Br. J. exp. Path.

(1976) 57, 663

COMPARATIVE EFFECTS OF CORTISONE, DIANABOL AND

ENOVID ON ISOPRENALINE-INDUCED MYOCARDIAL
INFARCTION IN ARTERIOSCLEROTIC VS
NONARTERIOSCLEROTIC RATS
B. C. WEXLER
From the May Institute for Medical Research of the Jewish Hospital and
Departments of Medicine and Pathology, University of Cincinnati,
College of Medicine, Cincinnati, Ohio 45229, U.S.A.
Received for publication June 21, 1976

Summary.-Male and female nonarteriosclerotic (virgin) and arteriosclerotic

(breeder) Sprague-Dawley rats were subjected to acute myocardial infarction with
isoprenaline. When myocardial necrosis was most intense, animals were given
cortisone (high and low doses), Dianabol, or Enovid. Animals receiving large doses
of cortisone manifested the best survival rate during the early stages of myocardial
infarction. Although their serum enzyme levels were least elevated and their hearts
showed the least amount of damage, these animals had undergone the most intense
body weight loss and began to die suddenly during the later stages of the experiment.
These animals also manifested hyperlipidaemia, hyperglycaemia, septicaemia,
severe disuse atrophy of their adrenal glands, and reduced Cmpd. B production.
Animals treated with low doses of cortisone or with the anabolic and androgenic
steroid, Dianabol, manifested none of the myocardial protective effects of the larger
dose of cortisone. These animals displayed a high incidence of left ventricular
aneurysm formation concomitant with extensive cartilaginous metaplasia within the
aneurysmal sites. Treatment with the contraceptive drug, Enovid, caused body
weight loss, hyperlipidaemia, hyperglycaemia, gonadal atrophy and reduction of
Cmpd. B production. Although the high dose of cortisone exercised definite salutary
effects during early myocardial infarction, chronic treatment led to adrenal disuse
atrophy and hypoadrenocorticism associated with sudden death during the later
stages of myocardial repair. These findings indicate that proper adjustment of the
dose and chronicity of corticosteroids used for treating the crisis of acute myocardial
infarction must be made in order to provide effective protection against untoward
pathophysiological conditions, acceleration of myocardial repair, but without sup-
pression of adrenal function.
THE USE of adrenal steroids for the The dilemma is that large doses of adrenal
treatment of acute myocardial infarction steroids impair wound healing and may
has generated intense interest and much prevent proper myocardial repair. Cur-
debate (Johnson et at., 1953; Dali and rently, there is considerable interest in
Peel, 1963; Lillehie et al., 1964; Motsay finding ways of circumventing the un-
et al., 1970; Haddy, 1970; Libby et al., toward effects of high doses of glucocorti-
1973; Spath, Lane and Lefer, 1974; coids either by adjusting the dose level of
Vyden et al., 1974; Glenn, 1974). One of the steroid used, the use of synthetic
the key problems is that exceptionally steroids, or the use of special vehicles for
large doses of cortisone are required to their administration (Glenn, 1974).
maintain life, counteract shock, and We have developed experimental
correct the metabolic derangements which models of arteriosclerosis and acute myo-
accompany acute myocardial infarction. cardial infarction which lend themselves
Reprint requests to Dr Bernard C. Wexler, May Institute for Medical Research, 421 Ridgeway Avenue,
Cincinnati, Ohio 45229, U.S.A.
664 B. C. WEXLER
well toward the exploration of the problem
of salutary vs deleterious aspects of the use
of steroids in acute myocardial infarction
with and without the complication of
co-existent arteriosclerosis. Repeatedly-
bred, male and female rats develop
hyperglycaemia, hyperlipidaemia, hyper-
tension and arteriosclerosis, spontaneously
(Wexler, 1964c.). Although male breeder
rats develop microscopic aortic lesions
only, compared to grossly-visible aortic
lesions in female breeders, the male
breeders die considerably earlier than the
female breeders, often due to an acute
myocardial infarction. We are able to
produce acute myocardial infarction in
both arteriosclerotic (breeder) and non-
arteriosclerotic (virgin) rats by giving
them 2 large, subcutaneous injections of
the potent, beta-adrenergic stimulating
agent, isoprenaline (Wexler, 1964c; Wexler
and Kittinger, 1965; Wexler and Lutmer,
1972; Wexler, Willen and Greenberg,
1974). When subjected to an acute
myocardial infarction, despite their genera-
lized arteriosclerosis, breeder rats, para-
doxically, manifest much less metabolic
derangement, e.g., serum enzymes, lipids,
glucose, steroids, etc., than virgin rats
with no arteriosclerosis. These drug-
induced myocardial infarcts are morpho-
logically identical to those which occur
spontaneously in arteriosclerotic breeder
rats and the attendant pathophysiological
changes mimic those which occur in
patients having an acute myocardial
infarction, e.g., changes in CPK, SGOT,
SGPT, LDH, triglycerides, free fatty acids,
cholesterol, glucose and steroids.
In order to simulate the clinical
dilemma associated with the use of steroids
in acute myocardial infarction as well as
the problem of the influence of the
coexistence or absence of arteriosclerosis
during acute myocardial infarction, we
subjected nonarteriosclerotic (virgin) and
arteriosclerotic (breeder) rats to an acute
myocardial infarction with isoprenaline.
Some of the animals received high doses of
cortisone while others received low doses
of cortisone during the acute necrosis and
repair phases of their myocardial infarct.
We have previously found adverse meta-
bolic and cardiovascular effects in non-
arteriosclerotic (virgin) and arteriosclerotic
(breeder) rats treated with contraceptive
drugs, e.g., Enovid (Wexler, 1974). Be-
cause of reports of myocardial infarction
and stroke in some women taking the
contraceptive " pill, " we elected to treat
arteriosclerotic and nonarteriosclerotic
animals with the contraceptive drug
Enovid during the course of their acute
myocardial infarction to learn whether
