Special Section: Anesthetic Preconditioning
Mechanisms of Desflurane-induced Preconditioning in Isolated Human Right Atria In Vitro
Hanouz, Jean-Luc M.D, Ph.D.*; Yvon, Alexandra B.Sc.†; Massetti, Massimo M.D.‡; Lepage, Olivier M.D.‡; Babatasi, Gérard M.D., Ph.D.‡; Khayat, André M.D.§; Bricard, Henri M.D.∥; Gérard, Jean-Louis M.D., Ph.D.#
Background: The authors examined the role of adenosine triphosphate-sensitive potassium (KATP) channels, adenosine A1 receptor, and α and β adrenoceptors in desflurane-induced preconditioning in human myocardium, in vitro.
: The authors recorded isometric contraction of human right atrial trabeculae suspended in oxygenated Tyrode's solution (34°C; stimulation frequency, 1 Hz). Before a 30-min anoxic period, 3, 6, and 9% desflurane was administered during 15 min. Desflurane, 6%, was also administered in the presence of 10 μm glibenclamide, a KATP
channels antagonist; 10 μm HMR 1098, a sarcolemmal KATP
channel antagonist; 800 μm 5-hydroxy-decanoate (5-HD), a mitochondrial KATP
channel antagonist; 1 μm phentolamine, an α-adrenoceptor antagonist; 1 μm propranolol, a β-adrenoceptor antagonist; and 100 nm 8-cyclopentyl-1,3-dipropylxanthine (DPX), the adenosine A1
receptor antagonist. Developed force at the end of a 60-min reoxygenation period was compared (mean ± SD).
: Desflurane at 3% (95 ± 13% of baseline), 6% (86 ± 6% of baseline), and 9% (82 ± 6% of baseline) enhanced the recovery of force after 60 min of reoxygenation as compared with the control group (50 ± 11% of baseline). Glibenclamide (60 ± 12% of baseline), 5-HD (57 ± 21% of baseline), DPX (63 ± 19% of baseline), phentolamine (56 ± 20% of baseline), and propranolol (63 ± 13% of baseline) abolished desflurane-induced preconditioning. In contrast, HMR 1098 (85 ± 12% of baseline) did not modify desflurane-induced preconditioning.
Conclusions: In vitro, desflurane preconditions human myocardium against simulated ischemia through activation of mitochondrial KATP channels, adenosine A1 receptor, and α and β adrenoceptors.
MYOCARDIAL ischemic preconditioning, i.e.
, pretreatment with transient ischemia, initially referred to the reduction in infarct volume 1
following a sustained ischemia, but its definition has been extended to include the beneficial effects on ischemia- and reperfusion-induced myocardial stunning. 2,3
The involvement of adenosine triphosphate-sensitive potassium (KATP
) channels, especially mitochondrial ones (mitoKATP
), has been shown using selective antagonists or openers. 4,5
Furthermore, stimulation of various sarcolemmal receptors, such as adenosine subtype 1 (A1
) receptor, 6
α and β adrenoceptors, 7,8
and δ-opioid receptor, 9
has been shown to mimic ischemic preconditioning.
A growing body of evidence indicates that volatile anesthetics may precondition the myocardium against ischemia and infarction. 10–14
Isoflurane-induced preconditioning of the myocardium has been related to the activation of KATP
stimulation of adenosine A1
and mechanogated channels. 12
Recently, sevoflurane and desflurane have been shown to precondition canine myocardium in vivo
through activation of KATP
Because we have recently shown that desflurane may induce intramyocardial catecholamines release in human myocardium in vitro
we tested the hypothesis that desflurane may also precondition isolated human myocardium through stimulation of α and β adrenoceptors. Furthermore, because halothane has been shown to protect rabbit 16
and rat 17
but not human 11
myocardium against ischemia and because species differences remain a critical issue in experimental studies, we reexamined the involvement of KATP
channels and adenosine A1
receptor in desflurane-induced preconditioning of human myocardium in vitro
Materials and Methods
After approval of the local medical ethics committee (Caen, France), right atrial appendages were obtained during cannulation for cardiopulmonary bypass from patients scheduled for routine coronary artery bypass surgery or aortic valve replacement. All patients received midazolam or propofol, sufentanil, etomidate, pancuronium, and isoflurane. Patients with atrial arrhythmia and those who were taking oral hypoglycemic medications were excluded from the study.
