Full text of DOI:10.1007/BF03344039

J. Endocrinol. Invest. 25: 463-468, 2002
Effects of long-term enalapril and losartan therapy of heart
failure on cardiovascular aldosterone
J.C. Xiu, P. Wu, J.P. Xu, Z. Guo, W. Lai, Y. Zhang, S. Li, J. Li, and Y. Liu
Department of Cardiology, Nan Fang Hospital, The First Military Medical University, Guangzhou,
People’s Republic of China
ABSTRACT. Plasma aldosterone escape is found
during long-term ACE inhibitor therapy of chronic
heart failure. Evidence for aldosterone production
in cardiovascular tissues raised the question of
whether aldosterone escape occurs or not in these
tissues. Rats with infarction-induced chronic heart
failure were treated with enalapril (20 mg/kg/d)
and losartan (15 mg/kg/d) for 20 weeks. Untreated
chronic heart failure and sham-operated rats were
used as positive and normal controls, respectively.
Ex vivo mesenteric artery and heart perfusion, high
performance liquid chromatography, and RIA for
aldosterone were performed. Chronic heart failure
due to myocardial infarction was associated with
tissue-specific activation of cardiovascular aldos-
terone synthesis. In the mesenteric artery, enalapril
significantly inhibited aldosterone production com-
pared to untreated, chronic heart failure rats, and
losartan lowered aldosterone production to that
of sham rats. In myocardium, enalapril failed to sig-
nificantly inhibit aldosterone production, and losar-
tan significantly inhibited aldosterone production
compared to untreated, chronic heart failure rats.
These results provide the first evidence that long-
term ACE inhibition therapy induces aldosterone
escape in myocardium but not in mesenteric artery
of chronic heart failure. The angiotensin II subtype
1 receptor blocker losartan tranquilized aldos-
terone levels in the cardiovascular tissues of chron-
ic heart failure rats.
(J. Endocrinol. Invest. 25: 463-468, 2002)
©2002, Editrice Kurtis
INTRODUCTION
Angiotensin II (Ang II) receptor blockers were de-
veloped as agents that would better block the RAS
and, thus, decrease the adverse effects seen with
ACEIs. Several reports indicate that treatment with
losartan, a kind of Ang II subtype 1 receptor (AT1)
blocker, lowered the level of plasma aldosterone,
but the longest duration of observation has only
been 3 months (5-7).
Until recently, it was assumed that aldosterone was
derived solely from adrenal glands via the circula-
tion; however, there is now convincing evidence,
including our own, that cells of the heart and vas-
culature express CYP11B1 and CYP11B2 genes,
which are responsible for 11ꢀ-hydroxylase and al-
dosterone synthase, respectively (8, 9). We under-
took this study to clarify the hypothetical possibili-
ty of aldosterone escape in cardiovascular tissues
during long-term ACE inhibition.
ACE inhibitors (ACEIs) are designed to block the
renin-angiotensin system (RAS) and can represent an
effective therapeutic approach to hypertension, con-
gestive heart failure, and myocardial infarction (MI).
In these cases, ACEIs produce an acute decrease in
plasma aldosterone levels. However, long-term (>3
months) ACE inhibition is associated with so-called
aldosterone escape (1-3). The Randomized Aldactone
Evaluation Study (RALES) has shown that 25 mg of
spironolactone added to ACE inhibition treatment is
safe and reduces all-cause mortality by 30% in pa-
tients with severe heart failure due to systolic left ven-
tricular dysfunction (4). Blockade of aldosterone in
these patients may be necessary to overcome aldos-
terone escape during chronic ACE inhibition.
Key-words: Aldosterone, myocardial infarction, chronic heart failure, ACEI,
AT1 receptor blocker.
METHODS
Correspondence: Dr. Pingsheng Wu, Department of Cardiology, Nan
Fang Hospital, The First Military Medical University, Guangzhou 510515,
People’s Republic of China.
Myocardial infarction model
Male Wistar rats (from the Chinese Academy of Medical Sciences
Animal Center) were used in this study. Weighing 180-220 g at
12 weeks of age, they were kept in separate cages under stan-
dard conditions with respect to food, humidity and light peri-
E-mail: wps@ fimmu.edu.cn
Accepted January 31, 2002.
