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Canadian Journal of Anesthesia 53:194-201 (2006)
© Canadian Anesthesiologists' Society, 2006
Neuroanesthesia and Intensive Care

Isoflurane tolerance against focal cerebral ischemia is attenuated by adenosine A1 receptor antagonists

[La tolérance à l’isoflurane contre l’ischémie cérébrale focale est diminuée par les antagonistes des récepteurs de l’adénosine A1]

Yanhong Liu, MD, Lize Xiong, MD, Shaoyang Chen, MD and Qiang Wang, MD

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

Address correspondence to: Dr. Lize Xiong, Department of Anesthesiology, Xijing Hospital, Xi’an, Shaanxi Province 710032, China. Phone: +86-29-84775337; Fax: +86-29-83244986; E-mail: lxiong{at}fmmu.edu.cn


   Abstract
TOP
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Purpose: To investigate the role of the adenosine A1 receptor in the rapid tolerance to cerebral ischemia induced by isoflurane preconditioning.

Methods: Seventy-five rats were randomly assigned into five groups (n = 15 each): Control, 8-cyclopentyl-1,3-dipropulxanthine (DPCPX), Isoflurane, DPCPX+Isoflurane and Vehicle+Isoflurane groups. All animals underwent right middle cerebral artery occlusion (MCAO) for two hours. Isoflurane preconditioning was conducted one hour before MCAO in Isoflurane, DPCPX+Isoflurane and Vehicle+Isoflurane groups by exposing the animals to 1.5% isoflurane in 98% oxygen for one hour. In the Control and DPCPX groups, animals were exposed to 98% oxygen one hour before MCAO for one hour. A selective adenosine A1 receptor antagonist, DPCPX, was administered (0.1 mg·kg–1) 15 min before isoflurane/oxygen exposure in the DPCPX and DPCPX+Isoflurane groups to evaluate the effect of adenosine A1 receptor antagonist on isoflurane preconditioning. Dimethyl sulfoxide, the solvent of DPCPX, was administered (1 mL·kg–1) 15 min before isoflurane exposure in the Vehicle+Isoflurane group. Neurological deficit scores and brain infarct volumes were evaluated 24 hr after reperfusion.

Results: Animals in the Isoflurane and Vehicle+Isoflurane groups developed lower neurological deficit scores and smaller brain infarct volumes than the Control group (P < 0.01). Animals in the DPCPX+Isoflurane group developed higher neurological deficit scores and larger brain infarct volumes than the Isoflurane and Vehicle+Isoflurane groups (P < 0.01).

Conclusion: The present study demonstrates that preconditioning with isoflurane reduces focal cerebral ischemic injury in rats, and the adenosine A1 receptor antagonist (DPCPX) attenuates the neuroprotection induced by isoflurane preconditioning.


   Introduction
TOP
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
THE phenomenon of ischemic tolerance in the heart was first reported by Murry et al.1 in 1986. Four years later, the phenomenon in the brain was reported by Kitagawa et al.2 Since then, studies on the mechanism and potential clinical applications of the phenomenon have been intense. A pharmacological agent to induce cerebral ischemic tolerance before surgery would be valuable. Unfortunately most pharmacological or chemical agents that induce cerebral tolerance, such as lipopolysaccharide,3 tumour necrosis factor-{alpha},4 and interleukin-1,5 are limited in their application to patients due to their toxicity.

Isoflurane is a volatile anesthetic that is often used as a primary anesthetic agent during neurosurgical procedures. In a recent study of severe forebrain ischemia, isoflurane-anesthetized rats had a better histological outcome than those administered fentanyl-nitrous oxide.6 The neuroprotective effect persists beyond the time of isoflurane administration and has therefore been termed anesthetic- or isoflurane-induced tolerance. This emphasizes the similarity between the isoflurane-induced neuroprotection and ischemic tolerance, the neuroprotection conferred by transient, sublethal cerebral ischemia. Indeed, the mechanisms underlying isoflurane-induced tolerance are not completely known, but studies of myocardial ischemia have shown that isoflurane-induced tolerance shared several cellular mechanisms with ischemic tolerance including opening of adenosine triphosphate-sensitive potassium channels (KATP channels), an adenosine receptor-mediated pathway, and a protein kinase C (PKC)-mediated pathway.7,8

