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Anesth Analg 2003;96:233-237
© 2003 International Anesthesia Research Society

NEUROSURGICAL ANESTHESIA

Preconditioning with Isoflurane Produces Dose-Dependent Neuroprotection via Activation of Adenosine Triphosphate-Regulated Potassium Channels After Focal Cerebral Ischemia in Rats

Lize Xiong, MD, Yu Zheng, MD, Mingchun Wu, MD, Lichao Hou, MD, Zhenghua Zhu, MD, Xijing Zhang, MD, and Zhihong Lu, MD

Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China

Address correspondence and reprint requests to Lize Xiong, MD, Department of Anesthesiology, Xijing Hospital, Xi’an, Shaanxi Province 710032, China. Address e-mail to lxiong{at}fmmu.edu.cn


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
In this study, we determined whether repeated brief isoflurane (Iso) anesthesia induces ischemic tolerance to focal cerebral ischemia in a dose-response manner and whether the effect is dependent on adenosine triphosphate-regulated potassium channels. In Experiment 1, 40 rats were randomly assigned to 4 groups: control animals received 100% oxygen 1 h/d for 5 days, whereas the isoflurane (Iso)1, Iso2, and Iso3 groups received 0.75%, 1.5%, or 2.25% Iso in oxygen 1 h/d for 5 days. In Experiment 2, 36 rats were randomly assigned to 4 groups: controls received 100% oxygen 1 h/d for 5 days; animals in the Iso and I+G (Iso+glibenclamide) groups received 2% Iso in oxygen 1 h/d for 5 days, and the I+G group received glibenclamide (GLB) (5 mg/kg intraperitoneally) before each Iso pretreatment. Animals in the GLB group received GLB (5 mg/kg intraperitoneally) once a day for 5 days. Twenty-four hours after the last pretreatment, the right middle cerebral artery was occluded for 120 min. Neurologic deficit scores (NDS) and brain infarct volumes were evaluated at 24 h. The NDS and infarct volumes of Iso2 and Iso3 were less than those of the controls (P < 0.05). The infarct volume in Iso3 was smaller than in Iso2 (P < 0.05). The NDS and infarct volume in the Iso group were less than in the control and I+G groups (P < 0.05). There was no statistical difference among the control, I+G, and GLB groups. The study demonstrated that repeated Iso anesthesia induces ischemic tolerance in rats in a dose-response manner. GLB, an adenosine triphosphate-regulated potassium channel blocker, abolished the tolerance induced by Iso.

IMPLICATIONS: Brief isoflurane anesthesia induces ischemic tolerance in the brain. The effect was found to be dose dependent in a rat focal cerebral ischemia model. Ischemic tolerance induced by isoflurane preconditioning is dependent on activation of adenosine triphosphate-regulated potassium channels.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Ischemic preconditioning-induced tolerance against ischemic injury in the brain was first reported by Kitagawa et al. (1) in 1990. This remarkable phenomenon is also induced by cytokines, endotoxin, potassium chloride, and the neurotoxin 3-nitropropionic acid (2–5). Preconditioning with isoflurane (Iso), a commonly used volatile anesthetic, induces ischemic tolerance in brain (6,7). However, the mechanism of the neuroprotective effect induced by Iso preconditioning is not known. Preconditioning has also been demonstrated in the heart. This process involves stimulation of adenosine triphosphate-regulated potassium (KATP) channels (8–12). This study was designed to evaluate both the dose-dependent effects of Iso pretreatment on cerebral ischemic injury and the role of KATP channels in the induction of ischemic tolerance by Iso by using a rat model of transient focal ischemia.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The experimental protocol was approved by the Ethics Committee for Animal Experimentation and was performed according to the Guidelines for Animal Experimentation of the Fourth Military Medical University. The animals were provided by the Experimental Animal Center of the Fourth Military Medical University. This study consisted of two experiments. In Experiment 1, 40 male Sprague-Dawley rats weighing 300–350 g were randomly assigned to 1 of 4 groups (n = 10 each): animals in the control group received 100% oxygen 1 h/d for 5 days; animals in the isoflurane (Iso)1, Iso2, and Iso3 groups received 0.75%, 1.5%, and 2.25% Iso in oxygen 1 h/d for 5 days, respectively. In Experiment 2, 36 male Sprague-Dawley rats weighing 300–350 g were randomly assigned to 1 of 4 groups (n = 9 each): animals in the control group received 100% oxygen 1 h/d for 5 days; animals in the Iso and I+G groups received 2% Iso in 98% oxygen 1 h/d for 5 days. The I+G (Iso+glibenclamide) group also received glibenclamide (GLB) (intraperitoneally [i.p.] 5 mg/kg) (Sigma Chemical Co., St. Louis, MO) just before each Iso pretreatment; animals in the GLB group received GLB i.p. 5 mg/kg once a day without Iso pretreatment for 5 days.

The rectal temperature of all the rats was maintained at 37.0°C ± 0.5°C during Iso pretreatments. The femoral arterial blood pressure was monitored during 2% Iso anesthesia (1 h) in another three rats. Arterial blood gases were measured in additional rats at the end of 1 h of exposure to 1.5% or 2% Iso (n = 4 each).