this kind of drug would have a benign or
adverse effect on the pathophysiological
course of myocardial infarction. Simi-
larly, anabolic steroids have been reported
to accelerate the reparative processes in
the infarcted myocardium (Bajusz, 1969).
Therefore, we also employed the anabolic
steroid Dianabol to determine whether an
anabolic agent would have an opposite
effect on the pathophysiologic course of
acute myocardial infarction in contrast to
potentially catabolic steroids, e.g., corti-
sone.
MATERIALS AND METHODS
General.-All of the animals used in these
experiments were purchased from ARS-Sprague-
Dawley Farms, Madison, Wisconsin, U.S.A.,
and were housed in our temperature-, light- and
humidity-controlled Research Animal Colony.
They were fed a commercial rat chow (Teklad)
which has a relatively low fat content (4%) and
were given tap water to drink ad libitum. The
nonarteriosclerotic, virgin rats were 8 months
old and the arteriosclerotic, breeder rats ranged
in age from 7 to 9 months. The breeder males,
which have microscopic aortic sclerosis, had
been engaged in active breeding since they were
90 days old. The breeder females, which have
grossly-visible aortic sclerosis ranging from
clear to minimal to moderate to severe, had
4-5 closely-spaced pregnancies and had been
allowed to suckle 5-10 pups for 21 days, each
time before the young were abruptly weaned.
The subjects were arranged into 4 basic groups:
nonarteriosclerotic, virgin males vs arterio-
sclerotic, breeder males; nonarteriosclerotic,
virgin females vs arteriosclerotic, breeder females.
Induction of myocardial infarction with
isoprenaline.-Because we deliberately wished
to induce massive myocardial necrosis and
because the Sprague-Dawley strain of rat is
 MYOCARDIAL INFARCTION: CORTISONE, DIANABOL AND ENOVID
relatively resistant to isoprenaline-induced myo-
cardial infarction, we were compelled to use large
doses of isoprenaline in these investigations.
Since only 50 to 60% of the animals subjected to
this form of myocardial infarction will survive if
not given therapeutic drugs, e.g., propranolol
(Wexler, 1973), provision of extra numbers of
subjects to insure adequate numbers of survivors
for each experimental group had to be made.
Over 1500 rats were used to complete these
experiments. Isoprenaline (Isuprel ®, Winthrop
Laboratories, New York, N.Y., 1-(3,4-dihydroxy-
phenyl)-2 isopropyl amino ethanol hydro-
chloride), was given as 2 single s.c. injections
spaced 24 h apart. The nonarteriosclerotic
virgin rats were given 50 mg of isoprenaline/
100 g body wt. The arteriosclerotic breeder rats
were given 25 mg of isoprenaline/100 g body wt.
It is important to point out that arteriosclerotic
breeder rats are 100 g heavier than nonarterio-
sclerotic rats (Judd and Wexler, 1969), and thus
receive a total dose comparable to the non-
arteriosclerotic rats. We have had extensive
experience with this dose regimen and the total
area or severity of myocardium infarcted (the
central issue in these studies) is very similar in
both the arteriosclerotic and nonarteriosclerotic
subjects despite the apparent disparity of dose.
Further, any dose of isoprenaline above 25 mg/
100 g body wt. given to arteriosclerotic breeder
rats leads to better than 60% mortality and
precludes any attempt to compare the response
of arteriosclerotic vs nonarteriosclerotic rats in
statistically significant numbers. Thus, we
were compelled to use the dose regimen described
wherein the severity of the myocardium
infarcted is comparable in each group and the
number of survivors (60%) permits reasonably
reliable interpretation of the data. (The area of
myocardium infarcted may be controlled by the
size of the dose of isoprenaline employed, i.e., a
low dose will cause apical infarction only, a
moderate dose patchy to confluent necrosis as
well as left ventricular necrosis and a large dose,
such as we employ, will cause atrial and
ventricular, through-and-through, myocardial
necrosis.)
Arteriosclerotic vs nonarteriosclerotic rats.-
Virgin rats do not develop spontaneous arterio-
sclerosis until they are senile, i.e., 2 to 3 years of
age. Arteriosclerotic male breeder rats have
microscopic lesions of their aortae and coronary,
mesenteric arteries, etc., by the time they have
been bred repeatedly and sired 5 to 6 litters
(Wexler and True, 1963; Wexler, 1964a,b;
Wexler, 1970). Arteriosclerotic, female breeders
have grossly-visible aortic sclerosis as well as
microscopic lesions of their coronary, mesenteric
arteries, etc., by the time they have delivered
and nursed-to-weaning 4 to 5 litters of pups in
rapid succession. The development of arterio-
sclerosis in actively bred rats is so consistent
665
that we can reliably predict the presence of
vascular disease by selecting animals on the
basis of their breeding history. Any animals
used as arteriosclerotic subjects which were
found not to have arterial disease at the time of
autopsy were discarded.
High vs low doses of cortisone.-In order to
compare the salutary vs deleterious effects of
cortisone during acute myocardial infarction, a
high dose of cortisone, known to be catabolic by
previous tests (Wexler and Saroff, 1969), and a
low, noncatabolic dose were used. Cortisone
acetate, suspended in sodium carboxymethy-
cellulose, polysorbate 80, sodium chloride,
benzyl alcohol (Upjohn), diluted with saline was
used for the injection of all treated animals.
The high (or catabolic) dose of cortisone was
2-5 mg/100 g body wt., s.c., every other day; the
low (or noncatabolic) dose of cortisone was
0-25 mg/rat, s.c., every other day. The injec-
tions of cortisone commenced on the third day
after the animals were given their 2 injections of
isoprenaline. (Myocardial infarction is at a
zenith on Day 3 post-isoprenaline (Wexler and
Kittinger, 1965; Wexler and Lutmer, 1972;
Wexler, Willen and Greenberg, 1974; Wexler,
1973). Cortisone injections were continued until
Day 30 when the animals were autopsied. All of
the animals were weighed every other day. The
high, catabolic dose of cortisone had to be
