72 Comparative Effects of Unilateraland Bilateral Carotid Artery Ligationin the Spontaneously Hypertensive Rat

BERNARD C. WEXLER, P H . D .

SUMMARY Male and female, spontaneously hypertensive rats (SHR) with blood pressures ranging from190-210 mmHg were subjected to unilateral or bilateral carotid artery Ugation. Representative numbers ofanimals were killed 2, 4, 6,8, 10,12, 24 and 48 hours later. Severe cerebral ischemia caused a significant andprotracted increase in the pre-exlstent high blood pressure, the enzymes CPK, SGOT and LDH triglycerides,free fatty acids, glucose, and corticosterone. Despite these marked pathophysiologic changes, the brains ofthese animals were free of real damage except for cerebral edema and scattered petechiae. Some of theanimals developed massive atrial thrombi and myocardial infarcts. It is suggested that severe cerebral ischemiaprecipitated the myocardial infarcts through the aegis of the hypothalamic-pituitary-adrenal stress response.

Stroke, Vol 11, No 1, 1980

IN EARLIER WORK involving unilateral vsbilateral carotid artery ligation in normotensiveSprague-Dawley rats, we encountered a spectrum ofdynamic pathophysiologic changes during the 48 hourperiod following the induction of acute cerebralischemia.1' Serum creatine phosphokinase andglutamic oxaloacetic transaminase rose abruptlywithin hours of carotid artery ligation. Circulatingtriglycerides, free fatty acids, and cholesterolalterations were commensurate with dissolution ofperipheral adipose tissue sites and fatty infiltration ofthe liver. These animals also manifested markedhyperglycemia and increased secretion of cor-ticosterone. The presence of arteriosclerosis prior tothe acute induction of cerebral ischemia served to ex-acerbate all of the pathophysiologic changes.13

Because of the well known relationship of hyperten-sion to cerebrovascular disease, we elected to in-vestigate the effects of pre-existing hypertension onthe pathophysiologic changes following acutely-induced cerebral ischemia of varying intensity, i.e.,unilateral vs bilateral carotid artery ligation, in spon-taneously hypertensive rats (SHR). Moreover, sincewe have found that both normotensive or hypertensivefemale rats subjected to acute myocardial infarctionmanifest less pathophysiologic changes, effectsuperior repair, and survive better than male rats,*"*we elected to compare male vs female SHR in theirability to withstand acute cerebral ischemia. The SHrat developed by Okamoto and Aoki7 is normotensiveat birth but becomes spontaneously hypertensive as itmatures, attaining systolic blood pressure levels of190-210 mm Hg when they are 100 days old. TheJapanese investigators, Ogata et al.,8 ligated thecarotid arteries of 5 to 9 month old SH rats and founddiffuse and extensive cerebral infarcts. Our SH rats,

From the May Institute for Medical Research of the JewishHospital and Departments of Medicine and Pathology, Universityof Cincinnati College of Medicine, Cincinnati, OH.

Supported in part by grants from the National Heart, Lung, andBlood Diseases Institute (HL-21418), the National Institute on Ag-ing (AG-585), and the Southwestern Ohio Heart Association.

Reprints: Dr. Wexler, May Institute for Medical Research, 421Ridgeway Avc., Cincinnati, OH 45229.

whose blood pressure ranged from 190 to 210 mm Hg,developed cerebral edema and petechiae, myocardialinfarction, and marked pathophysiologic changes,e.g., enzymes, lipids, etc., after carotid artery ligationbut no evidence of cerebral infarction.

MethodsMale and female, 100 day old, spontaneously

hypertensive rats born and raised in our AnimalResearch Colony were used. These animals werederived from the original Okamoto-Aoki (Kyoto)strain provided through the generosity of Dr. Carl T.Hansen, Animal Genetics Division, N.I.H. Theanimals were fed a commercial rat chow diet adlibitum which is relatively low in fat (4%). The animalswere housed in air-conditioned quarters where light,heat, and humidity were controlled and monitored.

