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Anesthesiology:
Laboratory Investigations

Isoflurane Mimics Ischemic Preconditioning via Activation of KATP Channels: Reduction of Myocardial Infarct Size with An Acute Memory Phase

Kersten, Judy R. MD; Schmeling, Todd J. BS; Pagel, Paul S. MD, PhD; Gross, Garrett J. PhD; Warltier, David C. MD, PhD

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Abstract

Background:: The authors tested the hypothesis that isoflurane directly preconditions myocardium against infarction via activation of K sub ATP channels and that the protection afforded by isoflurane is associated with an acute memory phase similar to that of ischemic preconditioning.
Methods:: Barbiturate‐anesthetized dogs (n = 71) were instrumented for measurement of systemic hemodynamics. Myocardial infarct size was assessed by triphenyltetrazolium chloride staining. All dogs were subjected to a single prolonged (60 min) left anterior descending coronary artery (LAD) occlusion followed by 3 h of reperfusion. Ischemic preconditioning was produced by four 5‐min LAD occlusions interspersed with 5‐min periods of reperfusion before the prolonged LAD occlusion and reperfusion. The actions of isoflurane to decrease infarct size were examined in dogs receiving 1 minimum alveolar concentration (MAC) isoflurane that was discontinued 5 min before prolonged LAD occlusion. The interaction between isoflurane and ischemic preconditioning on infarct size was evaluated in dogs receiving isoflurane before and during preconditioning LAD occlusions and reperfusions. To test whether the cardioprotection produced by isoflurane can mimic the acute memory of ischemic preconditioning, isoflurane was discontinued 30 min before prolonged LAD occlusion and reperfusion. The mechanism of isoflurane‐induced cardioprotection was evaluated in two final groups of dogs pretreated with glyburide in the presence or absence of isoflurane.
Results:: Myocardial infarct size was 25.3 +/‐ 2.9% of the area at risk during control conditions. Isoflurane and ischemic preconditioning produced significant (P < 0.05) and equivalent reductions in infarct size (ischemic preconditioning alone, 9.6 +/‐ 2.0; isoflurane alone, 11.8 +/‐ 2.7; isoflurane and ischemic preconditioning, 5.1 +/‐ 1.9%). Isoflurane‐induced reduction of infarct size also persisted 30 min after discontinuation of the anesthetic (13.9 +/‐ 1.5%), independent of hemodynamic effects during LAD occlusion. Glyburide alone had no effect on infarct size (28.3 +/‐ 3.9%), but it abolished the protective effects of isoflurane (27.1 +/‐ 4.6%).
Conclusions:: Isoflurane directly preconditions myocardium against infarction via activation of KATP channels in the absence of hemodynamic effects and exhibits acute memory of preconditioning in vivo.
Ischemic preconditioning is the most effective means of reducing myocyte death during prolonged periods of myocardial ischemia in the beating heart. Ischemic preconditioning was first described by Murry et al [1] in 1986. Four brief (5‐min) periods of ischemia elicited by coronary artery occlusion interspersed with 5‐min periods of reperfusion before a prolonged (40‐min) coronary artery occlusion dramatically decreased the extent of subsequent myocardial infarction by 70–80%. This remarkable phenomenon has been shown to be mimicked by adenosine, [2–4] a known activator of guanine regulatory proteins, [5] and by stimulation of protein kinase C. [6–9] Both of these pathways appear to involve stimulation of adenosine triphosphate‐regulated potassium (KATP) channels as a major component of their action. [5,10–14] Ischemic preconditioning also is characterized by an acute memory phase, during which time myocardium remains resistant to infarction for up to 2 h after the preconditioning stimulus. KATP channel activation has been shown to play an important role to mediate the acute memory phase of ischemic preconditioning. [15] Isoflurane, similarly to ischemic preconditioning, has recently been shown to modulate cardioprotective signal transduction in stunned myocardium. [16–18] Enhanced recovery of postischemic reperfused myocardium produced by isoflurane was partially mediated by activation of type 1 adenosine (A1) receptors coupled to KATP channels. [16–18] The present investigation tested the hypothesis that isoflurane directly preconditions myocardium against myocardial infarction via activation of KATP channels and that this effect is associated with an acute memory phase, thus mimicking ischemic preconditioning.
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Method and Materials

All experimental procedures and protocols used in this investigation were reviewed and approved by the Animal Care and Use Committee of the Medical College of Wisconsin. Further, all conformed to the Guiding Principles in the Care and Use of Animals of the American Physiologic Society and were in accordance with the Guide for the Care and Use of Laboratory Animals (National Academy Press, Washington, D.C., 1996).