463

J.C. Xiu, P. Wu, J.P. Xu, et al.
High performance liquid chromatography for
aldosterone
After washing the cartridge with 10 ml of distilled water, its con-
tents were extracted with 5 ml of methanol and then freeze-
dried. The dried eluate was dissolved in 30 μl of methanol, of
which 10 μl was used for high performance liquid chromatogra-
phy (HPLC), 10 μl for Ang II RIA.
The Sep-Pak C18 cartridge extract was chromatographed by re-
verse phase HPLC (Shimadzu, Japan) on an octadecyl silicea col-
umn with methanol (40%) and water (60%); the mobile phase had
a flow rate of 1.5 ml/min for 60 min. The retention time of authen-
tic aldosterone (Sigma) was confirmed to be 30 min at 280 mm on
an SPD–10AV ultraviolet spectrophotometer. Each 1.5 ml fraction
corresponding to authentic aldosterone was collected, freeze-dried,
and assessed by RIA (kits from Bei Fang Company, Beijing) for al-
dosterone.
odicity. Left ventricular infarction was produced by ligation of
the left anterior descending coronary artery as previously de-
scribed (10). Sham-operated animals were treated similarly, ex-
cept that the ligature around the coronary artery was not tied.
Four weeks after the operation, an electrocardiogram was
recorded under ether anesthesia in all surviving animals, and
those (no.=15) with no obvious electrical signs of MI were dis-
carded. The remaining rats with MI (no.=35) were randomly di-
vided into 3 groups. Each group received one of the following
treatments in their drinking water for 20 weeks: 1) enalapril
(no.=10, 20 mg/kg/d, MSD, American), 2) losartan (no.=10, 15
mg/kg/d, MSD, American), 3) untreated MI (no.=15), and 4)
sham-operated animals (no.=8) served as control groups.
Hemodynamic studies
After 20 weeks of treatment, the rats were anesthetized by in-
traperitoneal injection of pentobarbital sodium (30 mg/kg bw).
Aortic and left ventricular pressures were recorded by inserting
a catheter into the right carotid artery. The catheter was ad-
vanced into the aorta and then into the left ventricle. The fluid-
filled catheter was connected to a pressure transducer (P23 ID,
Gould Inc, U.S.A.). While the rat was breathing spontaneously,
pressures were recorded on a physiological recorder (SJ-42,
China). Carotid pressures were recorded as the mean values de-
termined by electronic averaging, and left ventricular systolic
pressure and left ventricular end-diastolic pressure (LVEDP) were
obtained by averaging their respective values over 10 beats.
Heart rate (HR) was determined from the tracing of artery pres-
sure (11).
Determination of infarction size
Transverse myocardial sections (5 μm thick) were stained with
Sirius red stain. Infarction size was determined by planimet-
ric measurement with digital image analysis software (QU500,
Germany), and the ratio of scare length to total length of each
slice was measured and expressed as a percentage, as pre-
viously described (10).
Statistical analysis
Data are expressed as the mean SE. One-way ANOVA was
used to assess each parameter in the experimental groups.
Student-Newman-Keuls comparisons of post hoc tests were then
performed to identify which group differences accounted for
the overall significant ANOVA. A value of p<0.05 was consid-
ered significant.
Ex vivo mesenteric artery and heart perfusion
After blood sampling, mesenteric arterial perfusion ex vivo was per-
formed as we previously reported (12). Briefly, under pentobarbi-
tal anesthesia, the mesenteric arteries of the rats were excised us-
ing the Miyamori method (13). The isolated arteries were perfused
with Krebs-Ringer solution (pH 7.4, at 37 C, and oxygenated with
a 95% O2 +5% CO2 gas mixture) at a constant flow rate of 4 ml/min
by an automated pump. Promptly, the hearts were isolated, can-
nulated from the aorta, and perfused with a modified Krebs-
Henseleit solution using a Langendorff apparatus according to
Curtis’ method (14, 15). The perfusion pressure was constantly mon-
itored by polygraph. Pre-perfusion (30 min) was performed for wash
out, and then 240 ml of perfusate (60 min) was collected and ex-
tracted on a Sep-Pak C18 cartridge (Waters Associates, Milford,
U.S.A.), which was pre-washed with 5 ml of methanol and 10 ml of
distilled water.
