| JOURNAL HOME | CME HOME | THIS MONTH | PAST ISSUES | ETOC | COLLECTIONS |
| AUTHORS | REVIEWERS | EDITORIAL BOARD | FEEDBACK | RSS | HELP |
 
|
|
|
||
|
|
Anesth Analg 2003;97:1370-1376 © 2003 International Anesthesia Research Society
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Several studies suggest that the cardioprotective effect of sevoflurane depends on protein kinase C (PKC) activation, mitochondrial K+ATP channel (mitoK+ATP) opening, and reactive oxygen species (ROS). However, evidence for their involvement was obtained in separate experimental models. Here, we studied the relative roles of PKC, mitoK+ATP, and ROS in sevoflurane-induced cardioprotection in one model. Rat trabeculae were subjected to simulated ischemia by applying metabolic inhibition (MI) through buffer containing NaCN, followed by 60-min reperfusion. Recovery of active force (Fa) was assessed as percentage of pre-MI force. In time controls, Fa amounted 60% ± 5% at the end of the experiment. The recovery of Fa after MI was reduced to 28% ± 5% (P = 0.045 versus time control), whereas sevoflurane reversed the detrimental effect of MI (Fa recovery, 67% ± 8%; P = 0.01 versus MI). The PKC inhibitor chelerythrine, the mitoK+ATP inhibitor 5-hydroxy decanoic, and the ROS scavenger N-(2-mercaptopropionyl)-glycine all completely abolished the protective effect of sevoflurane (recovery of Fa, 31% ± 8%, 33% ± 8%, and 24% ± 9% for chelerythrine, 5-hydroxy decanoic, and N-(2-mercaptopropionyl)-glycine, respectively). In conclusion, PKC activation, mitoK+ATP channel opening, and ROS production are all essential for sevoflurane-induced cardioprotection. These signaling events are arranged in series within a common signaling pathway, rather than in parallel cascades. Our findings implicate that the perioperative use of sevoflurane preserves cardiac function by preventing ischemia-reperfusion injury.
IMPLICATIONS: Protein kinase C, mitochondrial K+ATP channels and reactive oxygen species act within one downstream signaling pathway in mediating the cardioprotective effect of sevoflurane.
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Sevoflurane (sevo) has cardioprotective properties against perioperative ischemia and improved patient recovery after surgery (1–3). The cardioprotective effects of sevo and other volatile anesthetics depend on distinct downstream signaling and effector molecules, such as protein kinase C (PKC) and mitochondrial KATP channels (mitoK+ATP) (2–6). The activation of PKC in the cardioprotective effect of sevo was demonstrated in an isolated guinea pig heart model, whereas KATP channel activation by sevo was shown by means of the nonspecific KATP channel antagonist glyburide in pigs and dogs (2,4). Interestingly, more recent findings in rabbits also point to endogenous production of reactive oxygen species (ROS) in isoflurane-induced preconditioning (7).
Until now, most signal transduction processes underlying sevo-induced cardioprotection have been investigated in a variety of models, mostly focusing on singular elements in the preconditioning pathway. However, the interplay between individual elements in the protective downstream signaling cascade is as important as the individual roles of PKC, mitoK+ATP, and ROS. Therefore, we determined the relative contribution of PKC activation, the opening of the mitoK+ATP channels, and the endogenous production of ROS in sevo-induced preconditioning in one model, i.e., the isolated right ventricular rat trabecula. This model, which is extensively used in our laboratory, has the advantage that it is not limited by oxygen diffusion problems and has been proven suitable to study intracellular signaling events in combination with force of contraction (8–10). Applying metabolic inhibition (MI) by using cyanide was chosen to simulate the two main intracellular consequences of ischemia: adenosine triphosphate (ATP) depletion and Ca2+ overloading. Investigating the three signaling events, as mentioned above, within this well-defined functional, multicellular preparation provides the opportunity to assess their relative contribution to the preconditioning process. This may be the first step in unraveling the exact sequence of signaling molecules in this sevo-induced signal transduction cascade underlying cardioprotection.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The use of animals in this study was approved by the Institutional Animal Care and Use Committee. Male Wistar rats (275–420 g; n = 54) were anesthetized by pentobarbital sodium (60 mg/kg, intraperitoneally) and heparinized (1000 U, IV). Subsequently, the heart was excised and retrogradely perfused at room temperature with Tyrode solution (95% O2/ 5% CO2, with a pH value of 7.35). Standard solution contained (in mM): NaCl 120.0, KCl 5.0, CaCl2 1.0, MgSO4 1.22, NaH2PO4 1.99, NaHCO3 27.0, and glucose 10.1. Only during isolation of the trabecula was myocardial contraction prevented by 30 mM of 2,3-butanedione monoxime. A right ventricular trabecula, running from the atrioventricular ring to the free wall, was dissected. Subsequently, the trabecula was mounted between a force transducer (AE801, SensoNor, Norway), which was connected to a personal computer, and a micromanipulator in a closed, airtight muscle bath and superfused with standard solution. The trabecula was paced using 2 platinum electrodes (field stimulation, 5-ms duration) (8–10).