Involvement of adenosine A1 receptors and KATP channels in the development of cerebral ischemic tolerance induced by sublethal ischemia has been well studied. In our previous study, we found that glibenclamide, an adenosine triphosphate-regulated potassium channel blocker, abolished the tolerance to focal cerebral ischemia induced by repeated isoflurane anesthesia.9 Other findings suggest that adenosine receptor activity is modified by isoflurane and that adenosine receptor activation is a trigger by which KATP channels are activated.7,10 Based on these findings, we hypothesized that the adenosine A1 receptor activation is involved in the cerebral tolerance induced by isoflurane. Therefore, the present study was conducted to determine whether antagonism of the adenosine A1 receptor with 8-cyclopentyl-1,3-dipropulxanthine (DPCPX) attenuates the rapid cerebral tolerance induced by isoflurane preconditioning, in a rat model of focal cerebral ischemia and reperfusion.


   Methods
TOP
 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.

Experiment protocol
Seventy-five male Sprague-Dawley rats weighing 280 to 320 g were randomly assigned into five groups (n = 15 each) using the following randomization procedure. First, the rats were numbered from 1 to 75. Second, 75 random numbers were generated by a computer and each random number was assigned to a rat. The numbers were then arranged in numerical sequence. Rats in Control, DPCPX, Isoflurane, DPCPX+Isoflurane and Vehicle+Isoflurane (Figure 1Go) were 1 to 15, 16 to 30, 31 to 45, 46 to 60 and 61 to 75 respectively. All animals were subjected to transient focal cerebral ischemia by occlusion of the right middle cerebral artery for two hours. Isoflurane preconditioning was conducted one hour before cerebral ischemia in Isoflurane, DPCPX+Isoflurane and Vehicle+Isoflurane groups by exposing the animals to 1.5% Isoflurane in 98% oxygen for one hour. In the Control and DPCPX groups, animals were exposed to 98% oxygen one hour before cerebral ischemia for one hour. A selective adenosine A1 receptor antagonist, DPCPX (Sigma Chemical Co., St. Louis, MO, USA), was intraperitoneally administered (0.1 mg·kg–1) 15 min before isoflurane/oxygen exposure in the DPCPX and DPCPX+Isoflurane groups to evaluate the role of adenosine A1 receptor antagonist on isoflurane preconditioning. Dimethyl sulfoxide, the solvent of DPCPX, was intraperitoneally administered (1 mL·kg–1) 15 min before isoflurane exposure in the Vehicle+Isoflurane group. Neurological deficit scores and brain infarct volumes were evaluated 24 hr after reperfusion.


Figure 1
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  		FIGURE 1 Diagram of different experimental protocols. Iso = 1.5% Isoflurane (Iso) pretreatment for one hour; 8-cyclopentyl-1,3-dipropulxanthine (DPCPX) = ip 0.1 mg·kg–1 DPCPX was administered 15 min (0.25 hr) before 98% oxygen exposure for one hour; DPCPX+Iso = ip 0.1 mg·kg–1 DPCPX was administered 15 min (0.25 hr) before Iso pretreatment for one hour; Vehicle+Iso = ip 1 mL·kg–1 dimethyl sulfoxide (DMSO) was administered 15 min (0.25 hr) before Iso pretreatment for one hour.

 
Isoflurane or oxygen treatment was processed in an airtight container (50 cm x 30 cm x 20 cm) with an inlet and an outlet. The container was filled with 98% oxygen or 1.5% isoflurane in 98% oxygen according to the groups. The fresh gas flow was infused into the container at the rate of 4 L·min–1 via the inlet during the pretreatment. An anesthetic gas analyzer (Brüel & Kjae, Naerum, Denmark) was used to monitor the gas concentration inside. Soda lime was placed in the bottom of the container. The CO2 pressure inside was maintained lower than 1 mmHg during the treatment. The animals were kept spontaneously breathing during the pretreatment.

