiac protection.

Brief periods of cardiac ischemia and reperfusion exert a protective effect against subsequent longer ischemic periods, a phenomenon coined ischemic preconditioning. Similarly, repeated brief episodes of coronary occlusion and reperfusion at the onset of reperfusion, called post-conditioning, dramatically reduce infarct sizes. Interestingly, both effects can be achieved by the administration of any volatile anesthetic. In fact, cardio-protection by volatile anesthetics is an older phenomenon than ischemic pre- or post-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- or post-conditioning. In fact, adenosine signaling has been implicated in isoflurane-mediated cardioprotection. Adenosine acts via four receptors designated as A1, A2a, A2b, and A3. Cardioprotection has been associated with all subtypes, although the role of each remains controversial. Much of the controversy stems from the abundance of receptor agonists and antagonists that are, in fact, capable of interacting with multiple receptor subtypes. Recently, more specific receptor agonists and new genetic animal models have become available paving way towards new discoveries. As such, the adenosine A2b receptor was shown to be the only 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- or post-conditioning. In the current review, we will focus on adenosine signaling in the context of anesthetic cardioprotection and will highlight new discoveries, which could lead to new therapeutic concepts to treat myocardial ischemia using anesthetic preconditioning.

Ischemic heart disease and myocardial infarction continue to be leading causes of cardiovascular morbidity and mortality. Activation of opioid, adenosine, bradykinin, adrenergic and other G-protein coupled receptors has been found to be cardioprotective. κ- 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. The present review will focus on the protective effects of endogenously released opioid peptides as well as exogenously administered opioids such as morphine, fentanyl, remifentanil, butorphanol, and methadone against myocardial ischemia/reperfusion injury. Receptor heterodimerization and cross-talk as well as interactions with other cardioprotective techniques will be discussed. Implications for opioid-induced cardioprotection in humans and for future drug development to improve myocardial salvage will be provided.

In 2007, the American Heart Association (AHA) recommended (class IIa, level of evidence B) in their guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery volatile anesthetics as first choice for general anesthesia in hemodynamically stable patients at risk for myocardial ischemia. This recommendation was based on results from patients undergoing coronary artery bypass grafting (CABG) surgery and thus subject to criticism. However, since a “good anesthetic” often resembles a piece of art in the complex perioperative environment, and is difficult to highly standardize, it seems unlikely that large-scale randomized control trials in noncardiac surgical patients will be performed in the near future to tackle this question. There is growing evidence that ether-derived volatile anesthetics and opioids provide cardioprotection in patients undergoing CABG surgery. Since 2011, the American College of Cardiology Foundation/AHA have recommended a “volatile-based anesthesia” for these procedures (class IIa, level of evidence A). It is very likely that volatile anesthetics and opioids also protect hearts of noncardiac surgical patients. However, age, diabetes and myocardial remodeling diminish the cardioprotective benefits of anesthetics. In patients at risk for perioperative cardiovascular complications, it is essential to abandon the use of “anti-conditioning” drugs (sulfonylureas and COX-2 inhibitors) and probably glitazones. There is significant interference in cardioprotection between sevoflurane and propofol, which should not be used concomitantly during anesthesia if possible. Any type of ischemic “conditioning” appears to exhibit markedly reduced protection or completely loses protection in the presence of volatile anesthetics and/or opioids.

K+ channels play an essential role in the membrane potential of arterial smooth muscle, and also in regulating contractile tone. Especially, in vascular smooth muscle, the opening of adenosine triphosphate (ATP)-sensitive K+ (KATP) channels leads to membrane hyperpolarization, resulting in muscle relaxation and vasodilation. This activation also plays a role in tissues during pathophysiologic events such as ischemia, hypoxia, and vasodilatory shock. In this review, we will describe the physiological and pathophysiological roles of vascular smooth muscle KATP channels in relation to the effects of anesthetics. Although accumulated evidence suggests that many anesthetics modify the above function of K+ channels as a metabolic sensor, further studies are certainly needed to resolve certain issues, especially in clinical settings of anesthesia use.

