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494
Arterial Lesions in Repeatedly Bred SpontaneouslyHypertensive Rats
BERNARD C. WEXLER, PH.D., SAMUEL G. IAMS, PH.D., AND JOSEPH T. JUDD, PH.D.
SUMMARY Repeatedly bred male and female rats of manystrains develop hyperglycemia, hyperlipidemia, hypertension, andarteriosclerosis spontaneously. The intensity of their arterial diseaseand related metabolic derangements appears to be related to theirreproductive activity. Repeatedly bred spontaneously hypertensiverats (SHR) were found to have severe hypertension, hyperglycemia,hyperlipidemia, elevated creatine phosphokinase (CPK), serum glu-tamic oxaloacetic and glutamic pyruvic transaminase (SGOT,SGPT), and lactic dehydrogenase (LDH), as well as high circulatingcorticosterone levels. Despite these atherogenic metabolic derange-
ments and their severe hypertension, the breeder SHR did not developthe severe, generalized arteriosclerosis found in other strains ofbreeder rats. Instead, the arterial lesions, consisting of intimalhyalinization and fibrosis, medial hypertrophy, and occlusion of thelumen, were found only in male breeder SHR and were confined tothe intratubular arteries of the testes. It is suggested that the severehypertension, genetic influences, or differences in hypothalamic-pituitary-adrenal-gonadal function in breeder SHR may not havebeen conducive to the development of arteriosclerosis in this particu-lar strain of rats.
REPEATEDLY BRED male and female rats of severalstrains, e.g., Sprague-Dawley, Long-Evans, Wistar, andothers, have been shown to develop hyperlipidemia, hyper-glycemia, hypertension, arteriosclerosis, premature aging,and other degenerative changes spontaneously.1"4 The inci-dence and severity of these metabolic and pathophysiologi-cal changes1'4 have been shown to be related to the numberand frequency of breedings as well as, in the case of femalebreeders, to the number of young suckled and the time ofweaning.510 The arterial lesions remain microscopic duringthe first two to three breedings and consist of intimal groundsubstance swellings capped over by collagen followed byelastolytic and calcific changes in the media. As breedingand arterial disease progress in parallel, the aortic lesionsbecome grossly visible by the third or fourth breeding. Thelesions appear first in the abdominal aortic segment,progress in an anatomical order to the arch and thoracicaortic segments, and eventually spread into the coronary,carotid, mesenteric, renal, and peripheral arteries.1114 Al-though male breeder rats develop less complicated arteriallesions than female breeders, they die significantly earlierthan the females, most often as a result of myocardialinfarction.
The Japanese investigators, Okamoto and Aoki,15 haveraised an inbred strain of rats which manifest hypertensionspontaneously, i.e., the SHR strain. These geneticallyhypertensive rats are normotensive at birth but as theymature show increasingly elevated levels of blood pressurewith time. A special breeding colony of these SHR wasestablished in this laboratory to determine whether repeat-edly bred SHR would manifest, in addition to hyperten-
From the May Institute for Medical Research of the Jewish Hospital andthe Departments of Medicine. Pathology and Physiology, University ofCincinnati College of Medicine, Cincinnati, Ohio.
Supported in part by the Southwestern Ohio Heart Association and theNational Heart and Lung Institute (HL-13,222 and HL-15,304), NationalInstitutes of Health, U.S. Public Health Service.
Address for reprints: Dr. Bernard C. Wexler, Director, The May Insti-tute for Medical Research Of The Jewish Hospital Association, 421Ridgeway Avenue, Cincinnati, Ohio 45229.
Received October 29, 1975: accepted for publication February 27, 1976.
sion, the usual pathophysiological sequelae, e.g., arterio-sclerosis, hyperglycemia, hyperlipidemia, etc., commen-surate with the number and frequency of their breedings,as we have found for several other strains of rats.1'4- 1 1 1 4
Methods
The original spontaneously hypertensive rats (SHR) withwhich we established our SHR Breeding Colony wereobtained from the National Institutes of Health, Bethesda,Maryland. These SHR were from the original Kyoto-Wistarstrain developed by Okamoto and Aoki.15 These SHRmanifest increasing blood pressure after weaning and, by 8to 10 weeks, stable high blood pressure is established.
