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(Stroke. 1998;29:690-694.)
© 1998 American Heart Association, Inc.

Original Contributions

Susceptibility to Cerebral Infarction in the Stroke-Prone Spontaneously Hypertensive Rat Is Inherited as a Dominant Trait

Julie A. Gratton, PhD; Andre Sauter, PhD; Markus Rudin, PhD; Kennedy R. Lees, MD, FRCP; John McColl, MSc; John L. Reid, MD, FRCP; Anna F. Dominiczak, MD; I. Mhairi Macrae, PhD

From the Wellcome Surgical Institute (J.A.G., I.M.M.), the Department of Medicine and Therapeutics (K.R.L., J.L.R., A.F.D.), and the Department of Statistics (J.M.) of the University of Glasgow (Scotland) and Novartis Pharma Ltd. (A.S., M.R.), Basel, Switzerland.

Correspondence to I. Mhairi Macrae, PhD, Wellcome Surgical Institute & Hugh Fraser Neuroscience Laboratories, University of Glasgow, Garscube Estate, Glasgow G 61, 1QH, Scotland, UK. E-mail m.macrae{at}udcf.gla.ac.uk

	Abstract

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Background and Purpose—Susceptibility to cerebral infarction was compared in stroke-prone spontaneously hypertensive (SHRSP), normotensive Wistar-Kyoto (WKY) rats, and F₁ hybrids derived from a SHRSP/WKY cross.

Methods—The proximal left middle cerebral artery (MCA) was occluded under anesthesia and infarct volume assessed 24 hours later by magnetic resonance imaging and confirmed 5 days later by quantitative histopathology. Total hemispheric infarct volume was expressed as a percentage of the total brain volume.

Results—Infarct volumes measured by MRI in adult SHRSP (19.5±2.0%) and F₁ hybrid rats (19.4±1.9%) were significantly greater than in WKY (11.1±2.4; CI [6.07, 10.76]) and (5.93, 10.52), respectively, P<.001). Sensitivity to an ischemic insult was unrelated to blood pressure: although systolic blood pressures differed between young versus adult male SHRSP and between female versus male SHRSP and F₁ hybrids, infarct volumes were equal. A close correlation was found between infarct volumes measured by MRI and histology (r=.92, P<.0001).

Conclusions—Outcome to MCA occlusion (MCAO) measured with MRI provides a reproducible and nonterminal quantitative phenotypic marker of stroke susceptibility in the SHRSP. This is the first study to employ MCAO with MRI to quantify stroke susceptibility in F₁ hybrid rats and indicates a dominant mode of inheritance for this phenotype.

Key Words: cerebral infarction • genetics • hypertension • magnetic resonance imaging

	Introduction

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Permanent MCAO is the definitive model of focal cerebral ischemia.^{1 2} SHR and SHRSP have much larger and less variable infarcts after MCA occlusion than all other rat strains.^{3 4 5} Furthermore, this increased sensitivity to cerebral ischemia, which we believe is genetically determined, may be unrelated to hypertension because SHR and SHRSP suffer large infarcts at 5 weeks of age before hypertension and vascular hypertrophy are fully established.^{6 7} Studies by Coyle and coworkers suggested that in the SHRSP susceptibility to infarction was inherited as an autosomal recessive trait and that decreased luminal diameters in vascular anastomoses between the MCA and anterior cerebral artery were responsible for the pathophysiology.^{8 9} The importance of vascular anastomoses and genetic predisposition rather than blood pressure alone was stressed further by evidence that rats made hypertensive by deoxycorticosterone acetate and salt administration failed to develop large infarcts after MCA occlusion,³ whereas adult SHR and SHRSP, in which hypertension had been treated early, still developed large infarcts.^{10 11}

The analysis of previous data therefore suggests that the large infarcts induced by MCAO were due to inadequate collateral blood flow and that this phenotype is genetically associated with but not directly linked to hypertension.¹² This implies that a gene marker or markers for infarct susceptibility may exist both in animal models and perhaps also in humans. Rubattu and coworkers¹³ recently performed a genome-wide screening approach to an SHRSP/SHR cross using an alternative phenotype, latency to stroke after salt loading, as a marker of stroke proneness. They identified three major loci that contributed significantly to the variance of this stroke phenotype in F₂ hybrids. Thus, in SHRSP, primary blood pressure–independent genetic factors may play a critical role in both stroke onset and increased susceptibility to infarction.