A spinal cord injury leads to disturbances of sensory and motor signals due to the damage to white matter and myelinated fiber tracts. Moreover, the damage to gray matter causes segmental loss of interneurons of dorsal horn and motoneurons and restricts the therapeutic options. Neuroprotective strategies have the potential to improve the neurological outcome of patients. To achieve this, concerns to anesthetics or analgesics as neuroprotective interventions have been accumulating to explore neuroprotection during perioperative period. This review includes consideration of: 1) basic concepts of the pathophysiological mechanisms following spinal cord injury and 2) anesthetics and analgesics displaying neuroprotective potential. In particular, we review the application of isoflurane as an inhalational neuroprotectant and discuss evidence for the neuroprotection provided by barbiturates. In addition, 3) recent advances in stem cell biology, neural injury and repair, and progress toward the development of neuroprotective and regenerative interventions are the basis for increased optimism.

Since several clinical data have suggested that the incidence of neurological deficit after aortic surgery has not changed appreciably over the last 50 years, anesthesiologists as well as vascular surgeons have attempted to resolve this clinically important issue by employing various strategies to prevent ischemic spinal cord injury. With respect to inhalational anesthetics, it is thought that isoflurane as well as sevoflurane preconditioning might provide neuroprotective effects against spinal ischemia via activation of TWIK-related K channels-1 or the potassium ATP channel. Glutamate receptor antagonists, including ketamine, could also potentially provide some neuroprotection against spinal ischemia. However, it seems likely that decreased glutamate release could produce more neuroprotective effects against spinal ischemia than a blockade of the glutamate receptor. Although barbiturate alone failed to protect the spinal cord, a controversial issue has been the possible neuroprotective effects associated with local anesthetics including tetracaine, lidocaine and bupivacaine. Clinical cases and experimental studies have indicated that neuraxial opioids might be capable of exacerbating neurological deficits even after a non-injurious interval of spinal ischemia. Inhaled nitric oxide (iNO) therapy (40-80ppm), a common treatment for pulmonary hypertension, has been reported to prevent ischemic brain injury in animal studies by selective dilation of collateral arterioles. The vasodilating effects of iNO on the central nervous system might enhance the “collateral network” in the spinal cord during aortic cross-clamp, potentially protecting the spinal cord. In conclusion, some anesthetics, especially inhalational anesthetics, may provide neuroprotective effects against spinal cord ischemia, but administration of neuraxial opioid after spinal cord ischemia might exacerbate neurological dysfunction.

Anesthetics have been studied for nearly fifty years as potential neuroprotective compounds in both perioperative and resuscitation medicine. Although anesthetics present pharmacologic properties consistent with preservation of brain viability in the context of an ischemic insult, no anesthetic has been proven efficacious for neuroprotection in humans. After such effort, it could be concluded that anesthetics are simply not neuroprotective in humans. Moreover, pharmacologic neuroprotection with non-anesthetic drugs has also repeatedly failed to be demonstrated in human acute brain injury. Recent focus has been on rectification of promising preclinical neuroprotection data and subsequent failed clinical trials. This has led to consensus guidelines for the process of transferring purported therapeutics from bench to bedside. In this review we first examined the history of anesthetic neuroprotection research. Then, a systematic review was performed to identify major clinical trials of anesthetic neuroprotection. Both the preclinical neuroprotection portfolio cited to justify a clinical trial and the design and conduct of that clinical trial were evaluated using modern standards that include the Stroke Therapy Academic Industry Roundtable (STAIR) and Consolidated Standards of Reporting Trials (CONSORT) guidelines. In publications intended to define anesthetic neuroprotection, we found overall poor quality of both preclinical efficacy analysis portfolios and clinical trial designs and conduct. Hence, using current translational research standards, it was not possible to conclude from existing data whether anesthetics ameliorate perioperative ischemic brain injury. Incorporation of advances in translational neuroprotection research conduct may provide a basis for more definitive and potentially successful clinical trials of anesthetics as neuroprotectants.