After mounting the trabeculae, the protocol started with a stabilization period of 45 min (27°C; 0.5 Hz). During the stabilization period, muscle diameter was measured using a microscope (50x magnification) using a calibrated reticule. The length of the trabeculae was determined by a force-length relation and set at an equivalent of 85% of the optimum sarcomere length, L0.85, as described by Schouten et al. (11). In the last phase of the stabilization period, the stimulation voltage was set at two times the stimulation threshold. After 45 min of stabilization, the muscle bath temperature was decreased to 24°C, which was maintained throughout the experiment, and the pacing frequency to 0.2 Hz. After a subsequent 10-min stabilization period, initial active force of contraction (Fa,start) and maximal force (Fmax,start) were determined. Fmax,start was determined (basal stimulation frequency of 0.2 Hz) using a postextrasystolic potentiation (PESP) protocol, as described previously (12). Briefly, PESP is based on the addition of an increasing number of multiple, extra-systolic contractions, which result in a gradual and maximal filling of the sarcoplasmic reticulum (SR) with Ca2+ and thus in the concurrent development of maximal contractile force. Preparations were excluded when they did not stabilize within the equilibration period, exhibited spontaneous contractions, or failed to show PESP.
Figure 1 displays an overview of the experimental protocol for the different experimental groups. Except for time controls (Time), trabeculae were subject to MI and 60 min of reperfusion. MI was achieved by exposure to standard solution without glucose and containing 2 mM of NaCN and an increase of the pacing frequency to 1 Hz. During MI, Fa decreased to zero, and a rigor contracture developed (10). Here, we used a rigor period of 30 min, and at the end of the rigor period, the superfusion and pacing frequency were switched back to control conditions. Subsequently, the trabeculae were superfused for 60 min, and the recovery of Fa, Fmax, and passive force were recorded. The recovery of force after reperfusion was expressed as the ratio of Fa and Fmax after reperfusion to Fa,start and Fmax,start (initial force values before MI), respectively. Isometric force was normalized to the cross-sectional area calculated from muscle diameters in two perpendicular directions measured at the end of each experiment. Figure 2 shows two typical recordings from an MI and preconditioning experiment. In the time control group, trabeculae were paced at 0.2 Hz and superfused with standard solution for an equal time period as the MI and preconditioning group.
|
|
During the preconditioning period, superfusion was switched to standard solution (95% O2/5% CO2). Sevo 3.8% was vaporized into the gas supply, and the buffer solution was equilibrated with the gas mixture (13). The concentration of the anesthetic was monitored using a calibrated anesthetic. In three distinct experimental groups, the PKC catalytic-site inhibitor chelerythrine (chel) (2 µM) (14), the highly selective mitoK+ATP channel blocker 5-hydroxy decanoic acid sodium (5-HD) (100 µM), and the ROS scavenger N-(2-mercaptopropionyl)-glycine (MPG) (300 µM) were applied. The inhibitors and scavenger were dissolved in water and remained present in the superfusion medium from the preincubation period until the onset of MI. In three additional control groups, the effects of chel, 5-HD, and MPG on recovery after MI were investigated without pretreatment of sevo (blocker controls). All chemicals were obtained from Sigma-Aldrich (Zwijndrecht, Netherlands).
