Published online before print January 3, 2008, doi: 10.1161/STROKEAHA.107.495788
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(Stroke. 2008;39:421.)
© 2008 American Heart Association, Inc.
Original Contributions |
Temporal Thresholds for Infarction and Hypothermic Protection in Long-Evans Rats
Factors Affecting Apparent ‘Reperfusion Injury’ After Transient Focal Ischemia
From the Department of Neurology, University of Tennessee Health Science Center, Memphis, Tenn.
Correspondence to Thaddeus S. Nowak Jr, Department of Neurology, University of Tennessee, 855 Monroe Ave, Link 415, Memphis, TN 38163. E-mail tnowak{at}utmem.edu
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Abstract |
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Background and Purpose— Some previous studies in Long-Evans rats noted larger infarcts after transient middle cerebral artery (MCA) occlusions than after permanent occlusions, interpreted to demonstrate "reperfusion injury." Recent experiments failed to reproduce this phenomenon, prompting an investigation of the sources of variability in this animal model.
Methods— Male Long-Evans rats were subjected to surgical occlusion of the right MCA and ipsilateral common carotid artery. Variables tested included duration of occlusion and halothane anesthesia exposure and targeting of proximal or distal MCA occlusion sites. The temporal window for hypothermic protection was also investigated.
Results— MCA occlusions at the level of the rhinal fissure produced graded increases in infarct volume with ischemia duration, and lesion size did not differ between 3-hour and permanent occlusions independent of anesthesia duration. Occlusions at a more distal site produced infarcts of comparable size after transient 3-hour occlusions and after permanent occlusions accompanied by prolonged anesthesia, but significantly smaller infarcts were seen when permanent occlusions were followed by rapid anesthesia termination. Hypothermia conferred protection only when initiated before reperfusion after transient proximal occlusions.
Conclusions— These results indicate that previously described "reperfusion injury" after transient MCA occlusions conversely reflects unexpected injury reduction when rats with permanent occlusions experience early anesthesia termination. More rapid blood pressure recovery under such conditions permits improved collateral perfusion. The absence of a detectable postischemic window for hypothermic protection further argues against a significant component of delayed postreperfusion injury in this model.
Key Words: brain • focal ischemia • reperfusion injury • Long-Evans rat strain
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Introduction |
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The region of infarction after transient focal cerebral ischemia typically increases with occlusion duration, reaching a plateau volume equivalent to that seen after permanent occlusions.1,2 A striking exception was noted in some studies involving the Long-Evans rat strain, in which temporary occlusion of the middle cerebral artery (MCA) and ipsilateral common carotid artery (CCA) yielded infarct volumes notably larger than those produced by permanent occlusions, interpreted as evidence for "reperfusion injury" as a contributor to pathophysiology.3,4 Similar but less marked trends have sometimes been noted in Sprague-Dawley and Wistar strains.1,5 Initial studies from this laboratory replicated the observation of an anomalous temporal threshold relation in Long-Evans rats, under which conditions a more prolonged window for postischemic hypothermic protection was also noted.1 However, subsequent studies were negative, with large infarcts observed after permanent occlusions,6 and others have also used this strain in permanent-ischemia models.7 The present experiments were therefore designed to address potential sources of variability in the response to focal ischemia of Long-Evans rats.