Previous studies in SHR and SHRSP used histological methods to assess infarct size. These methods are very time-consuming, difficult to perform in the large number of animals required for genetic cosegregation analysis, and involve a terminal end point. In the current study, MRI was used to measure infarct volume after MCAO both in adult (24-week-old) and young (9-week-old) SHRSP, in their normotensive reference strain—the WKY rat, and in adult F₁ hybrids obtained by crossing SHRSP and WKY rats. Quantitative histology at 5 days postischemia was carried out to confirm the sensitivity and accuracy of the MRI measurements.

A preliminary report of these results has been published in abstract form.¹⁴

	Materials and Methods

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Experimental Animals
Inbred colonies of SHRSP and WKY rats have been maintained in the Department of Medicine and Therapeutics at the University of Glasgow since 1991.¹⁵ The breeding animals were a gift from Dr D.F. Bohr at the University of Michigan where they have been maintained as inbred colonies for more than 15 years. F₁ hybrids were produced by mating two SHRSP females with one WKY male. SHRSP, WKY, and F₁ hybrids were weaned at 4 weeks, divided by sex, and maintained in family groups (3 to 4 per cage) in constant temperature at 21°C and 12-hour light/dark cycle (7 AM to 7 PM). SBP and heart rate were measured in all animals by plethysmography as previously described.¹⁶ To verify these physiological measurements, littermates of SHRSP, WKY, and F₁ hybrids underwent direct blood pressure and heart rate recordings using a telemetry system.¹⁶ MCAO was performed on SHRSP and WKY at 9 weeks (SHRSP, n=15; WKY, n=10) and 24 weeks (SHRSP, n=10, WKY, n=9) of age. F₁ hybrids underwent MCAO at 24 weeks of age (n=11). All experiments were carried out in accordance with institutional and Home Office guidelines.

Surgical Intervention to Produce MCA Occlusion
Rats were anesthetized with isoflurane (1% to 2%) in oxygen–nitrous oxide (1:2) via a face mask. The left MCA was permanently occluded by electrocoagulation using the technique of Tamura et al¹ with minor modifications.¹⁷ Anesthesia was given for no longer than 15 minutes.

MRI
A Biospec 47/15 spectrometer (Bruker) with imaging facility was used. The radiofrequency probe was a home-built Alderman-Grant type resonator¹⁸ with a 40-mm inner diameter and a length of 50 mm. Twelve coronal sections, 1 mm thick, that covered the whole forebrain were taken 24 hours after MCAO using a spin echo (SE) sequence with an echo delay of 60 ms and a repetition delay of 2000 ms (SE 2000/60). The spatial resolution in the imaging plane (pixel dimension) was 0.16x0.16 mm² (field of view=40 mm). Further experimental details are described elsewhere.^{17 19} Infarct area in each section was determined using a semiautomated segmentation procedure based on intensity thresholding. Regional resolution into cortical and striatal infarction involved interactive drawing of a borderline between the respective structures prior to intensity thresholding. The infarct size determined either by thresholding alone or by adding up cortical and striatal values yielded identical numbers within error limits. The total infarct volume was calculated by summation of the number of pixels in each slice and multiplication by the pixel size and slice thickness. Infarct volumes generated by MRI and histology were expressed as a percentage of total brain volume to account for brain swelling and differences in brain size between sexes and strains. Image analysis was carried out by a person unaware of strain, age, or sex of the animal.

Histology
Five days after MCAO, the rats were decapitated, and their brains removed and immediately frozen on a block of dry ice. Coronal cryostatic sections 20 µm thick were cut at 12 equidistant levels (1 mm apart, covering the entire forebrain), mounted on glass slides, and stained with cresyl violet. The area of infarct in each section was determined using a calibrated digitizing tablet from a video-image analyzer. The sum of the infarct areas in the twelve sections, multiplied by the slice thickness, was taken as total infarct volume. All infarct volumes have been expressed as a percentage of the total brain volume.