Unless stated otherwise, the recovery of Fa is expressed as percentage of the initial value Fa,start at the start of the experiment. All data are expressed as mean ± SEM of six trabeculae. Between-group comparisons were performed using analysis of variance and evaluated with Tukey post hoc tests. Differences were considered to be significant at P < 0.05.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Muscle dimensions (cross-sectional area) and Fa,start were not different between groups (Table 1), although Fa,start varied between groups, being smallest in the sevo+MI+chel group (27.9 ± 5.2 mN/mm2) and largest in the MI+MPG group (48.8 ± 11.3 mN/mm2). Overall, passive force values at L0.85 before MI and after reperfusion were not different between groups (mean amounts to 1.5 ± 0.1 and 1.6 ± 0.2 mN/mm2, respectively; not significant). Furthermore, Fmax,start and the Fa at the end of the preincubation and washout phase were similar in all groups. Finally, in time controls the Fmax, start decreased from 63.0 ± 6.7 mN/mm2 (initial value) to 46.3 ± 7.9 mN/mm2 at the end of the experiment. MI worsened this decrease (54.8 ± 7.7 to 33.4 ± 7.9 mN/mm2), and preconditioning with sevo did not prevent this decrease in Fmax,start.
|
At the onset of MI, the force typically decreased to a lower level and decreased to zero, followed by a rapid increase in passive force (rigor state; Fig. 2; time scale of 155 min). Time to rigor (approximately 31 min) and maximal rigor force (approximately 117% of Fmax, start) were comparable in all groups (Table 1). The volume percentage of sevo in the vapor phase greater than the equilibrated solution was not different between groups.
Sevo depressed the force by approximately 20%, which was completely reversed in the washout period (Fig. 3). In time controls, the force at the end of the experiment amounted to 60% ± 5% of Fa,start. MI reduced the recovery of Fa to 28% ± 5%, which is significantly less than in time controls (P = 0.045). Pretreatment with sevo preserved Fa after MI and reperfusion to 67% ± 8%, which was significantly higher compared with the MI group (P = 0.01) and similar to time controls. Thus, the depressant effect of MI was completely counteracted by pretreatment with sevo.
|
Figure 4 shows the relative importance of PKC, mitoK+ATP channels, and ROS in the protective action of sevo (panel A). Recovery of Fa after preconditioning with sevo in the presence of the PKC inhibitor chel (31% ± 8%) was not different from MI alone (28% ± 5%). Furthermore, inhibition of mitoK+ATP channels by 5-HD (Sevo+MI+5-HD; Fa amounted 33% ± 8%) or ROS by MPG (Sevo+MI+MPG; Fa amounted 24% ± 9%) also abolished the sevo-induced cardioprotective effect after MI. In three control groups without administration of sevo, the effects of chel, 5-HD, and MPG alone on recovery of Fa after MI were assessed. After 60 min of reperfusion, Fa amounted to 32% ± 6%, 27% ± 7%, and 24% ± 6% for chel, 5-HD, and MPG, respectively. These values did not differ from recovery of Fa in the MI group.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
We demonstrated that sevo has potent cardioprotective properties because it completely restored Fa to time-control values after MI and reperfusion in isolated rat trabeculae. Furthermore, it is shown that the cardioprotective effect of sevo depends on PKC activation, the opening of mitoK+ATP channels, and the endogenous production of ROS. These results suggest that all three of these signaling events are active within the common intracellular signaling cascade of sevo-induced cardioprotection.
Pretreatment with sevo results in an improvement of postischemic contractile recovery in rat trabeculae, further strengthening clinical observations (1). Most volatile anesthetics render the heart resistant to the depressant effects of ischemia/reperfusion injury in a variety of in vivo and in vitro experimental models, with different outcome variables (15). In an in vivo dog model, isoflurane and desflurane improved postischemic contractile performance (4,5), and sevo (3) reduced infarct size. In contrast, Roscoe et al. (6) did not observe an improved postischemic contractile recovery in human trabeculae after preconditioning with halothane. The protective effects of sevo were also observed in perfused guinea pig hearts (2). Interestingly, the time point of administration determines the protection capacity against ischemia/reperfusion damage. Although application of sevo in the reperfusion period induces cardioprotective effects as well, postischemic contractile and metabolic recovery was significantly better in hearts that were preconditioned before ischemia (13).