Male (280 ± 10 gms) and female (203 ± 5 gms)SHR, selected randomly, served as controls and ex-perimental animals. Just prior to surgery, the systolicblood pressure of each animal was determined underlight Seconal (secobarbital) anesthesia (1 to 2 mg/100gm bw, ip) using the Friedman:Freed microphonicmanometer and tail cuff which measures systolicblood pressure. The experimental animals were givena supplemental injection of secobarbital (4 mg/100gm bw, sc) and were then subjected to unilateral orbilateral carotid artery ligation as previouslydescribed.13 The carotid artery was carefullyseparated from the jugular vein and vagus nerve and asingle ligature placed about the common carotidartery 2 cm below the bifurcation of the carotid arteryinto the external and internal carotid arteries. Theligature was tied snugly to occlude but not damage thevessel. (Previous experience demonstrated that shamcarotid artery manipulation did not cause any signifi-cant changes in the blood constituents measured. Forthis reason, all of the animals prepared surgically wereused as experimental subjects.) A large number ofanimals were used to ensure a sufficient number of sur-vivors, i.e., 12 animals for each control group and aminimum of 8 for each experimental group. Followingcarotid artery ligation, the animals were killed 2, 4, 6,8, 10, 12, 24 and 48 hours later to establish a dynamic

by guest on May 2, 2018

http://stroke.ahajournals.org/D

ownloaded from

CAROTID ARTERY LIGATION IN SHR/Wexler 73

record of the pathophysiologic sequelae which attendacute cerebral ischemia. The blood pressure wasrecorded again at each of the time intervals. Theanimals were killed by instant decapitation and bloodwas collected from the severed neck vessels. The bloodof each animal was spun in a refrigerated centrifugeand the plasma frozen and stored until time foranalysis. The following blood chemistries weremeasured by means of automated techniques (Auto-analyzer, Technicon): creatine phosphokinase (CPK),glutamic oxaloacetic and pyruvic transaminases(SGOT and SGPT), lactic dehydrogenase (LDH),triglycerides, free fatty acids, total cholesterol,glucose, and blood urea nitrogen (BUN). Circulatingcorticosterone, the main adrenocortical steroid in therat, was also measured by an automated fluorometricmethod" as an index of adrenocortical secretion. Atautopsy each animal was examined carefully for anyevidence of cerebral or cardiovascular damage. Perti-nent tissues such as brain, heart, thymus, adrenal,liver, and kidney were weighed and fixed in 10%neutral formalin for histopathological examination.Tissues were embedded in paraffin and sectioned at3n. Frozen sections for demonstration of lipids werecut at \0n. Adjacent sections were stained withhematoxylin and eosin for routine analysis, alcian blueand toluidine blue for metachromasia, the Hale stainfor mucopolysaccharides, the von Kossa method todemonstrate calcium, oil red O and Sudan black B forlipids, and the Kluver-Barrera stain for brain tissue.

All of the data were subjected to analysis ofvariance using Student's f-test to determine statisticalsignificance; p values less than 0.05 were considerednon-significant.10

Results

A. General Observations

None of the SHR subjected to unilateral carotidartery occlusion manifested any outward signs ofcerebral ischemia whereas 82% of the bilaterallyligated SHR (male and female) either convulsed, dis-played Horner's syndrome, paralysis, or extensorrigidity.

Only 2 males and 3 females died of the 64 male and64 female SHR subjected to unilateral carotid arteryligation; 13 male and 15 female SHR died of the 64male and 64 female SHR subjected to bilateral carotidartery ligation. Of special note was the fact thatfemale SHR subjected to bilateral carotid artery liga-tion did not recover from the anesthesia until 8 h post-ligation. Whereas male SHR (bilateral ligation) beganto succumb immediately after ligation, females(bilateral ligation) did not die until they began torecover from the anesthesia. Nine of the 15 deathsamong the female SHR (bilateral ligation) occurredbetween 24 and 48 h post-ligation.

B. Changes in Systolic Blood Pressure

Although blood pressures were elevated greatly inthese spontaneously hypertensive rats, the acute in-

duction of cerebral ischemia caused the blood pressureto rise even further (fig. 1). Mild cerebral ischemia(unilateral) caused an acute rise in the blood pressureof male and female SHR but this increase was evanes-cent in the male and prolonged in the female (fig. 1).Severe cerebral ischemia (bilateral) caused a verysignificant and sustained increase in blood pressure inboth males and females, attaining levels of 240 mmHg (fig. 1).

