Volatile Anesthetic Preconditioning Research Articles

Volatile anesthetic preconditioning modulates oxidative stress and nitric oxide in patients undergoing coronary artery bypass grafting.

Background:Myocardial preconditioning using volatile anesthetics such as isoflurane and sevoflurane have beneficial effects in decreasing morbidity in cardiac surgical patients. Studies in animal models have indicated that reactive oxygen and nitrogen species probably play a role in mediating these effects. However, data from human studies are scarce and the differential effect of sevoflurane vs. isoflurane on reactive oxygen species (ROS) and reactive nitrogen species (RNS) has not been studied extensively.Materials and Methods:Randomized clinical control trial comparing preconditioning effects of volatile agents isoflurane and sevoflurane when administered during coronary artery bypass surgeries on cardiopulmonary bypass (CPB). Serum samples were collected at 3 time points before induction, after cross clamp release and one hour after separation from CPB. Levels of oxidative stress markers and nitric oxide were analyzed in these samples.Results:Hemodynamic indices, cardio-pulmonary bypass duration, and ICU stay were similar between the groups. CKMB values 12 hours post-op were decreased in majority of patients in the sevoflurane group compared to isoflurane. Serum malondialdehyde and nitrate levels were lower with sevoflurane (P < 0.05) when compared to the isoflurane group, but no significant differences in protein carbonyl content or protein thiol content were evident between the 2 groups. Sevoflurane also prevented the decrease in total thiols during later stages of surgery.Conclusions:Volatile anesthetics, isoflurane and sevoflurane modulate oxidative and nitrosative stress during CABG. Between the two pre-conditioning agents, isoflurane seems to provide better protection during the pre-bypass period, while sevoflurane provides protection during both pre- as well as post-bypass period.

Total Intravenous Anesthesia for Myocardial Protection and Preconditioning

AbstractPerioperative myocardial injury is common after any major surgical procedure even with best possible anesthesia and surgical management. Organ preservation during surgical procedure prevents morbidity and mortality. The effect of ischemic preconditioning on myocardial as well as other organ protection is well known. A variety of other agents also shown to have preconditioning thus protective effect on myocardium during anesthesia and surgery. The beneficial effect of volatile anesthetic preconditioning is well studied. However, the effect of intravenous anesthetic agents on this context is still way to go. This review is an attempt to look into the latest available research regarding the preconditioning and myocardial protective effect of intravenous anesthetic agents.

Sevoflurane Preconditioning Confers Delayed Cardioprotection by Upregulating AMP-Activated Protein Kinase Levels to Restore Autophagic Flux in Ischemia-Reperfusion Rat Hearts

BackgroundVolatile anesthetic preconditioning confers delayed cardioprotection against ischemia/reperfusion injury (I/R). AMP-activated protein kinase (AMPK) takes part in autophagy activation. Furthermore, autophagic flux is thought to be impaired after I/R. We hypothesized that delayed cardioprotection can restore autophagic flux by activating AMPK.Material/MethodsAll male rat hearts underwent 30-min ischemia and 120-min reperfusion with or without sevoflurane exposure. AMPK inhibitor compound C (250 μg/kg, iv) was given at the reperfusion period. Autophagic flux blocker chloroquine (10 mg/kg, ip) was administrated 1 h before the experiment. Myocardial infarction, nicotinamide adenine dinucleotide (NAD+) content, and cytochrome c were measured. To evaluate autophagic flux, the markers of microtubule-associated protein 1 light chain 3 (LC3) I and II, P62 and Beclin 1, and lysosome-associated membrane protein-2 (LAMP 2) were analyzed.ResultsThe delayed cardioprotection enhanced post-ischemic AMPK activation, reduced infarction, CK-MB level, NAD+ content loss and cytochrome c release, and compound C blocked these effects. Sevoflurane restored impaired autophagic flux through a lower ratio of LC3II/LC3I, downregulation of P62 and Beclin 1, and higher expression in LAMP 2. Consistently, compound C inhibited these changes of autophagy flux. Moreover, chloroquine pretreatment abolished sevoflurane-induced infarct size reduction, CK-MB level, NAD+ content loss, and cytochrome c release, with concomitant increase the ratios of LC3II/LC3I and levels of P62 and Beclin 1, but p-AMPK expression was not downregulated by chloroquine.ConclusionsSevoflurane exerts a delayed cardioprotective effects against myocardial injury in rats by activation of AMPK and restoration of I/R-impaired autophagic flux.