Statistical Analyses
The effects of systolic blood pressure, sex, strain, and age on infarct volume established by MRI were examined using ANOVA and ANCOVA. The Table displays the sample mean±SEM of SBP and infarct volume for all groups of rats. Since no data were available from young F₁ rats, two main analyses were required. In the first, the (population) mean infarct volumes for adult and young SHRSP and WKY rats were compared. In the second, (population) mean infarct volumes of adult SHRSP, WKY, and F₁ rats were compared.

View this table: [in this window] [in a new window]   Table 1. Mean Blood Pressure and Infarct Volumes in All Groups

Both sets of analyses began by fitting a model containing all main effects and interactions. Nonsignificant effects were then eliminated beginning with the highest-order interaction or interactions. The final model included all statistically significant interactions along with lower-order terms in the same variables. Multiple comparisons were investigated using Tukey's method with an overall 95% confidence level.

A paired t test was used to compare infarct volumes obtained by MRI with infarct volumes obtained by quantitative histology.

	Results

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Lack of Influence of BP on Infarct Volume in Adult and Young Parental Strains
The relationship between infarct volume and blood pressure can be judged from the Table. This shows that infarct volumes are much smaller for the WKY rats (of both sexes and all ages) than for the SHRSP and F₁ rats, which also generally have higher blood pressures. There is, however, no evidence of a correlation between infarct volume and blood pressure within any group of rats: (adult SHRSP r=.360, P=.307; adult WKY r=-.245, P=.526; young SHRSP r=.262, P=.346; young WKY r=.039, P=.921; F₁ hybrids r=-.275, P=.414).

When the full ANCOVA model was fitted to the data for young and adult SHRSP and WKY rats, no single term involving blood pressure was statistically significant. Subsequent removal of these terms, beginning with the highest-order interaction, did not result in lower-order terms involving blood pressure becoming significant.

Consequently, a model was fitted that did not include the main effect of blood pressure, or any interaction involving blood pressure. This reduced model was tested within the full model previously fitted, and was not rejected (F=0.425, df=8, 28, P=.90). It was concluded that blood pressure did not influence infarct volume, on average, in any group of rats.

The reduced model was an ANOVA model in three explanatory variables, namely strain, age (adult or young), and sex. No individual term involving sex was statistically significant and, after checking intermediate models, all of these terms were removed. Again, this reduced model was tested within the previous model and was not rejected (F=0.627, df=4, 36, P=.63). It was concluded that there was no difference, on average, between infarct volumes for male and female rats in either age group of either strain. Consequently, data for both sexes were combined for further comparisons of age groups and strains.

Sensitivity to Ischemic Insult in Adult and Young Parental Strains
In the reduced ANOVA model, which included only strain and age group, the interaction term was not statistically significant (P=.214), but the main effects of both strain and age were statistically significant. Mean infarct volumes were significantly greater in SHRSP than in WKY rats in the same age group (95% confidence interval [7.96 to 10.96], P<.001). Also, overall mean infarct volumes were significantly greater in adult rats than in young rats (95% confidence interval [0.25 to 3.25], P=.023).

Lack of Influence of Blood Pressure on Infarct Volume in Adult Parental and F₁ Hybrids
Again, when a full ANCOVA model was fitted to the data from adult rats of all three strains, no term involving blood pressure was statistically significant. Proceeding as before, a reduced model that omitted all the terms involving blood pressure was tested within the full model, and was not rejected (F=0.811, df=6, 18, P=.58). We concluded that blood pressure did not influence infarct volume, on average, in any group of adult rats.

In the reduced ANOVA model, which included sex and strain only, neither the interaction term nor the main effect of gender was statistically significant. A reduced (one-way) ANOVA model in strain alone was tested within the previous model and was not rejected (F=0.441, df=5, 24, P=.82). We concluded that there was no difference, on average, between infarct volumes for male and female rats in any strain of adult rat. Consequently, data for both sexes were combined for a further analysis of the three strains.