reduced periodically on a per 100 g of body wt.
basis, in keeping with each animal's loss of body
weight.
Dianabol therapy.-In man, Dianabol ® (Ciba)
or methandrostenolone is the most potent
anabolic steroid (Liddle and Burke, 1960).
Like cortisone, Dianabol therapy was begun on
Day 3 post-isoprenaline. Injections of 5*0 mg/
100 g body wt., s.c., suspended in saline, were
given once weekly, i.e., a total of 4 doses during
the 30-day period of this experiment.
Enovid.-Although the contraceptive drugs
do not cause any apparent ill effects in most
women, there are reports of cases where the
contraceptive " pill " has caused hyper-
glycaemia, hyperlipidaemia, hypertension,
atherosclerosis, myocardial infarction and
"stroke " (Wexler, 1974). We have found
adverse cardiovascular and metabolic changes
in nonarteriosclerotic (virgin) and arterio-
sclerotic (breeder), male and female rats given
the contraceptive drug, Enovid. Therefore,
these animals were also treated with Enovid'9
(Searle) which is a combination of the progestin,
norethynodrel and the oestrogen, mestranol,
i.e., a ratio of 9-85 mg of norethynodrel to
0-15 mg of oestrogen. Pills containing this ratio
of progestogen and oestrogen that are contracep-
tive in the human were ground into a fine
powder and suspended in saline. The animals
were given 0-10 mg of this saline suspension of
Enovid, once weekly, on a per 100 g body wt.
666 B. C. WEXLER
basis. Like cortisone and Dianabol, injections
commenced on Day 3 post-isoprenaline, i.e., a
total of 4 injections during the 30-day period of
the experiment. Like the high dose of cortisone,
the dose of Enovid had to be reduced pro-
gressively because of its catabolic effect.
Autopsy.-All of the animals were killed by
decapitation to avoid the stress of anaesthesia.
Any animal that did not have confirmed
arteriosclerosis either by gross inspection (female
breeders) or subsequent histological (male
breeders) examination, was discarded. At
autopsy, careful examination and record was
made of the presence and severity of myocardial
infarction in each animal. Key organs, e.g.,
hearts, kidneys, adrenals and thymus glands,
were trimmed of excess tissue and weighed for
eventual gravimetric analysis and comparison,
and fixed in 10% neutral formalin for histo-
pathological examination, i.e., paraffin and
frozen sections. In addition to haematoxylin
and eosin, special stains were used to demon-
strate metachromasia and mucopolysaccharides
(alcian and toluidine blue, Hale stain), lipids
(Sudan black B), elastic tissue (Verhoeff, van
Giesen), calcium (von Kossa) and beta cell
granulation of the islets of Langerhans (aldehyde
fuchsin Ponceau). Blood collected from the
severed neck vessels of each animal was centri-
fuged (refrigerated) and the serum stored in a
deep freeze until time for analysis. The
following biochemical parameters (serum) of
each animal were analysed using the Auto-
analyser (Technicon): creatine phosphokinase
(CPK), transaminases, i.e., glutamic oxaloacetic
(SGOT), and glutamic pyruvic (SGPT), lactic
dehydrogenase (LDH), triglycerides, free fatty
acids, total cholesterol, glucose and blood urea
nitrogen (BUN). All of the above automated
procedures are detailed in the manual published
by the Technicon Co., Automation in Analytical
Chemistry, Technicon, Mediad, Inc., New York.
Serum corticosterone (Cmpd. B) levels were
measured by the fluorometric method of
Guillemin et al. (1959) as an index of adreno-
cortical activity. Analysis of variance and
biostatistical analyses followed the procedures
and tables cited by Snedecor's text (Statistical
Methods, 5th ed., Iowa State College Press,
Cedar Falls, 1956).
RESULTS
(A) General observations
When rats are subjected to an iso-
prenaline-induced, massive, myocardial
infarct, they characteristically exhibit a
readily observable sequence of events
consisting of the prompt development of
tachycardia, dyspnoea, hyperventilation,
anuria, prostation and shock, within
minutes of receiving the first injection of
isoprenaline. Twelve to 24h following
the first injection of isoprenaline, those
animals which survive their initial bout of
tachycardia, relative cardiac ischaemia
and anoxia, walk about, eat, and drink
normally. These animals were no excep-
tion. Following the second injection of
isoprenaline, anuria, signs of shock and
prostration promptly recur. After the
second injection of isoprenaline, myocardial
necrosis becomes definitely established.
During the first and second day of drug-
induced myocardial ischaemia, animals
characteristically are found to have pro-
gressively increasing, severe, congestive
heart failure concomitant with their anuria.
On the third day, surviving animals exhibit
marked diuresis concomitant with reduc-
tion of their hydrothorax. The animals
in this experiment displayed these same
signs and conditions. It was remarkable
that those animals which were given the
high dose of cortisone on Day 3 manifested
an immediate beneficial response. None
of the cortisone-treated animals died;
their hydrothorax was completely resolved,
while the other animals manifested per-
sisting residual quantities of fluid in their
thorax. It is of interest that although the
female rats survived myocardial infarction
in significantly greater numbers (Table),
they manifested much more severe signs
of acute stress than the male subjects
under the same conditions. Paradoxically,
breeder rats with pre-existing arterio-
sclerosis also manifested fewer signs of
distress than their nonarteriosclerotic vir-
gin counterparts and survived in greater
numbers (Table). Myocardial necrosis
reaches a zenith on Day 3 and repair is
comparatively rapid in the rat so that by
Day 7, despite acute and massive myo-
cardial necrosis, repair is virtually com-
plete. This was generally true of these
animals with the notable exception of
those receiving the high dose of cortisone.
Although the death rate had subsided in
all of the treated groups by Day 7,
animals receiving the high dose of cortisone
 -X
MYOCARDIAL INFARCTION: CORTISONE, DIANABOL AND ENOVID 667