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Materials and Methods |
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Ischemia Model
Male Long-Evans rats (260 to 300 g, n=209) were obtained from Harlan Laboratory Animals, Inc (Indianapolis, Ind). Animals were subjected to transient or permanent focal ischemia by tandem occlusion of the right MCA and CCA as previously described,8 in accordance with a protocol approved by the animal care and use committee, University of Tennessee Health Science Center. In brief, animals that had been fasted overnight were anesthetized with halothane, intubated, and ventilated with 0.5% to 1% halothane in 30% O2/70% N2, with temperature monitored and maintained by a rectal probe and feedback-controlled heating pad and heat lamp. (Isoflurane replaced halothane in a subset of follow-up perfusion and histology studies where indicated.) A tail artery was cannulated to allow continuous monitoring of mean arterial blood pressure and periodic sampling for blood gasses and glucose measurement. The carotid artery was isolated via a neck incision and either cauterized for permanent occlusions or fitted with a polytetrafluoroethylene/silicone elastomer occluding device for transient occlusions. The skull was exposed rostral to the zygoma, a burr hole was drilled, and the MCA was elevated
1 mm with use of a small micromanipulator-controlled hook. Brain surface temperature was kept at 37±0.1°C with a thermostated saline drip (SH-27B in-line heater with TC-324B controller; Warner Instruments, Inc, Hamden, Conn). Elevation of the MCA was maintained for the duration of temporary occlusions, or the artery was immediately cauterized to produce a permanent occlusion. For routine "proximal" occlusions, this was done at the level of the rhinal fissure, whereas "distal" occlusions were produced 3 mm dorsal to this position. Transient occlusions were terminated by lowering the MCA and releasing the carotid clasp. Incisions were closed, anesthesia was discontinued after intervals specified for individual experiments, and animals were weaned from the respirator, after which rectal temperature was monitored and maintained until spontaneous mobility returned.
Temperature Control and Modulation
Hypothermic protection was examined at various intervals of occlusion or during reperfusion, essentially as previously described.1,9 Cooling was achieved by resetting the control point for systemic temperature and packing the animals in ice to reach 32±0.2°C with a time course of 20 to 30 minutes. At the same time, the saline superfusate temperature setpoint was adjusted to 27°C, requiring 10 minutes to reach a mean temperature of 26.8±0.3°C in the saline pool overlying the exposed MCA. Stable hypothermia was maintained for various intervals as indicated for individual experiments, followed by removal of the saline drip, closure of the surgical site, and systemic warming over a period of 20 to 30 minutes. This procedure avoids the physiologic complications of deeper systemic hypothermia but when combined with superfusate cooling facilitates brain temperature reduction, achieving epidural temperatures in the range of 28°C to 30°C in the distal MCA territory. When applied during early reperfusion, this intervention is highly protective after transient focal ischemia, with persistent protection verified through 1 week.9
Perfusion Studies
Regional cerebral blood flow (CBF) was quantitatively assessed by autoradiography after injection of [14C]iodoantipyrine by an indicator fractionation method10 as recently detailed.11 In brief, animals were fitted with femoral arterial and venous cannulas during preparative surgery for occlusions. Tracer (15 µCi) in 0.4 mL saline was administered by bolus intravenous injection while arterial blood was withdrawn by syringe pump at a rate of 1 mL/min. After 6 seconds, the pump was stopped and the animal was simultaneously decapitated. The brain was rapidly frozen in hexane at –40°C, 20-µm cryostat sections were thaw-mounted on slides, and images were obtained on Kodak Biomax MR film. Images were captured and calibrated from blood radioactivity and coincidently imaged 14C standards.
Relative perfusion was monitored by laser Doppler flowmetry (LaserFlo BPM 403A, Vasamedics, Inc, St. Paul, Minn) with the probe positioned in an additional burr hole overlying the core MCA territory (5 mm lateral and 2.5 mm caudal to bregma).
Histologic Evaluation
Infarct volumes were routinely evaluated at 1-day survival, although a 3-day interval was examined in a small follow-up study. Animals were anesthetized and decapitated, after which brains were removed and rapidly frozen in hexane chilled to –40°C. Frozen sections (20 µm) were collected at 1-mm intervals through the MCA territory and stained with hematoxylin/eosin. Infarct volumes were determined from lesion areas summed across all intervals and corrected for edema swelling.12 Statistical comparisons involved ANOVA and Scheffe’ F test for multiple groups and an unpaired t test for 2 groups with use of StatView software (SAS Institute, Inc, Cary, NC), with P<0.05 considered significant. Data are presented graphically as mean±SD except for those documenting interactions between occlusion site and anesthesia duration, in which case a box plot illustrates the median (horizontal line), 25th to 75th percentiles (box), and 10th to 90th percentiles (brackets), as well as outliers.