Sensitivity to Ischemic Insult in Adult Parental and F₁ Hybrids
There was a highly significant effect of strain on the average infarct volume (P<.001). Simultaneous confidence intervals for all pairwise comparisons showed that adult SHRSP had a significantly greater mean infarct volume than adult WKY rats(confidence interval 6.07 to 10.76). Adult F₁ rats, too, had a significantly higher mean infarct volume than adult WKY rats (confidence interval 5.93 to 10.52). There was no significant difference between the mean infarct volumes of adult SHRSP and F₁ rats (confidence interval –2.03 to 2.42); indeed the sample mean infarct volumes of these two groups were virtually identical (see Table).

MRI Correlated With Histology
The use of MRI for mapping infarct volume was validated by comparison with measurements made by quantitative histology 4 days after the animals were initially imaged by MRI. Fig 1 illustrates the strong association between the two measurements in adult and young SHRSP and WKY rats, which generated a sample correlation coefficient of r=.92 (P<.0001).

View larger version (15K): [in this window] [in a new window]   Figure 1. Scattergram illustrating the significant correlation between infarct volume measured by MRI and histology.

Although this indicates that the two measures were strongly related, it should be noted that the MRI measurement was greater than the histological measurement in almost every rat because of acute edema of the infarcted area at 24 hours, which would have resolved to a certain extent by 5 days postischemia. A 95% confidence interval for the mean paired difference between the MRI and histological measurements on the same rat is 4.35 to 5.72, P<.0001.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References Introduction  References

 
Infarct volume after MCA occlusion is a highly relevant phenotype for demonstrating sensitivity to an ischemic insult. MRI is a precise, nonterminal method for quantitation of infarct volume. The current study is the first to demonstrate that combination of this phenotype and technique provides a very powerful means of investigating the genetics of stroke.

The present results confirm the bimodal distribution of the MCAO phenotype in parental SHRSP and WKY strains (Fig 2), which has been reported previously.^{3 4 5 6 7 8} Two further important findings are presented. First, a number of results in this study support the hypothesis that sensitivity to an ischemic insult in the SHRSP is independent of blood pressure: (1) SBP is significantly lower in young versus adult male SHRSP while there is no difference in infarct volume; (2) in young animals, before hypertension is established, there is no significant difference in SBP in male SHRSP and WKY but infarct volume is significantly greater in the SHRSP; and (3) in adult SHRSP and F₁ hybrids, SBP is significantly higher in males than females but there is no sex-related difference in infarct volume.

View larger version (49K): [in this window] [in a new window]   Figure 2. A, Representative T2-weighted MRI images obtained 24 hours after MCA occlusion in adult SHRSP and WKY rats. B, Comparison of infarct volumes (mean±SEM) measured by MRI 24 hours post-MCAO in adult and young SHRSP and WKY, *P<.001.

The second and most interesting finding is that the distribution of infarct volumes in F₁ rats was virtually identical to the distribution in the SHRSP, strongly suggesting a dominant mode of inheritance for this phenotype. The significance of this finding has prompted a genome-wide screen in F₂ hybrids (F₁xF₁ cross) to investigate genetic markers for stroke severity.²⁰ Previous studies that examined the genetics of stroke in the SHRSP include an earlier cosegregation study by Coyle et al in which focal ischemia was used to characterize the stroke-prone phenotype⁸ and two studies^{13 21} in which an alternative phenotype was used, latency to stroke on a high salt diet. Coyle's studies suggested a single recessive gene was responsible for the pathogenesis of stroke in the SHRSP. Possible reasons for the different conclusion from the current study may include their use of outbred normal Wistar rats instead of inbred WKY rats and the possibility that there was a less severe, more distal occlusion in much younger animals (F₁ hybrids 8 to 12 weeks old). When they used latency to stroke, Nagaoka et al²¹ reported this phenotype to be characterized by a polygenic inheritance and more recently, Rubattu et al¹³ performing a genome-wide screen on an F₂ cross (SHRSPxSHR) identified three major quantitative trait loci that together accounted for 28% of the overall phenotypic variance. However, it should be stated that the genes responsible for the latency to stroke with a high salt diet may be quite independent of those that determine the size of infarct after cerebral vessel occlusion (ischemic sensitivity genes).