RESULTS
Infarction size, cardiac hypertrophy, and
physiological data
Fifteen animals died during the experimental peri-
od. The numbers of remaining animals in each group
were as follows: enalapril (no.=7), losartan (no.=6),
untreated MI (no.=7), and sham-operated (no.=8).
Mean infarction size and bw did not differ signifi-
cantly between the experimental groups (Table 1).
MI induced cardiac hypertrophy, as demonstrated
by the increased ratio of heart weight to bw by 1.2
Table 1 - Infarct size and anatomic and physiological parameters.
MI (%) BW (g)
HW (mg) HW/BW (mg/g) MAP (mmHg) LVSP (mmHg) LVDEP (mmHg) HR (bpm)
Sham (no.=8)
MI (no.=7)
-
419 12 1029 27
441 8 1311 34**
2.47 0.06
2.91 0.04**
2.48 0.09°°
2.60 0.14°
121 3
111 4
134 4
127 5
3 1
374 10
389 19
408 4
35 2
30 2**
22 2**°°
23 1**°°
MI+Ena (no.=7)
MI+Los (no.=6)
36 2 414 12 1025 30
38 4 406 15 1048 32
94 4**°°
97 3**°°
108 3**°°
108 2**°°
412 12
Ena: enalapril; HR: heart rate; HW: heart weight; Los: losartan; LVEDP: left ventricular end-diastolic pressure; LVSP: left ventricular systolic pressure;
MAP: mean artery pressure; MI: myocardial infarction; Sham: sham–operated rat. *p<0.05 vs Sham-operated rat; **p<0.01 vs Sham-operated rat;
°p<0.05 vs MI; °°p<0.01 vs MI; +p<0.05 vs Ena; ++p<0.01 vs Ena.
464

Enalapril and losartan vs cardiovascular aldosterone
Levels of Ang II and aldosterone in heart perfusion
fold. All treatments prevented such cardiac hyper-
trophy and decreased the mean arterial pressure.
Heart failure was confirmed by the increase of LVEDP,
which was decreased in both treatment groups com-
pared with that of the untreated MI group, but high-
er than that of the sham group.
Figure 3 illustrates that the level of Ang II in un-
treated MI rats was higher than that of sham-oper-
ated (p<0.01) and losartan-treated groups (p<0.05),
but not significantly different from that of enalapril-
treated. The level of aldosterone in the heart per-
fusion of untreated MI rats was higher than that of
losartan-treated rats, but not significantly different
from that of the enalapril-treated group (p=0.522).
Compared to that of sham-operated rats, neither
enalapril- nor losartan-treated groups lowered al-
dosterone to the sham-operated level (p<0.01). The
level of aldosterone in the heart of enalapril-treat-
ed rats is higher than that of losartan-treated rats.
Levels of Ang II and aldosterone in plasma
Figure 1 shows that Ang II and aldosterone levels
increased in the MI groups. Losartan significantly
increased plasma Ang II compared to that of un-
treated MI rats.
Levels of Ang II and aldosterone in mesenteric
artery perfusion
Figure 2 indicates that MI was associated with a 1.5-
fold increase in Ang II content. Both treatments sig-
nificantly inhibited the increase, and losartan low-
ered it to the sham-operated level. The level of al-
dosterone in the mesenteric artery of untreated MI
rats was significantly higher than that of the other
groups. Compared to sham rats, losartan lowered
aldosterone to the sham level (p=0.135). The level
of aldosterone in the mesenteric artery of enalapril
is higher than that of sham-operated rats and losar-
tan-treated rats.
DISCUSSION
Aldosterone production was proved in vascular en-
dothelial and smooth muscle cells, and in both ho-
mogenate and perfusate of isolated rat hearts (8, 9).