Effects of volatile anesthetic preconditioning on expression of NFkB-regulated genes in aged rat myocardium.

Volatile anesthetic preconditioning has been shown to be a potent way to provide myocardium protection against ischemia/reperfusion (I/R) injury; however, this cardioprotection is lost in senescent animal models and elderly patients. NFkB-regulated genes have been linked to myocardial I/R injury and anesthetic preconditioning. Here, we investigated NFkB activation related to anesthetic preconditioning in aging rat myocardium. Isolated, Langendorff perfused rat hearts from Fischer 344 male rats, 24 months old, were randomly assigned to one of the three groups. The hearts of the control group were perfused with physiologic solution without any intervention. The hearts in the I/R group were subjected to 25 minutes ischemia and followed by 60 minutes reperfusion. The hearts in the treatment group were subjected to 10 minutes 2.5% sevoflurane, followed by 20 minutes washout and by 25 minutes ischemia and 60 minutes of reperfusion, respectively. Left ventricular developed pressure (LVDP) and left ventricular end-diastolic pressure (LVEDP) were measured. Western blot analysis was used to measure inhibitor of kB (IkB) and anti-apoptotic genes: A1, ILP, c-IAP-2, Bcl-2, caspase 8 and caspase 9. Ischemia and reperfusion significantly decreased LVDP and increased LVEDP in aged rat hearts. Anesthetic preconditioning with sevoflurane did not change the effects I/R on LVDP and LVEDP, despite the fact that after treatment with anesthetic preconditioning, the levels of IκB, A1, ILP, caspase 8 and caspase 9 were significantly different compared to those of the control hearts. In conclusion, anesthetic preconditioning with sevoflurane does not improve myocardial systolic and diastolic functions. Our results suggest that the activation of NFkB regulated genes is different in the senescent myocardium and could account for loss of cardioprotection with aging.

The Slo(w) path to identifying the mitochondrial channels responsible for ischemic protection.

Mitochondria play an important role in tissue ischemia and reperfusion (IR) injury, with energetic failure and the opening of the mitochondrial permeability transition pore being the major causes of IR-induced cell death. Thus, mitochondria are an appropriate focus for strategies to protect against IR injury. Two widely studied paradigms of IR protection, particularly in the field of cardiac IR, are ischemic preconditioning (IPC) and volatile anesthetic preconditioning (APC). While the molecular mechanisms recruited by these protective paradigms are not fully elucidated, a commonality is the involvement of mitochondrial K+ channel opening. In the case of IPC, research has focused on a mitochondrial ATP-sensitive K+ channel (mitoKATP), but, despite recent progress, the molecular identity of this channel remains a subject of contention. In the case of APC, early research suggested the existence of a mitochondrial large-conductance K+ (BK, big conductance of potassium) channel encoded by the Kcnma1 gene, although more recent work has shown that the channel that underlies APC is in fact encoded by Kcnt2 In this review, we discuss both the pharmacologic and genetic evidence for the existence and identity of mitochondrial K+ channels, and the role of these channels both in IR protection and in regulating normal mitochondrial function.