In a separate experiment, we measured the physiological variables in nine additional rats weighing 280 to 320 g during the isoflurane treatment. The animals were randomly assigned into one of three groups (n = 3 each): Isoflurane, DPCPX+Isoflurane and Vehicle+Isoflurane groups. Anesthesia was induced with 4% isoflurane and was maintained with 2% isoflurane delivered by a mask. The right femoral artery was cannulated for continuous monitoring of blood pressure and for arterial blood sampling. A rectal probe was inserted to monitor core temperature. After five minutes stabilization, animals were put into the container for isoflurane treatment (1.5% isoflurane in oxygen for one hour). Arterial blood gases and plasma glucose were measured five minutes before isoflurane treatment and at the end of the treatments.

Focal cerebral ischemia
The rats were fasted for 12 hr but were allowed free access to water before surgery. Anesthesia was induced with 4% isoflurane and was maintained with 2% isoflurane delivered by a mask. Focal cerebral ischemia was induced as described by Longa et al.11 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., Tokyo, 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 to 18 mm distal to the carotid bifurcation until a mild resistance was felt. Occlusion of the origins of the anterior cerebral artery, the middle cerebral artery, and the posterior communicating artery was thereby achieved. Reperfusion was accomplished by withdrawing the suture after 120 min of ischemia. After withdrawing the suture, the rats were returned to their cages with free access to food and water. The incision sites were infiltrated with 0.25% bupivacaine hydrochloride for postoperative analgesia. Rectal temperature was monitored (Spacelabs Medical Inc., Redmond, WA, USA) and maintained at 37.0 to 37.5°C by surface heating and cooling.

Neurological deficit score
The animals were neurologically assessed 24 hr after reperfusion by an investigator who was unaware of animal grouping. A six-point scale modified from that previously described by Longa et al.11 was used for neurological 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.

Infarct volume assessment
After the neurological assessment, the rats were reanesthetized with 4% isoflurane in oxygen and decapitated. The brains were rapidly removed and cooled in iced saline for ten minutes. Six 2-mm-thick coronal sections were cut with the aid of a brain matrix. Sections were incubated for 30 min in a 2% solution of 2, 3, 5-triphenyltetrazolium chloride at 37°C and fixed by immersion in a 10% buffered formalin solution. Unstained areas were defined as infarcted tissue. Brain slices on a piece of plotting paper were photographed with a digital camera (Kodak DC240, Eastman Kodak Co., Rochester, NY, USA) connected to a computer with an image analysis software (Adobe Photoshop 6.0.1, Windows). An investigator blinded to the experimental groups then outlined the zones of infarction, the zones of 1 mm2 from a piece of photographed plotting paper, as well as the outlines of both hemispheres in each section on the computer screen. The unstained areas and the areas of both hemispheres were calculated for each brain slice. The uncorrected infarct volume was calculated by measuring the unstained area in each slice, multiplying it by slice thickness, and then summating all six slices. The corrected infarct volume was calculated to compensate for the effect of cerebral edema. The difference between the areas of the right and the left hemisphere in a slice was considered to be edema and subtracted from the infarct area of that slice (corrected infarct volume = uncorrected infarct volume – [right hemisphere’s volume - left hemisphere’s volume]).12 The result was multiplied by slice thickness and all six slices were summated to find the total corrected infarct volume.

Statistical analysis
Physiological data and infarct volumes are expressed as mean ± SD. Physiological variables were analyzed using multivariate analysis of variance. The infarct volumes were analyzed by one-factor analysis of variance (ANOVA) followed by post hoc least significant difference test. Neurological deficit scores (NDS) were analyzed using Kruskal-Wallis test followed by the Mann-Whitney U test with Bonferroni correction. P < 0.05 was considered statistically significant.


   Results
TOP
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
No differences were found in the rectal temperature, mean arterial blood pressure, arterial pH, PaCO2, PaO2 and blood glucose values during treatment with 1.5% isoflurane among groups (Table IGo). Isoflurane tended to decrease mean arterial blood pressure and core temperature during the treatment period, but the reduction did not reach statistical significance. Arterial blood gases showed that there was no respiratory depression during isoflurane treatment. After recovery from isoflurane pretreatment, no animal showed abnormal behaviour.


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  		TABLE I Physiological variables
 
Focal cerebral ischemia was performed on 75 rats; all rats survived until 24 hr after reperfusion. Animals in Control and DPCPX groups developed severe neurological damage, with NDS of 2 (1–3) and 2 (1–4) respectively (Table IIGo). Isoflurane pretreatment reduced the neurological damage with the NDS of 1 (0–3) in Isoflurane and Vehicle+Isoflurane groups (P < 0.01 vs Control group). Administration of DPCPX before isoflurane treatment attenuated the neuroprotective effect of isoflurane with the NDS of 2 (1–3) in the DPCPX+Isoflurane group (P < 0.01 vs Isoflurane group).