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General Preparation
Implantation of instruments has been described previously in detail. [16] Briefly, open chest mongrel dogs anesthetized with sodium barbital (200 mg/kg) and sodium pentobarbital (15 mg/kg) were ventilated via positive pressure with an air and oxygen mixture after tracheal intubation. A double, pressure transducer‐tipped catheter was inserted into the aorta and left ventricle for measurement of aortic and left ventricular pressures and the maximum rate of increase of left ventricular pressure (dP/dtmax). Catheters were inserted into the left atrial appendage and the right femoral artery for administration of radioactive microspheres and withdrawal of reference blood flow samples, respectively. A silk ligature was placed around the left anterior descending coronary artery (LAD), immediately distal to the first diagonal branch for production of coronary artery occlusion and reperfusion. Hemodynamics were continuously monitored on a polygraph during experimentation and digitized via a computer interfaced with an analog‐to‐digital converter.
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Experimental Protocol
Figure 1
Figure 1
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The experimental design is illustrated in Figure 1. Ninety minutes after instrumentation was completed and calibrated, baseline systemic hemodynamics were recorded. Dogs were randomly assigned to one of seven experimental groups. All dogs were subjected to a prolonged 60‐min LAD occlusion followed by 3 h of reperfusion. Control experiments had no previous intervention before prolonged (60‐min) occlusion and reperfusion. Another group of dogs were preconditioned with four 5‐min LAD occlusions interspersed with 5‐min periods of reperfusion, followed by prolonged LAD occlusion and reperfusion. The actions of isoflurane to decrease myocardial infarct size were studied in a third group of dogs receiving 1 minimum alveolar concentration (MAC) isoflurane that was discontinued 5 min before prolonged LAD occlusion and reperfusion. The interaction between isoflurane and ischemic preconditioning was examined in a fourth group of dogs receiving isoflurane (1 MAC) before and during ischemic preconditioning followed by prolonged LAD occlusion and reperfusion. To determine if the cardioprotective action of isoflurane is associated with an acute memory phase of ischemic preconditioning, isoflurane (1 MAC) was discontinued 30 min before prolonged LAD occlusion and reperfusion in a fifth group of dogs. The mechanism of the cardioprotective effect of isoflurane was evaluated in two additional groups of dogs pretreated with the KATP channel antagonist, intravenous glyburide (0.1 mg/kg), in the presence or absence of 1 MAC isoflurane, which was discontinued 30 min before LAD occlusion. Regional myocardial blood flow was measured at baseline, at 30 min after the onset of prolonged LAD occlusion, and 1 h after final reperfusion. End‐tidal concentrations of isoflurane were measured at the tip of the endotracheal tube by an infrared anesthetic analyzer that was calibrated with known standards before and during experimentation. Dogs that developed ventricular fibrillation during LAD occlusions or reperfusions were defibrillated with an internal, single 15–20 J pulse of direct current. Dogs that developed intractable ventricular fibrillation and those with a subendocardial coronary collateral blood flow more than 0.15 ml [center dot] min sup ‐1 [center dot] g sup ‐1 were excluded from the analysis.
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Measurement of Myocardial Infarct Size
At the end of each experiment, the LAD was reoccluded and cannulated just distal to the occlusion site. Ten milliliters of saline and 10 ml of patent blue dye were injected at equal pressure into the LAD and left atrium, respectively, to delineate the anatomic area at risk (AAR) subjected to prolonged occlusion and reperfusion and the nonischemic normal zone. The heart was immediately fibrillated, removed, and sliced into serial transverse sections 6–7 mm in width. The unstained AAR was separated from the blue‐stained normal area, and the two regions were incubated at 37 [degree sign] Celsius for 20–30 min in 1% 2,3,5‐triphenyltetrazolium chloride (TTC) in 0.1 M phosphate buffer adjusted to pH 7.4. TTC stains noninfarcted myocardium a brick red color because of the presence of a formazan precipitate, resulting from reduction of TTC by dehydrogenase enzymes present in viable tissue. Infarcted myocardium remains unstained. After overnight storage in 10% formaldehyde, infarcted and noninfarcted myocardium within the AAR were carefully separated and weighed. Infarct size (IF) was expressed as a percentage of the AAR (IF [center dot] AAR sup ‐1 [center dot] 100).