Male and female SHR were paired at 60 days of age.Record was kept of the number of pregnancies, young born,suckled, and weaned after 21 days of nursing. When thefemale breeders had completed four to five pregnancies,both the male and female breeders were killed after the lastlitter of young had been weaned, i.e., a total of 35 pairs ofSHR breeders. For purposes of comparison, 24 pairs ofSprague-Dawley breeder rats from our Research BreedingColony were autopsied after they had completed four to fivebreedings on a similar basis. In addition, 24 male and femalevirgin SHR and Sprague-Dawley rats of the same age as thebreeder rats (6-7 months) also were killed for purposes ofcomparison. All of the rats were kept in our ResearchAnimal Colony where temperature, humidity, and light werecarefully controlled and monitored. The rats were fed acommercial rat chow (Purina) which has a relatively low fatcontent (4%) and were given tap water to drink ad libitum.
Prior to autopsy, blood pressures were recorded underlight secobarbital (Seconal) anesthesia using the Friedman-Freed microphonic manometer and indirect tail cuff methodwhich measures systolic blood pressure only. Immediatelythereafter and prior to autopsy, blood samples were with-drawn from the aorta, centrifuged (refrigerated) and assayedfor creatine phosphokinase (CPK), glutamic oxaloacetic andglutamic pyruvic transaminase (SGOT and SGPT), lac-tic dehydrogenase (LDH), glucose, free fatty acids,triglycerides, cholesterol, and blood urea nitrogen
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ARTERIAL LESIONS IN BREEDER SHR RATS/Wexleretal. 495
(BUN), using the automated techniques prescribed forthe Auto-Analyzer (Technicon Instruments). Corticos-terone (compound B), as an index of adrenocorticalsecretory activity, was measured by the fluorometricmethod of Guillemin et al.16
In searching for the presence of spontaneous arterioscle-rosis in breeder rats, we exposed the aorta so that the heart,carotid, mesenteric, iliac, and proximal portions of thefemoral arteries were visualized. In the case of the femalebreeders of most strains of rat, the arterial lesions often canbe seen on gross inspection by the time the rats have givenbirth to three or four litters. Rats with no grossly visibleplaques in their aorta are classified as "clear," those withraised plaques in only the abdominal aorta as "minimal,"those with plaques only in the abdominal and aortic archsegments as "moderate," and those with plaques throughoutthe aorta as "severe." For microscopic confirmation of thepresence or absence of arteriosclerosis, we routinely tookrepresentative samples from prescribed segments of thesystemic aorta. The arch of the aorta was taken so that itincluded the base of the innominate and common carotidarteries. The thoracic aorta was removed from a level justcaudal to where the azygos vein crosses the aorta to wherethe aorta leaves the thorax between the folia of thediaphragm. The abdominal aorta was taken from the levelof the diaphragm down to and including portions of the iliacarteries. The aortas of male breeder rats were examined andsampled in the same manner. The iliac arteries of malebreeders of most strains of rat occasionally show scleroticplaques that can be detected by gross examination.1- "~M
All segments of the aorta were fixed in 10% bufferedneutral formalin (Lillie) for histological study. The brains,hearts, kidneys, and carotid arteries of these rats wereremoved so that the cerebral, coronary, renal, and the maincarotid artery and its branches could be examined micro-scopically. Pertinent organs from each rat were trimmedand weighed. The hearts were dropped into saline andallowed to pump out residual blood, blotted, and weighed,i.e., as a gravimetric index of cardiac hypertrophy. Organsand tissues were embedded in paraffin and sectioned at 3jim. Frozen sections used for lipid studies were cut at 5-10^m. Adjacent sections were stained with hematoxylin-eosinfor routine analysis; Verhoeffs, Van Gieson's, and Gomori'saldehyde fuchsin stains for elastic tissue; Alcian Blue andtoluidine blue for metachromasia; the Hale stain for muco-polysaccharides; the von Kossa method for calcium. SudanII and III, oil red O, and Sudan black B were used todemonstrate lipids in both frozen and paraffin sections.Statistical analysis of results was performed using a one-wayanalysis of variance, chi square test, or Student's /-test."