We used right ventricular rat trabeculae to study the mechanisms underlying sevo-induced preconditioning. This well-defined model has been extensively applied in our laboratory, is not limited by oxygen diffusion, and can be used for intracellular signaling as well as for functional studies. Experiments were performed at 27°C to maintain a stable preparation over several hours and to prevent oxygen limitation (9–12). We used NaCN, a glucose-free buffer and an increased stimulation frequency, to induce simulated ischemia. NaCN induces ATP depletion and Ca2+ overloading, which both characterize ischemia. This model has been used in several studies performed by our group and provides similar results as compared with hypoxia-induced ischemia-reperfusion injury (9,10). We administered sevo as pretreatment before the simulated ischemia period, followed by a washout period. Thus, the negative inotropic effect of sevo on contractile force did not interfere with the MI period, and it can therefore be concluded that cardiodepression during MI is not the cause of sevo-induced cardioprotection. After 60 minutes of reperfusion, the recovery of force was sufficient to provide information about the ischemia-induced injury.
There was no significant difference in Fa between groups at the end of the washout period, indicating complete elimination of the anesthetic in the experimental setup before starting MI. In all groups, except for time-controls, Fmax was equally decreased, regardless of the specific treatment of the preparation. Thus, preconditioning with sevo improves Fa, but not Fmax, after MI. This suggests that the number of functional contractile filaments may be reduced after MI (i.e., necrosis). Furthermore, it implies that the saturation of force (Fa/Fmax) was less in all groups after MI, except for time controls and the sevo+MI group.
Chel, 5-HD, and MPG are common inhibitors for studying PKC, mitoK+ATP, and ROS, respectively, and are frequently used in studies dealing with ischemic and pharmacological preconditioning. Therefore, we used concentrations of these inhibitors that are comparable with concentrations used in other studies. The present study shows a role for PKC activation in the preconditioning process leading to sevo-induced cardioprotection. Toller et al. (4) showed that isoform-unspecific PKC inhibition by a small dose of bisindolylmaleimide produces cardioprotection, and isoflurane further enhances this protection. However, a large dose of bisindolylmaleimide alone did not prevent the cardioprotective effect of isoflurane. In addition, Cope et al. (15) reported that the protective effect of halothane in rabbits is abolished by chel.
There are strong indications that PKC activation during the preconditioning process opens mitoK+ATP channels through decreasing the ATP-binding affinity of these channels (16–18). Furthermore, the cardioprotective effects of sevo could be reversed by other nonselective inhibitors of the mitoK+ATP channel than used in this study (2,3,19). Direct evidence for sevo-induced opening of mitoK+ATP channels was obtained by Kohro et al. (20) in guinea pig myocytes. Here, evidence was obtained supporting these data because the specific mitoK+ATP channel inhibitor 5-HD abolished the protective effect of sevo entirely, whereas pretreatment with the inhibitor alone had no effect. The significance of mitoK+ATP channel opening for mitochondrial function and, more specifically, how this protects the myocardium against ischemic damage is not fully understood. However, from our data, it can be concluded that both PKC activation and mitoK+ATP channel opening are essential in the process of sevo-induced cardioprotection.
Evidence has accumulated suggesting that phosphorylation of the mitoK+atp channels by PKC reduces the affinity for ATP of these channels, thereby decreasing the threshold for mitoK+atp opening during intracellular ATP depletion. Liu et al. (21) showed that mitoK+ATP channels close quickly after the removal of the K+ATP channel opener diazoxide, whereas its preconditioning effect lasts for a long time. In addition, diazoxide-induced preconditioning was not abolished when blocking the mitoK+ATP channels after the administration of diazoxide itself (22). Furthermore, endogenous production of ROS is essential in diazoxide-induced protection (23). In fact, both the improved postischemic functional recovery and the reduction of infarct size after isoflurane preconditioning depend on the release of ROS (7). These findings are suggestive for the activation of a possible downstream mediator of the process. Our present findings provide evidence that scavenging of endogenous ROS production by MPG abolishes sevo-induced cardioprotection. However, the origin and nature of the ROS remains unknown because MPG is a thiol-compound, which scavenges both the hydroxyl and peroxynitrite radical.
Sources of ROS production during hypoxia are the mitochondria. 5-HD attenuates the production of ROS during diazoxide preconditioning, suggesting that mitoK+ATP channels induce ROS (23). The endogenous production of oxygen radicals may serve as a functional signaling molecule between the open state of the mitoK+ATP channels and the activation of PKC or an additional kinase system. The latter was supported by data showing that dimethyl-thiourea, a hydroxyl radical scavenger, inhibited an increased tyrosine kinase phosphorylation observed during ischemic preconditioning, whereas PKC activation and translocation were not affected (24). We suggest that sevo induces a limited, benign ROS production, which preserves the system against the subsequent detrimental amount of ROS production associated with ischemia-reperfusion protocols.