Right atrial trabeculae (one to two per appendage) were dissected and suspended vertically between an isometric force transducer (UC3; Gould, Cleveland, OH) and a stationary stainless clip in a 200-ml jacketed reservoir filled with daily prepared Tyrode's modified solution containing 120 mm NaCl, 3.5 mm KCl, 1.1 mm MgCl2, 1.8 mm NaH2PO4, 25.7 mm NaHCO3, 2.0 mm CaCl2, and 11 mm glucose. The jacketed reservoir was maintained at 34°C with use of a thermostatic water circulator (Polystat micropros; Bioblock, Illkirch, France). The bathing solution was bubbled with carbogen (95% O2–5% CO2), resulting in a pH of 7.40 and a partial pressure of oxygen of 600 mmHg. 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 (Lmax). At the end of the stabilization period, trabeculae were randomized to experimental groups detailed below. The force developed was measured continuously, digitized at a sampling frequency of 400 Hz, and stored on a Writeable Compact Disc 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 was calculated from its weight and length assuming a cylindric shape and a density of 1. To avoid core hypoxia, trabeculae included in the study should have a cross-sectional area less than 1.0 mm2, an active isometric force normalized per cross-sectional area (AF) greater than 5.0 mN/mm2, and a ratio of resting force/total force (RF/TF) less than 0.45.
In a time control group (n = 10), we measured the AF of isolated human atrial trabeculae every 10 min during 120 min.
In all other groups, ischemia—reperfusion was simulated 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 (I-R protocol).
In the control group (control; n = 11) muscles were exposed to the I-R protocol alone. Anoxic preconditioning (APC; n = 6) was induced by a 4-min anoxic period followed by a 7-min oxygenated period before the I-R protocol. 9,11
The mechanisms involved in APC were studied by 15 min of pretreatment with 10 μm glibenclamide (n = 7), a nonselective KATP
channel antagonist; 10 μm HMR 1098 (n = 6), a selective sarcolemmal KATP
channel antagonist; 800 μm 5-hydroxydecaoate (5-HD; n = 7), a selective mitochondrial KATP
channel antagonist; 0.1 μm 8-cyclopentyl-1,3-dipropylxanthine (DPX; n = 6), a selective adenosine A1
receptor antagonist; 1 μm propranolol (n = 6), a β-adrenoceptor antagonist; and 1 μm phentolamine (n = 6), an α-adrenoceptor antagonist. Concentrations used have been validated in previous experimental studies in human myocardium in vitro
In the desflurane treatment groups, desflurane was delivered to the organ bath by bubbling with 95% O2–5% CO2 passing through a specific calibrated vaporizer. Desflurane concentration in the carrier gas phase was measured with an infrared calibrated analyzer (Capnomac; Datex, Helsinki, Finland). After a 15-min exposure to 3% (n = 5), 6% (n = 6), and 9% (n = 5) desflurane, muscles underwent the I-R protocol. Mechanisms involved in desflurane-induced preconditioning were studied with 6% desflurane. Thus, 6% desflurane was administered after 15 min of pretreatment with 10 μm glibenclamide (n = 6), 10 μm HMR 1098 (n = 6), 800 μm 5-HD (n = 6), 10 nm DPX (n = 6), 1 μm propranolol (n = 6), and 1 μm phentolamine (n = 6).
In additional groups, the I-R protocol was performed after 15 min of pretreatment with 10 μm glibenclamide (n = 4), 10 μm HMR 1098 (n = 4), 800 μm 5-HD (n = 4), 0.1 μm DPX (n = 4), 1 μm propranolol (n = 4), and 1 μm phentolamine (n = 4).
Glibenclamide, 5-HD, DPX, and phentolamine were purchased from ICN Pharmaceuticals (Orsay, France), and desflurane was purchased from GlaxoWellcome (Marly-le-Roi, France). HMR 1098 was a gift from Aventis Pharma (Frankfurt am Main, Germany).
Data are expressed as mean ± SD. Baseline values of main mechanical parameters and values of AF at 60 min of reperfusion were compared by a univariate analysis of variance (ANOVA). If an F value was less than 0.05, Newman-Keuls post hoc analysis was used. Within-group data were analyzed over time using univariate ANOVA for repeated-measures and Newman-Keuls post hoc analysis. All P values were two-tailed, and a P value of less than 0.05 was required to reject the null hypothesis. Statistical analysis was performed using Statview 5 software (Deltasoft, Meylan, France).