Detection of a Bithionol Sensitive Potassium Channel in Cardiac Mitochondria Absent in Slo2.1 Knockouts

Mitochondrial K+ channels are important mediators of cell protection against stress, however less is known about their physiologic roles. Using mouse knockout models our lab has recently reported the absolute requirement of the Na+-activated-K+ channel Slo2.1 for volatile anesthetic preconditioning against cardiac ischemia reperfusion injury [PMID: 26845140]. Functional examination of this channel in isolated mitochondria using a Tl+ flux assay demonstrated the presence of a bithionol-sensitive mitochondrial Tl+ uptake in wildtype cardiac mitochondria that was absent in those from Slo2.1 knockout. Herein we combine pharmacologic activation (bithionol) and inhibition (quinidine) of Slo2 channels with patch clamp of isolated mitochondrial inner membranes (mitoplasts) from wildtype and Slo2.1-/- mice, to demonstrate the presence of Slo2.1 activity in cardiac mitochondria at the single channel level. Additional analysis of these Slo2.1-/- mice at the whole animal, heart, cardiomyocyte, and mitochondrial level has revealed a metabolic phenotype comprising differential substrate preference under stress conditions, indicating a functional relationship between mitochondrial K+ channels and the regulation of mitochondrial metabolism. These data demonstrate a role for Slo2.1 in the regulation of cardiac mitochondrial function.

Sevoflurane Preconditioning Confers Neuroprotection via Anti-apoptosis Effects.

Neuroprotection against cerebral ischemia afforded by volatile anesthetic preconditioning (APC) has been demonstrated both in vivo and in vitro, yet the underlying mechanism is poorly understood. We previously reported that repeated sevoflurane APC reduced infarct size in rats after focal ischemia. In this study, we investigated whether inhibition of apoptotic signaling cascades contributes to sevoflurane APC-induced neuroprotection. Male Sprague-Dawley rats were exposed to ambient air or 2.4 % sevoflurane for 30 min per day for 4 consecutive days and then subjected to occlusion of the middle cerebral artery (MCAO) for 60 min at 24 h after the last sevoflurane intervention. APC with sevoflurane markedly decreased apoptotic cell death in rat brains, which was accompanied by decreased caspase-3 cleavage and cytochrome c release. The apoptotic suppression was associated with increased ratios of anti-apoptotic Bcl-2 family proteins over pro-apoptotic proteins and with decreased activation of JNK and p53 pathways. Thus, our data suggest that suppression of apoptotic cell death contributes to the neuroprotection against ischemic brain injury conferred by sevoflurane preconditioning.

Slo2.x Potassium Channels are Involved in the Regulation of Heart Mitochondrial Function

Mitochondrial potassium channels (MKCs) are believed to be important in stress response in the heart. Volatile anesthetic preconditioning (APC) is a method of protecting the heart from ischemia-reperfusion injury which elicits evolutionarily-conserved protective signaling pathways that converge at the mitochondrial level. Work in C. elegans has focused attention on the Slo2 gene product as a transducer of APC effects on hypoxic survival and recent data from our lab demonstrate that this protective role is conserved in mammals. Slo2 in mammals has diverged into two paralogs, Slo2.1 (KCNT2; Slick) and Slo2.2 (KCNT1; Slack). These genes code for Na+-activated K+ channels and are highly expressed in brain, but their function in cardiomyocytes and/or mitochondria is unknown. Examination of these channels has been limited to pharmacologic profiling which is hampered by overlapping sensitivities and off-target effects of small molecules. Herein we employed novel genetic deletions of Slo2.1 and Slo2.2 double knockout, Slo2.x dKO, in mice to confirm the role of these potassium channels in APC and identify their role in endogenous cardiac mitochondrial function. Preliminary data obtained using Slo2.x dKO reveal novel metabolic and morphologic phenotypes, indicating a functional relationship between mitochondrial potassium channels and regulation of mitochondrial oxidative phosphorylation. These data demonstrate a role of the Slo2.x gene product in the regulation of cardiac mitochondrial function.