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Determination of Regional Myocardial Blood Flow
Carbonized plastic microspheres (15 +/‐ 2 mm [SD] in diameter) labeled with141 Ce,103 Ru, or95 Nb were used to measure regional myocardial perfusion as previously described. [16] Briefly, microspheres were administered into the left atrium as a bolus over a 10‐s period and flushed in with 10 ml of warm (37 [degree sign] Celsius) saline. A few seconds before the microsphere injection, a timed collection of reference arterial flow was started from the femoral arterial catheter and withdrawn at a constant rate of 7 ml/min for 3 min. Transmural tissue samples were selected from the ischemic region (distal to the LAD occlusion and reperfusion) and were subdivided into subepicardial, midmyocardial, and subendocardial layers of approximately equal thickness. Samples were weighed, placed in scintillation vials, and the activity of each isotope determined. Similarly, the activity of each isotope in the reference blood flow sample was assessed. Tissue blood flow (ml [center dot] min sup ‐1 [center dot] g sup ‐1) was calculated as Qr [center dot] Cm [center dot] Cr sup ‐1, where Qr = rate of withdrawal of the reference blood flow sample (ml/min); Cm = activity (cpm/g) of the myocardial tissue sample; and Cr = activity (cpm) of the reference blood flow sample. Transmural blood flow was considered as the average of subepicardial, midmyocardial, and subendocardial blood flows.
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Statistical Analysis
Statistical analysis of data within and between groups during baseline conditions, during anesthetic interventions, and after LAD occlusion and reperfusion was performed with multiple analysis of variance (MANOVA) for repeated measures followed by application of Student's t test with Duncan's correction for multiplicity. Changes within and between groups were considered statistically significant when the P value was less than 0.05. All data are expressed as mean +/‐ SEM.
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Results

Table 1
Table 1
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Seventy‐one dogs were instrumented to obtain 59 successful experiments. Six dogs were excluded from data analysis because of intractable ventricular fibrillation (2 each in the isoflurane and control groups; 1 in the isoflurane with 30 min of memory, and 1 in the isoflurane with glyburide‐pretreatment group). An additional six dogs were excluded because subendocardial collateral blood flow exceeded 0.15 ml [center dot] min sup ‐1 [center dot] g sup ‐1 (1 in the isoflurane, 2 in the ischemic preconditioning, and 3 in the control group). Arterial blood gases were maintained within a physiologic range. Transmural blood flow to ischemic myocardium (Table 1) was significantly (P < 0.05) decreased from baseline values during coronary artery occlusion in each group. There were no differences in blood flow to ischemic myocardium among groups at baseline or during LAD occlusion.
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Hemodynamics during LAD Occlusion and Reperfusion
Table 2
Table 2
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Table 3
Table 3
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There were no differences in hemodynamics between experimental groups during baseline conditions after instrumentation. Hemodynamics during control experiments are shown in Table 2. Ischemic preconditioning (Table 3) caused decreases in left ventricular systolic pressure and increases in left ventricular end‐diastolic pressure that returned to baseline values before prolonged LAD occlusion. No differences in hemodynamics during prolonged LAD occlusion were observed between dogs in the presence and absence of ischemic preconditioning.
Table 4
Table 4
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Table 5
Table 5
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Table 6
Table 6
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Table 7
Table 7
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Table 8
Table 8
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Isoflurane caused significant decreases in heart rate, mean arterial and left ventricular systolic pressures, rate‐pressure product, and dP/dtmax (Table 4, Table 5, Table 6, Table 7). Dogs receiving isoflurane until 5 min before prolonged LAD occlusion and reperfusion in the absence (Table 4) or presence (Table 5) of preconditioning coronary artery occlusions had significantly lower mean arterial pressure and rate‐pressure product during prolonged coronary artery occlusion compared with dogs not receiving isoflurane. In contrast, 30 min after isoflurane was discontinued (Table 6 and Table 7), hemodynamics returned to baseline values and were not different from those observed in control dogs either before or during prolonged LAD occlusion. No end‐tidal isoflurane was detectable during LAD occlusion in 8 of 9 dogs when isoflurane was discontinued 30 min before prolonged LAD occlusion. In one dog, however, an end‐tidal isoflurane concentration of 0.02% was measured at 30 min after the onset of prolonged LAD occlusion. Hemodynamics were similar in dogs receiving glyburide (Table 8) compared with control experiments. No differences in hemodynamics during reperfusion were observed between control, preconditioned, isoflurane‐treated, or glyburide‐pretreated groups.