In the present study, the relative contribution of three known mediators of the cardioprotective process was assessed within one model. The cardioprotective effect of sevo was abolished by the inhibition of any one of these three mediators. Figure 5 represents the proposed mechanism underlying sevo-induced cardioprotection. PKC, mitoK+ATP, and ROS are all involved in sevo-induced cardioprotection, which suggests that the three signaling events are arranged in series within a common signaling pathway rather than in distinct, parallel cascades. However, it is also possible that sevo directly induces ROS, independent of PKC activation and mitoK+ATP channel opening. Furthermore, additional effects of sevo on the SR might directly preserve Ca2+ regulation of the cardiomyocyte and thus induce cardioprotection. Our suggestions are supported by a comparable relative effect of PKC, mitoK+ATP, and ROS inhibition on the cardioprotection induced by sevo, suggesting an equally important role of these three signaling molecules. Finally, the relatively new role for ROS as a signaling molecule in sevo-induced cardiac preconditioning provides new mechanistic insight into the intracellular actions of volatile anesthetics.
|
|
Acknowledgments |
|---|
Supported, in part, by the Institute for Cardiovascular Research Vrije Universiteit (ICaR-VU), Amsterdam, the Netherlands.
The support and contribution to our discussions of Willem J. van der Laarse, PhD, (Laboratory for Physiology, VUmc, Amsterdam, the Netherlands) has been greatly appreciated.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
- El Azab AS, Scheffer GJ, Rosseel PM, de Lange JJ. Induction and maintenance of anaesthesia with sevoflurane in comparison to high dose opioid during coronary artery bypass surgery. Eur J Anaesthesiol 2000; 17: 336–8.[Medline]
- Novalija E, Fujita S, Kampine JP, Stowe DF. Sevoflurane mimics ischemic preconditioning effects on coronary flow and nitric oxide release in isolated hearts. Anesthesiology 1999; 91: 701–12.[Web of Science][Medline]
- Toller WG, Kersten JR, Pagel PS, et al. Sevoflurane reduces myocardial infarct size and decreases the time threshold for ischemic preconditioning in dogs. Anesthesiology 1999; 91: 1437–46.[Web of Science][Medline]
- Toller WG, Montgomery MW, Pagel PS, et al. Isoflurane-enhanced recovery of canine stunned myocardium: role for protein kinase C? Anesthesiology 1999; 91: 713–22.[Web of Science][Medline]
- Toller WG, Gross ER, Kersten JR, et al. Sarcolemmal and mitochondrial adenosine triphosphate-dependent potassium channels: mechanism of desflurane-induced cardioprotection. Anesthesiology 2000; 92: 1731–9.[Web of Science][Medline]
- Roscoe AK, Christensen JD, Lynch C. Isoflurane, but not halothane, induces protection of human myocardium via adenosine A1 receptors and adenosine triphosphate-sensitive potassium channels. Anesthesiology 2000; 92: 1692–701.[Web of Science][Medline]
- Mullenheim J, Ebel D, Frabetadorf J, et al. Isoflurane preconditions myocardium against infarction via release of free radicals. Anesthesiology 2002; 96: 934–40.[Web of Science][Medline]
- de Ruijter W, Stienen GJ, van Klarenbosch J, de Lange JJ. Negative and positive inotropic effects of propofol via L-type calcium channels and the sodium-calcium exchanger in rat cardiac trabeculae. Anesthesiology 2002; 97: 1146–55.[Medline]
- Musters RJ, van der Meulen ET, Zuidwijk M, et al. PKC-dependent preconditioning with norepinephrine protects sarcoplasmic reticulum function in rat trabeculae following metabolic inhibition. J Mol Cell Cardiol 1999; 31: 1083–94.[Web of Science][Medline]
- Musters RJ, van der Meulen ET, Van der Laarse WJ, van Hardeveld C. Norepinephrine pretreatment attenuates Ca2+ overloading in rat trabeculae during subsequent metabolic inhibition: improved contractile recovery via an alpha 1-adrenergic, PKC-dependent signaling mechanism. J Mol Cell Cardiol 1997; 29: 1341–54.[Web of Science][Medline]
- Schouten VJ, Allaart CP, Westerhof N. Effect of perfusion pressure on force of contraction in thin papillary muscles and trabeculae from rat heart. J Physiol 1992; 451: 585–604.