Twenty-four hours after the last pretreatment, focal cerebral ischemia was induced in all rats. The rats were fasted for 12 h but were allowed free access to water before surgery. Anesthesia was induced with 4% Iso and was maintained with 2% Iso delivered by a mask. Focal cerebral ischemia was induced as described by Longa et al. (13). Briefly, the right common carotid artery and the right external carotid artery were exposed through a ventral midline neck incision and were ligated proximally. A 3-0 nylon monofilament suture (Ethicon nylon suture; Ethicon Inc., Japan) with its tip rounded by heating near a flame was inserted through an arteriectomy in the common carotid artery just below the carotid bifurcation and then advanced into the internal carotid artery approximately 17–18 mm distal to the carotid bifurcation until a mild resistance was felt, thereby occluding the origins of the anterior cerebral artery, the middle cerebral artery, and the posterior communicating artery. Reperfusion was accomplished by withdrawing the suture after 120 min of ischemia. The incision sites were infiltrated with 0.25% bupivacaine hydrochloride. Rectal temperature was monitored (Spacelabs Medical, Inc., Redmond, WA) and maintained at 37.0°C–37.5°C by surface heating and cooling.

After the suture was withdrawn, the rats were returned to their cages and had free access to food and water. Twenty-four hours after reperfusion, the animals were neurologically assessed by an investigator who was unaware of animal grouping. A six-point scale modified from that previously described by Longa et al. (13) was used for neurologic assessment: 0, no deficit; 1, failure to extend left forepaw fully; 2, circling to the left; 3, falling to the left; 4, no spontaneous walking, with a depressed level of consciousness; 5, dead.

Twenty-four hours after reperfusion, the rats were reanesthetized with 4% Iso in oxygen and decapitated. The brains were rapidly removed and cooled in iced saline for 10 min. Six 2-mm-thick coronal sections were cut with the aid of a brain matrix. Sections were immersed in 2% 2,3,5-triphenyltetrazolium chloride at 37°C for 30 min and then transferred to 10% buffered formalin solution for fixation. At 24 h after fixation, the brain slices were photographed with a digital camera (Kodak DC240; Eastman Kodak Co., Rochester, NY) connected to a computer. Unstained areas were defined as infarct and were measured by using image analysis software (Adobe Photoshop 5.0CS for Windows; Adobe Systems Inc., San Jose, CA). The infarct volume was calculated by measuring the unstained area in each slice, multiplying it by slice thickness (2 mm), and then summating all six slices.

Infarct volumes are expressed as mean ± SD. One-factor analysis of variance was used to compare infarct volumes among experimental groups. Neurologic deficit scores were analyzed with the Kruskal-Wallis test followed by the Mann-Whitney U-test with Bonferroni correction. P < 0.05 was considered statistically significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
All rats survived until 24 h after reperfusion. The neurologic deficit scores of the Iso2 and Iso3 groups at 24 h after reperfusion were lower than those of the control group (P < 0.05 and 0.01, respectively), and the neurologic deficit scores in the Iso3 group were lower than those of the Iso1 group (P < 0.01) (Table 1). Iso preconditioning reduced cerebral infarct volume in a dose-dependent manner (Fig. 1). In Experiment 2, neurologic deficit scores in the Iso group at 24 h after reperfusion were lower than those of the control and I+G groups (P < 0.01 and 0.05, respectively). There was no statistical difference among the control, I+G, and GLB groups (Table 2). The infarct volume of the Iso group was smaller than that of the control and I+G groups (P < 0.05). No statistical difference was found among the control, I+G, and GLB groups (Fig. 2).


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  		Table 1. Neurologic Deficit Scores 24 Hours After Reperfusion from 120 Minutes of Middle Cerebral Artery Occlusion in the Rat
 


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  		Figure 1. Infarct volumes at 24 h after reperfusion in the rats with 120-min middle cerebral artery occlusion. *P < 0.01 compared with the control and Iso1 groups; #P < 0.05 compared with the Iso2 group. Data are presented as mean ± SD. Iso1 = preconditioning with 0.75% isoflurane; Iso2 = preconditioning with 1.50% isoflurane; Iso3 = preconditioning with 2.25% isoflurane.

 

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  		Table 2. Neurologic Deficit Scores 24 Hours After Reperfusion from 120 Minutes of Middle Cerebral Artery Occlusion in the Rat
 


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  		Figure 2. Infarct volumes at 24 h after reperfusion in the rats with 120-min middle cerebral artery occlusion. *P < 0.05 compared with the control and I+G groups. Data are presented as mean ± SD. Iso = pretreatment with 2% isoflurane in oxygen 1 h/d for 5 days; I+G = administration of glibenclamide before each pretreatment with 2% isoflurane in oxygen 1 h/d for 5 days; GLB = administration of glibenclamide once a day for 5 days.