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Results |
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Temporal Threshold for Infarction After MCA Occlusion
In initial studies, ischemia was produced as described for varied intervals, with consistent targeting of the MCA at the level of the rhinal fissure. In 1 series, all animals experienced a constant anesthesia duration of 3 hours after the onset of ischemia, corresponding to the duration required for the longest interval of transient occlusion, whereas in the other series, anesthesia was discontinued as quickly as possible after each surgical procedure was completed. Results for the 2 series, each carried out by a separate investigator, are compared in Figure 1. The 3-hour groups that, by design, experienced the same anesthesia duration in the 2 series exhibited comparable edema-corrected infarct volumes at 24 hours, and none of the other groups differed significantly between the series. Most important, 3-hour occlusions did not produce larger infarcts than those obtained after permanent occlusions, whether compared within each series or pooled (combined means, 96±29 vs 99±37 mm3, respectively). These results failed to provide evidence for an experimentally discernable component of "reperfusion injury" under the indicated conditions. Comparable results were obtained at a 3-day survival interval, with mean infarct volumes of 74±14 (n=5) and 85±27 (n=7) mm3 after 3-hour and permanent occlusions, respectively. The trend toward smaller lesions in both 3-day groups may reflect a better-maintained blood pressure during the isoflurane anesthesia used in the latter study, averaging 112±6 mm Hg versus the 80 to 90 mm Hg found under halothane anesthesia (the Table). No hemorrhagic transformation was evident at the survival intervals evaluated in these studies.
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Distal Occlusions and the Impact of Anesthesia Management
Experiments examining the interaction between occlusion site and anesthesia duration were carried out concurrently by the same investigator who performed the sustained-anesthesia component of the first study, and those 3-hour and permanent occlusion groups were included in the subsequent comparisons. Under conditions of prolonged anesthesia, more distal occlusions of the MCA did not substantially change the maximum infarct volumes that could be observed after either transient or permanent occlusions (Figure 2), although it increased the frequency of very small infarcts. However, this effect was more prominent when anesthesia was terminated immediately after surgery to produce permanent occlusions, significantly decreasing infarct volume in the distal group. Edema volumes averaged 40±6% of the total lesion and did not vary among groups. Physiologic parameters were consistently maintained during anesthesia in all groups (the Table). Inherent to the study design, animals subjected to sustained halothane exposure experienced a correspondingly longer interval of reduced blood pressure. However, in addition, blood pressure recovery 2 hours after anesthesia termination was blunted in those animals that experienced more prolonged exposure, reaching statistical significance for the transient-occlusion groups.
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Efficacy of Reperfusion
Quantitative autoradiographic measurement of CBF at 30 minutes’ reperfusion after 3-hour occlusions verified uniform hyperemia in the MCA territory in each of 3 animals evaluated (Figure 3, upper panel), with flow values of 101±31 and 273±90 mL/100 g per minute in the contralateral and ipsilateral cortex, respectively. Laser Doppler measurements during occlusion and early reperfusion likewise verified a hyperemic response in each of 4 animals examined, although this was very transient in 1 rat, in which intraischemic flow reduction had also been more modest (Figure 3, lower panel). In these follow-up studies carried out under isoflurane anesthesia, blood pressure was stably maintained at 110 mm Hg. However, a marked drop in perfusion seen in 1 animal was associated with an incidental interval of hypotension to 70 mm Hg. Although the changes in CBF were rapid, flow was closely coupled to blood pressure during both falling and rising components of this transient, demonstrating the sensitivity of postischemic CBF to blood pressure variation in the range encountered under halothane anesthesia in the initial histopathology study (the Table).