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Myocardial Infarct Size
Figure 2
Figure 2
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The area of the left ventricle at risk (AAR) for myocardial infarction was not different (P = not significant) between groups (control, 32.9 +/‐ 1.5; ischemic preconditioning, 34.6 +/‐ 2.1; isoflurane, 34.2 +/‐ 1.4; isoflurane before and during ischemic preconditioning, 32.0 +/‐ 1.6; isoflurane discontinued 30 min before prolonged coronary artery occlusion, 35.9 +/‐ 1.5; isoflurane after glyburide‐pretreatment, 37.9 +/‐ 1.9; and glyburide alone, 37.5 +/‐ 1.8%. Myocardial infarct size expressed as a percentage of the AAR was 25.3 +/‐ 2.9% in control dogs (Figure 2). Preconditioning resulted in a significant reduction of myocardial infarct size to 9.6 +/‐ 2.0% of the AAR compared with dogs not receiving preconditioning stimuli. Similar protection was afforded by isoflurane in the absence (11.8 +/‐ 2.7%) or presence of ischemic preconditioning (5.1 +/‐ 1.9%). Isoflurane also was equally protective (13.9 +/‐ 1.5%) when discontinued 30 min before LAD occlusion and reperfusion compared with ischemic preconditioning alone (9.6 +/‐ 2.0%). Glyburide alone had no effect on myocardial infarct size (28.3 +/‐ 3.9%) but abolished the protective effect of isoflurane (27.1 +/‐ 4.6%).
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Discussion
Experimental evidence indicates that volatile anesthetics exert myocardial protective effects after global [19–24] or regional ischemia, [16,17,25–28] and in models of reversible (myocardial stunning) [16,17,25] and irreversible (myocardial infarction) tissue injury. [29,30] The mechanisms responsible for anesthetic‐induced beneficial effects are unclear. Recent findings suggest that isoflurane modulates cardioprotective signal transduction [16–18] in a similar fashion to an endogenous mechanism that mediates ischemic preconditioning through activation of A1 receptors coupled to KATP channels. [4,5] The present results show that isoflurane directly preconditions myocardium against myocardial infarction via activation of KATP channels, confirming and extending previous findings. The present results also show that cardioprotection produced by isoflurane is associated with an acute memory phase similar to that observed during ischemic preconditioning.
Ischemic preconditioning decreased myocardial infarct size by 62% compared with control dogs subjected to a single 60‐min period of coronary artery occlusion. These findings are similar to those previously reported in dogs. [1,10] The extent of myocardial infarction after LAD occlusion depends on the size of the AAR and the degree of native coronary collateral perfusion. Area at risk and coronary collateral blood flow were similar between experimental groups in the present investigation. Administration of isoflurane before, but not during, prolonged LAD occlusion resulted in a reduction in myocardial infarct size similar to that observed with ischemic preconditioning. However, isoflurane reduced major hemodynamic determinants of myocardial oxygen consumption during prolonged LAD occlusion, in contrast to dogs receiving ischemic preconditioning alone. A previous study [30] demonstrated that isoflurane reduced myocardial infarct size and decreased myocardial oxygen consumption when administered during coronary artery occlusion. Thus, decreases in heart rate, myocardial contractility, and myocardial oxygen consumption produced by isoflurane during myocardial ischemia may have contributed to reductions in infarct size observed in the previous [30] and present investigations. However, favorable alterations in myocardial oxygen supply and demand relations produced by isoflurane may not solely account for these experimental findings. [16]
The direct effects of isoflurane to remotely precondition myocardium against infarction also were examined. Isoflurane caused initial reductions in arterial pressure, heart rate, and dP/dtmax, but systemic hemodynamics returned to baseline values 30 min after discontinuation of this volatile anesthetic. Hemodynamics immediately before and during prolonged coronary artery occlusion in dogs receiving remote isoflurane exposure were similar from those observed in control dogs. Even in the absence of hemodynamic effects during ischemia, previous exposure to isoflurane decreased myocardial infarct size to an equivalent extent as ischemic preconditioning. These results indicate that isoflurane produces direct preconditioning of myocardium against infarction. The results also show that isoflurane‐induced cardioprotection is associated with an acute memory phase because discontinuation of this volatile anesthetic 30 min before prolonged LAD occlusion results in sustained cardioprotection. The possibility that residual isoflurane may be present in myocardium 30 min after its discontinuation cannot be completely excluded and may have influenced the present results. However, the absence of isoflurane‐induced hemodynamic effects and undetectable end‐tidal isoflurane concentrations provide evidence that residual isoflurane remaining in the myocardium did not account for remote cardioprotection.