Abstract 110: Anesthetic Preconditioning and Mitochondrial Slo K + Channel Activity Require Slo2.1

Introduction: Volatile anesthetic preconditioning (APC) protects the heart from ischemia-reperfusion (IR) injury. APC elicits evolutionarily-conserved protective signaling pathways that converge at the mitochondrial level, where the Slo family of K + channels is thought to mediate protection through an unknown mechanism. Recent work in C. elegans has focused attention on the Slo2 gene product as a transducer of APC effects on hypoxic survival. In mammals, Slo2 has diverged into two paralogs, Slo 2.1 (KCNT2; Slick) and Slo2.2 (KCNT1; Slack). These genes code for Na + -activated K + channels and are highly expressed in brain, but their function in cardiomyocytes and/or mitochondria is unknown. Methods: The contribution of Slo channels to cardiac physiology was characterized using knockout mice, including Slo1 and two novel Slo2.x alleles. APC was assessed through ex-vivo cardiac IR injury. Isolated mitochondrial K + channel activity was assessed using a Tl + flux assay, and by patch-clamp of cardiac mitoplasts. Electron microscopy was used to assess mitochondrial morphology in primary cardiomyocytes and Seahorse extracellular flux analysis used to assess bioenergetics. Results: The Slo2.x ( double KO ) and the Slo2.1 single KO mice could not be protected from cardiac IR injury by APC. Physiologic approaches demonstrated that Slo2.1 is present in mitochondria and Slo2.1 -dependent mitochondrial K + transport can be triggered directly by volatile anesthetics. Cardiomyocytes from Slo2.x dKO mice exhibited profound metabolic remodeling and electron microscopy revealed that Slo2.1 knockouts had enlarged circular mitochondria. In contrast, Slo1 KO mice responded normally to APC and exhibited wild type mitochondrial physiology. Conclusion: Slo2.1 activation protects against cardiac IR, and is required for APC. Slo2.1 also contributes to mitochondrial metabolic homeostasis. As a molecular target for APC, identification of Slo2.1 may facilitate development of targeted therapeutic molecules that can protect the heart and minimize the side effects of volatile anesthetics.

Effect of ischemic and pharmacological preconditioning of lower limb muscle tissue on tissue oxygenation measured by near-infrared spectroscopy--a pilot study.

BackgroundIschemic or volatile anesthetic preconditioning is defined as tissue protection from impending ischemic cell damage by repetitive short periods of tissue exposure to ischemia or volatile anesthetics. Objective of this study was to elucidate, if ischemic preconditioning and pharmacological preconditioning with sevoflurane have effects on muscle tissue oxygen saturation in patients undergoing surgical revascularization of the lower limb.MethodsIn this prospective randomized pilot study ischemic and pharmacological (sevoflurane) preconditioning was performed in 40 patients with lower limb arterial occlusive disease undergoing surgical revascularization. Sevoflurane preconditioning was performed in one group (N = 20) by repetitive application of sevoflurane for six minutes interspersed by six minutes of washout. Thereafter, ischemic preconditioning was performed in all patients (N = 40) by repetitive clamping of the femoral artery for six minutes interspersed by six minutes of reperfusion. The effect of both procedures on leg muscle tissue oxygen saturation (rSO2) was measured by near-infrared spectroscopy during both procedures and during surgery and reperfusion (INVOS® 5100C Oxymeter with Small Adult SomaSensor® SAFB-SM, Somanetics, Troy, Michigan, USA).ResultsRepetitive clamping and reperfusion of the femoral artery resulted in significant cyclic decrease and increase of muscle rSO2 (p < 0.0001). Pharmacological preconditioning with sevoflurane resulted in a faster and higher increase of rSO2 during postoperative reperfusion (Maximal 111% baseline ± 20 versus 103% baseline ± 14, p = 0.008) consistent with an additional effect of pharmacological preconditioning on leg perfusion.ConclusionsIschemic preconditioning of lower limb muscle tissue and pharmacological preconditioning with sevoflurane have an effect on tissue oxygenation in patients with lower limb occlusive arterial disease.Trial registrationThe trial has been registrated at http://www.ClinicalTrial.gov, Trial Number: NCT02038062 at 14 January 2014.