C. Changes in Blood Chemistry

Enzymes

Using the rise and fall of circulating enzymes (CPK,SGOT, SGPT and LDH) as an index of cerebral,myocardial, and hepatic damage, we found definite in-creases in circulating CPK levels with maximallyelevated levels in male SHR subjected to bilateralcarotid artery ligation (fig. 2). The zenith of CPKelevation occurred between 4 and 12 h post-ligation.The SGOT levels of all animals rose progressivelyfollowing the induction of cerebral ischemia, reachinga zenith 10 to 12 h post-ligation, promptly receding tonormal thereafter (fig. 3). There was no apparentpattern or significant change in circulating SGPTlevels. Male and female SHR displayed peak levels oflactic dehydrogenase at 6 and 12 h, respectively (fig.4). There was little differentiation between enzyme in-crease and severity of cerebral ischemia.

240 r

230

I220

210 -

200

190 -

180 -SS

Carotid Artery Ligation• — — 0Male unilateral

O ~ — OFemale unilateral

• # M a l e bilateral

O OFemale bilateral170 -

160 -

FIGURE 1. Changes in systolic blood pressure levels ofmale and female SHR rats subjected to mild or severecerebral ischemia by unilateral or bilateral ligation of thecommon carotid artery. Each point depicted is theMean ± Standard Error; n = 12 for controls, n = 8 for ex-perimentals. The same protocol applies to figs. 2 through 8.

by guest on May 2, 2018

http://stroke.ahajournals.org/D

ownloaded from

74 STROKE VOL 11, No 1, JANUARY-FEBRUARY 1980

5OO Carotid Artery Ligotlon• — • Mai* unilateralO- - O Female unilateral

• • Male bilateralO — O Female bilateral

225 r

6 8 10 12HOURS

FIGURE 2.

levels.

Changes in plasma creatine phosphokinase

Carotid Artery Ligotion• - - • M a l e unilateralO - - O Female unilateral

• ©Male bilateralO Female bilateral

6 8 10 12HOURS

FIGURE 4. Changes in plasma lactic dehydrogenase levels.

Lipids

All of the animals manifested a brisk andstatistically significant (p < 0.001) increase in cir-culating triglycerides within 2 to 4 h after acute

cerebral ischemia (fig. 5). The maximum increase intriglyceride levels occurred in those animals subjectedto severe cerebral ischemia. All of the animalsdeveloped an acute elevation of free fatty acids in theirblood with a supernormal increase in male SHR sub-

Carotid Artery Ligation• • Male unilateral

O- - O Female unilateral

Male bilateral

Female bilateral

240 r-

220 -

Carotid Artery Ligation• ~ "•Mole unilateralO O Female unilateral

• ©Male bilateralO Female bilateral

FIGURE 3. Changes in plasma glutamic oxaloacetic trans-

aminase levels.

2 4 6 8 10 12HOURS

FIGURE 5. Changes in plasma triglyceride levels.

by guest on May 2, 2018

http://stroke.ahajournals.org/D

ownloaded from

CAROTID ARTERY LIGATION IN SHR/Wexler 75

jected to mild cerebral ischemia. SHR subjected tosevere cerebral ischemia displayed unusually high andprolonged elevation of free fatty acid levels (fig. 6).Circulating total cholesterol levels ranging between 72and 113 mg % (normal = 93 mg % for males, 104 mg% for females) did not exhibit any significant changesduring the 48 h course of the experiment.

Glucose

SHR of our strain are spontaneously hyperglycemic(glucose = 150 ± 5 mg %); these SHR were nor-moglycemic (fig. 7). Those animals exposed to mildcerebral ischemia manifested acute and significanthyperglycemia; those subjected to severe cerebralischemia exhibited a more delayed rise but becamemuch more hyperglycemic and on a more sustainedbasis (fig. 7).

Blood Urea Nitrogen

BUN levels ranged between 15 and 31 mg % (nor-mal = 26 mg %) during the 48 h period. There was nosignificant pattern of change in the BUN levels.