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  		TABLE II Neurological deficit scores 24 hr after reperfusion from 120 min of MCAO in rats
 
The uncorrected and corrected brain infarct volumes are presented in Figure 2Go. Both the uncorrected and corrected infarct volumes in three isoflurane-treated groups were smaller than those of the Control group (uncorrected volume 287.2 ± 90.3 mm3 and corrected volume 217.3 ± 79.5 mm3). A significant reduction was observed in the Isoflurane group (uncorrected volume 137.4 ± 84.8 mm3 and corrected volume 106.5 ± 60.0 mm3) and the Vehicle+Isoflurane group (uncorrected volume 138.0 ± 84.2 mm3 and corrected volume 104.7 ± 60.9 mm3), (P < 0.01). The infarct volumes of DPCPX+Isoflurane group (uncorrected volume 250.1 ± 102.8 mm3 and corrected volume 191.0 ± 80.0 mm3) were significantly larger than those of the Isoflurane and Vehicle+Isoflurane groups (P < 0.01). Eight-cyclopentyl-1,3-dipropulxanthine treatment without isoflurane preconditioning in the DPCPX group did not change the infarct volume compared with the Control group.


Figure 2
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  		FIGURE 2 Uncorrected and corrected brain infarct volumes 24 hr after reperfusion from 120 min middle cerebral artery occlusion (MCAO). Data are presented as mean ± SD, and were analyzed by one-factor analysis of variance followed by post hoc least significant difference test. *P < 0.01 compared with the control, 8-cyclopentyl-1,3-dipropulxanthine (DPCPX) and DPCPX+Iso groups. Iso = pre-treatment with one hour of 1.5% isoflurane (Iso) in oxygen one hour before MCAO; Vehicle +Iso = administration of DMSO before pretreatment with one hour of 1.5% Iso in oxygen one hour before MCAO; DPCPX+Iso = administration of DPCPX before pretreatment with one hour of 1.5% Iso in oxygen one hour before MCAO; DPCPX = administration of DPCPX without Iso pretreatment.

 

   Discussion
TOP
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The purpose of the present study was to evaluate the beneficial effects of isoflurane preconditioning on focal cerebral ischemia in rats and whether the presence of DPCPX, a selective adenosine A1 receptor antagonist, would alter the effects of isoflurane preconditioning. The results show that brief preconditioning with isoflurane diminishes the focal cerebral ischemic injury with improved neurological outcome and reduced brain infarct volume in rats, and DPCPX attenuated the neuroprotective effect of isoflurane preconditioning.

It has been reported previously that preconditioning with volatile anesthetics such as isoflurane induces tolerance to myocardial ischemia.7,13 In our previous study, we found that repeated isoflurane anesthesia induced cerebral ischemic tolerance in rats in a dose-dependent manner.9 Kapinya et al. demonstrated that pretreatment with 1.4% isoflurane for three hours at zero, 12, and 24 hr before middle cerebral artery occlusion (MCAO) could induce neuroprotection in a rat focal cerebral ischemia model.14 The results of this study confirm our previous findings and those from Kapinya et al.14 Furthermore, we demonstrated that isoflurane preconditioning for one hour could induce acute tolerance to subsequent transient MCAO.

The concentration and duration of isoflurane inhalation chosen in this study were based on our previous report.9 The concentration of 1.5% isoflurane equals 1.0 minimum alveolar anesthetic concentration.15,16 To exclude the possible influence of hypotension, hypothermia, or respiratory depression on the beneficial effects of isoflurane, we measured the physiological variables during isoflurane pretreatment. The results showed no obvious changes in physiological variables during isoflurane preconditioning. In the present study, we did not measure the cerebral blood flow after the occlusion of the middle cerebral artery. In previous reports, it has been demonstrated that cerebral blood flow does not explain the beneficial effects of isoflurane on outcome from near-complete forebrain ischemia in rats.17