TABLE. Percent Survival Rate of Male and Female, Nonarteriosclerotic (Virgin) and
Arteriosclerotic (Breeder) Sprague-Dawley Rats, 30 Days Post Isoprenaline-Induced
Myocardial Infarction
Male* Female*
Breedert- Breeder:-
Virgint no microscopic Virgin: no grossly visible
Treatment arteriosclerosis arteriosclerosis arteriosclerosis arteriosclerosis
Controls-No treatment 100 100 100 100
Isoprenaline + high dose cortisone 16 46 20 48
Isoprenaline + low dose cortisone 44 56 40 68
Isoprenaline + Dianabol 46 58 60 62
Isoprenaline + Enovid 28 48 62 70
Isoprenaline 44 44 64 58
* The average survival rate of all males vs females regardless of treatment or the presence or absence
of
arteriosclerosis was only 38% for males and 55% for females.
t The average survival rate for nonarteriosclerotic (virgin) males regardless of treatment was 26% vs
50% for their arteriosclerotic (breeder) male cohorts.
I The average survival rate for nonarteriosclerotic (virgin) females regardless of treatment was 49% vs
610% for their arteriosclerotic (breeder) female cohorts.

M ALE
0
o Virgins no Arteriosclerosis
40 Breeders microscopic Arteriosclerosis
High dose Cortisone
Low dose Cortisone
-- Dianabol
500 t s - ~- Enovid
- soproterenol
450

(,, 400 F
-350 k _
_- *

' O **--...
LJ 300
* 0..
C) 250 F 0*..
l0 *
200 [ I I I~~~~~~

150
5 15 2010 25 30
DAYS
FIG. 1. Changes in body weight of male, nonarteriosclerotic (virgin) and arteriosclerotic (breeder),
Sprague-Dawley rats during a 30-day period, following the induction of an acute and massive
myocardial infarction by the potent beta-adrenergic stimulating agent, isoprenaline. On Day 3
when myocardial necrosis reaches a zenith, some of the animals were given either a high or low dose
of cortisone, Dianabol or Enovid, throughout the course of their 30-day convalescence.
44
668 B. C. WEXLER

began to die, so that by the close of the there is marked loss in body weight despite
experiment (Day 30), this group showed fluid retention due to anuria and con-
the poorest survival rate (Table). Mor- gestive heart failure. In this experiment,
bidity was particularly high in the non- after this initial acute loss of body weight,
arteriosclerotic (virgin) males followed by most of the nonarteriosclerotic (virgin)
nonarteriosclerotic (virgin) females treatedrats began to gain weight as would be
with high doses of cortisone (Table). As expected in adult, but still growing rats
in our past experience, males were more (Figs. 1 and 2). The arteriosclerotic
prone than females to succumb to their (breeder) rats, which are characteristically
myocardial infarct and, paradoxically, much more obese than their nonarterio-
arteriosclerotic animals survived better sclerotic (virgin) counterparts (Figs. 1 and
than nonarteriosclerotic animals (Table). 2), did not show any increased increment
Of special interest was the fact that in body weight but did maintain their
nonarteriosclerotic (virgin) males treated body weight at a plateau level (Figs. 1
with Enovid showed an unusually high and 2). However, both the male and
mortality rate (Table). female, arteriosclerotic (breeder) and non-
arteriosclerotic (virgin) rats given the high
(B) Gravimetric analysis dose of cortisone exhibited marked loss in
During the acute stages of isoprenaline- body weight (Figs. 1 and 2). Although
induced myocardial infarction in the rat, both the arteriosclerotic (breeder) and

FE MALE

400 qj

350
10 O

300
to
_ Io
"-
250
-

*0.*~~*| @0
$O 200 0~~~~~~~~~~

q 150 o Virgins no Arteriosclerosis °

* Breeders Grossly- visible Arteriosclerosis
. . High Dose Cortisone

100 . Low Dose Cortisone

-- Dianabol
-- Enovid
- Isoproterenol
50

0
5 10 15 20 25 30
D AYS
FIG. 2.-Changes in body weight of female, nonarteriosclerotic (virgin) and arteriosclerotic (breeder),
Sprague-Dawley rats. Same protocol as in Fig. 1.
 MYOCARDIAL INFARCTION: CORTISONE, DIANABOL AND ENOVID 669

nonarteriosclerotic (virgin) males treated ficantly heavier adrenal glands whereas

with Enovid showed considerable loss in
body weight, only the nonarteriosclerotic
(virgin) females treated with Enovid
showed a similar loss in body weight
(Figs. 1 and 2). The adrenal glands
become greatly hypertrophied and haem-
orrhagic during the acute stages of
isoprenaline-induced myocardial infarc-
tion. In this experiment, by Day 30
post-infarction, the adrenal glands of
those animals treated with cortisone (low
dose), Dianabol, and isoprenaline alone,
although still slightly hypertrophied, were
within the range of normal adrenal
glandular weight (Fig. 3). The notable
exceptions were those treated with Enovid
and cortisone (high dose). All of the
animals treated with Enovid had signi-
MALE
Virgins 13reeders*
no X microscopic
Arteriosclerosis I Arteriosclerosis
E Controls I
E1 High Dose Cortisone + I soprot.
J
$ Low Dose Cortisone+ lsoprot.
60
ll Dianabol + Isoprot.
(24)
to4 (14)
(28
T291
(2221
%J30 23
~
23)
(4)22)1(4
(4
those treated with the high dose of corti-
sone had adrenal glands which were signi-
ficantly reduced in size and weight (Fig. 3).
The thymi of arteriosclerotic (breeder) rats
are characteristically involuted and an
acute isoprenaline-induced myocardial in-
farct is associated with thymus gland
involution (Fig. 4). Both the high dose of
cortisone and Enovid caused unusually
extensive thymus gland involution (Fig. 4).
An acute isoprenaline-induced myocardial
infarct is invariably accompanied by an
increase in cardiac weight. Cardiac hyper-
trophy was pronounced in all of these
animals but there were no significant
differences between the various treated
groups. The same relationship applied in
the case of kidney weight. The high dose
FEMALE
Virgins I Breeder;
no I grossly -visible
Arteriosclerosis I Arteriosclerosis
III Enovid + Isoprot.
Isoproterenol I
(35)
(3)1 1
(20) 3
1 29)
34
(24) 32)I

t20 (24)I

8
I ~~~~~~~~10I
10 23 ~*

FIG. 3.-Changes in adrenal gland weight of male and female, nonarteriosclerotic (virgin) and
arteriosclerotic (breeder), Sprague-Dawley rats 30 days after a massive myocardial infarction
induced by isoprenaline. Throughout the post-infarction period, some of the animals were treated
with cortisone (a high and a low dose), Dianabol, or Enovid. The height of each column indicates
the mean ± standard error. The number of samples is given in ( ). All of the remaining figures
(Figs 4 to 11) follow the same protocol.
670)
350
ffi 300 I U
23) 4
3: 250 1 ~~~~~~(30)
200
I(24)
5 '
6 150
Cl)
100
K
50 1 3
FIG. 4.-Changes in thymus gland weight.
of cortisone was definitely anti-gonado-
trophic, producing both lowered testicular
and ovarian weight. Those animals
treated with Enovid exhibited the
most marked antigonadotrophic effects
(Fig. 5).
(C) Blood chemistry: enzymes
The acute elevation of serum enzymes,
e.g., CPK, SGOT, SGPT, LDH, etc., is
used as an index of acute myocardial
infarction. The distinctly elevated serum
enzymes observed in these animals, albeit
on Day 30 post-infarction, is interpreted
as being indicative of acute or on-going
myocardial cell damage.
Creatine phosphokinase (CPK).-The
serum CPK levels were most significantly
elevated in those animals which received
isoprenaline alone, and less elevated in
those receiving the combined treatment of
B. C. WEXLER
O Controls
I High Dose C
I3Low Dose C
I Dionabol 4
I Enovid + Is
Isoproterer
(24)
(20
(32
~~~~1031
isoprenaline + Enovid or Dianabol or the
low dose of cortisone (Fig. 6). Those
animals which were given the high dose of
cortisone manifested considerable reduc-
tion of the circulating CPK level, which
usually attends an isoprenaline-induced
myocardial infarct (Fig. 6).
Glutamic oxaloacetic transaminase
(SCOT). The SGOT levels were similarly
greatly elevated in all animals subjected
to myocardial infarction. Again, con-
comitant treatment with Enovid, Diana-
bol, cortisone (low dose) and cortisone
(high dose) caused progressively more
effective reduction in SGOT levels in that
order (Fig. 7).
Glutamic pyruvic transaminase
(SGPT).-The same pattern of increased
CPK levels due to myocardial infarction
but reduced levels in animals due to drug
treatment applied in the case ofthe enzyme
 MYOCARDIAL INFARCTION: CORTISONE, DIANABOL AND ENOVID 671

2000 (28)
)
(2 2
1800

1600 31) -60

8 30) (24)
23
'-1400 -50

1200 II I
24.
~~~40~
(24) s
1000 I ~~~30
1o IR
800 20~