Corticosterone

Because these animals were lightly anesthetizedduring the initial recording of blood pressure, the con-trol blood corticosterone levels were above normal,i.e., anesthesia constitutes a mild stress and inhyperreactive SHR will cause substantial increases incorticosterone (fig. 8). There was a distinctdichotomous pattern in adrenal secretory patternsbetween those animals subjected to mild vs severecerebral ischemia. Mild cerebral ischemia caused onlya slight and evanescent increase in adrenal secretory

I 1M( I( II I

( I

I '

I I

Carotid Artery Ligation9 • Male unilateralO O Female unilateral

• • Male bilateral

O O Femalebilateral

*

650

600

550

\ 500

4 0 0

350

3 0 0

250 -

2 4 6 8 10 12 7 r2A~HOURS

FIGURE 6. Changes in plasma free fatty acid levels.

250 r

230 -

Carotid Artery Ligation• # M a l e unilateralO ~ ~ O Female unilateral

Male biloteralFemale bilateral

FIGURE 7.

8 10 12HOURS

Changes in plasma glucose levels.

activity, whereas severe cerebral ischemia wasmirrored by supernormal increases in corticosterone 2to 12 h post-ligation (fig. 8).

D. Gross and Microscopic Pathology

Concomitant with their hyperlipidemia, all of theanimals showed progressively worsening fatty infiltra-

Carotid Artery Ligatian• - • Male unilateral

O - O Female unilateral

• • Male bilateral

O — O Female bilateral

48. .r-s

2 4 6 8 10 12 24HOURS

FIGURE 8. Changes in plasma corticosterone levels.

48

by guest on May 2, 2018

http://stroke.ahajournals.org/D

ownloaded from

76 STROKE VOL 11, No 1, JANUARY-FEBRUARY 1980

tion of the liver accompanied by grossly visible dis-appearance of peripheral adipose tissue sites, e.g.,peri-adrenal and mesenteric fat. The fatty liver condi-tion was much more intense in animals exposed tosevere cerebral ischemia.

There were no additional untoward changes foundin the SHR subjected to mild ischemia. At autopsy,several SHR with severe cerebral ischemia had ex-travasated thoracic fluid, i.e., hydrothorax, and 12%of the males and 7% of the females had massivemyocardial infarcts (fig. 9) which occurred late, post-ligation. Many of the hearts also displayed large,occlusive, atrial thrombi (fig. 10).

Despite the ubiquitous presence of advancedcerebral edema and scattered petechiae in SHR withsevere cerebral ischemia, there was no evidence ofnecrosis or damage by gross and microscopic ex-amination.

Discussion

In our earlier work, normotensive Sprague-Dawleyrats manifested many untoward changes in responseto unilateral carotid artery occlusion.13 Paradox-ically, despite the pre-existent, severe hypertension inSHR, the induction of acute cerebral ischemia did notcause any cerebral necrosis. We have found that SHrats are usually resistant to alloxan-induced diabetes,11

myocardial infarction,12 increased dietary saline,13 andthe induction of arteriosclerosis.14-15 This wouldsuggest that SHR have different hormonal, metabolic,and cardiovascular attributes than normotensivestrains of rats. Ogata et al.,8 and I examined thecerebral cortex, corpus striatum, callosal radiation,

hippocampus and midbrain but Ogata et al.,8 foundbilateral, diffuse and extensive cerebral infarcts intheir SHR involving the frontal, medial, and occipitalregions. Our animals were 100 days old and hadequally severe hypertension, whereas Ogata's animalsranged from 5 to 9 months of age. This would suggestthat aging or the chronicity rather than the severity ofhypertension is the prime vector in conditioningnecrosis of the cerebrum. The fact that the mildcerebral ischemia of unilateral carotid artery ligation,combined with hypertension, caused only brainedema, petechiae, paralysis and a few deaths could bedue to the fact that collateral cerebral arteries can sus-tain brain tissue under conditions of impeded supply.16

SHR have adequate connecting arteries between thecarotid and vertebrobasilar systems.8 It has beenshown that experimental occlusion of one carotidartery will cause a 100% increase in basilar arteryblood flow; occlusion of both common carotid arteriescauses a 300% increase in basilar artery flow.16

Although male rats are much more prone to succumbto acute myocardial infarction,4'6 there was no ap-parent sex difference in response to the acutely-induced cerebral ischemia. It is noteworthy thatfemale rats in general have less efficient hepaticcapacity than males to metabolize barbiturates17 andthe more prolonged anesthesia in the female SHR ap-parently protected them from the untoward effects ofcerebral ischemia until they began to recover from theanesthesia in the later hours post-ligation.