A number of hypotheses have been put forward to explain the increased ischemic sensitivity in the SHRSP. The most commonly cited hypotheses propose that the SHRSP exhibit arterial hypertrophy in cerebral arteries, resulting in decreased functional compliance with limited dilatation to ischemia. This may be particularly important in collateral vessels where a reduction in anastomotic diameter would result in collateral flow impairment during ischemia. In support of this, MCAO in normotensive animals is associated with a marked increase in nitric oxide release in the ischemic region.²² Since central nervous system nitric oxide synthase activity is reduced in SHRSP compared with WKY,²³ defective nitric oxide release may be a contributory factor in the impaired collateral perfusion of the ischemic area in SHRSP. In addition, SHRSP may also demonstrate an intensified inflammatory response to the ischemic insult that could further compromise flow.²⁴ Indirect evidence for an impaired collateral supply comes from neuroprotection studies in hypertensive strains in which drugs with flow-enhancing properties (eg, L-type calcium channel blockers) are found to be more effective than NMDA glutamate antagonists with proven efficacy in normotensive strains.^{25 26}

The present findings are consistent with a dominant mode of inheritance for ischemic sensitivity in the SHRSP. Recent studies from our laboratory²⁰ and from Rubattu and coworkers¹³ provide strong evidence for the existence of primary blood pressure independent genetic factors which influence both latency to stroke¹³ and sensitivity to an ischemic insult²⁰ in the SHRSP. Whether outcome to stroke has a genetic basis in man needs to be examined further but such research should be strongly encouraged in view of these results.

	Selected Abbreviations and Acronyms

 

MCA = middle cerebral artery MCAO = MCA occlusion SBP = systolic blood pressure SHR = spontaneously hypertensive rat SHRSP = stroke prone SHR substrain WKY = Wistar-Kyoto

	Acknowledgments

 
This work was funded by the Wellcome Trust (Grant No. 045924/95) and the Cunningham Trust. Dr Dominiczak is a British Heart Foundation Senior Research Fellow.

Received October 3, 1997; revision received December 5, 1997; accepted January 5, 1998.

	References

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1. Tamura A, Graham DI, McCulloch J, Teasdale GM. Focal cerebral ischaemia in the rat: 1. Description of technique and early neuropathological consequences following cerebral artery occlusion. J Cereb Blood Flow Metab. 1981;1:53–60.[Medline] [Order article via Infotrieve]

2. Ginsberg MD, Busto R. Rodent models of cerebral ischaemia. Stroke. 1993;20:1627–1642.[Abstract/Free Full Text]

3. Coyle P. Outcomes to middle cerebral artery occlusion in hypertensive and normotensive rats. Hypertension. 1984;6(suppl I):69–74.

4. Coyle P. Different susceptibilities to cerebral infarction in spontaneously hypertensive (SHR) and normotensive Sprague-Dawley rats. Stroke. 1986;17:520–525.[Abstract/Free Full Text]

5. Duverger D, Mackenzie ET. The quantitation of cerebral infarction following focal ischaemia in the rat: Influence of strain, arterial pressure, blood glucose concentration and age. J Cereb Blood Flow Metab. 1988;8:474–485.[Medline] [Order article via Infotrieve]

6. Coyle P, Jokelainen PT. Differential outcome to middle cerebral artery occlusion in spontaneously hypertensive stroke-prone rats (SHRSP) and Wistar-Kyoto (WKY) rats. Stroke. 1993;14:605–611.[Abstract/Free Full Text]

7. Coyle P. Middle cerebral artery occlusion in the young rat. Stroke. 1982;13:855–859.[Abstract/Free Full Text]

8. Coyle P, Odenheimer DJ, Sing CF. Cerebral infarction after middle cerebral artery occlusion in progenies of spontaneously stroke-prone and normal rats. Stroke. 1984;15:711–716.[Abstract/Free Full Text]

9. Coyle P, Heistad DD. Blood flow through cerebral collateral vessels in hypertensive and normotensive rats. Hypertension. 1986;8(suppl II):67–71.