[Abstract/Free Full Text] - Schouten VJ, van Deen JK, de Tombe P, Verveen AA. Force-interval relationship in heart muscle of mammals: a calcium compartment model. Biophys J 1987; 51: 13–26.[Web of Science][Medline]
- Varadarajan SG, An J, Novalija E, Stowe DF. Sevoflurane before or after ischemia improves contractile and metabolic function while reducing myoplasmic Ca(2+) loading in intact hearts. Anesthesiology 2002; 96: 125–33.[Web of Science][Medline]
- Liu Y, Cohen MV, Downey JM. Chelerythrine, a highly selective protein kinase C inhibitor, blocks the anti-infarct effect of ischemic preconditioning in rabbit hearts. Cardiovasc Drugs Ther 1994; 8: 881–2.[Web of Science][Medline]
- Cope DK, Impastato WK, Cohen MV, Downey JM. Volatile anesthetics protect the ischemic rabbit myocardium from infarction. Anesthesiology 1997; 86: 699–709.[Web of Science][Medline]
- Sato T, O’Rourke B, Marban E. Modulation of mitochondrial ATP-dependent K+ channels by protein kinase C. Circ Res 1998; 83: 110–4.
[Abstract/Free Full Text] - Wang Y, Hirai K, Ashraf M. Activation of mitochondrial ATP-sensitive K+ channel for cardiac protection against ischemic injury is dependent on protein kinase C activity. Circ Res 1999; 85: 731–41.
[Abstract/Free Full Text] - Wang Y, Ashraf M. Role of protein kinase C in mitochondrial KATP channel-mediated protection against Ca2+ overload injury in rat myocardium. Circ Res 1999; 84: 1156–65.
[Abstract/Free Full Text] - Mathur S, Farhangkhgoee P, Karmazyn M. Cardioprotective effects of propofol and sevoflurane in ischemic and reperfused rat hearts: role of K(ATP) channels and interaction with the sodium-hydrogen exchange inhibitor HOE 642 (cariporide). Anesthesiology 1999; 91: 1349–60.[Web of Science][Medline]
- Kohro S, Hogan QH, Nakae Y, et al. Anesthetic effects on mitochondrial ATP-sensitive K channel. Anesthesiology 2001; 95: 1435–40.[Web of Science][Medline]
- Liu Y, Sato T, O’Rourke B, Marban E. Mitochondrial ATP-dependent potassium channels: novel effectors of cardioprotection? Circulation 1998; 97: 2463–9.
[Abstract/Free Full Text] - Pain T, Yang XM, Critz SD, et al. Opening of mitochondrial K(ATP) channels triggers the preconditioned state by generating free radicals. Circ Res 2000; 87: 460–6.
[Abstract/Free Full Text] - Forbes RA, Steenbergen C, Murphy E. Diazoxide-induced cardioprotection requires signaling through a redox-sensitive mechanism. Circ Res 2001; 88: 802–9.
[Abstract/Free Full Text] - Das DK, Maulik N, Sato M, Ray PS. Reactive oxygen species function as second messenger during ischemic preconditioning of heart. Mol Cell Biochem 1999; 196: 59–67.[Web of Science][Medline]
This article has been cited by other articles:
|
|
 |
|
  S. Lorsomradee, S. Cromheecke, S. Lorsomradee, and S. G De Hert Cardioprotection with Volatile Anesthetics in Cardiac Surgery Asian Cardiovasc Thorac Ann, June 1, 2008; 16(3): 256 - 264. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Bouwman, R. J. P. Musters, B. J. van Beek-Harmsen, J. J. de Lange, R. R. Lamberts, S. A. Loer, and C. Boer Sevoflurane-induced cardioprotection depends on PKC-{alpha} activation via production of reactive oxygen species Br. J. Anaesth., November 1, 2007; 99(5): 639 - 645. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Bouwman, F. N. G. van't Hof, W. de Ruijter, B. J. van Beek-Harmsen, R. J. P. Musters, J. J. de Lange, and C. Boer The mechanism of sevoflurane-induced cardioprotection is independent of the applied ischaemic stimulus in rat trabeculae Br. J. Anaesth., September 1, 2006; 97(3): 307 - 314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Symons and P. S. Myles Myocardial protection with volatile anaesthetic agents during coronary artery bypass surgery: a meta-analysis Br. J. Anaesth., August 1, 2006; 97(2): 127 - 136. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