600 14 I0

400L
FIG. 5. Changes in testi lCIular and ovarian weight.

SGPT. That is, isoprenaline alone caused Blood chemistry: lipids

the highest increase in SGPT, Enovid
treatment caused moderate reduction,
Dianabol somewhat more effective reduc-
tion, the low dose of cortisone caused an
even greater reduction, and the high dose
of cortisone caused the most effective
reduction in SGPT levels.
Lactic dehydrogenase (LDH). Again,
the same pattern of elevated enzyme
levels, i.e., CPK, SGOT and SGPT, 30
days post-infarction was observed in the
case of LDH. LDH levels were reduced in
those animals treated with ancillary drugs
and in the same increasing order of
effectiveness, i.e., Enovid was the least
effective and the high dose of cortisone
was the most effective.
Arteriosclerotic (breeder) rats charac-
teristically manifest hyperlipidaemia, e.g.,
triglycerides, free fatty acids and chol-
esterol, spontaneously (Figs. 8 and 9).
There is an acute and intense hyperlip-
aemia, i.e., triglycerides, free fatty acids,
but not cholesterol, when rats are sub-
jected to an acute myocardial infarction
with isoprenaline.
Triglycerides. On Day 30, the acute
hyperlipaemia which accompanies acute
myocardial necrosis had subsided in most
of the animals. However, those animals
receiving ancillary treatment with Enovid
or high doses of cortisone exhibited con-
siderable elevation of their triglyceride
levels above the others (Fig. 8).
672 B. C. WEXLER

N.

6600
800

~700
,]D~i.23 (23) 1

(2(14
. X

(28)
(22~~~~2
(24
(

500

Q400

(8 1 (24:
~200
(24I

FIG. 6.-Changes in seru mn creatine phosphokinase.

Free fatty acids.-The same conditions
observed for triglycerides also applied in
the case of circulating, free fatty acids,
i.e., definitely elevated free fatty acids in
the case of those animals treated with
Enovid or with the high dose of cortisone.
Cholesterol.-Despite the very consis-
tent pattern observed for circulating
triglycerides and free fatty acids in these
animals, the pattern of change for serum
cholesterol was strikingly different. Serum
cholesterol levels are not acutely elevated
as are triglycerides and free fatty acids
when rats are subjected to an isoprenaline-
induced myocardial infarction. The serum
cholesterol levels of the rats 30 days
post-infarction, in most of the experi-
mental groups in this study, were normal
or near normal (Fig. 9). However, there
were 2 notable exceptions. Animals
which survived their myocardial infarct
and were treated with a high dose of
cortisone exhibited supernormal levels of
cholesterol. By direct contrast, animals
treated with Enovid exhibited greatly
reduced levels of cholesterol (Fig. 9).
Blood chemistry: carbohydrate
Arteriosclerotic (breeder) rats develop
hyperglycaemia spontaneously, and when
 MYOCARDIAL INFARCTION: CORTISONE, DIANABOL AND ENOVID 673

400
14J

g 350

; ;. 300
"
an
% f 250
c \
I%. 200

C)- 150

M 100

50
FIG. 7.-Changes in serum glutamic oxaloacetic transaminase.

arteriosclerotic (breeder) and nonarterio- exacerbation of their hyperglycaemia (Fig.

sclerotic (virgin) rats are subjected to an
isoprenaline-induced myocardial infarct,
they invariably become markedly hyper-
glycaemic during the acute necrosis phase
(Days 1 to 3) with the hyperglycaemia
becoming progressively less severe as
myocardial repair proceeds (Days 4 to 7).
Glucose.-All of the animals, except
nontreated, nonarteriosclerotic (virgin)
controls, were definitely hyperglycaemic
(Fig. 10). In general, although the male
and female arteriosclerotic (breeder) rats
were typically hyperglycaemic, their glu-
cose levels were not further elevated 30
days post-infarction (Fig. 10). However,
those arteriosclerotic (breeders) which
received isoprenaline alone or isoprenaline
plus adjunctive therapy with either Enovid
or the high dose of cortisone did exhibit
10).
Blood chemistry: protein
We consistently observe a brisk in-
crease in BUN levels in animals subjected
to an isoprenaline-induced myocardial
infarct and arteriosclerotic (breeder) rats
characteristically have much higher BUN
levels than nonarteriosclerotic (virgin)
rats.
Blood urea nitrogen (BUN).-In addi-
tion to the conditions described above, all
of the animals exhibited greatly elevated
BUN levels (ranging from 25 to 40 mg%)
30 days post-infarction. Ancillary drug
treatment did not appear to increase or
decrease these elevated BUN levels.
Animals treated with isoprenaline +
Enovid, regardless of sex, presence or
674 B. C. WEXLER

300 -
E Low Dose Cortisone + isoprc
E* Dionabol + Isoprot.
>250 -

(14)
~200
(8)
150
SO (2
:22) 28
4

io 24~ 3

5 01

Fic. 8. Changes iria serum triglycerides.