In the brain, preconditioning required several hours to develop. However, recent studies suggest that rapid preconditioning with a time course similar to that in the heart, can protect synaptic activity after anoxia in the brain slices and after ischemia in the intact brain.18–20 The similarities in time course for preconditioning in the heart and brain suggest that preconditioning mechanisms may be similar in both organs. This assumption was supported by findings that activation of KATP channel plays important roles both in the cardiac and cerebral preconditioning.21–24 The possible involvement of adenosine A1 receptors as mediators of cardiac preconditioning has been proven by studies in several animal models.7,25,26 It has been suggested that adenosine receptors may be activated by preconditioning and, in turn, activate KATP channels, possibly through an intermediate such as PKC.27,28 Whether adenosine receptors play important roles in isoflurane preconditioning in cerebral ischemia is unclear. Nevertheless, as a ubiquitous neuromodulator, adenosine and its analogue have been proposed frequently as candidates for clinical development in treatment of cerebral ischemia and stroke. Substantial studies have shown that pre- and postischemic administration of these drugs result in a significant reduction of postischemic brain damage while A1 receptor antagonists blocked such neuroprotection effect induced by adenosine and its analogue.29–31 We hypothesized that adenosine and the adenosine A1 receptor were essential for the induction of ischemic tolerance induced by isoflurane preconditioning in the brain. The results of the present study prove that the neuroprotection induced by isoflurane pretreatment was significantly attenuated by DPCPX.

Besides activating PKC and KATP channels, the activation of the adenosine receptor could also inhibit neurotransmitter release, stabilize the membrane potential and limit postsynaptic depolarization.25,32,33 It has been suggested that excitatory amino acids are involved in the induction of ischemic/hypoxic damage in the brain. Excitatory amino acids are released immediately after ischemic injury, and they induce a sequence of changes ranging from excessive membrane depolarization to a rise in intracellular Ca2+ level which leads to cell death. Selective agonists of A1 receptors, such as 2-chloroadenosine, R-N6-phenylisopropyloadenosine, cyclohexyladenosine or N6-cyclopentyladenosine, given either systemically or locally into the striatum or hippocampus attenuate the neuronal loss induced by non-depolarizing blocking agents, kainate, quisqualate or ibotenate. On the other hand, adenosine receptor antagonists such as DPCPX exacerbate the neurotoxic effect of kainic acid in the hippocampus.34 Therefore, it seems that, as in animal models of ischemia/hypoxia, A1 receptor agonists exert neuroprotective effects on the excitatory amino acid-induced excitotoxicity, a process which has been implicated in a variety of neuropathological conditions.35

The ischemic model used in our experiments is widely accepted.3,9,12,36 In the present study, the infarct areas were measured by using Adobe Photoshop, the method was also used for measuring the infarct areas in the heart.37 Many other image analysis softwares are used for measuring the infarct areas in different experiments.3,12,14 In our experiment, two hours of MCAO in control animals resulted in the infarct volume of 217.3 ± 79.5 mm3 (corrected infarct volume), which is similar with the infarct volume of 210.39 ± 31.25 mm3 (corrected infarct volume) after two hours of MCAO in another report.36

The isoflurane-induced rapid tolerance to cerebral ischemia might be used to manage patients undergoing surgical procedures in which cerebral ischemia may occur. The results of the present study also provide a clue for further preclinical studies on the possibility of developing selective agonists of the adenosine A1 receptors as neuroprotective agents. However, substantially more information on isoflurane-induced tolerance and the agonists of adenosine A1 receptors must be obtained before these indications can be advocated in humans.

In conclusion, isoflurane preconditioning induces neuroprotection to subsequent transient MCAO in rats, and administration of the adenosine A1 receptor antagonist (DPCPX), shortly before isoflurane pretreatment, significantly attenuates the beneficial effects of isoflurane. Our work suggests that isoflurane-induced ischemic tolerance in the brain may depend on the activation of adenosine A1 receptors.


   Footnotes
 
This work was supported by the National Natural Science Foundation of China (grant 30170907 and grant 30471664 to Lize Xiong).

Accepted for publication May 25, 2005. Revision accepted September 8, 2005.


