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CARDIOVASCULAR ANESTHESIOLOGY

Reactive Oxygen Species Mediate Sevoflurane- and Desflurane-Induced Preconditioning in Isolated Human Right Atria In Vitro

Jean-Luc Hanouz, MD, PhD^*, Lan Zhu, MD, Sandrine Lemoine, BSc, Charline Durand, BSc, Olivier Lepage, MD, Massimo Massetti, MD, PhD, André Khayat, MD, Benoît Plaud, MD, PhD^*, and Jean-Louis Gérard, MD, PhD^*

From the *Department of Anesthesiology; Laboratory of Experimental Anesthesiology and Cellular Physiology; and Department of Cardiac and Thoracic Surgery, CHU Caen, France.

Address correspondence and reprint requests to Dr. Jean-Luc Hanouz, Département d’Anesthésie-Réanimation, CHU de Caen, Avenue Côte de Nacre, 14033 Caen Cedex, France. Address e-mail to hanouz-jl{at}chu-caen.fr.

Abstract

BACKGROUND: We examined the role of reactive oxygen species (ROS) in sevoflurane- and desflurane-induced preconditioning on isolated human right atrial myocardium.

METHODS: We recorded isometric contraction of human right atrial trabeculae suspended in an oxygenated Tyrode’s solution (34°C, stimulation frequency 1 Hz). In all groups, a 30-min hypoxic period was followed by 60 min of reoxygenation. Ten minutes before hypoxia reoxygenation, muscles were exposed to 5 min of sevoflurane 2% or desflurane 6%. In separate groups, the sevoflurane 2% (Sevo + N-(2-mercaptopropionyl)-glycine [MPG]) or desflurane 6% (Des + MPG) was administered in the presence of 0.1 mM MPG, a ROS scavenger. The effect of 0.1 mM MPG alone was tested. Recovery of force after a 60-min reoxygenation period was compared between groups (mean ± sd).

RESULTS: Preconditioning with sevoflurane 2% (85% ± 4% of baseline) or desflurane 6% (86% ± 7% of baseline) enhanced the recovery of the force of myocardial contraction after 60 min reoxygenation compared with the control group (53% ± 11% of baseline, P < 0.001). This effect was abolished in the presence of MPG (56% ± 12% of baseline for Sevo + MPG, 48% ± 13% of baseline for Des + MPG). The effect of MPG alone on the recovery of force was not different from the control group (57% ± 7% of baseline versus 53% ± 11%; P = NS).

CONCLUSIONS: In vitro, sevoflurane and desflurane preconditioned human myocardium against hypoxia through a ROS-dependent mechanism.

Reactive oxygen species (ROS) have been shown to play a key role in ischemic preconditioning (IPC). During IPC, small amounts of ROS are released from mitochondria (1). Additionally, ROS scavengers abolish the protection afforded by IPC (1,2), whereas external administration of low concentrations of ROS before prolonged ischemia have been shown to induce a cardioprotective effect (1,3).

Volatile anesthetics have been shown to limit the extent of myocardial ischemic injury in various experimental models and species including human myocardium (4–7). The mechanisms underlying anesthetic preconditioning (APC) involve a complex system of intracellular signaling pathways, many of which are shared by IPC (6). As is the case with IPC, experimental evidence indicates that ROS are involved in APC. ROS scavenger attenuated isoflurane- and sevoflurane-induced preconditioning in rabbits (8,9). Additionally, isoflurane and sevoflurane were capable of producing small amounts of ROS that were correlated with a preconditioning effect (10,11).

The role of ROS in APC has not been studied in human myocardium. Contradictory results strongly suggest that APC could be dependent on species and experimental models. Isoflurane (12) and sevoflurane (13) failed to precondition rat heart and rabbit myocardium respectively, but they preconditioned dog and human myocardium (6). Finally, although ROS have been shown to be involved in isoflurane- and sevoflurane-induced preconditioning (10,11), their role in desflurane-induced preconditioning is unknown. Consequently, we performed an experimental study to test the hypothesis that ROS may be involved in sevoflurane- and desflurane-induced APC on isolated human myocardium exposed to simulated hypoxia reoxygenation.

METHODS

After the approval of local medical ethics committee and written inform consent, human right atrial trabeculae were obtained from patients scheduled for routine coronary artery bypass surgery or aortic valve replacement. The specimens were the normally discarded right atrial appendage removed during cannulation for cardiopulmonary bypass as previously described (7). All patients received total IV anesthesia with propofol and sufentanil. Patients with atrial dysrhythmia and those taking oral hypoglycemic medications were excluded from the study. Patients’ demographic data, preoperative drug treatment, and preoperative left ventricular ejection fraction are reported in Table 1.