The slight increase in the pre-existent high bloodpressure following mild cerebral ischemia and theprotracted and greatly exacerbated high blood

FIGURE 9. Left ventricle of a male SHR 24 hours after being subjected to bilateral carotidartery ligation. There is extensive edema and wbc infiltration with only a few islands of viablemyocardium. H & E, X 75

by guest on May 2, 2018

http://stroke.ahajournals.org/D

ownloaded from

CAROTID ARTERY LIGATION IN SHR/Wexler

FIGURE 10. Left atrium of same animal shown in Fig. 9. The entire atrial chamber is occludedby a massive thrombus and the atrial tissue itself shows extensive hemorrhage and wbc infiltra-tion. H & E, X 25

pressure following severe cerebral ischemia is in keep-ing with experimental18 and clinical19 observations.For example, during the temporary occlusion of thecarotid artery during the procedure of carotid end-arterectomy, systemic blood pressure often rises todangerously high levels.19 This pressor response is at-tributed to activation of the sympathetic nervoussystem due to the ischemia or ligation-inducedblockade of the baroreceptor endings.18

Although the waxing and waning of the variousserum enzyme levels, CPK, SGOT, and LDH, did notcorrelate well with the severity of induced cerebralischemia following carotid artery ligation, thedynamic rise and fall of these enzymes indicated thatcerebral damage became manifest immediately afterligation and reached a zenith between 4 to 12 h withrestoration to normal 12 to 48 h post-ligation. In ourprevious work with normotensive Sprague-Dawleyrats1'2 and the gerbil,3 we found these serum enzymesto be an excellent index of the severity of cerebralischemia as well as the time of greatest damage.

In all previous investigations, our strain of SHRwas consistently hyperglycemic and hyperlipidemic.14

It is difficult to explain why these SHR were nor-moglycemic and normolipidemic. Nonetheless, it is ofinterest that like the gerbil and normotensive rats,these SHR responded to the acute duress of cerebralischemia by a most dynamic dissolution of peripheraladipose tissue sites, hypertriglyceridemia, supernor-mal free fatty acid levels, no change in circulatingtotal cholesterol, and the rapid appearance of a fattyliver. Most likely, the great increase in adrenocorticalsecretion (see below) which attends the duress ofcerebral ischemia exercised intense lipid-mobilizing

effects causing dissolution of peripheral adipose tissuesites and active transport of liberated triglycerides andfree fatty acids to the liver.

It is well known that many patients who suffer anacute myocardial infarction will manifest abnormalglucose tolerance during the immediate myocardial in-farct period becoming normoglycemic during themyocardial repair phase. Similar findings have beenmade in patients who have survived acute cerebral in-farction.20 Since cerebrovascular damage is oftenassociated with disruption of normal hypothalamic-pituitary trophic hormone release, it is tempting tosuggest that in patients and in these cerebral ischemicSHR, the protracted hyperglycemia was due toderangement of hypothalamic-pituitary trophic hor-mone release, e.g., ACTH, growth hormone, etc.

It should be emphasized that the circulating cor-ticosterone levels of these SHR prior to carotid arteryligation were above normal due to the unavoidablehandling of the animals and the use of anesthesia priorto surgery. SHR are hyperreactive and show extraresponsiveness to relatively mild stress compared tonormotensive rats.21 Nonetheless, the supernormal in-crease in circulating corticosterone levels coincidentwith the rise in blood pressure, the increase in CPKlevels, hypertriglyceridemia and hyperglycemia,served as the best index of the stressful nature of thecerebral ischemia induced by bilateral vs unilateralcarotid artery ligation.