absence of arteriosclerosis, consistently compared to other drug-treated animals

had the highest BUN levels.
Blood chemistry: steroids
Arteriosclerotic (breeder) rats first
develop hyperadrenocorticism but with
continued breeding eventually become
hypoadrenocorticoid. When rats are sub-
jected to isoprenaline-induced myo-
cardial infarction, they become acutely
hyperadrenocorticoid.
Corticosterone (Cmpd. B).-Animals
treated with isoprenaline alone were still
producing extra quantities of Cmpd. B 30
days post-infarction (Fig. 11). Animals
treated with isoprenaline + Dianabol or
the low dose of cortisone had normal or
near normal levels of Cmpd. B. However,
animals treated with isoprenaline +
Enovid or the high dose of cortisone had
definitely suppressed levels of Cmpd. B
(Fig. 11).
(D) Pathology
Gross.-The morphological nature of
the spontaneous arteriosclerosis which
appears in breeder rats was not altered by
subjecting these rats to myocardial infarc-
tion. Because the nature of the arterial
disease in breeder rats has been described
in detail (Wexler and True, 1963; Wexler,
1964a,b,c; Wexler, 1970), it will not be
repeated here. On gross inspection, the
hearts of most of the animals exhibited a
high incidence of left ventricular aneurysm
formation 30 days post-infarction, where-
as the remaining portions of the heart
manifested little or no evidence of the
extensive and usually confluent myocardial
necrosis which reaches a zenith on Day 3
post-isoprenaline. Those animals which
 MYOCARDIAL INFARCTION: CORTISONE, DIANABOL AND ENOVID 675

ISO
~~I70 ~~~~(.23)

150 0

1I30

90 2)29)
(23)~ ~ 29
(23)
k
70
. ~~23) ~2

(24. '

50
ote evdne fdmae
In urhr
30
FIG.,. 9.-Changes in serum total cholesterol.

received the high dose of cortisone had
exceptionally well-repaired hearts on gross
inspection, and showed no signs of
aneurysm formation, cardiac necrosis or
any other evidence of damage. Further,
animals treated with isoprenaline + high
doses of cortisone had a high incidence of
grossly visible hepatic steatosis and atro-
phied adrenal glands. The animals treated
with isoprenaline + Enovid also had a
high incidence of grossly-visible hepatic
steatosis and cirrhosis, but haemorrhagic,
greatly enlarged adrenal glands, atrophic
testes and ovaries, and greatly enlarged
and ballooned-out uteri.
Microscopic.-When the hearts and
organs were examined histopathologically,
it was found that those animals treated
with isoprenaline + high doses of
cortisone had hearts which were virtually
free of any signs of infarction (Fig. 12).
However, several of these animals had
miliary streptococcal infection, i.e., in-
volving the heart, kidney and other
organs. Fatty infiltration of the liver,
which was detectable grossly, proved to be
most extensive histologically (Fig. 13).
Most notable was the advanced atrophy
of the adrenal cortices in these animals,
i.e., selective atrophy and lipid depletion
of the zona fasciculata, but preservation,
hypertrophy, and lipid repletion of the
zona glomerulosa (Fig. 14). This histo-
logical appearance of specific adreno-
676 B. C. WEXLER

200 _ tJ

180 (23)1
(14 (23)
(23

to.1 (29
(822'i 1(24 28
LiF 140

(24

80 I

Animals~~~~~.
trae ihiornln

FIG. 10 -Change3s in serum glucose.

alone,~~~~24
ispenln + ow does o

cortical zones is typical of adrenal disuse DISCUSSION

atrophy which follows steroid overdose or
hypophysectomy.
Animals treated with isoprenaline
alone, isoprenaline ± low doses of
cortisone or Dianabol almost all displayed
dilatation and extensive cartilaginous
metaplasia of the left ventricle (Figs. 15
and 16). Animals treated with isopren-
aline + Enovid also displayed this ex-
tensive dilatation and cartilaginous meta-
plasia of the left ventricle and, in addition,
showed marked pancreatic islet beta cell
degranulation, fatty and cirrhotic livers
(Fig. 13), ovarian and testicular involu-
tion, and adrenal glands that were greatly
hypertrophied and haemorrhagic, exten-
sively depleted of lipid from the inner
cortical zones and with occasional foci of
cortical thromboses (Fig. 17).
The salutary effects of administering
high doses of cortisone during the acute
stages of myocardial infarction were
clearly demonstrated in this experiment.
Animals given a high dose of cortisone on
Day 3, when isoprenaline-induced myo-
cardial infarction reaches a zenith, not
only survived in greatest numbers but also
manifested the least amount of congestive
heart failure and displayed little or no
signs of shock or prostration. In this same
connection, it is of interest that regardless
of treatment, the female rats survived in
greater number than males and animals
with pre-existing arteriosclerosis survived
better than those with no arterial disease.
Apparently, the salutary effects of the
high dose of cortisone were short-lived or
 MYOCARDIAL INFARCTION: CORTISONE, DIANABOL AND ENOVID
S 50
\ 0
(3O
0.
Zt 30
lz
K
6 20
C
ti
k 10
FIG:. 11. Changes in
limited to the early stages of myocardial
infarction, in view of the numerous and
sudden deaths of these animals com-
mencing after Day 7. These sudden and
numerous deaths are in conflict with the
fact that these cortisone-treated rats had
fully repaired the myocardial necrosis
which occurred between Days 1 and 3.
The fact that Enovid-treated animals also
sohwed poor survival by the close of the
experiment suggests that this drug may
have caused depression of the hypo-
thalamic-pituitary-adrenal axis similar
to the pituitary gland-depressing effects
of chronic treatment with high doses of
cortisone. The similarity of the changes
produced by cortisone (high dose) and
Enovid was borne out by the marked
catabolic effects of each, e.g., loss in body
weight. However, the changes induced
by these 2 drugs were sharply divergent
insofar as adrenal weight was concerned,
i.e., cortisone (high dose) caused disuse
677
serum corticosterone.
atrophy and marked reduction in adrenal
weight vs Enovid-induced adrenal hyper-
trophy and increased glandular weight.
Both cortisone (high dose) and Enovid
caused severe involution of the thymus
gland. The severity of thymus gland
involution was much greater than that
which we usually observe following an
acute myocardial infarction in rats (Wexler
and Kittinger, 1965). In addition to the
thymus gland atrophy, cortisone (high
dose) caused involution of the reticulo-
endothelial system in general, as demon-
strated by the severe streptococcal septi-
caemia found in these animals. Similarly,
both cortisone (high dose) and Enovid
caused involution of the gonads. It is
well known that high doses of steroids will
cause involution of the testes and ovaries.
We have also observed that Enovid, even
in the relatively low doses employed, will
cause gonadal involution in both male and
female rats (Wexler, 1974). In this
678 B. C. WEXLER