Experimental Preparation
Trabeculae were suspended vertically between an isometric force transducer (UC3, Gould, Cleveland, OH) and a stationary stainless steel clip in a 200 mL jacketed reservoir filled with daily prepared Tyrode’s modified solution containing (mM) 120 NaCl, 3.5 KCl, 1.1 MgCl₂, 1.8 NaH₂PO₄, 25.7 NaHCO₃, 2.0 CaCl₂, and 5.5 glucose. The jacketed reservoir was maintained at 34°C using a thermostatic water circulator (Polystat micropros, Bioblock, Illkirch, France). The bathing solution was insufflated with carbogen (95% O₂–5% CO₂), resulting in a pH of 7.40 and a partial pressure of oxygen of 600 mm Hg. Isolated muscles were field-stimulated at 1 Hz by two platinum electrodes with rectangular wave pulses of 5 ms duration 20% above threshold (CMS 95107, Bionic Instrument, Paris, France).

Trabeculae were equilibrated for 60–90 min to allow stabilization of their optimal mechanical performance at the apex of the length-active isometric tension curve (L_max) and randomly assigned to one of six experimental groups. When several atrial trabeculae were dissected from one appendage they were included in different randomized experimental groups. The force developed was measured continuously, digitized at a sampling frequency of 400 Hz, and stored on a Writable Compact Disk for analysis (MacLab, AD Instrument, Sydney, Australia).

At the end of each experiment, the length and the weight of the muscle were measured. The muscle cross-sectional area (CSA) was calculated from its weight and length assuming a cylindric shape and a density of 1. To avoid core hypoxia, trabeculae included had to have a CSA <1.0 mm², a force of contraction (FoC) normalized per CSA >5.0 mN/mm², and a ratio of resting force/total force <0.45. We have previously shown that mechanical variables of isolated human trabeculae remain stable at least 2 h (7).

Experimental Protocol
In all experimental groups, hypoxia was performed by replacing 95% O₂–5% CO₂ with 95% N₂–5% CO₂ in the buffer for 30 min, followed by a 60 min oxygenated recovery period. In the control group (control; n = 10), muscles were exposed to a 30-min hypoxic period, followed by a 60-min oxygenated recovery period. In the APC groups, sevoflurane or desflurane was delivered to the organ bath by passing the insufflated 95% O₂–5% CO₂ gas first through a specific calibrated vaporizer. To minimize evaporation of anesthetic vapors, the jacketed reservoir was nearly hermetically sealed with a thin paraffin. Anesthetic concentrations in the gas phase were continuously measured with an infrared calibrated analyzer (Capnomac, Datex, Helsinki, Finland). After a 5 min exposure to 2% sevoflurane (n = 8) or to 6% desflurane (n = 8), a 10 min washout period was performed and muscles underwent the hypoxia-reoxygenation protocol. We studied the implication of ROS in sevoflurane- and desflurane-induced preconditioning using 0.1 mM N-(2-mercaptopropionyl)-glycine (MPG), a ROS scavenger administered 5 min before and throughout exposure to 2% sevoflurane (Sevo + MPG; n = 6) or to 6% desflurane (Des + MPG; n = 6). A MPG control group was included to study the effects of 10 min administration of 0.1 mM MPG (MPG; n = 6) prior the hypoxia-reoxygenation protocol. Concentrations of MPG between 0.1 and 0.3 mM have been shown to inhibit the ROS-mediated effect on isolated myocardium (14). MPG was purchased from ICN Pharmaceuticals (ICN Pharmaceuticals, Orsay, France), desflurane was purchased from Baxter (Baxter, Maurepas, France), and sevoflurane was purchased from Abbott France (Abbott, Rungis, France).

Statistical Analysis
Data are expressed as mean ± sd. Age, left ventricular ejection fraction, baseline values of main mechanical variables, and values of FoC at 60 min of reperfusion (FoC₆₀ end-point of the study) were compared by a one-way analysis of variance with Newman–Keuls post hoc analysis. Within-group data were analyzed over time using univariate analysis of variance for repeated-measures and Newman–Keuls post hoc analysis. All P values were two-tailed, and a P value <0.05 was required to reject the null hypothesis. Statistical analysis was performed using Statview 5 software (Deltasoft, Meylan, France).

RESULTS

Forty-four human right atrial trabeculae were obtained from 42 patients. Two atrial appendages enabled the dissection of two trabeculae. There were no differences in control values for L_max, CSA, resting force/total force, and FoC among all groups (Table 2). Six experiments (one in the sevoflurane group, one in the desflurane group, two in the sevoflurane + MPG group, one in the desflurane + MPG group, and one in the MPG group) were discarded because atrial trabeculae did not meet inclusion criteria. Mean patient age for the MPG group was higher compared with the desflurane and Des + MPG groups (Table 1). There was no difference in preoperative left ventricular ejection fraction and treatments among groups.