   References
TOP
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986; 74: 1124–36.[Abstract/Free Full Text]

2 Kitagawa K, Matsumoto M, Tagaya M, et al. ‘Ischemic tolerance’ phenomenon found in the brain. Brain Res 1990; 528: 21–4.[Medline]

3 Bordet R, Deplanque D, Maboudou P, et al. Increase in endogenous brain superoxide dismutase as a potential mechanism of lipopolysaccharide-induced brain ischemic tolerance. J Cereb Blood Flow Metab 2000; 20: 1190–6.[Medline]

4 Ginis I, Schweizer U, Brenner M, et al. TNF-alpha pre-treatment prevents subsequent activation of cultured brain cells with TNF-alpha and hypoxia via ceramide. Am J Physiol 1999; 276: C1171–83.

5 Ohtsuki T, Ruetzler CA, Tasaki K, Hallenbeck JM. Interleukin-1 mediates induction of tolerance to global ischemia in gerbil hippocampal CA1 neurons. J Cereb Blood Flow Metab 1996; 16: 1137–42.[Medline]

6 Mackensen GB, Nellgard B, Miura Y, et al. Sympathetic ganglionic blockade masks beneficial effect of isoflurane on histologic outcome from near-complete forebrain ischemia in the rat. Anesthesiology 1999; 90: 873–81.[Medline]

7 Roscoe AK, Christensen JD, Lynch C III. Isoflurane, but not halothane, induces protection of human myocardium via adenosine A1 receptors and adenosine triphosphate-sensitive potassium channels. Anesthesiology 2000; 92: 1692–701.[Medline]

8 Aizawa K, Turner LA, Weihrauch D, Bosnjak ZJ, Kwok WM. Protein kinase C-epsilon primes the cardiac sarcolemmal adenosine triphosphate-sensitive potassium channel to modulation by isoflurane. Anesthesiology 2004; 101: 381–9.[Medline]

9 Xiong L, Zheng Y, Wu M, et al. Preconditioning with isoflurane produces dose-dependent neuroprotection via activation of adenosine triphosphate-regulated potassium channels after focal cerebral ischemia in rats. Anesth Analg 2003; 96: 233–7.[Abstract/Free Full Text]

10 Gassmayr S, Stadnicka A, Suzuki A, Kwok WM, Bosnjak ZJ. Isoflurane sensitizes the cardiac sarcolemmal adenosine triphosphate-sensitive potassium channel to pinacidil. Anesthesiology 2003; 98: 114–20.[Medline]

11 Longa EZ, Weinstein PR, Carlson S, Cummins R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 1989; 20: 84–91.[Abstract/Free Full Text]

12 Tatlisumak T, Takano K, Carano RA, Miller LP, Foster AC, Fisher M. Delayed treatment with an adenosine kinase Inhibitor, GP683, attenuates infarct size in rats with temporary middle cerebral artery occlusion. Stroke 1998; 29: 1952–8.[Abstract/Free Full Text]

13 Kersten JR, Schmeling TJ, Pagel PS, Gross GJ, Warltier DC. Isoflurane mimics ischemic preconditioning via activation of KATP channels. Reduction of myocardial infarct size with an acute memory phase. Anesthesiology 1997; 87: 361–70.[Medline]

14 Kapinya KJ, Lowl D, Futterer C, et al. Tolerance against ischemic neuronal injury can be induced by volatile anesthetics and is inducible NO synthase dependent. Stroke 2002; 33: 1889–98.[Abstract/Free Full Text]

15 Engelhard K, Werner C, Reeker W, et al. Desflurane and isoflurane improve neurological outcome after incomplete cerebral ischaemia in rats. Br J Anaesth 1999; 83: 415–21.[Abstract/Free Full Text]

16 Russell GB, Graybeal JM. Differences in anesthetic potency between Sprague-Dawley and Long-Evans rats for isoflurane but not nitrous oxide. Pharmacology 1995; 50: 162–7.[Medline]

17 Mackensen GB, Nellgard B, Kudo M, Sheng H, Pearlstein RD, Warner DS. Periischemic cerebral blood flow (CBF) does not explain beneficial effects of isoflurane on outcome from near-complete forebrain ischemia in rats. Anesthesiology 2000; 93: 1102–6.[Medline]

18 Nakamura M, Nakakimura K, Matsumoto M, Sakabe T. Rapid tolerance to focal cerebral ischemia in rats is attenuated by adenosine A1 receptor antagonist. J Cereb Blood Flow Metab 2002; 22: 161–70.[Medline]