Systemic inflammatory response syndrome (SIRS) is triggered by various factors such as surgical operation, trauma, burn injury, ischemia, pancreatitis and bacterial translocation. Sepsis is a SIRS associated with bacterial infection. SIRS and sepsis tend to trigger excessive production of inflammatory cytokines and other inflammatory molecules and induce multiple organ failure, such as acute lung injury, acute kidney injury and inflammatory cardiac injury. Epithelial and endothelial cells in some major organs express inflammatory receptors on the plasma membrane and work as alert cells for inflammation, and regulation of these alert cells could have a relieving effect on the inflammatory response. In inflammatory conditions, initial cardiac dysfunction is mediated by decreased preload and adequate infusion therapy is required. Tachyarrhythmia is a complication of inflammatory conditions and early control of the inflammatory reaction would prevent the structural remodeling that is resistant to therapies. Furthermore, there seems to be crosstalk between major organs with a central focus on the kidneys in inflammatory conditions. As an alert cell strategy, volatile anesthetics, sevoflurane and isoflurane, 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. On the other hand, in terms of intravenous anesthetics, propofol and ketamine, their current status is still controversial as there is a lack of confirmatory evidence on whether they have an organ-protective effect in inflammatory conditions. The local anesthetic lidocaine suppressed inflammatory responses upon both systemic and local administration. For the control of inflammatory conditions, anesthetic agents may be a target of drug development in accordance with other treatments and drugs.

Thrombotic events occurring in either arteries or veins are the primary causes of fatal perioperative cardiovascular events. Risk factors for deep vein thrombosis, several of which are evidently associated with specific surgical procedures, are quite different from those for arterial thrombosis (e.g., aging or atherosclerotic diseases). Thrombus formed in arteries consists mainly of platelets coated with fibrin (i.e., white thrombus), while venous thrombus formed at relatively lower shear stress consists of all blood components including erythrocytes as well as leukocytes infiltrated with fibrin (red thrombus). Clinical evidence indicates beneficial roles of neuraxial anesthesia/ analgesia in the prevention of VTE for patients undergoing high risk surgical procedures. To date, mechanisms of action of drugs used for neuraxial anesthesia/analgesia to prevent venous thrombosis are uncertain. However, accumulation of clinical as well as experimental findings points to the involvement of immune cells (especially monocytes) in red thrombus generation and to the interaction of anesthetics with these cells. We also suggest that adhesion molecules associated with the formation of monocyte platelet aggregates as well as substance P: neurokinin-1 receptor (SP/NK1R) pathway that involves neurogenic inflammation are crucial. Local anesthetics and NK1R antagonists are candidate drugs that may possess the capability to prevent venous thrombotic disorders in perioperative settings.

Opioids i.e., compounds with morphine–like actions, and their receptors have been demonstrated to be involved in cardioprotection, at least in scientific studies, which makes sense as cardiomyocytes express most of the known opioid receptors and their agonists. In vitro and in vivo studies have demonstrated that the opioid system plays various important roles in maintaining cardiac function; i.e., it influences cardiac rhythm, cell stress, and even developmental processes. In support of these research findings, there is also good clinical evidence that opioids are effective as cardioprotective drugs. In fact, in the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines for coronary artery bypass graft surgery opioids and volatile halogenated anesthetics are referred to as anti-ischemic or conditioning agents. Although opioids are administered to all patients who undergo surgery as well as patients admitted to the ICU, including those that suffer heart attacks, 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. Opioids have been used as pain control agents in the clinical setting for a long time. As such, surgical, critical care, and cancer patients routinely receive them. On the other hand, ischemic heart disease continues to be a leading cause of morbidity and mortality in developed countries, and opioid therapy might be useful for treating the condition. This review examines recent clinical trials of the effects of opioids on ischemic heart disease and discusses the barriers to the use of opioids for cardioprotection.