Effects of Hypoxia and Reoxygenation on Contractile Force
The time course of FoC for the control group is shown in Figure 1. Hypoxia induced a marked decrease in FoC. After 30 min of hypoxia, FoC was 13% ± 7% of baseline. Reoxygenation induced a partial recovery of FoC in the control group (FoC₆₀: 53% ± 11% of baseline).

View larger version (17K): [in this window] [in a new window]   Figure 1. Time course of force of contraction of isolated human right atrial trabeculae during a 30 min hypoxic challenge followed by 60-min reoxygenation period in control, desflurane, sevoflurane, Des + N-(2-mercaptopropionyl)-glycine (MPG), Sevo + MPG, and MPG, groups. Des + MPG = desflurane in the presence of MPG; Sevo + MPG = sevoflurane in the presence of MPG; WO = washout period. Data are mean ± sd. *P < 0.05 versus baseline value.

Five minute exposure to 2% sevoflurane (92% ± 10%; P = 0.09 versus baseline value), 6% desflurane (96% ± 9%; P = 0.21, versus baseline value), and to MPG (92% ± 11%; P = 0.11 versus baseline value) did not modify FoC. In contrast, in the presence of MPG, desflurane- (88% ± 11%; P < 0.05 versus baseline value), and sevoflurane-induced (87% ± 7%; P < 0.05 versus baseline value) decrease in FoC was significantly different from the baseline value but not from the other groups.

Sevoflurane- and Desflurane-Induced Preconditioning
Recovery of FoC₆₀ for each experimental group is shown in Figure 2. Recovery of FoC₆₀ was significantly increased by 5 min exposure to 2% sevoflurane (85% ± 4% vs 53% ± 11% of baseline; P < 0.001) and 6% desflurane (86% ± 7% vs 53% ± 11% of baseline; P < 0.001) before 30 min hypoxia. In the presence of MPG sevoflurane- (56% ± 12%, P = 0.61) and desflurane- (48% ± 13%, P = 0.43), induced enhanced recovery of FoC₆₀ was abolished compared with that observed at baseline in the control group (53% ± 11%). As shown in Figures 1 and 2, MPG (57% ± 7% vs 53% ± 11% of baseline; P = 0.44) did not modify the time course of FoC nor the recovery of FoC₆₀.

View larger version (11K): [in this window] [in a new window]   Figure 2. Recovery of force of contraction of isolated human right atrial trabeculae at the end of the 60-min reoxygenation period after the 30 min hypoxic challenge. These data correspond to the final data point in Figure 1. MPG = N-(2-mercaptopropionyl)-glycine; Des + MPG = desflurane in the presence of MPG; Sevo + MPG = sevoflurane in the presence of MPG. Data are mean ± sd. *P < 0.05 versus control, Des + MPG, Sevo + MPG, and MPG.

DISCUSSION

The present study shows that, in isolated human atrial myocardium, sevoflurane- and desflurane-induced preconditioning was inhibited by MPG suggesting a role for ROS as mediators of the cardioprotective signaling pathway triggered by volatile anesthetics.

It is now well reported that, in the experimental setting, anesthetics may trigger a preconditioning signal resulting in protection against the deleterious effects of myocardial ischemia and reperfusion (i.e., reduced infarct size, attenuated contractile dysfunction, and reduction in arrhythmias) (6). Importantly, APC might be effective in clinical use as suggested by several studies (4,5). Nevertheless, the mechanisms involved in APC have not been completely elucidated and the protective effect varies among different experimental models and among species (12,13,15). For example, isoflurane failed to provide a preconditioning effect in an isolated rat heart (12), but it has been observed in rabbit, dog, and human myocardial experimental models (6,13). Further, sevoflurane failed to limit ischemic myocardial injury in rabbit myocardium in vivo (15) but has been shown to provide preconditioning in whole animal dog and guinea pig models (6,16). These results clearly indicate species differences in APC emphasizing the need for studies on human myocardium (17). The present results confirm previous ones showing that brief exposure to sevoflurane at 2% and desflurane at 7% before a 30-min hypoxic period enhanced the recovery of FoC during the reoxygenation period in human atrial trabeculae (7,16). Mechanisms involved in APC in human myocardium include increased opening of adenosine triphosphate-sensitive potassium (K_ATP) channels, modulation of adenosine A1 receptors, and modulation of adrenoceptors (7,13,17).