One hundred forty-two human right atrial trabeculae were studied. There were no differences in baseline values for Lmax
, cross-sectional area, RF/TF, and AF among all groups (table 1
Stability with Time of Isolated Human Atrial Trabeculae
In the time control group, AF slightly decreased with time (fig. 1
). This decrease became significant at 80 min (AF: 93 ± 7% of baseline;P
< 0.05). At 120 min, AF was 90 ± 10% of baseline. Resting force was not significantly modified with time and was 97 ± 10% of baseline at 120 min.
Effects of Simulated Ischemia and Reperfusion on Contractile Force of Human Right Atrial Trabeculae
shows the time course of AF for the control group. Simulated ischemia induced a marked decrease in AF. After 30 min of simulated ischemia, AF was 14 ± 10% of baseline. The 60-min reoxygenation period resulted in a recovery of AF at 50 ± 11% of baseline (figs. 1 and 2
Effects of Glibenclamide, 5-HD, HMR 1098, DPX, Propranolol, and Phentolamine on Simulated Ischemia-Reperfusion
The decease in AF induced by pretreatment with glibenclamide (AF: 94 ± 4% of baseline), 5-HD (AF: 94 ± 1% of baseline), HMR 1098 (AF: 86 ± 12% of baseline), DPX (AF: 97 ± 3% of baseline), propranolol (AF: 89 ± 4% of baseline), and phentolamine (AF: 96 ± 2% of baseline) was not different among groups. As shown in figure 1
the time course of AF in the control group was not modified by 15 min of pretreatment with glibenclamide, 5-HD, HMR 1098, DPX, propranolol, and phentolamine. The recovery of AF at 60 min of reoxygenation measured in the control group (50 ± 11% of baseline) was not different from groups pretreated with glibenclamide (61 ± 7% of baseline), 5-HD (56 ± 11% of baseline), HMR 1098 (62 ± 6% of baseline), DPX (47 ± 4% of baseline), propranolol (53 ± 15% of baseline), and phentolamine (58 ± 8% of baseline).
Mechanisms of Anoxic Preconditioning on Human Right Atrial Trabeculae
shows the time course of AF for APC group. The 4-min anoxic challenge induced a marked decrease in AF (37 ± 16% of baseline) followed by complete recovery after 7 min of reoxygenation (107 ± 5% of baseline). In the APC group, AF after 30 min of simulated ischemia was 22 ± 10% of baseline. At the end of the 60-min reoxygenated period, the recovery of AF in the APC group was significantly greater than that measured in the control group (91 ± 3 vs.
50 ± 11% of baseline;P
As shown in figure 3
, the enhanced recovery of AF induced by APC was significantly decreased by pretreatment with glibenclamide (50 ± 11% of baseline), HMR 1098 (59 ± 15% of baseline), 5-HD (56 ± 19% of baseline), and DPX (63 ± 16% of baseline) and was no more different from the recovery of AF measured in the control group. In contrast, phentolamine (90 ± 19% of baseline) and propranolol (97 ± 6% of baseline) did not modify the enhanced recovery of AF induced by APC (fig. 3
Direct Inotropic Effects of Desflurane
Desflurane at 3% (93 ± 2% of baseline;P
< 0.05), 6% (87 ± 12% of baseline;P
< 0.05), and 9% (76 ± 5% of baseline;P
< 0.05) induced a dose-dependent decrease in AF. At a concentration of 6%, the desflurane-induced decrease in AF was not different among groups pretreated with glibenclamide (AF: 90 ± 7% of baseline), 5-HD (AF: 78 ± 6% of baseline), HMR 1098 (AF: 77 ± 10% of baseline), DPX (AF: 89 ± 4% of baseline), propranolol (AF: 72 ± 8% of baseline), and phentolamine (AF: 67 ± 15% of baseline). As shown in figure 4
, the decrease in AF induced by 6% desflurane was significantly greater in the presence of propranolol and phentolamine.