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Hypothermic Protection After Transient Focal Ischemia
To examine the temporal window for hypothermic protection under the conditions of these studies, animals were subjected to 2-hour transient "proximal" MCA/CCA occlusion with cooling initiated at varied intervals and for varied durations as indicated in Figure 4. Stable maintenance of physiologic variables during these studies is documented in the supplemental Table I, available online at http://stroke.ahajournals.org. For those groups that included an interval of postischemic cooling, preliminary analyses indicated no difference in outcome for hypothermia extending through 1- or 2-hour recirculation, and illustrated results therefore represent pooled data for these animals. Control animals experienced the same intervals of normothermic anesthesia after release of occlusion. Significant reductions in infarct volume were observed only when cooling was initiated during the interval of ischemia. Hypothermia initiated after the release of occlusion was no longer effective. This result fails to demonstrate a detectable postrecirculation window for hypothermic protection.
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Discussion |
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The present results indicate that increased infarct volume after transient relative to permanent occlusion, considered an operational definition of "reperfusion injury" in Long-Evans rats,4 rather involves an interaction between the occlusion site and anesthesia management in the model. No anomalies in the temporal threshold for infarction were apparent after MCA occlusion at the level of the rhinal fissure, independent of anesthesia duration (Figure 1). However, the frequency of small infarcts after more distal permanent occlusion was markedly increased when animals were released from anesthesia immediately after surgery (Figure 2). The absence of an extended postischemic protection window for brief hypothermia after transient proximal occlusions (Figure 4) is likewise now consistent with results previously obtained in other strains subjected to the same occlusion and cooling methods but fails to confirm earlier results suggesting a longer protection window in Long-Evans rats.1 Consideration must be given to the factors contributing to the current observations and their relevance to previous studies.
Outcome Modulation After Focal Ischemia
The importance of physiologic control and anesthesia management in experimental stroke is generally well recognized, primarily in the context of transient occlusions that typically involve longer procedures. Blood pressure reduction profoundly worsens outcome when extended below the autoregulatory range.13 Even modest hypotension, hypercapnia, and acidosis were associated with significantly increased infarct volumes and mortality in spontaneously breathing, anesthetized rats relative to those that were mechanically ventilated during focal ischemia.14 Conversely, blood pressure elevation during ischemia or early reperfusion can reduce insult severity.15–17 The effect observed here was not associated with differences in measured physiologic parameters during the surgical procedure, but blood pressure was detectably higher at 2 hours after termination in animals that experienced only brief halothane anesthesia (the Table). More important, these animals had recovered to a mean arterial blood pressure of 130 mm Hg at a time, relative to the onset of occlusion, when animals still under anesthesia remained at <90 mm Hg. Although anesthetics such as halothane can be themselves protective,18 perhaps in part due to vasodilatory effects and increased perfusion,19 timely increases in blood pressure appear to be of greater benefit under the conditions of this study. The efficacy of collateral perfusion would be greater during distal MCA occlusion, accounting in turn for the selective reduction in infarct volume observed in this group under conditions of rapid blood pressure recovery after brief anesthesia (Figure 2). Perfusion of the previously ischemic territory proved highly sensitive to blood pressure variation in the range encountered in these studies (Figure 3), and the higher blood pressure maintained under isoflurane anesthesia may also have contributed to the trend toward smaller infarcts noted in the 3-day survival study.
The present results further document the increasingly general observation that permanent occlusions in rat strains with sufficient collateral vascularization can be sensitive to interventions in the absence of overt reperfusion. Thus, a brief interval of cooling soon after permanent occlusion can be protective in Wistar1,20,21 and Sprague-Dawley22 but not spontaneously hypertensive1,23 rats. The N-methyl-D-aspartate receptor antagonist, MK-801, which globally increases CBF,24,25 demonstrates efficacy with a single early administration in a model of permanent MCA occlusion in Fischer-344 rats26 but not in spontaneously hypertensive rats.26,27
Conversely, results in the proximal-occlusion model essentially confirm previous demonstrations of experimentally accessible reperfusion injury with a very short temporal window, based on the protective efficacy of acute cooling initiated before reperfusion1,9 (group F in Figure 4), although protection remained just short of stringent statistical significance in this limited study. Comparable injury mechanisms may operate for a more protracted time course during permanent occlusions under conditions of robust collateral perfusion.