Activation of prosurvival signaling pathways during the memory phase of volatile anesthetic preconditioning in human myocardium: a pilot study

According to a compelling body of evidence anesthetic preconditioning (APC) attenuates the deleterious consequences of ischemia-reperfusion and protects the heart through a mechanism similar to ischemic preconditioning. The present study was purported to investigate the intracellular signaling pathways activated in human myocardium in response to a preconditioning protocol with two different volatile anesthetics, namely isoflurane and sevoflurane. To this aim, phosphorylation of PKCα and -δ, ERK1/2, Akt, and GSK3β was determined at the end of the APC protocol, in human atrial samples harvested from patients undergoing open-heart surgery. The results demonstrate that preconditioning with volatile anesthetics triggers the activation of PKCδ and -α isoforms and of prosurvival kinases, ERK1/2, and Akt, while inhibiting their downstream target GSK3β during the memory phase.

The changes of technetium-99m-labeled annexin-V in delayed anesthetic preconditioning during myocardial ischemia/reperfusion

This study was designed to use real-time imaging to test the hypothesis that delayed cardiac protection induced by volatile anesthetics inhibits apoptosis. Rats were divided into two groups. One group was exposed to 120 min of 33 % O2 [control group (CON group)] and the other group was exposed to 2.5 % sevoflurane in 33 % O2 for 120 min [sevoflurane group (SEVO group)]. Both groups were allowed to return to their cages for 24 h. After 24 h recovery, all rats underwent 30 min myocardial ischemia by occluding coronary artery followed by 2 h of reperfusion. After reperfusion, technetium-99m-labeled annexin-V was administered intravenously to identify apoptosis. Left ventricular samples were obtained to measure infarct size and radionuclide imaging and caspase-3. Radionuclide imaging indicated that apoptosis was reduced in SEVO group (0.78 % ± 0.82) when compared with the CON group (1.15 % ± 0.61), and the infarct size was also decreased in the SEVO group (40 % ± 7). The transferase dUTP nick end labeling (TUNEL)-positive cardiomyocytes in the SEVO group (16 % ± 6) were significantly decreased in the peri-infarct zone when compared with the CON group (28 % ± 4). After reperfusion, caspase-3 expression was significantly blunted in the SEVO group than in CON group (50 % ± 11 vs. 68 % ± 10, p < 0.05). This study used technetium-99m-labeled annexin-V of real-time imaging to detect cardiomyocyte apoptosis and the results were confirmed by the TUNEL assay and caspase-3 expression. We concluded that delayed volatile anesthetic preconditioning (APC) protects against I/R in vivo. The method of technetium-99m-labeled annexin-V of real-time imaging can be used to detect cardiomyocyte apoptosis in delayed APC during ischemia/reperfusion.

Hypercholesterolemia blocked sevoflurane-induced cardioprotection against ischemia–reperfusion injury by alteration of the MG53/RISK/GSK3β signaling

Recent studies have demonstrated that volatile anesthetic preconditioning confers myocardial protection against ischemia-reperfusion (IR) injury through activation of the reperfusion injury salvage kinase (RISK) pathway. As RISK has been shown to be impaired in hypercholesterolemia, we investigate whether anesthetic-induced cardiac protection was maintained in hypercholesterolemic rats. Normocholesteolemic or hypercholesterolemic rat hearts were subjected to 30 min of ischemia and 2 h of reperfusion. Animals received 2.4% sevoflurane during three 5 min periods with and without PI3K antagonist wortmannin (10 μg/kg, Wort) or the ERK inhibitor PD 98059 (1 mg/kg, PD). The infarct size, apoptosis, p-Akt, p-ERK1/2, p-GSK3β were determined. Two hundred and six rats were analyzed in the study. In the healthy rats, sevoflurane significantly reduced infarct size by 42%, a phenomenon completely reversed by wortmannin and PD98059 and increased the phosphorylation of Akt, ERK1/2 and their downstream target of GSK3β. In the hypercholesterolemic rats, sevoflurane failed to reduce infarct size and increase the phosphorylated Akt, ERK1/2 and GSK3β. In contrast, GSK inhibitor SB216763 conferred cardioprotection against IR injury in healthy and hypercholesterolemic hearts. Hyperchoesterolemia abrogated sevoflurane-induced cardioprotection against IR injury by alteration of upstream signaling of GSK3β and acute GSK inhibition may provide a novel therapeutic strategy to protect hypercholesterolemic hearts against IR injury.