Results
GENERAL OBSERVATIONS
The breeder SHR appeared to be as fecund asSprague-Dawley breeder rats. However, the average numberof pups per litter was eight for SHR dams, whereas theaverage for Sprague-Dawley female breeders was 12. TheSHR dams do not lactate as copiously as theSprague-Dawley and the average body weight of weanling
SHR (21 days postparturition and nursing) was 35.0 g vs.45.0 g for Sprague-Dawley weanlings.
BLOOD PRESSURE
The arteriosclerotic male and female Sprague-Dawley,breeder rats had significantly elevated blood pressure com-pared to nonarteriosclerotic virgin rats, as did the breedervs. virgin SHR (P < 0.001) (Fig. 1). The blood pressures ofthe SHR were significantly greater (ranging from 175 ± 5 to220 ± 5 mm Hg) than that of Sprague-Dawley rats (rangingfrom 80 ± 2 to 120 ± 3 mm Hg).
GRAVIMETRIC DATA
Breeder rats are characteristically more obese than virginrats of the same age, as was observed here for both theSprague-Dawley and SHR strains (Table 1). The SHR weregenerally of shorter head to tail length and were less heavythan the Sprague-Dawley rats. Although the weight of thepituitary glands of most animals is not susceptible tochanges except under unusual physiological conditions,there were marked and statistically significant differences inthe pituitary gland weights of these rats. Except in the caseof the female breeder SHR, the weights of the pituitaryglands of all the breeder rats were considerably greater thanthose of their virgin counterparts (Table 1). Similarly, withthe exception of the female breeder SHR, the puitary glandsof the SHR were heavier than those of the Sprague-Dawleyrats, as were the pituitary glands of female vs. male rats(Table 1). The weights of the adrenal glands of virgin andbreeder SHR were statistically much less (P < 0.001) thanthose of their Sprague-Dawley counterparts (Table 1).Although the weight of the thymus gland is usually inverselyproportional to the weight (and secretory activity) of theadrenal gland, the Sprague-Dawley rats with significantly
225
75
D Sprogue-DawleyH Spontaneously
Hypertensive
rVirgins
Breeders
FIGURE 1 Systolic blood pressure of male (n = 24) and female (n= 24) virgin Sprague-Dawley rats compared with male (n = 24) and
female (n = 24) Sprague-Dawley breeder rats as well as male (n =24) and female (n = 24) virgin spontaneously hypertensive rats(SHR) compared with male (n = 24) and female (n = 24) breederSHR. The height of each column depicts the mean and standard
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496 CIRCULATION RESEARCH VOL. 38, NO. 6, JUNE 1976
TABLE 1 Gravimetric Comparison of Male and Female, Nonarteriosclerotic (Virgin) vs. Arteriosclerotic (Breeder)Sprague-Dawley Rats with Nonarteriosclerotic (Virgin) and Arieriosclerolic (Breeder) Spontaneously HypertensiveRats(SHR)
MalesVirgins
Nonarteriosclerotic, Sprague-Dawley
Nonarteriosclerotic, SHR
BreedersMicroscopic arteriosclerosis, Sprague-Dawley
Microscopic arteriosclerosis, SHR
FemalesVirgins
Nonarteriosclerotic, Sprague-Dawley,
Nonarteriosclerotic, SHR
BreedersGrossly visible arteriosclerosis, Sprague-Dawley
Microscopic arteriosclerosis, SHR
Finalbodywt(g)
380 ± 10(24)
382 ± 13(24)
425 ± 12(24)
415 ± 11(35)
248 ± 8(24)
220 ± 4*(24)
310 ± 10(24)
255 ± 8*(35)
Pituitarygland
wt (mg)
6.5 ± 0.5(24)
7.6 ± 0.3(24)
8.5 ± 0.4(24)
10.4 ± 0.4'(35)
8.1 ±0.3(24)
14.2 ± 1.1*(24)
10.5 ±0.8(24)
10.0 ±0.5(35)
Adrenalgland
wt (mg)
19.5 ± 1.6(24)
16.1 ± 1.0*(24)
28.0 ± 2.0(24)
19.0 ± 1.0*(35)
34.2 ± 1.0(24)
22.4 ± 1.0*(24)
35.0 ± 1.5(24)
27.3 ± 1.0*(35)
Heartwt (mg)
1010 ± 10(24)
1705 ± 15*(24)
1300 ±40(24)
1650 ± 25*(35)
905 ±2(24)
945 ± 10*(24)
I1O5± 15(24)
1230 ± 25*(35)
Teslesovary
wt (mg)
2036 ± 25(24)
1506 ±48*(24)
1906 ±21(24)
1630 ± 26*(35)
60.0 ± 20(24)
28.2 ± 15*(24)
63 ± 18(24)
46 ± 11(35)
Results are given as mean ± SE. The numbers in parentheses denote the number of rats.• Statistically significant differences, P < 0.001.