Comparisons With Previous Studies
Some notable differences in experimental procedures preclude direct comparison of the present work with those initially describing an anomalous temporal threshold in Long-Evans rats.4 However, these also offer a sound framework within which to interpret the contrasting conclusions reached. Perhaps the most critical difference is the use of chloral hydrate anesthesia without mechanical ventilation in the earlier experiments, a combination subsequently associated with particularly poor control of blood pressure and respiration.14 The 3- to 4-hour occlusion groups of the original study received a second dose to maintain anesthesia until recirculation, and the 5-hour group was reanesthetized at the time of occlusion release, in both cases prolonging the interval during which physiologic control was at risk.4 Blood pressure and blood gases were stated to have been monitored, but results were not presented. Temperature control was maintained during ischemia and the first hour of reperfusion, but the duration of monitoring and control after permanent occlusion was not specified. Based on the accumulating evidence in a number of rat strains noted above, any incidental cooling that might have occurred during sustained anesthesia in the initial hours after occlusion could also have contributed to reduced infarct volume in this group. Finally, although the site of MCA occlusion in the initial study corresponded closely to the more proximal site at the rhinal fissure targeted here, the previous study could have selected for those animals in which collateral perfusion had been better maintained, because animals exhibiting more severe injury associated with hemorrhagic transformation had been specifically excluded.4 It is important to note that when both carotid arteries were occluded, more severely limiting perfusion, permanent occlusions produced large infarcts in that study. Temporary bilateral CCA ligation accompanying permanent occlusion of the MCA is a common approach to modeling focal ischemia in Long-Evans rats,28 as well as in other strains with appreciable collateral perfusion.29 However, very proximal permanent occlusion of the MCA alone can produce infarcts in Long-Evans rats.7
Somewhat problematic is the discrepancy between the present results and those previously reported from this laboratory,1 which had in part replicated the original phenomenon and also noted an extended postischemic window for hypothermic protection in the Long-Evans model. The investigator who carried out those experiments had also obtained a more protracted temporal threshold relation in other rat strains (investigator A of that previous study) and among other potential variables could have systematically targeted a more distal occlusion site. A final source of variability to be considered is the strain itself. There is a growing literature documenting the sometimes striking heterogeneity in experimental stroke outcome among rats of a given outbred strain obtained from different colonies.6,30 Although noted variations in microvascular anastomoses among groups failed to predict the observed differences in infarct volume in 1 such study,30 anatomic heterogeneity of larger supplying vessels cannot be excluded. All animals used in the present study were obtained from the same source within a comparatively short time interval (6 months). This supplier had also provided the Long-Evans rats for both previous studies in which permanent occlusions had produced small infarcts,1,4 albeit years earlier. It was recently suggested that the anomalous circle of Willis anatomy that makes the Mongolian gerbil a simple model for the study of global cerebral ischemia had changed with time, reducing occlusion efficacy in a large population of commercially available animals.31 Although differences in experimental procedures remain the likely source of divergent results, a drift toward reduced capacity for collateral perfusion in the Long-Evans rats used in the present study, leading to more severe insults after proximal MCA/CCA occlusion, remains a formal possibility.
Conclusions
In summary, the phenomenology previously interpreted to reflect "reperfusion injury" could be reproduced in Long-Evans rats when insult severity was limited by more distal MCA occlusion. However, rather than demonstrating increased injury after reperfusion, this reflects a reduction in infarct size after permanent occlusion, associated with more rapid blood pressure recovery. This is consistent with diverse studies identifying an early postocclusion window during which outcome can be modulated in the absence of overt reperfusion in rat strains with the capacity for appreciable collateral perfusion. The precise physiologic, metabolic, and/or hemodynamic mechanisms that impact infarct evolution under such conditions remain to be identified. Nevertheless, these observations emphasize the need for stringent attention to experimental variables in stroke modeling.
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Acknowledgments |
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Source of Funding
This work was supported by US Public Health Service grant NS42267-TSN.
Disclosures
None.
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Footnotes |
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Dr Hashimoto is currently at the Department of Regenerative Medicine, National Research Institute for Child Health and Development, Tokyo, Japan.
Received June 6, 2007; accepted July 3, 2007.
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