10. Slivka A. Effect of antihypertensive therapy on focal stroke in spontaneously hypertensive rats. Stroke. 1991;22:884–888.[Abstract/Free Full Text]

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12. Jacewicz M. The hypertensive rat and predisposition to cerebral infarction. Hypertension. 1992;19:47–48.[Free Full Text]

13. Rubattu S, Volpe M, Kreutz R, Ganten U, Ganten D, Lindpaintner K. Chromosomal mapping of quantitative trait loci contributing to stroke in a rat model of complex human disease. Nat Genet. 1996;13:429–434.[Medline] [Order article via Infotrieve]

14. Gratton J, Sauter A, Rudin M, Macrae I, Lees K, McColl J, Reid J, Dominiczak A. Susceptibility to cerebral infarction in offspring from crossbreeding stroke-prone SHR and WKY assessed with MRI. J Hypertens. 1996;13(suppl 1):S204.

15. Dominiczak AF, McLaren Y, Kusel JR, Ball DL, Goodfriend TL, Bohr DL, Reid JL. Lateral diffusion and fatty acid composition in vascular smooth muscle membrane from stroke prone spontaneously hypertensive rats. Am J Hypertens. 1993;6:1003–1008.[Medline] [Order article via Infotrieve]

16. Davidson AO, Schork N, Jacques B, Sutcliffe RG, Reid JL, Dominiczak AF. Blood pressure in genetically hypertensive rats: influence of the Y chromosome. Hypertension. 1995;26:452–459.[Abstract/Free Full Text]

17. Sauter A, Rudin M. Calcium antagonists reduce the extent of infarction in rat middle cerebral artery occlusion model as determined by quantitative magnetic resonance imaging. Stroke. 1986;17:1228–1234.[Abstract/Free Full Text]

18. Alderman DW, Grant DM. An efficient decoupler coil design which reduces heating in conductive samples in superconducting spectrometers. J Magn Res Med. 1979;36:447–450.

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20. Jeffs B, Clark JS, Anderson NH, Gratton J, Brosnan MJ, Gaugier D, Reid JL, Macrae IM, Dominiczak AF. Sensitivity to cerebral ischaemic insult in a rat model of stroke is determined by a single genetic locus. Nat Genet. 1997;16:364–367.[Medline] [Order article via Infotrieve]

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Editorial Comment

David F. Bohr, MD, Guest Editor

Department of Physiology, University of Michigan Medical School, Ann Arbor, Michigan

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References Introduction  References

 
The most widely used experimental model of cerebral infarction results from MCA occlusion in the rat. The severity of this infarct is quantified by its volume, and in the current decade MRI has been established as a precise tool for monitoring this volume. Using these techniques, the Glasgow investigators observed much larger infarcts in the hypertensive SHRSP rats than in the normotensive WKY, yet they firmly established that infarct size was independent of blood pressure. They do discuss alternative hypotheses that could explain a decrease in collateral blood flow and thereby be responsible for the large infarcts in SHRSP. Most attractive among these hypotheses are arterial hypertrophy and a deficit in nitric oxide release.¹ Following cross-breeding between SHRSP and WKY rats, they found that the infarct size in the F1 generation rat was as large as that in the SHRSP parental strain. This clear evidence for dominance of the genetic trait of the large infarct size adds to the spectacular identification by these investigators of the quantitative trait locus on chromosome 5 as responsible for stroke size in SHRSP.²

It is of special interest to see Glasgow University regaining its leadership role in hypertension-related research.

	Selected Abbreviations and Acronyms

 

MCA = middle cerebral artery MCAO = MCA occlusion SBP = systolic blood pressure SHR = spontaneously hypertensive rat SHRSP = stroke prone SHR substrain WKY = Wistar-Kyoto

Received October 3, 1997; revision received December 5, 1997; accepted January 5, 1998.

	References

Top Abstract Introduction Materials and Methods Results Discussion References Introduction  References

 
1. Cabrera CL, Bealer SL, Bohr DF. Central depressor action of nitric oxide is deficient in genetic hypertension. Am J Hypertens.. 1996;9:237–241.

2. Jeffs B, Clark JS, Anderson NH, Gratton J, Brosnan MJ, Gaugier D, Reid JL, Macrae IM, Dominiczak AF. Sensitivity to cerebral ischemic insult in a rat model of stroke is determined by a single genetic locus. Nat Genet.. 1997;16:364–367.

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