FIGURE 2 Intratubular arteries of a male breeder SHR. The tunica media is hypertrophied and the tunica intima contains extensive quantitiesoj hyaiin. There hyalin deposits stain very positively for mucopolysaccharide and collagenous material. H <& E; 150x.
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498 CIRCULATION RESEARCH VOL. 38, No. 6, JUNE 1976
parenchymatous distribution of lipid found in Sprague-Dawley breeders but equally as severe on the basis oflipid infiltration. The hypertrophied, hemorrhagic, andthrombotic adrenal glands generally found in Sprague-Dawley breeder rats18 also were found in the Sprague-Dawley breeders used in the present experiment. Al-though the adrenal glands of the breeder SHR were red incolor, they were not hemorrhagic. Further, unlike theadrenal glands of Sprague-Dawley breeder rats, the breederSHR adrenals showed extensive lipid depletion from thezona fasciculata and zona reticularis (Fig. 4). Also, thezona glomerulosa of SHR breeder rats was especially nar-row but full of lipid, whereas this zone in Sprague-Dawleybreeder rats was greatly hypertrophied and greatly de-pleted of lipid.
The myocardium of the SHR showed definite evidence ofmarked hypertrophy and numerous, scattered, healed foci ofmyocardial infarction, as did the Sprague-Dawley breederrats. The islets of Langerhans were hypertrophied in thebreeder rats of both strains and their beta cells weredegranulated, indicative of sparse insulin reserve. The kid-neys of the Sprague-Dawley breeder rats displayed theircharacteristic glomerulosclerosis and arteriolosclerosis, nu-merous colloid casts, and kidney stones as previouslydescribed.'- N The kidneys of breeder SHR manifestedhyalinized glomerulosclerosis, colloid casts, and occasional
kidney stones (males only), but the SHR renal pathologywas much less extensive and less severe than that found inSprague-Dawley breeders.
The enlarged pituitary glands of virgin SHR contained nodistinctive characteristics. However, breeder SHR, likeSprague-Dawley breeders, displayed definite basophilia,frequent adenomas, and colloid-filled cysts. Although thetestes and ovaries of the SHR were greatly reduced in size,aside from the testicular arterial lesions found in malebreeder SHR, there was no distinctive evidence of histopath-ological change except that the ovaries of female breederSHR, like Sprague-Dawley female breeders, showed numer-ous hyperplastic corpora lutea with very few Graafianfollicles.
BIOCHEMISTRY
Concomitantly with their progressive development ofspontaneous arteriosclerosis, breeder rats of all of the strainstested by us also develop progressively worsening hyper-glycemia, hyperlipidemia, serum enzyme changes, and, mostoutstanding, marked changes in adrenal steroidogenesis.Because of this, the same serum parameters were measuredfor the SHR to determine whether repeated breeding in thisspontaneously hypertensive strain also would be accompa-nied by similar endogenous metabolic alterations.