The acute memory of ischemic preconditioning has recently come under intense investigation. [15,31] Protection against myocardial infarction afforded by ischemic preconditioning is characterized by an acute memory phase, such that the preconditioning stimulus may precede the prolonged period of ischemia by 30 min to 2 h, during which time the heart remains resistant to infarction. [31] Previous findings in dogs suggest that A1 receptor stimulation by adenosine triggers ischemic preconditioning, although activation of A sub 1 receptors alone is not sufficient to sustain the acute memory phase of preconditioning. [15] In contrast, the KATP channel antagonist, glyburide, administered 50 min after ischemic preconditioning, totally abolished preconditioning‐induced reductions in myocardial infarct size. [15] These results showed that KATP channels play an essential role in the acute memory phase of ischemic preconditioning. [15] Yao et al [15] recently showed that infusions of adenosine or the KATP channel agonist, bimakalim, failed to decrease myocardial infarct size when the drug‐free interval before sustained coronary artery occlusion was extended from 15 min [13] to 60 min. [15] In contrast, simultaneous administration of adenosine and bimakalim produced a synergistic effect to decrease myocardial infarct size after 60 min, extending the time window of acute memory that was otherwise limited with either drug alone. These results indicate that pharmacologic activation of KATP channels and adenosine receptors closely mimics the conditions present during ischemic preconditioning and may be responsible for the acute memory phase observed with isoflurane in this setting. Previous evidence indicates that isoflurane‐induced cardioprotection is mediated by KATP channel and A1 receptor activation in myocardium. [16–18] Glyburide abolished [16] and the selective A1 receptor antagonist DPCPX attenuated [18] isoflurane‐enhanced recovery of contractile function of stunned myocardium. The present findings indicate that KATP channel activation by isoflurane plays a critical role to precondition myocardium against infarction because glyburide pretreatment abolished the reduction in myocardial infarct size observed after remote isoflurane administration. The contribution of A1 receptor activation by isoflurane to mimic ischemic preconditioning and further characterization of the time course of the acute memory period of isoflurane remain to be evaluated.
The potential additive effects of isoflurane and ischemic preconditioning were examined in dogs receiving isoflurane before and during brief episodes of coronary occlusion and reperfusion. Simultaneous administration of isoflurane and ischemic preconditioning produced no additional effects to further decrease myocardial infarct size compared with isoflurane or ischemic preconditioning alone. The absence of additive effects may have been related to each intervention alone serving as a maximal stimulus to induce cardioprotection, to activation of similar cardioprotective mechanisms by isoflurane and ischemic preconditioning, or to inadequate statistical power to detect differences in the degree of protection between groups. Previous findings show that activation of KATP channels lowers the threshold for ischemic preconditioning. [32] A single 3‐min coronary artery occlusion or a 3‐min intracoronary infusion of bimakalim failed to precondition myocardium against myocardial infarction. In contrast, bimakalim infused during a 3‐min LAD occlusion markedly decreased myocardial infarct size to a similar extent as that of classic ischemic preconditioning. Whether isoflurane similarly reduces the threshold for ischemic preconditioning when administered in a concentration that alone does not directly precondition myocardium remains to be evaluated.
In summary, the present results show that isoflurane mimics ischemic preconditioning and causes marked reductions in myocardial infarct size in the absence of hemodynamic effects. The results also show that isoflurane‐induced cardioprotection is mediated by KATP channel activation and is characterized by an acute memory phase that persists for at least 30 min after discontinuation of the anesthetic.
The authors thank David Schwabe for technical assistance and Angela Barnes for assistance in preparation of this manuscript.
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Journal of Anesthesia
Delayed anesthetic preconditioning protects against myocardial infarction via activation of nuclear factor-kappa B and upregulation of autophagy
Qiao, SG; Xie, H; Wang, C; Wu, XM; Liu, H; Liu, CF
Journal of Anesthesia, 27(2): 251-260.
10.1007/s00540-012-1494-3
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Keywords:
Adenosine triphosphate‐regulated potassium channels, antagonists: glyburide; Anesthetics, volatile: isoflurane; Heart, ischemic preconditioning, myocardial infarction, myocardial ischemia.

© 1997 American Society of Anesthesiologists, Inc.

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