Delayed anesthetic preconditioning protects against myocardial infarction via activation of nuclear factor-κB and upregulation of autophagy

Delayed volatile anesthetic preconditioning (APC) can protect against myocardial ischemia/reperfusion (I/R) injury; the delayed phase is called the second window of protection (SWOP), but the underlying mechanism is unclear. Nuclear factor-κB (NF-κB) is involved in the myocardial protection conferred by APC in the acute phase; autophagy has been reported to confer apoptosis inhibition and infarction reduction. We hypothesized that APC initiates delayed cardioprotection against I/R injury via the activation of NF-kB and upregulation of autophagy, thus attenuating the inflammatory response and apoptosis After a rat I/R model was set up, left ventricular samples were obtained before I/R to assess NF-κB-DNA binding activity and microtubule-associated protein 1 light chain 3 (LC3) and cathepsin B protein expression, and to examine autophagosomes with a transmission electron microscope. Infarct size and the expressions of tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and caspase-3 were measured at the end of 2-h reperfusion. The infarct size was significantly reduced in the SWOP group (30±3%) when compared with that in the I/R group (47±7%, P<0.05), and this finding was associated with increased NF-κB-DNA binding activity and autophagosomes. In addition, the expressions of LC3-II and cathepsin B were also up-regulated, and the expressions of TNF-α, IL-1β, and caspase-3 were attenuated in the SWOP group when compared with the findings in the I/R group. However, this protection was abolished by the administration of parthenolide (PTN) before sevoflurane inhalation, which resulted in an infarct size that was significantly increased (47±5%, P<0.05 PTN+SWOP vs. SWOP group). Delayed APC protected the rat heart from I/R injury. The underlying mechanisms may include NF-κB activation, upregulation of autophagy, and the attenuation of TNF-α, IL-1β, and caspase-3 expressions.

No renal protection from volatile-anesthetic preconditioning in open heart surgery

Acute kidney injury (AKI) is a common complication of open heart surgery (OHS). Preconditioning with volatile anesthetics is well proven to provide myocardial protection. Renal protection provided by volatile-anesthetic preconditioning has also been investigated; however, it is still controversial at the clinical level. This study aimed to investigate whether preconditioning with volatile anesthetics could mediate renal protection in OHS. A retrospective analytic study was designed. Medical records of patients (age ≥20 years) who had undergone OHS were reviewed. Types of anesthesia were classified as 'opioid-based anesthesia' (O group) and 'volatile-anesthetic-based anesthesia' (V group) according to the definitions given in the main text. Some medical records that had incomplete or ambiguous data were excluded. Renal protection was considered to be present if there was no clinical renal dysfunction as defined by the criteria given in the main text. AKI was considered to be present when there was a decrease of the postoperative estimated glomerular filtration rate (eGFR) that was >25 % of the preoperative eGFR. Also, postoperative 24-h oliguria (post-oliguria) and the provision of postoperative 48-h dialysis (post-dialysis) were considered. Differences between the O and V groups were tested by the appropriate statistics. A p value of <0.05 indicated significance. A total of 1,122 patients (702 males) were included in this study. The O and V groups included 704 and 418 patients, respectively. AKI was present in 9.52 and 8.37 % of the patients in the O and V groups, respectively (p = 0.532). Post-oliguria was found in 36.08 and 37.79 % of the patients in the O and V groups; and post-dialysis was provided in 3.98 and 4.31 %, respectively, of these patients; these two parameters showed no significant differences between the groups. This study could not demonstrate volatile-anesthetic-mediated renal protection in OHS. Therefore, in practice, pharmacological preconditioning with volatile anesthetics did not seem to be beneficial.