There is evidence that volatile anesthetics cause the release of small amounts of ROS which may trigger APC. Müllenheim et al. (8) showed that MPG and another ROS scavenger Mn(III)tetrakis(4-benzoic acid) porphyrine chloride abolished the myocardial protective effect of isoflurane in rabbit hearts. Similarly, in isolated guinea pig hearts, sevoflurane-induced preconditioning was found to be inhibited by the combination of superoxide dismutase, catalase, and glutathione (9). The results of our investigation confirm and extend these findings and indicate that the ROS scavenger MPG abolished sevoflurane-induced preconditioning measured by the recovery of FoC in isolated human atrial trabeculae. The results further demonstrate that desflurane-induced preconditioning was also abolished by ROS scavenger. This may be important because the mechanisms of desflurane-induced preconditioning have been shown to involve adrenoceptors in contrast with other volatile anesthetics (7). Interestingly, -1 adrenoceptors pathway has also been shown to involve ROS which could activate the mitogen/extracellular signal-regulated kinase 1/2 pathway (18).

Our results indirectly imply that ROS may be involved in sevoflurane and desflurane induced APC. Other studies have shown that isoflurane and sevoflurane directly increase superoxide anion generation as detected by dihydroethidium fluorescence (10,11). Additionally, it has been shown that mitochondrial K_ATP channel activation by isoflurane participates in isoflurane-induced ROS generation (19), and that ROS generated during sevoflurane exposure precede translocation and activation of protein kinase C- (20). Little is known about the exact source and mechanism of ROS formation during the preconditioning anesthetic exposure. Several investigations showed that the mitochondrial electron transport chain Complex I and III are involved in isoflurane- and sevoflurane-induced ROS production (21,22). Although the role of ROS in APC has been widely studied, the involvement of reactive nitrogen species in the triggering pathway of APC has received less attention. Novalija et al. (9) have shown that reactive nitrogen species may participate in sevoflurane-induced preconditioning in isolated guinea pig hearts. The present study could not examine the role of reactive nitrogen species which could be better studied in experimental models with intact endothelial cells such as isolated hearts.

The downstream signal transduction pathways that may be modulated by ROS during myocardial preconditioning remain unclear. ROS have been shown to activate protein kinase C (23), mitogen-activated protein kinase family such as p38 mitogen-activated protein kinase (24) and extracellular signal-regulated kinase 1/2 (25), and G_i and G_o (26). Thus, ROS are a key step in the described reperfusion injury salvage kinase pathway involved in both preconditioning and postconditioning (27). Furthermore, the specific reactive molecule(s) that are generated during APC are not known. Superoxide, hydrogen peroxide, hydroxyl radical, and reactive nitrogen species have been shown to induce translocation and phosphorylation of protein kinase C or tyrosine kinase. In contrast to the generation of small amounts of ROS that may initiate myocardial ischemic protection, during the exposure phase, APC is also characterized by decreased ROS formation during the reperfusion phase. Novalija et al. (28) have shown that sevoflurane-induced preconditioning decreases ROS generation after ischemia reperfusion in mitochondria isolated upon initial reperfusion from guinea pig hearts.

The present findings should be interpreted within the constraints of several potential limitations. First, the effects of anesthetic drugs, diseases, or treatments received by the studied patients before obtaining the atrial specimens cannot be excluded. However, the patients included in this study are representative of the patients in whom APC may be useful. In clinical situations, the preoperative disease and/or their treatments would be present. Although mean patient age was higher in the MPG group as compared with Desflurane and Des + MPG group, it has been shown that age between 60 and 90 yr did not modify recovery of developed force after hypoxia reoxygenation, in isolated human myocardium (29). Second, the use of opioids during anesthesia of patients included in this study could have theoretically preconditioned the appendage. However, experimental studies were initiated at least 90 min after removal of the atrial appendage. Most importantly, comparisons have been made with control experiments. Third, rather than the true ischemia obtained by coronary occlusion, we used a 30 min hypoxic period to simulate ischemia. It has been shown that anoxia is as effective as ischemia in inducing myocardial preconditioning (30). Furthermore, this model has been shown to be useful to study volatile anesthetic-induced preconditioning in isolated human myocardium (7,16). Fourth, our experiments were performed at 34°C which may have decreased the effect of preconditioning (31). However, a moderate hypothermia may occur during surgical procedures.

In conclusion, we showed in the human atrial trabeculae model that ROS trigger sevoflurane- and desflurane-induced preconditioning. Knowledge of the mechanism of APC may help us to modify or mimic useful cardiac protective effects of anesthetics in the clinical setting.

Footnotes

Accepted for publication August 3, 2007.

Support was provided solely from Université de Caen Basse Normandie and Centre Hospitalier Universitaire de Caen.

The authors have no conflicts of interest to report.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Hanouz, J.-L. Articles by Gérard, J.-L. Search for Related Content PubMed Articles by Hanouz, J.-L. Articles by Gérard, J.-L. Related Collections Cardiovascular Mechanisms Pharmacology