Enzymes. The serum levels of CPK, SGOT, SGPT,
FIGURE 4 Adrenal cortex of a male breeder SHR showing a relatively narrow but lipid-rich zona glomerulosa subtended by a comparativelynarrow and lipid-poor zona fasciculata. Sudan black B; 75 x.
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ARTERIAL LESIONS IN BREEDER SHR RATS/ Wexlerei al. 499
TABLE 2 Differences in Serum Biochemistry between Male and Female Nonaneriosclerolic (Virgin) vs. Arteriosclerotic(Breeder) Sprague-Dawley Rats and Nonarteriosclerolic (Virgin) and Arteriosclerotic (Breeder) Spontaneously HypertensiveRats (SHR)
CPKOimol/liter)
LDH(pmol/liter)
Trigly-ce rides(mg%)
Free fattyacids
(mEq/liter)
Totalcholesterol
(mg%)Glucose(mg%)
BUN(mg%)
MalesVirgins
Nonarteriosclerotic, Sprague-Dawley
Nonarteriosclerotic, SHR
BreedersMicroscopic arteriosclerosis, Sprague-Dawley
Microscopic arteriosclerosis, SHR
FemalesVirgins
Nonarteriosclerotic, Sprague-Dawley
Nonarteriosclerotic, SHR
BreedersGrossly visible arteriosclerosis, Sprague-Dawley
Microscopic arteriosclerosis, SHR
100 ± 5(11)
298 ± 40*(12)
135 ± 8(15)
160 ± 10(10)
80 ± 5(12)
330 ± 5*(12)
80 ± 7(15)
140 ± 9*(15)
130 ± 5(12)
480 ± 2*(12)
135 ± 7(15)
122 ± 1(10)
120 ±0.5(12)
418 ± 2*(12)
140 ± 3(15)
140 ± 2(15)
80 ± 2(12)
50 ± 3 *(12)
150 ± 7( ID
80 ± 2 *(12)
70 ± 2(12)
130 ± 2*(12)
150 ± 10(12)
200 ± 12*(12)
220 ± 20(12)
400 ± 26*(12)
410 ±25(11)
640 ± 2 1 *(12)
380 ± 15(12)
352 ± 12(12)
455 ± 5(12)
810 ± 18*(12)
60 ±8(12)
138 ± 7 *(12)
75 ±8(11)
165 ± 10*(12)
71 ±7(12)
138 ± 6 *(12)
90 ±3(12)
164 ± 2 *(12)
90 ± 2(15)
124 ± 30*(15)
144 ± 1(15)
159 ± 3*(15)
90 ± 1(15)
146 ± 3*(15)
152 ± 1(9)
157 ± 5(9)
16 ± 1(15)
19± 1(15)
20 ± 1(15)
16 ± 1(15)
22 ± 1(15)
16± 1*(15)
42 ±3(9)
16± 1*(9)
CPK •= creatine phosphokinase; LDH = lactic dehydrogenase; BUN - blood urea nitrogen. Results are given as mean ± SE. Numbers in parentheses denotenumber of rats.
• Statistically significant difference, P < 0.001.
and LDH serve as an index of myocardial infarction in manand in animals. We have found these enzymes to be a goodindex of the myocardial damage frequently found in repeat-edly bred rats, regardless of whether the myocardial damageis acute or chronic.
In this particular experiment, the characteristic, greatercirculating levels of CPK were observed in the male, but notthe female, Sprague-Dawley breeder rats (Table 2). TheSHR showed an inverse relationship in that the CPK levelsof virgin SHR were greatly increased (P < 0.001) comparedto their repeatedly bred counterparts (Table 2). The samepattern of enzyme changes obtained in the case of SGOTand SGPT, except that these enzymes in both male andfemale breeder Sprague-Dawley rats were characteristicallymuch greater than those found in the nonarterioscleroticvirgin Sprague-Dawley controls. Again, the inverse condi-tion obtained in the SHR rats, i.e., as in the case of CPK,the SGOT, SGPT, and LDH levels (Table 2) were higher invirgin SHR compared to breeder SHR.