Effects of Desflurane on Simulated Ischemia-Reperfusion
As depicted in figure 5
, 15 min of exposure to desflurane at 3% (AF: 86 ± 6% of baseline), 6% (AF: 5 ± 13% of baseline), and 9% (AF: 82 ± 6% of baseline) prior to the 30-min anoxic period resulted in a significant increase in the recovery of AF after 60 min of reoxygenation as compared with the control group (AF: 50 ± 11% of baseline). Recovery of AF at 60 min of reoxygenation measured in the 3, 6, and 9% desflurane groups was not different from that measured in APC group (fig. 5
Pretreatment with glibenclamide (60 ± 12% of baseline), 5-HD (57 ± 21% of baseline), DPX (63 ± 19% of baseline), phentolamine (56 ± 20% of baseline), and propranolol (63 ± 13% of baseline) abolished desflurane-induced enhanced recovery of AF. In contrast, pretreatment with HMR 1098 (85 ± 12% of baseline) did not modify the enhanced recovery of AF induced by desflurane (fig. 6
The main results of our study are as follows: brief exposure to desflurane (3, 6, and 9%) preconditions isolated human right atrial myocardium against 30 min of simulated ischemia; mechanisms involved in desflurane-induced preconditioning are opening of mitochondrial KATP channels and stimulation of adenosine A1 receptor and α and β adrenoceptors.
Strong evidence supports the cardioprotective effects of volatile anesthetics against prolonged ischemia. Isoflurane has been shown to decrease infarct size in canine myocardium in vivo10
and to improve functional recovery of isolated human myocardium. 11
Recently, sevoflurane and desflurane have been shown to exert similar cardioprotective effects in dogs. 13,14
channels have been shown to play a pivotal role in mediating anesthetic-induced preconditioning. 10–14
It has been suggested that activation of both sarcolemmal KATP
) and mitoKATP
could be involved in the cardioprotection conferred by volatile anesthetics. 14
Furthermore, the participation of adenosine A1
receptor stimulation and mechanogated channel activation has recently been suggested in isoflurane-induced preconditioning. 11,12
The present results confirm and extend findings of Toller et al.
who showed that brief exposure to desflurane exerts cardioprotective effects against irreversible ischemia. Our study showed that 15 min of exposure to desflurane prior to 30 min of simulated ischemia enhanced contractile recovery of isolated human myocardium during the reoxygenation period. In addition, we showed that this effect was blocked by glibenclamide, indicating that opening of KATP
channels was implicated. Furthermore, specific blockade of mitoKATP
channels with 5-HD abolished desflurane-induced preconditioning, suggesting that opening of mitoKATP
channels is involved in desflurane-induced preconditioning. In contrast, specific blockade of sarcKATP
channels with HMR 1098 did not abolished desflurane-induced preconditioning but abolished APC. These results suggest that opening of sarcKATP
is involved in APC but not in desflurane-induced preconditioning. Although current opinion favors a predominant role for mitoKATP
channels in ischemic preconditioning, there is evidence demonstrating that sarcKATP
channels are important mediators of protection during the reoxygenation phase of injury. 19,20
At this time, the precise role and timing of activation of sarcKATP
channels during ischemic preconditioning remains unresolved. The results of Toller et al.14
showing that both mitoKATP
channels were implicated in desflurane-induced preconditioning are not in accordance with our results showing that the specific inhibition of sarcKATP
channels failed to abolished desflurane-induced preconditioning. This discrepancy may be related to major differences in experimental models. First, it should be emphasized that HMR 1098 should be an effective blocker of sarcKATP
channels at 10 μm since its IC50
value has been reported at 0.8 μm. 20,21
Thus, an HMR 1098 concentration of 10 μm has been used to block more than 90% of sarcKATP
channels in various experimental models. 18–21
Second, Toller et al.14
measured myocardial infarct size after 60 min of coronary artery occlusion and 3 h of reperfusion, whereas we measured recovery of force of contraction in isolated myocardium after 30 min of anoxia and 60 min of reoxygenation. Recent findings suggest distinct roles of sarcKATP
channels in myocardial ischemic preconditioning benefits in infarct volume and contractile recovery. 19,20
Third, we administered KATP
channels blockers prior to the administration of desflurane, whereas Toller et al.14
channels blockers prior to and during the administration of desflurane. The timing of pharmacologic agent administration has been suggested to be critical in the preconditioning phenomenon. 7,22
Fourth, interspecies differences may be a factor that helps to explain the different results. Thus, halothane has been shown to precondition rabbit 16
but not rat 17
and human 11
myocardium, and isoflurane has been shown to precondition rabbit 12
and human 11
but not rat 23
myocardium. Finally, differences between atrial and ventricular myocardium, influence of surgical stress, and barbiturate anesthesia in dogs cannot be ruled out.