19 Perez-Pinzon MA, Born JG. Rapid preconditioning neuroprotection following anoxia in hippocampal slices: role of the K+ATP channel and protein kinase C. Neuroscience 1999; 89: 453–9.[Medline]

20 Perez-Pinzon MA, Born JG, Centeno JM. Calcium and increase excitability promote tolerance against anoxia in hippocampal slices. Brain Res 1999; 833: 20–6.[Medline]

21 Tanaka K, Weihrauch D, Ludwig LM, Kersten JR, Pagel PS, Warltier DC. Mitochondrial adenosine triphosphate-regulated potassium channel opening acts as a trigger for isoflurane-induced preconditioning by generating reactive oxygen species. Anesthesiology 2003; 98: 935–43.[Medline]

22 Zaugg M, Lucchinetti E, Spahn DR, Pasch T, Schaub MC. Volatile anesthetics mimic cardiac preconditioning by priming the activation of mitochondrial KATP channels via multiple signaling pathways. Anesthesiology 2002; 97: 4–14.[Medline]

23 Yoshida M, Nakakimura K, Cui YJ, Matsumoto M, Sakabe T. Adenosine A1 receptor antagonist and mitochondrial ATP-sensitive potassium channel blocker attenuate the tolerance to focal cerebral ischemia in rats. J Cereb Blood Flow Metab 2004; 24: 771–9.[Medline]

24 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.[Abstract/Free Full Text]

25 Hiraide T, Katsura K, Muramatsu H, Asano G, Katayama Y. Adenosine receptor antagonists cancelled the ischemic tolerance phenomenon in gerbil. Brain Res 2001; 910: 94–8.[Medline]

26 Reichelt ME, Willems L, Molina JG, et al. Genetic deletion of the A1 adenosine receptor limits myocardial ischemic tolerance. Circ Res 2005; 96: 363–7.[Abstract/Free Full Text]

27 Cleveland JC Jr, 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.[Medline]

28 Phillis JW, Goshgarian HG. Adenosine and neurotrauma: therapeutic perspectives. Neurol Res 2001; 23: 183–9.[Medline]

29 Deckert J, Gleiter CH. Adenosine–an endogenous neuroprotective metabolite and neuromodulator. J Neural Transm Suppl 1994; 43: 23–31.[Medline]

30 Von Lubitz DK, Beenhakker M, Lin RC, et al. Reduction of postischemic brain damage and memory deficits following treatment with the selective adenosine A1 receptor agonist. Eur J Pharmacol 1996; 302: 43–8.[Medline]

31 Von Lubitz DK, Lin RC, Bischofberger N, et al. Protection against ischemic damage by adenosine amine congener, a potent and selective adenosine A1 receptor agonist. Eur J Pharmacol 1999; 369: 313–7.[Medline]

32 Dolphin AC, Archer ER. An adenosine agonist inhibits and a cyclic AMP analogue enhances the release of glutamate but not GABA from slices of rat dentate gyrus. Neurosci Lett 1983; 43: 49–54.[Medline]

33 Toller WG, Montgomery MW, Pagel PS, Hettrick DA, Warltier DC, Kersten JR. Isoflurane-enhanced recovery of canine stunned myocardium: role for protein kinase C? Anesthesiology 1999; 91: 713–22.[Medline]

34 Matsuoka Y, Okazaki M, Takata K, et al. Endogenous adenosine protects CA1 neurons from kainic acid-induced neuronal cell loss in the rat hippocampus. Eur J Neurosci 1999; 11: 3617–25.[Medline]

35 Wardas J. Neuroprotective role of adenosine in the CNS. Pol J Pharmacol 2002; 54: 313–26.[Medline]

36 Thiyagarajan M, Sharma SS. Neuroprotective effect of curcumin in middle cerebral artery occlusion induced focal cerebral ischemia in rats. Life Sci 2004; 74: 969–85.[Medline]

37 Yamamoto S, Yang G, Zablocki D, et al. Activation of Mst1 causes dilated cardiomyopathy by stimulating apoptosis without compensatory ventricular myocyte hypertrophy. J Clin Invest 2003; 111: 1463–74.[Medline]




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