Lipids. Sprague-Dawley breeder rats are invariably obeseand hyperlipidemic, and have a fatty liver. The breeder SHRhad statistically significant (P < 0.001) greater tri-glyceridemia than their virgin counterparts, as was the casein the Sprague-Dawley strain (Table 2). Free fatty acids(Table 2) and total cholesterol (Table 2) exhibited the samepattern of increase in breeder vs. virgin rats and were muchmore elevated in the SHR strain than in theSprague-Dawley strain.
Carbohydrate. The hyperlipidemic, hypertensive, andarteriosclerotic Sprague-Dawley breeder rat is also hyper-
glycemic. In these experiments we found the Sprague-Dawley breeder rats to be definitely hyperglycemic com-pared to their virgin sisters and brothers (Table 2). Thesame was true of the breeder SHR compared to virgin SHR(Table 2). However, the circulating glucose levels of thevirgin SHR were comparatively greatly elevated comparedto SHR breeders and particularly when compared to theirSprague-Dawley virgin counterparts (Table 2).
Protein. The BUN levels are consistently elevated inbreeder vs. virgin Sprague-Dawley rats and especially in thefemale. The same was true in the Sprague-Dawley rats usedin this experiment (Table 2). However, the SHR did notexhibit any particular evidence of deranged protein metabo-lism (Table 2).
Steroids. Female rats have larger adrenal glands andproduce much more corticosterone (compound B) than domale rats. Although the female Sprague-Dawley breeder ratinitially secretes considerably greater quantities of corticos-terone, by the time she has delivered and nursed four to fivelitters of young and has developed advanced arteriosclerosisand the other pathophysiological changes described, corti-costerone production becomes greatly reduced (Fig. 5),whereas the male Sprague-Dawley breeder increases itsability to produce corticosterone (Fig. 5). In these experi-ments we found that the SHR produced much morecorticosterone than their Sprague-Dawley counterparts(Fig. 5); this is in spite of the fact that the adrenal glands ofSHR are considerably smaller than those ofSprague-Dawley rats (Table 1). Further, both the male andfemale breeder SHR produced considerably less corticoster-
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500 CIRCULATION RESEARCH VOL.38 , No. 6, JUNE 1976
one than their virgin counterparts (Fig. 5).
Discussion
The major finding in this investigation is that althoughrepeatedly bred SHR manifest essentially the same sponta-neous pathophysiological sequelae as Sprague-Dawleybreeder rats (as well as other strains), they do not developadvanced arterial disease despite their more severe hyperten-sion. It is of special interest that although SHR have severehypertension and other atherogenic metabolic changes, thevirgin SHR remain resistant to arterial disease. Further,unlike other strains of breeder rats for which the femaledisplays the most advanced arterial disease, it is only themale breeder SHR which, thus far, have been found to havespontaneous arterial lesions of any kind, and interestingly,these lesions were found exclusively in their testes.
It is of interest that breeder SHR become obese, as doSprague-Dawley breeder rats.10 It is true that SHR aresmaller than Sprague-Dawley rats. However, regardless ofhow the organ weight data are expressed, i.e., on the basis ofabsolute weight or as organ weight to body weight ratio, themarked organ weight differences remained statisticallyhighly significant. It is remarkable that despite the obesity,hyperlipidemia, and fatty liver observed both in arterioscle-rotic Sprague-Dawley and breeder SHR, the arterial lesionscontained very little lipid and were of the connective tissueand ground substance variety.