The opening of KATP
channels has been shown to be an important mediator of ischemic and pharmacologic preconditioning. 3–6
Initially, it has been proposed that the decrease in action potential duration induced by opening of sarcKATP
resulted in better preservation of energy stores and suppression of deleterious downstream events, such as Ca2+
overload. However, a lack of correlation between the extent of action potential shortening and the reduction of infarct size has been shown. 24
Furthermore, cardioprotection conferred by KATP
channel openers has been shown to occur on quiescent myocardium. 18
The participation of mitoKATP
in ischemic preconditioning has been supported by numerous studies using specific antagonists or openers. 4,5,18
The mechanism of mitoKATP
-induced cardioprotection may involve alterations in mitochondrial Ca2+
handling, the optimization of energy production, and modulation of reactive oxygen species during ischemia or reperfusion. The precise role and importance of sarcKATP
during ischemic preconditioning remain unresolved. At the present time, the influence of volatile anesthetics on KATP
channel function has been poorly studied. Recently, Roscoe et al.11
showed that isoflurane does not modify sarcolemmal KATP
activation, whereas halothane partially blocked it in isolated human myocytes. These findings suggest that cardioprotective effects of isoflurane do not implicate a direct effect on sarcKATP
channel function but rather an effect on mitoKATP
and upstream intermediates, such as G protein-coupled receptors and PKC. Thus, it has been shown that volatile anesthetic-induced cardioprotection was attenuated by adenosine A1
receptor antagonist 11,16
and PKC inhibitors. 25
In addition, it has recently been shown that activation of Gi
proteins was implicated in isoflurane-induced preconditioning. 26
Further studies are needed to determine the precise effects of volatile anesthetics on KATP
channels and signaling pathways leading to the preconditioned state.
This is the first study showing that specific blockade of adenosine A1
receptors with DPX abolishes the desflurane-enhanced postischemic recovery of force. Previous results showed that cardioprotection conferred by isoflurane was mediated through activation of adenosine A1
suggesting a role of adenosine in volatile anesthetic-induced preconditioning. However, further studies are required to elucidate the mechanisms through which volatile anesthetics interact with adenosine receptors.
Our findings show that specific blockade of α and β adrenoceptors abolishes the desflurane-enhanced postischemic contractile function recovery. These results strongly suggest that stimulation of α and β adrenoceptors plays a role in desflurane-induced preconditioning. In contrast to other volatile anesthetics, desflurane has been reported to induce sympathetic activation in healthy volunteers 27
but also to release intrinsic store of catecholamines in isolated rat 28
and human 15
myocardium. A growing body of evidence suggests that stimulation of α1
adrenoceptors could mediate ischemic preconditioning in human myocardium. 7,29
However, Loubani et al.7
showed that activation of α1
adrenoceptors before ischemia is protective but is detrimental during ischemia. Recently, involvement of the β-adrenergic signal transduction pathway in ischemic preconditioning has been suggested, 30
and isoproterenol has been shown to precondition isolated rat heart through activation of PKC. 8
The main advantage of isolated human preparations in studying myocardial preconditioning is that the effect of variable myocardial collateral flow, which may occur in in vivo
models, could be eliminated. However, our results must be interpreted within the constraints of several possible limitations. First, the effects of anesthetics drugs, diseases, or treatments received by the patients cannot be eliminated. Therefore, patients taking oral hypoglycemic medications were excluded from the study. Furthermore, we have previously reported that preoperative treatment, such as β-adrenergic blocking drugs, do not mask desflurane-induced adrenoceptor stimulation. 15
The use of isoflurane and opioids during anesthesia of patients included in this study could have theoretically precondition the appendage. However, in vitro
studies were initiated at least 90 min after removal of the atrial appendage. Most importantly, comparisons have been made with control experiments. Nevertheless, a superimposed effect of opioids or isoflurane used during the surgical procedure cannot be ruled out. Second, rather than the true ischemia obtained by coronary occlusion, we used 30 min of anoxic superfusion to simulate ischemia. However, it has been shown in various experimental models that anoxia is as effective as ischemia in inducing preconditioning. 31
Third, we measured postischemic contractile function recovery but not infarct size. However, it has been shown that the improved recovery of contractile function produced by preconditioning was proportional to reduced infarct size. 32
In addition, our results, as well as previous ones, showed that this model provides a useful tool to study the mechanisms involved in ischemic preconditioning in human myocardium. 2,3,11
Fourth, our experiments were performed at 34°C, which may have decreased KATP
channel sensitivity 33
and the effect of preconditioning. 34
However, during surgical procedures, moderate hypothermia may occur in patients.
In conclusion, desflurane exerts a cardioprotective effect in anoxic-challenged isolated human right atrial myocardium. This effect involves, at least in part, mitoKATP channels, and stimulation of adenosine A1 receptor and α and β adrenoceptors.