 
Arterial blood gases showed that 1.5% Iso pretreatment could induce neuroprotection without respiratory depression (pH 7.40 ± 0.01; PaO2, 86 ± 7 mm Hg; PaCO2, 45 ± 3 mm Hg), whereas animals treated with 2% Iso had respiratory depression (pH 7.25 ± 0.06; PaO2, 87 ± 8 mm Hg; PaCO2, 73 ± 13 mm Hg). No hypotension was found during 2% Iso anesthesia (at 30 min, systolic blood pressure was 114 ± 13 mm Hg; at 1 h, it was 110 ± 10 mm Hg).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This study demonstrated that repeated preischemic Iso exposure induces tolerance to transient middle cerebral artery occlusion (MCAO) in rats in a dose-dependent manner. The administration of GLB, a KATP channel blocker, before each Iso pretreatment abolished the ischemic tolerance induced by Iso.

It has been previously reported that preconditioning with volatile anesthetics such as Iso can induce ischemic tolerance in the heart (8–10,14). In our previous study, we found that 2% Iso-induced ischemic tolerance also existed in the brain (7). Kapinya et al. (6) demonstrated in a rat focal cerebral ischemia model that pretreatment with 1.4% Iso for 3 hours at 0, 12, and 24 hours before MCAO could induce neuroprotection. This study further demonstrated that Iso pretreatment (1 h/d for 5 days) could attenuate the ischemia/reperfusion injury in transient MCAO rats in a dose-dependent manner. Iso 2.25% pretreatment induced greater tolerance than 1.5% Iso pretreatment. Iso 1.5% pretreatment was sufficient to induce ischemic tolerance, whereas 0.75% Iso pretreatment was not; this suggests that a threshold concentration is needed to induce ischemic tolerance by Iso.

The Iso pretreatment protocol used in our study was based on the protocol of preconditioning with hyperbaric oxygenation described by Wada et al. (15) and our group (16). Bhardwaj et al. (17) demonstrated in an MCAO rat model that short-duration exposure to halothane (less than one hour) before MCAO attenuated infarct volume but that a similar duration of propofol or a long exposure (eight hours) to halothane did not. Kapinya et al. (6) found that pretreatment with Iso for three hours induced tolerance against ischemic neuronal injury. The optimal duration of Iso exposure for the induction of ischemic tolerance has not been defined.

The largest Iso concentration examined in our study was 2.25% because the animals were kept spontaneously breathing during the pretreatment sessions. The concentrations of 0.75%, 1.5%, and 2.25% Iso inhaled during pretreatment were 0.5, 1.0, and 1.5 minimum alveolar anesthetic concentration (MAC), respectively (8,18–20). On the basis of the findings that 1.5% (1.0 MAC) and 2.25% (1.5 MAC) Iso pretreatments were able to induce significant ischemic tolerance in Experiment 1, 2% Iso was used for pretreatment in Experiment 2 to induce the most benefit with the least possibility of respiratory depression by Iso. However, 2% Iso did produce respiratory acidosis. Therefore, whether repeated episodes of increased CO2 during the pretreatment contribute to the observed beneficial effect needs to be further elucidated.

Our results showed that GLB, a nonspecific KATP channel blocker, could abolish the neuroprotection induced by 2% Iso pretreatment if administered before each Iso pretreatment. Previous evidence indicates that Iso-induced cardioprotection is mediated by activation of KATP channels, A1 receptors, and protein kinase C in myocardium (8–10,14,21,22). We postulated that the intracellular signal transduction pathways for Iso preconditioning in the brain might be similar to those in the heart. This study did indicate that the neuroprotection induced by Iso preconditioning in the brain is mediated by activation of KATP channels, although we were unable to determine whether this effect is at the cellular or the mitochondrial membrane. The contribution of the A1 receptor and protein kinase C activation in Iso preconditioning-induced neuroprotection remains to be evaluated.

An apoptotic mechanism could be involved in the induction of ischemic tolerance by Iso. Wise-Faberowski et al. (23) reported that oxygen and glucose deprivation (30, 60, and 90 minutes) caused significant apoptosis of cerebral cortical cultured neurons. However, pretreatment and continued treatment during the period of oxygen and glucose deprivation with halothane or Iso resulted in a concentration-dependent attenuation of neuronal apoptosis. Therefore, activation of KATP channels by Iso pretreatment could decrease, or at least delay, neuronal apoptosis.

The results of this study might be used clinically. In cerebral aneurysm surgical procedures, temporary brain artery occlusion is often used to facilitate surgical access and reduce bleeding. Temporary vessel occlusion might produce focal cerebral ischemic injury. If neurosurgical patients with possible temporary vessel clipping are preconditioned with repeated Iso pretreatment, cerebral ischemic damage might be prevented. However, substantially more information about Iso-induced preconditioning must be collected before this can be advocated.

In conclusion, this study demonstrated that repeated one-hour Iso anesthetics induce dose-dependent neuroprotection against subsequent ischemic injury induced by transient MCAO in rats and that the ischemic tolerance in the brain induced by Iso pretreatment occurs via activation of KATP channels.


   Acknowledgments
 
Supported in part by the National Natural Science Foundation of China (Grant 30170907 to LX).

The authors thank Adrian W. Gelb, Professor of Anesthesia, The University of Western Ontario, Canada, for critically reviewing the manuscript.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication September 25, 2002.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press