The fact that SHR pituitary glands were heavier thanthose of Sprague-Dawley rats points to the possibility thatthere may be fundamental hormonal differences betweenthese strains, since it is well established that the weight of thepituitary gland is seldom altered except under unusualhormonal conditions. The possibility of hormonal differ-ences between SHR and Sprague-Dawley breeder rats isalso reflected in the adrenal glandular histopathology ofthese two strains. The adrenal glands of breeder SHR didnot show any of the extensive hyperplasia, hemorrhage,thromboses, or pheochromocytomas observed in Sprague-Dawley breeder rats.18 Further, the histopathologicalsignificance of a narrow and lipid-rich zona glomerulosain the adrenal glands of SHR breeders vs. the extensivelyhypertrophied and lipid-free zona glomerulosa ofSprague-Dawley breeder rats suggests that the Sprague-Dawley breeder rats are very actively synthesizing andreleasing mineralocorticoids, e.g., aldosterone, whereasthe breeder SHR are less actively synthesizing and releasingmineralocorticoids. Our consistent finding of pituitary baso-philia, adenomatosis, and colloid-filled cysts and changes inthe ovaries and testes of breeder SHR as well as inrepeatedly bred rats of other strains, is in keeping with ourrecent report of deranged hypothalamic-pituitary releasingfactors and trophic hormone interrelationships inSprague-Dawley breeder rats,19 and suggests that the samemay be true for SHR breeders.
In our investigations of spontaneous and drug-inducedmyocardial infarction in nonarteriosclerotic vs. arterioscle-rotic r a t s j 0 " " we have found that the serum enzymes CPK,SGOT, SGPT, and LDH are a good index of the mass ofmyocardium infarcted or repaired..20- 24"26 and that arterio-sclerotic breeder rats show definitely less change in these
1 |Virgins
J LHBreeders
FIGURE 5 Comparison of serum corlicoslerone levels of male (n =24) and female (n = 24) virgin Sprague-Dawley rats compared withmale (n = 24) and female (n = 24) Sprague-Dawley breeder rats aswell as male (n = 24) and female (n = 24) virgin SHR comparedwith male (n = 24) and female (n — 24) breeder SHR. The height ofeach column depicts the mean and standard error.
serum enzymes and other associated metabolic parametersthan nonarteriosclerotic, virgin rats.21- 22- 24"28 The seem-ingly paradoxical and considerably greater elevation ofserum enzymes in nonarteriosclerotic virgin SHR is inkeeping with our previous experience. Our finding of moresevere hyperlipidemia in breeder vs. virgin SHR also coin-cides with our previous experience with virgin vs. breederrats of other strains. Because the SHR and Sprague-Dawley breeder rats were fed a relatively low fat diet, webelieve that their hyperlipidemia was due to the lipid-mobilizing effects of endogenous adrenocortical steroidsproduced during repeated breeding.4- 29'31 Similarly, thegreater hyperglycemia found in breeder vs. virgin SHR andSprague-Dawley rats is in keeping with the greater islethyperplasia and beta cell degranulation in breeder vs. virginrats. We have found progressively worsening islet hyper-plasia, beta cell degranulation, glucose tolerance, and seruminsulin changes to parallel repeated breeding and progres-sively worsening arteriosclerosis.31'34 We believe that theseabnormalities, like the aforementioned abnormalities inlipid metabolism, are due to the gluconeogenic or beta cellreserve depleting effects of the abnormal glucocorticoidsproduced by repeatedly bred rats. We have no ready expla-nation for the unusually greater hyperglycemia found in thevirgin hypertensive SHR. The absence of any increasedBUN levels in SHR suggests that good renal function ismaintained despite their severely elevated blood pressure.Corticosterone is the predominant steroid produced by therat adrenal cortex. The decreased production of corticos-terone by breeder SHR vs. virgin SHR indicates that re-peated breeding leads to reduced or impaired steroidogene-sis. Of special interest is the fact that SHR produced muchmore corticosterone than Sprague-Dawley rats despite thesmaller size of their adrenals.
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ARTERIAL LESIONS IN BREEDER SHR RATS/ Wexler etal. 501
AcknowledgmentsWe thank D. Conatser, E. Domingo, W. Goodhew, N. Wexler, and D.
Dube for their special efforts in this research project, and Dr. A. Sjoerdsma ofthe National Institutes of Health for generously providing the original SHRstrain.
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B C Wexler, S G Iams and J T JuddArterial lesions in repeatedly bred spontaneously hypertensive rats.
Print ISSN: 0009-7330. Online ISSN: 1524-4571 Copyright © 1976 American Heart Association, Inc. All rights reserved.is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation Research
doi: 10.1161/01.RES.38.6.4941976;38:494-501Circ Res.
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