1. Murry CE, Jennings RB, Reimer KA: Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. Circulation 1986; 74: 1124–36
2. Speechly-Dick ME, Grover GJ, Yellon DM: Does ischemic preconditioning in the human involve protein kinase C and the ATP-dependent K+ channel? Studies of contractile function after simulated ischemia in an atrial in vitro model. Circ Res 1995; 77: 1030–5
3. Walker DM, Walker JM, Pugsley WB, Pattison CW, Yellon DM: Preconditioning in isolated superfused human muscle. J Mol Cell Cardiol 1995; 27: 1349–57
4. O'Rourke B: Myocardial KATP channels in preconditioning. Circ Res 2000; 87: 845–55
5. Garlid KD, Paucek P, Yarov-Yarovoy V, Murray HN, Darbenzio RB, D'Alonzon AJ, Lodge NJ, Smith MA, Grover GJ: Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP-sensitive K+ channels Possible mechanism of cardioprotection. Circ Res 1997; 81: 1072–82
6. Cleveland JC, Meldrum DR, Rowland RT, Banerjee A, Harken AH: Adenosine preconditioning of human myocardium is dependent upon the ATP-sensitive K+ channel. J Mol Cell Cardiol 1997; 29: 175–82
7. Loubani M, Galinanes M: Alpha1-adrenoceptors during simulated ischemia and reoxygenation of the human myocardium: Effect of the dose and time of administration. J Thorac Cardiovasc Surg 2001; 122: 103–12
8. Miyawaki H, Ashraf M: Isoproterenol mimics calcium preconditioning-induced protection against ischemia. Am J Physiol 1997; 272: H927–36
9. Bell SP, Sack MN, Patel A, Opie LH, Yellon DM: Delta opioid receptor stimulation mimics ischemic preconditioning in human heart muscle. J Am Coll Cardiol 2000; 36: 2296–302
10. Kersten JR, Schmeling TJ, Hettrick DA, Pagel PS, Gross GJ, Warltier DC: Mechanism of myocardial protection by isoflurane: Role of adenosine triphosphate–regulated potassium (KATP) channels. A nesthesiology 1996; 85: 794–807
11. 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. A nesthesiology 2000; 92: 1692–701
12. Piriou V, Chiari P, Knezynski S, Bastien O, Loufoua J, Lehot JJ, Foëx P, Annat G, Ovize M: Prevention of isoflurane-induced preconditioning by 5-hydroxydecanoate and gadolinium. A nesthesiology 2000; 93: 756–64
13. Toller WG, Kersten JR, Pagel PS, Hettrick DA, Warltier DC: Sevoflurane reduces myocardial infarct size and decreases the time threshold for ischemic preconditioning in dogs. A nesthesiology 1999; 91: 1437–46
14. Toller WG, Gross ER, Kersten JR, Pagel PS, Gross GJ, Warltier DC: Sarcolemmal and mitochondrial adenosine triphosphate-dependent potassium channels: Mechanism of desflurane-induced cardioprotection. A nesthesiology 2000; 92: 1731–9
15. Hanouz JL, Masseti M, Guesne G, Chanel S, Babatasi G, Rouet R, Ducouret P, Khayat A, Galateau F, Bricard H, Gérard JL:In vitro effects of desflurane, sevoflurane, isoflurane, and halothane in isolated human right atria. A nesthesiology 2000; 92: 116–24
16. Cope DK, Impastato WK, Cohen MV, Downey JM: Volatile anesthetics protect the ischemic rabbit myocardium from infarction. A nesthesiology 1997; 86: 699–709
17. Boutros A, Wang J, Capuano C: Isoflurane and halothane increase adenosine triphosphate preservation, but do not provide additive recovery of function after ischemia, in preconditioned rat hearts. A nesthesiology 1997; 86: 109–17
18. Ghosh S, Standen NB, Galinanes M: Evidence for mitochondrial KATP channels as effectors of human myocardial preconditioning. Cardiovasc Res 2000; 45: 934–40
19. Toyoda Y, Friehs I, Parker RA, Levitsky S, McCully JD: Differential role of sarcolemmal and mitochondrial KATP channels in adenosine-enhanced ischemic preconditioning. Am J Physiol 2000; 279: H2694–703
20. Light PE, Kanji HD, Fox JE, French RJ: Distinct myoprotective roles of cardiac sarcolemmal and mitochondrial KATP channels during metabolic inhibition and recovery. FASEB J 2001; 15: 2586–94
21. Gögelein H, Hartung J, Englert HC, Schölkens BA: HMR 1883 a novel cardioselective inhibitor of the ATP sensitive potassium channel: Part I. Effect on cardiomyocytes, coronary flow and pancreatic b-cells. J Pharmacol Exp Ther 1998; 286: 1453–64