12

FIG. 12.-Apex and left ventricle of an arteriosclerotic, male (breeder) rat which had been treated
with a high dose of cortisone for 30 days after a massive myocardial infarct. Virtually all of the
necrosis has been completely resolved. H. and E. x 80.
 MYOCARDIAL INFARCTION: CORTISONE, DIANABOL AND ENOVID 679

Fr a ".-V

R ..
.. A~~~~~~~~~~

14 ta

FIG. 13.-Severely fatty liver with beginning cirrhosis in a nonarteriosclerotic, male (virgin) rat which
had been treated with a high dose of cortisone or Enovid during a 30-day period following myo-
cardial infarction. H. and E. x 175.
FIG. 14.-Frozen section of an adrenal gland from a nonarteriosclerotic, male (virgin) rat which had
been treated with a high dose of cortisone for 30 days post-myocardial infarction. Note the marked
atrophy of the cortex (shades of grey and black in photo), the extensive lipid depletion from the
zonae reticularis and fasciculata but the hyperplasia and lipid repletion (deep black material in
photo is lipid) in the zona glomerulosa. These conditions are typical of hypophysectomy or
adrenal disuse atrophy. The adrenal medulla (light grey area in photo) is normal. Sudan
black B. x 64.
680 B. C. WEXLER

Jli

FiG. 15. Apex and left ventricle showing aneurysmal dilatation, thinning of the myocardial wall and
replacement of much of the cardiac muscle by fibroblasts and cartilaginous metaplasia (deep black
in photo). This condition is typical of any of the animals treated with Dianabol, Enovid or the
low dose of cortisone during their 30 days' convalescence from an acute myocardial infar tion.
H. and E. x 60.
FIG. 16. High power view of a focus of cartilaginous metaplasia from the specimen shown in Fig. 15.
H. and E. x 94.
 MYOCARDIAL INFARCTION: CORTISONE, DIANABOL AND ENOVID 681

17.