Volatile anesthetic preconditioning attenuated sepsis induced lung inflammation

BackgroundThis study aimed to evaluate the differential protective effects of isoflurane or sevoflurane on lung inflammation in a rat model of cecal ligation and puncture (CLP) induced sepsis. MethodsSeventy-two rats were assigned to control, sevoflurane, or isoflurane groups. At 2 and 4 h, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), nitrate/nitrate levels (NO), total antioxidant capacity (TAC), and intercellular cell adhesion molecule-1 (ICAM-1) were determined. At 12 and 24 h, malondialdehyde (MDA), myeloperoxidase (MPO), and histologic changes were evaluated. Survival was monitored for 7 d after CLP. ResultsSevoflurane (75%) and isoflurane (63%) significantly improved survival rate compared with control rats (38%). When sevoflurane and isoflurane groups were compared, sevoflurane pretreatment showed significant decrease in NO at 2 h [1045 (803–1274)/1570 (1174–2239) and 4 h [817 (499–1171)/1493 (794–2080)]; increase in TAC at 4 h [580.0 (387–751)/320 (239–512)]; decrease in MDA at 12 h [2.5 (1.1–4.2)/5.4 (4–73)] and 24 h [10.8 (6.0–14.0)/15.9 (9–28)]; and decrease in MPO at 24 h [145.8 (81–260)/232 (148–346)]. The difference in the ICAM-1 expression of the isoflurane and sevoflurane groups was not significant at both measurement times. The architectural integrity of the alveoli was preserved in all the groups. The injury scores of the three groups at 12 and 24 h did not show any significant difference. ConclusionsBoth sevoflurane and isoflurane attenuated inflammatory response, lipid peroxidation, and oxidative stress. Furthermore, sevoflurane was more effective in modulating sepsis induced inflammatory response at the chosen concentration in sepsis model.

Delayed Preconditioning by Sevoflurane Elicits Changes in the Mitochondrial Proteome in Ischemia-Reperfused Rat Hearts

Delayed myocardial preconditioning by volatile anesthetics involves changes in DNA transcription and translation. Mitochondria play a central role in myocardial ischemia/reperfusion (I/R) injury and in ischemic or pharmacologic preconditioning. In this study, we investigated whether there are alterations in myocardial mitochondrial protein expression after volatile anesthetic preconditioning (APC) to examine the underlying mechanisms of delayed cardioprotection. Thirty-six Sprague-Dawley rats were randomly assigned to 1 of 3 groups (n = 12 for each group). Rats in the delayed APC group were exposed to sevoflurane (2.5% for 60 minutes) 24 hours before myocardial ischemia was induced. Myocardial ischemia in the I/R and APC groups was induced by left coronary artery occlusion for 30 minutes, followed by 120 minutes of reperfusion. The control group received no treatment. The mitochondria fractions were prepared by differential centrifugation with density gradient isolation for proteomic analysis. Two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization with time-of-flight mass spectrometry was used to identify differences in the protein expression from mitochondria of the rat hearts. Fifteen differentially expressed mitochondrial proteins between the APC group and I/R group were identified and the expression patterns of 2 of the proteins were confirmed by Western blot analysis. These proteins were associated with mitochondrial substrate metabolism, respiration, and adenosine triphosphate (ATP)/adenosine diphosphate transport. The modifications of the mitochondrial proteome suggest an enhanced capacity of mitochondria to maintain myocardial ATP levels after I/R injury. Delayed sevoflurane myocardial preconditioning induces mitochondrial proteome remodeling, which mainly involves proteins that are related to ATP generation and transport. Therefore, proteomic changes related to bioenergetic balance may be the mechanistic basis of delayed anesthetic myocardial preconditioning.

Sevoflurane preconditioning confers neuroprotection via anti-inflammatory effects

Neuroprotection afforded by volatile anesthetic preconditioning (APC) has been demonstrated in both in vivo and in vitro experiments, yet the underlying mechanism is poorly understood. We therefore investigated whether suppression of p38 MAPK, NF-kappa B and the downstream pro-inflammatory signaling cascade contribute to sevofurane APC-induced neuroprotection. Male Sprague-Dawley rats were exposed for 30 min/day on 4 consecutive days to ambient air or to sevoflurane (1.2% or 2.4%). Then rats were subjected to filament occlusion of the middle cerebral artery (MCAO) for 60 min, and euthanized 3 days after MCAO for measuring infarct volume. APC with sevofurane markedly improved neurological performance of stroke rats, significantly decreased infarct volume, and robustly suppressed activation of NF-kappa B and p38 MAPK, and expression of inflammatory cytokines. Furthermore, APC with sevofurane showed a direct inflammation-suppressing effect in rat brain receiving intracerebroventricular infusion of a dose of LPS that doesn't cause overt brain damage. Thus, the data suggest that APC with sevoflurane confers neuroprotection against focal ischemic brain injury, at least in part, by the anti-inflammatory effects of sevoflurane.