22. Pain T, Yang XM, Critz SD, Yue Y, Nakano A, Liu GS, Heusch G, Cohen MV, Downey JM: Opening of mitochondrial KATP channels triggers the preconditioned state by free radicals generating. Circ Res 2000; 87: 460–6
23. Martini N, Preckel B, Thamer V, Schlack W: Can isoflurane mimic ischaemic preconditioning in isolated rat heart? Br J Anaesth 2001; 86: 269–71
24. Yao Z, Gross GJ: Effects of the KATP channel opener bimakalin on coronary blood flow, monophasic action potential duration, and infarct size in dogs. Circulation 1994; 89: 1769–75
25. Toller WG, Montgomery MW, Pagel PS, Hettrick DA, Warltier DC, Kersten JR: Isoflurane-enhanced recovery of canine stunned myocardium: A role for protein kinase C? A nesthesiology 1999; 91: 713–22
26. Toller WG, Kersten JR, Gross ER, Pagel PS, Warltier DC: Isoflurane preconditions myocardium against infarction via activation of inhibitory guanine nucleotide binding proteins. A nesthesiology 2000; 92: 1400–7
27. Ebert TJ, Muzi M: Sympathetic hyperactivity during desflurane anesthesia in healthy volunteers: A comparison with isoflurane. A nesthesiology 1993; 79: 444–53
28. Gueugniaud PY, Hanouz JL, Vivien B, Lecarpentier Y, Coriat P, Riou B: Effects of desflurane in rat myocardium: comparison with isoflurane and halothane. A nesthesiology 1997; 87: 599–609
29. Cleveland JC Jr, Meldrum DR, Rowland RT, Cain BS, Meng X, Gamboni-Robertson F, Barnejee A, Harken AH: Ischemic preconditioning of human myocardium: Protein kinase C mediates a permissive role for alpha-adrenoceptors. Am J Physiol 1997; 273: H902–8
30. Lochner A, Genade S, Tromp E, Podzuweit T, Moolman JA, Med M: Ischemic preconditioning and the β-adrenergic signal transduction pathway. Circulation 1999; 100: 958–66
31. Lasley RD, Anderson GM, Mentzer RM: Ischemic and hypoxic preconditioning enhance postischemic recovery of function in the rat heart. Cardiovasc Res 1993; 27: 565–70
32. Cohen MV, Liu GS, Downey JM: Preconditioning causes improved wall motion as well as smaller infarcts after transient coronary occlusion in rabbits. Circulation 1991; 84: 341–9
33. Saito W, Noguchi K, Okazaki K, Matsuda T, Kato Y, Tanaka H, Shigenobu K: Temperature-sensitive effects of potassium channel openers on isolated guinea pig myocardium and aorta. J Cardiovasc Pharmacol 1998; 31: 327–9
34. Dote K, Wolff RA, Van Winkle DM: Hypothermia increases the threshold for ischemic preconditioning. J Thorac Cardiovasc Surg 1998; 116: 319–26
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Cardiac Preconditioning by Anesthetic Agents: Roles of Volatile Anesthetics and Opioids in Cardioprotection
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Anesthesia and AnalgesiaEtomidate has no effect on hypoxia reoxygenation and hypoxic preconditioning in isolated human right atrial myocardiumAnesthesia and Analgesia
Journal of AnesthesiaVolatile anesthetic-induced cardiac preconditioningJournal of Anesthesia
Antioxidants & Redox Signaling
Cardiac preconditioning by volatile anesthetic agents: A defining role for altered mitochondrial bioenergetics
Antioxidants & Redox Signaling, 6(2):
Acta Anaesthesiologica ScandinavicaSevoflurane- and Desflurane-induced human myocardial post-conditioning through Phosphatidylinositol-3-kinase/Akt signallingActa Anaesthesiologica Scandinavica
Vascular PharmacologyCardioprotection by volatile anestheticsVascular Pharmacology
British Journal of AnaesthesiaCardioprotective effects of desflurane: effect of timing and duration of administration in rat myocardiumBritish Journal of Anaesthesia
Anesthesia and AnalgesiaReactive oxygen species mediate sevoflurane- and desflurane-induced preconditioning in isolated human right atria in vitroAnesthesia and Analgesia
Diabetes & MetabolismDesflurane-induced postconditioning of diabetic human right atrial myocardium in vitroDiabetes & Metabolism