FIG. 17.-Frozen section of an adrenal cortex of a male, nonarteriosclerotic (virgin) rat treated with
Enovid for 30 days following an acute myocardial infarction. Unlike the severely atrophied,
cortisone-treated, adrenal gland shown in Fig. 14, this adrenal cortex is hypertrophied and hyper-
plastic. However, only the zona glomerulosa contains a normal complement of lipid. All of the
inner zones of the adrenal cortex are extensively depleted of lipid. This histopathological condition
is indicative of intense stimulation of adrenocortical secretion on an acute basis culminating with
inability of the cortex to replenish its lipid stores or to restore cortical steroidogenesis on a normal
basis. H. and E. x 100.
682 B. C. WEXLER
experiment, as well as in our previous
experiments, we believe that the gonadal
involution caused by Enovid is due to
biofeedback inhibition of gonadotrophic
hormone release, i.e., FSH and LH from
the pituitary gland.
The elevated levels of serum enzymes,
i.e., CPK, SGOT, SGPT and LDH,
despite the relatively long interim since
the acute induction of myocardial infarc-
tion, i.e., 30 days post-infarction, indicated
that destruction of myocardial cells was
on-going at this relatively late time.
Since the elevation of serum enzymes
such as CPK is a good index of the severity
of myocardial infarction, it would appear
that the high dose of cortisone offered the
best protection against myocardial cell
damage because serum enzyme levels in
these animals were the least elevated,
whereas isoprenaline alone was associated
with the highest serum enzyme levels or
the most severe myocardial damage on
Day 30. We have consistently observed
disparate changes in circulating lipids
during the acute stages of myocardial
infarction, i.e., acute elevations in serum
triglycerides and free fatty acid levels but
little or no change in cholesterol (Wexler,
1973). Although the usual acute elevation
of triglycerides and free fatty acids had
subsided in most animals by Day 30, it is
of interest that those animals treated with
cortisone (high dose) and Enovid had
persistent, supernormal levels of trigly-
cerides and free fatty acids. This acute
hyperlipaemia in the case of cortisone is
ascribed to the lipid-mobilizing effects of
glucocorticoids. We and others have
observed that Enovid will cause hyper-
lipaemia in animals and in humans
(Wexler, 1974). The normal levels of
circulating cholesterol found in miost of
the treated animals is consistent with our
previous experience. The greatly elevated
cholesterol levels, only in those animals
treated with the high dose of cortisone, is
most likely due to cortisone's potent
lipid-mobilizing effects. However, we
cannot explain the specific cholesterol-
lowering effect of Enovid vs its ability to
increase triglyceride and free fatty acid
levels in these same animals. Similarly,
we have consistently observed hyper-
glycaemia in rats during the acute phase
of myocardial infarction (Wexler, 1973).
The animals in this experiment manifested
persistent hyperglycaemia even at Day 30
post-infarction. The even greater eleva-
tion of circulating glucose levels in
Enovid and cortisone (high dose)-treated
animals again attests to the potent
gluconeogenic effects of each of these
drugs, e.g., it is not unusual to observe
" steroid diabetes " in patients receiving
high doses of glucocorticoids on a chronic
basis and women taking the contraceptive
" pill " may develop abnormal glucose
tolerance (Wexler, 1974). The elevated
BUN levels in all of the animals subjected
to myocardial infarction (regardless of
treatment) is consistent with our previous
experience (Wexler, 1973). The unusually
elevated BUN levels in those treated with
Enovid would suggest that along with
Enovid's ability to suppress pituitary
release of FSH and LH, it may also
suppress other pituitary trophic factors,
e.g., growth hormone or a renotrophic
factor. As indicated earlier, acute myo-
cardial infarction is accompanied by
acute hyperadrenocorticism (Days 1 to 3),
culminating with relatively mild hypoad-
renocorticism (Days 4 to 7) (Wexler and
Kittinger, 1963). Judging from the greatly
depressed Cmpd. B levels (Cmpd. B is the
main steroid secreted by the rat's adrenal
cortex) in those animals treated with
Enovid and cortisone (high dose), steroido-
genesis was unusually compromised in
these animals.
The gross and histopathological changes
in these animals correlates well with their
outward behaviour as well as with the
gravimetric, biochemical and physiological
changes. The absence of grossly visible
necrosis in the myocardium at 30 days
post-infarction is in keeping with our past
experience, i.e., the initial, severe, myo-
cardial necrosis is resolved by Day 7. We
have found that myocardial repair in the
rat involves ground substance, e.g., muco-
 MYOCARDIAL INFARCTION: CORTISONE, DIANABOL AND ENOVID
polysaccharides, and related myocardial
connective tissue elements, e.g., fibro-
blasts, which are vital for proper repair of
the early myocardial damage (Judd and
Wexler, 1969, 1970). Evidently, many of
these animals were unable effectively to
repair the severe myocardial damage, as
evidenced by the finding of a high
incidence of left ventricular aneurysm
formation. The fact that animals treated
with high doses of cortisone showed
excellent resolution of their initial myo-
cardial necrosis, e.g., absence of ventricular
aneurysm and other indications of cardiac
damage, indicates that the anticipated
interference with wound healing asso-
ciated with high doses of cortisone did not
occur in these rats. This protection or
resolution of the damage is probably due
to the anti-inflammatory and lysosome-
stabilizing effects of cortisone. It would
appear that the therapeutic use of high
doses of cortisone afforded excellent pro-
tection against the acute untoward effects
of myocardial infarction, e.g., superior
survival and absence of congestive heart
failure. However, with the prolonged
use of cortisone, despite the salutary
effects on myocardial repair, the untoward
effects of the excess cortisone led to
generalized catabolism, e.g., body weight
loss and involution of the gonadal and
reticuloendothelial systems. In addition,
the chronic use of a high dose of cortisone
caused fatty infiltration of the liver,
hyperlipidaemia (due to lipid-mobilizing
effects), hyperglycaemia (because of gluco-
neogenesis), and decreased Cmpd. B
production and adrenal disuse atrophy
(because of the biofeedback effect on the
pituitary gland induced by chronic over-
dose of cortisone). Thus, although the
acute effects of high dose of cortisone
afforded good protection against the
myocardial infarction, and had no adverse
effects on myocardial repair, nonetheless
animals treated with cortisone succumbed
in great numbers because of the untoward
physiological effects of chronic overdose,
i.e., pituitary gland suppression and
involution of the adrenal gland. The
45
683
dichotomous similarity of the changes
found in Enovid-treated animals to those
treated with cortisone (high dose) is
particularly provocative. Although
Enovid treatment did not have an
ameliorative effect on myocardial repair
like cortisone, Enovid also caused marked
body weight loss, hyperlipidaemia, and
hepatic steatosis, islet beta cell degranula-
tion and hyperglycaemia and gonadal
involution. In direct contrast to cortisone,
Enovid caused adrenal hyperplasia but,
despite adrenal hyperplasia, adrenal
steroidogenesis was depressed. In contrast
to the reduced Cmpd. B production due to
adrenal atrophy induced by cortisone, we
believe that Enovid caused a temporary
state of relative hyperadrenocorticism
which would account for the body weight
loss, hyperlipidaemia (except for chol-
esterol) and fatty liver, hyperglycaemia
and elevated BUN levels. This temporary
and relative hyperadrenocorticism ascribed
to Enovid was not sufficiently intense to
have the positive ameliorative effects on
the course of myocardial infarction as in
those treated with the high dose of
cortisone. Apparently, during the 30-day
period, adrenal glands overstimulated by
Enovid passed from a state of hyper-
adrenocorticism to hypoadrenocorticism
as evidenced by the depressed Cmpd. B
levels. We believe that these reduced
Cmpd. B levels were due to a defect in
proper release of ACTH in the Enovid-
treated rats and this alleged defect was
related to the concomitant reduction of
FSH and LH through biofeedback mech-
anisms induced by oestrogens and proges-
togens. For example, it is well known that
oestrogens will stimulate ACTH release.
Thus, the initial hyperadrenocorticism
and adrenocortical hyperplasia could be
ascribed to the acute stimulating effects
of the oestrogen component in Enovid;
the eventual cortical lipid depletion and
Cmpd. B reduction could be ascribed to
the more chronic biofeedback effects of
the combined components in Enovid, i.e.,
oestrogen and progestogen.
In summary, these experimental find-
684 B. C. WEXLER
ings indicate that although large doses of
cortisone protected animals against shock
and other untoward pathophysiological
conditions during the acute stages of
myocardial infarction, and although the
large doses of cortisone actually enhanced
myocardial wound repair, chronic treat-
ment with cortisone induced intense body
weight loss, septicaemia, hyperglycaemia,
hyperlipidaemia and hypoadrenocorticism.
The anabolic steroid, Dianabol, which has
potent androgenic effects, and in con-
junction with ACTH and adrenal steroids
can cause liver impairment, oedema, and
abnormal glucose tolerance (Liddle and
Burke, 1960), was equally as effective as
the low dose of cortisone and did not
exhibit any unusual salutary or deleterious
effects. The contraceptive drug, Enovid,
like cortisone, caused body weight loss,
hyperlipidaemia, hyperglycaemia and
adrenocortical hyperplasia. Apparently,
if the initial Enovid-induced adreno-
cortical hyperplasia was associated with
any increased adrenal steroid secretion, it
was not of sufficient intensity, as was the
high dose of cortisone, to protect the
animals against shock, congestive failure
and death, nor did it manifest any
salutary effects on myocardial repair. It
would appear that if the dose of cortisone
could be adjusted so that it is sufficient to
protect against the shock and other
untoward effects of acute myocardial
infarction and, at the same time, if the
dose was not so large that it would inter-
fere with connective tissue processes vital
to myocardial repair, induce adrenal
disuse atrophy or untoward metabolic
changes, e.g., hyperglycaemia, hyperlipi-
daemia, etc., then cortisone would serve
as a particularly effective therapeutic
agent in the treatment of acute myo-
cardial infarction.
I am indebted to the following research
technicians for their expertise and dedica-
tion in this demanding series of experi-
mental investigations: Dil Conatser, E.
Domingo, G. Eggert, W. Goodhew and
N. Wexler.
This work was sponsored, in part, by
grants from the Southwestern Ohio Heart
Association and the National Heart and
Lung Institute (HL-13, 222 and HL-15,
304), N.I.H., U.S. Public Health Service.
During the tenure of this work, Dr Wexler
was supported by the Research Career
Award Program of the National Heart and
Lung Institute (HL-K3-1734), N.I.H.,
U.S.P.H.S.
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