Another intriguing finding in this investigation isthe appearance of copious (5 to 6 ml) thoracic fluid ex-udate suggestive of congestive heart failure, occlusiveatrial thrombi, and massive myocardial infarction. Inancillary investigations, it has been found that the

by guest on May 2, 2018

http://stroke.ahajournals.org/D

ownloaded from

78 STROKE VOL 11, No 1, JANUARY-FEBRUARY 1980

combined insult of myocardial infarction (iso-proterenol) superimposed upon cerebral ischemia(carotid artery ligation) are synergistic and greatly ex-acerbate the usual pathophysiologic changes whichwould attend each maneuver by itself." All of theabove pathophysiologic changes are even further ex-acerbated if pre-existent chronic hypertension hadbeen present.23 We21' ** and others"28 have suggestedthat cerebrovascular damage may give rise to extraadrenocortical steroid and catecholamine productionwhich would pave the way for myocardial damage,i.e., a brain-heart interaction. Further, it has beenamply demonstrated experimentally that carotidartery ligation will cause ACTH release, increasedblood pressure, tachycardia, increased myocardialcontractility, and increased cardiac output1' all ofwhich would favor myocardial anoxia, ischemia, andinfarction.

Fujishima et al.,2" assert that when strokes occur inchronically hypertensive patients, the cortical lesionsare usually found deeply situated whereas strokes innormotensive patients show large cortical and subcor-tical damage. Diligent inspection by gross andmicroscopic examination failed to discern any realdamage in the brains of these severely hypertensiveanimals with acute ischemia other than advancededema and scattered petechiae. The consensus is thatcarotid artery ligation in the rat, as in higher forms oflife, need not be detrimental to cerebrovascular flow.It is also well known that sensitivity to cerebralischemia can range greatly according to animal strain,age, level of blood pressure, and hormonal influences.Pregnant women with stroke suffer a much highermortality than men or nonpregnant women.17 Adrenaland gonadal hormones greatly influence cerebralblood flow. The current epidemiologic emphasis onhypertension, diabetes, age, sex, and the world-wideuse of the contraceptive medication, calls for muchmore intensive investigation of the interrelationship ofthe above vectors and cerebrovascular disease. Theavailability of such a unique animal model as the SHRwith spontaneous hypertension, hyperglycemia,hyperlipidemia, and a propensity towards human-likecerebral infarction affords an unprecedented oppor-tunity for investigators.

Acknowledgment

The author is grateful for the exceptional dedication and expertiseof Nancy C. Brothers, Evangeline Domingo, Dilmon Conatser,William Goodhew, and Jean Wexler.

References

1. Wexler BC, SarofT J: Metabolic changes in response to acutecerebral ischemia following unilateral carotid artery ligation inarteriosclerotic versus nonartcriosclerotic rats. Stroke 1:38-51,1970

2. Wexler BC: Metabolic changes in response to acute cerebralischemia following bilateral carotid artery ligation inarteriosclerotic versus nonarteriosclerotic rats. Stroke 1:112-121, 1970

3. Wexler BC: Pathophysiologic responses to acute cerebralischemia in the gerbil. Stroke 3: 71-78, 1972

4. Wexler BC, Kittinger GW: Myocardial necrosis in rats: serumenzymes, adrenal steroid and histopathological alterations. Circ

Res 13: 159-171, 19635. Lewis BK, Wexler BC: Metabolic response following

isoproterenol-induced myocardial infarction in arterioscleroticbreeder vs nonarteriosclerotic virgin vs gonadectomized malerats. Proc Soc Exp Biol Med 148: 1177-1183, 1975

6. Lewis BK, Wexler BC: Metabolic response followingisoproterenol-induced myocardial infarction in arterioscleroticbreeder vs nonarteriosclerotic virgin and ovariectomized femalerats. Atherosclerosis 21: 361-370, 1975

7. Okamoto K, Aoki K: Development of a strain of spontaneouslyhypertensive rats. Jpn Circ J 27: 282-293, 1963

8. Ogata J, Fujishima M, Morotoni Y et al: Cerebral infarctionfollowing bilateral carotid artery ligation in normotensive andspontaneously hypertensive rats: a pathological study. Stroke 7:54-60, 1976

9. Guillemin R, Clayton GW, Lipscomb HS et al: Measurementof free corticosteroids in rat plasma: physiological validation ofa method. Endocrinology 63: 349-358, 1958

10. Sncdccor GW: Statistical Methods. Ed 6. Iowa State Univer-sity Press, Ames, Iowa 1967

11. lams SG, Wexler BC: Alloxan diabetes in spontaneouslyhypertensive rats: gravimetric, metabolic and histopathologicalterations. Br J Exp Pathol 50: 177-199, 1977