European Journal of Cardio-Thoracic SurgeryDesflurane preconditioning in coronary artery bypass graft surgery: a double-blinded, randomised and placebo-controlled studyEuropean Journal of Cardio-Thoracic Surgery
Annales Francaises D Anesthesie Et De ReanimationAnaesthetic-induced myocardial preconditioning: fundamental basis and clinical implicationsAnnales Francaises D Anesthesie Et De Reanimation
Journal of Muscle Research and Cell Motility
Signaling and cellular mechanisms in cardiac protection by ischemic and pharmacological preconditioning
Journal of Muscle Research and Cell Motility, 24():
Heart Surgery ForumCardioprotective Effects of Sevoflurane, Isoflurane, and Propofol in Coronary Surgery Patients: A Randomized Controlled StudyHeart Surgery Forum
Anesthesia and AnalgesiaIsoflurane activates human cardiac mitochondrial adenosine triphosphate-sensitive K+ channels reconstituted in lipid bilayersAnesthesia and Analgesia
British Journal of AnaesthesiaMyocardial injury and its prevention in the perioperative settingBritish Journal of Anaesthesia
British Journal of AnaesthesiaAnaesthetics and cardiac preconditioning. Part I. Signalling and cytoprotective mechanismsBritish Journal of Anaesthesia
Anaesthesia and Intensive Care
Mechanism of cardiac preconditioning with volatile anaesthetics
Anaesthesia and Intensive Care, 37(4):
Anasthesiologie & Intensivmedizin
Organ protection by volatile anaesthetics
Anasthesiologie & Intensivmedizin, 46():
Journal of Molecular and Cellular CardiologyK-ATP channels and preconditioning: A re-examination of the role of mitochondrial KATpchannels and an overview of alternative mechanismsJournal of Molecular and Cellular Cardiology
Journal of Cardiothoracic and Vascular AnesthesiaDesflurane-Induced Preconditioning Has a Threshold That Is Lowered by Repetitive Application and Is Mediated by beta(2)-Adrenergic ReceptorsJournal of Cardiothoracic and Vascular Anesthesia
Journal of Cardiothoracic and Vascular AnesthesiaDesflurane-Induced Cardioprotection Against Ischemia-Reperfusion Injury Depends On TimingJournal of Cardiothoracic and Vascular Anesthesia
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie
Beta-blockers and anesthetic preconditioning: friend or foe?
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie, 54(4):
British Journal of AnaesthesiaMyocardial protection with volatile anaesthetic agents during coronary artery bypass surgery: a meta-analysisBritish Journal of Anaesthesia
American Journal of Physiology-Renal PhysiologyAnti-inflammatory and antinecrotic effects of the volatile anesthetic sevoflurane in kidney proximal tubule cellsAmerican Journal of Physiology-Renal Physiology
British Journal of AnaesthesiaAnaesthetics and cardiac preconditioning. Part II. Clinical implicationsBritish Journal of Anaesthesia
Journal of Cardiothoracic and Vascular Anesthesiabeta-Blockers and Volatile Anesthetics May Attenuate Cardioprotection by Remote Preconditioning in Adult Cardiac Surgery: A Meta-analysis of 15 Randomized TrialsJournal of Cardiothoracic and Vascular Anesthesia
Journal of Cardiothoracic and Vascular AnesthesiaMyocardial Protection by Volatile Anesthetics in Patients Undergoing Cardiac Surgery: A Critical Review of the Laboratory and Clinical EvidenceJournal of Cardiothoracic and Vascular Anesthesia
CirculationLetter by Zaugg and Lucchinetti Regarding Article, "Randomized Comparison of Sevoflurane Versus Propofol to Reduce Perioperative Myocardial Ischemia in Patients Undergoing Noncardiac Surgery"Circulation
European Journal of Anaesthesiology (EJA)Isoflurane preconditioning‐induced cardio‐protection in patients undergoing coronary artery bypass graftingEuropean Journal of Anaesthesiology (EJA)
European Journal of Anaesthesiology (EJA)The effect of anaesthetics on the myocardium ‐ new insights into myocardial protectionEuropean Journal of Anaesthesiology (EJA)
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