Mechanism of volatile anesthetic preconditioning-induced "second window" protection against myocardial ischemia/reperfusion injury

Volatile anesthetic preconditioning can elicit acute and delayed (also called as second window) myocardial protection,and the latter may be more clinicaUy significant in decreasing the risk of myocardial ischemia/reperfusion injury for patientswith cardiovascular disease.The second protection might be achieved by stimulating myocardium to trigger adenosine and nitric oxide release,passing through protein kinase C and nuclear factor-κB signal transduction pathways,activating the ATP-sensirive potassium channel and reactive oxygen species as the final effectors,presenting a delayed myocardial protective effect.This review summarizes the latest studies about volatile anesthetic preconditioning-induced second protection. Key words: Anesthetics; inhalation; Ischemic preconditioning; Myocardial reperfusion injury; Second window of protection

Beta-blockers and anesthetic preconditioning: friend or foe?

To the Editor: We read with interest the recently-published article by Yu and Beattie reporting a meta-analysis investigating the effects of volatile anesthetics on morbidity and mortality in patients undergoing coronary artery bypass graft surgery.1 It was reported that volatile anesthetics do not reduce mortality compared to iv anesthesia, but reduce postoperative levels of troponin I as a marker of myocardial ischemic damage. Strikingly, patients receiving iv anesthetics had a significantly higher incidence (28%) of beta-blocker utilization compared to patients receiving volatile anesthetics. This is an extraordinarily important finding. Yu and Beattie conclude that “some myocardial protective effects of the inhalation anesthetics may have been counteracted as beta-blocker utilization was unequally distributed...”. We agree with this conclusion insofar as the disproportion of beta-blocker use may have influenced the results. However, we surmise that concurrent beta-blocker therapy inhibited the cardioprotective effects of volatile anesthetics and that the beneficial effects of the volatile anesthetics would have been even more pronounced, if no beta blockers had been used at all. This contention is derived from the fact that volatile anesthetic preconditioning is mediated by beta-adrenergic signalling. Unspecific blockade of beta-adrenergic receptors abrogates desflurane-induced preconditioning in isolated human atrial myocardium.2 Furthermore, volatile anesthetic preconditioning is abolished by concurrent blockade of beta1-adrenergic receptors by esmolol and downstream protein kinase A by the selective blocker H-89 in the rabbit heart in vivo.3 This result can also be obtained using the beta1 selective blocker metoprolol.4 Perioperative beta-blocker therapy is recommended by the American College of Cardiology/American Heart Association in cardiac high risk patients. However, evidence is emerging that the beneficial effects of perioperative beta-blocker therapy are less impressive than originally assumed.5 Patients at low cardiac risk might even be harmed by inadvertent bradycardia and hypotension.6 Thus, novel cardioprotective strategies need to be considered that are of equal benefit to low and high risk patients. Volatile anesthetic preconditioning is such a promising new strategy in perioperative cardioprotection. However, interactions with beta-blockers and other cardiovascular medications, potentially abrogating preconditioning need to be considered when anesthetic preconditioning is to be utilized for cardioprotection. The experimental data and this interesting finding of the meta-analysis suggest that volatile anesthetic preconditioning and beta-blocker therapy are incompatible cardioprotective strategies. This might, among other factors, explain the limited effects of volatile anesthetics on mortality and perioperative myocardial infarction in certain patient populations. Further studies are needed to investigate the interactions between cardiovascular medications and volatile anesthetic preconditioning.