12. Wexler BC: Isoproterenol-induced myocardial infarction inspontaneously hypertensive rats (SHR). Cardiovasc Res: 13:450-458, 1979

13. Wcxler BC: Arterial lesions and hypertension induced by saline,unilateral nephrectomy, and deoxycorticosterone in spon-taneously hypertensive (SHR) rats. Paroi Arterielle (Paris)(Arterial Wall), In press, 1979

14. Wexler BC, lams SG, Judd JT: Arterial lesions in repeatedlybred spontaneously hypertensive (SHR) rats. Circ Res 38:494-501, 1976

15. Wexler BC, lams SG, Judd JT: Comparative effects of adrenalregeneration hypertension on non-arteriosclerotic andarteriosclerotic Sprague-Dawley vs spontaneously hypertensiverats. Atherosclerosis 26: 1-15, 1977

16. Fukuyama GS, Himwich WA: Canine basilar arterial flow andeffects of common carotid occlusion. Am J Physiol 219:525-527, 1970

17. Cooney AH: Pharmacological implications of microsomal en-zyme induction. Pharm Rev 19: 317-354, 1967

18. Wang H, Chai CY, Kuo JS, Wang SC: Participation of cardiacand peripheral sympathetic^ in carotid occlusion response. AmJ Physiol 218: 1548-1554, 1970

19. Lehr MS, Salzman EW, Silen W: Hypertension complicationcarotid endartercctomy. Stroke 1: 307-313, 1970

20. Huff TA, Lebovitz HE, Heyman A et al: Serial changes inglucose utilization and insulin growth hormone secretion inacute cerebrovascular disease. Stroke 3: 543-552, 1972

21. lams SG, McMurtry JP, Wexler BC: Aldosterone, deoxycor-ticosterone, corticosterone and prolactin changes during thelifespan of chronically hypertensive SHR rats. Endocrinology104: 1357-1363, 1979

22. Wexler BC: Combined effects of acute cerebrovascularischemia and myocardial infarction in arteriosclerotic, maleSprague-Dawley rats. Angiology 28: 624-643, 1977

23. Wexler BC: Acute cerebrovascular and myocardial ischemiasuperimposed upon chronically hypertensive andarteriosclerotic male Sprague-Dawley rats. Angiology 28:653-670, 1977

24. Feibel JH, Hardy PM, Campbell RJ et al: Prognostic value ofthe stress response following stroke. JAMA 238: 1374-1376,1977

25. Burch GE, Sun SC, Colcolough HL et al: Acute myocardiallesions following experimentally induced intracranialhemorrhage in mice. A histological and histochemical study.Arch Pathol 84: 517-521, 1967

26. Hunt D, Gore I: Myocardial lesions following experimental in-tracranial hemorrhage: Prevention with propranolol. Am HeartJ 83: 232-236, 1972

27. Fujishima M, Owae T, Takeya et al: Prognosis of occlusivecerebrovascular diseases in normotensive and hypertensive sub-jects. Stroke 7: 472-476, 1976

28. Payan HM, Conrad JR: Carotid ligation in gerbils: Influence ofage, sex, and gonads. Stroke 8: 194-196, 1977

by guest on May 2, 2018

http://stroke.ahajournals.org/D

ownloaded from

B C Wexlerhypertensive rat.

Comparative effects of unilateral and bilateral carotid artery ligation in the spontaneously

Print ISSN: 0039-2499. Online ISSN: 1524-4628 Copyright © 1980 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Stroke doi: 10.1161/01.STR.11.1.72

1980;11:72-78Stroke. 

http://stroke.ahajournals.org/content/11/1/72World Wide Web at:

The online version of this article, along with updated information and services, is located on the

  http://stroke.ahajournals.org//subscriptions/

is online at: Stroke Information about subscribing to Subscriptions: 

http://www.lww.com/reprints Information about reprints can be found online at: Reprints:

  document. Permissions and Rights Question and Answer available in the

Permissions in the middle column of the Web page under Services. Further information about this process isOnce the online version of the published article for which permission is being requested is located, click Request

can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office.Stroke Requests for permissions to reproduce figures, tables, or portions of articles originally published inPermissions:

by guest on May 2, 2018

http://stroke.ahajournals.org/D

ownloaded from