Aldosterone receptors exist in cardiac myocytes, en-
docardial endothelial cells, cardiac fibroblasts, and
vascular endothelial and smooth muscle cells. To rule
out the possibility of release from the receptors,
Takeda et al. (8, 15) carefully proved that it can reflect
de-novo synthesis of aldosterone in cardiovascular
A 300
**++
A
300
250
200
150
100
50
**
250
**ꢀꢀ
*
200
150
100
50
*
ꢀꢀ++
0
0
Sham
MI
**
Ena
Los
Sham
MI
**
Ena
Los
B
300
250
200
150
100
50
B
1200
1000
800
600
400
200
0
ꢀꢀ
**ꢀꢀ
ꢀꢀ+
0
Sham
MI
Ena
Los
Sham
MI
Ena
Los
Fig. 2 - Levels of angiotensin II (A) and aldosterone (B) in mesen-
teric artery perfusion. Values are the mean SE (Sham no.=8; MI
no.=7; MI+Ena no.=7; MI+Los no.=6; respectively). *p<0.05 vs
sham-operated rat; **p<0.01 vs sham-operated rat; °p<0.05 vs
MI; °°p<0.01 vs MI; +p<0.05 vs enalapril; ++p<0.01 vs enalapril.
Ang II: angiotensin II; Ena: enalapril; Los: losartan; MI: myocardial
infarction; Sham: sham–operated rat.
Fig. 1 - Levels of angiotensin II (A) and aldosterone (B) in plas-
ma. Values are the mean SE (Sham no.=8; MI no.=7; MI+Ena
no.=7; MI+Los no.=6; respectively). *p<0.05 vs sham-operat-
ed rat; **p<0.01 vs sham-operated rat; °p<0.05 vs MI; °°p<0.01
vs MI; +p<0.05 vs enalapril; ++p<0.01 vs enalapril. Ang II: an-
giotensin II; Ena: enalapril; Los: losartan; MI: myocardial infarc-
tion; Sham: sham–operated rat.
465

J.C. Xiu, P. Wu, J.P. Xu, et al.
A 250
One potential strategy to further improve morbid-
ity and mortality in these patients may be blockade
of aldosterone. It has been demonstrated that al-
dosterone can cause cardiac hypertrophy and fi-
brosis independent of the blood pressure (20). We
do not know yet the effects of long-term ACEI and
AT1 antagonists on aldosterone produced in car-
diovascular tissues. The present study indicated that
long-term ACEI enalapril produced aldosterone es-
cape in perfusate of myocardium but not in the
mesenteric artery. As we know, several serine pro-
teases, such as tonin and cathepsin G, have been
shown to hydrolyze Ang II precursors. Recently, an
aspartyl protease with cathepsin D–like properties
was shown to convert angiotensinogen to Ang I in
adult rat myofibroblasts isolated from ventricular
scar tissue. The ꢁ-chymases include human, dog
and rat chymase-3, which convert Ang I to Ang II
by cleaving the Phe8-His9 bond in Ang I. The Ang
II generated is not further degraded, because the
Tyr4-Ile5 bond is resistant to cleavage by ꢁ-chy-
mases (21). The aldosterone escape and Ang II re-
bound might be related to Ang II-forming pathways
within tissues. Akasu et al. (22) examined tissue Ang
II–forming activities and identified the responsible
enzyme in several organs including heart and aor-
ta in various species (human, hamster, rat, rabbit,
dog, pig, and marmoset). In the heart, the highest
total Ang II–forming activity was observed in hu-
mans, and a chymase-like enzyme was dominant in
all of the species except rabbit and pig. Aorta ex-
hibited a relatively high total Ang II–forming activ-
ity, with a predominance of chymase-like activity in
all of the species except rabbit and pig, in which
ACE was dominant. Their results indicate that there
were remarkable differences in Ang II–forming
pathways among the species and organs examined.
Activation on AT1 leads to vasoconstriction and stim-
ulation of the release of catecholamines, aldos-
terone, and antidiuretic hormone (23, 24). Here, we
identified that an AT1 blocker did decrease both
plasma and cardiovascular tissue aldosterone levels
in chronic heart failure during long-term therapy, al-
though it increased the plasma Ang II levels. On the
other hand, we are having difficulty interpreting the
fact that Ang II levels were not increased in the
mesenteric artery and cardiac effluent in the losar-
tan group, which is in agreement with what Silvestre
et al. (11) observed in their myocardial infarction rat
study. Stimulation of the AT2 receptor by means of
Ang II is assumed to counteract vascular/myocardial
remodeling and may possibly induce vasodilation
(25). A combination of ACEI and AT1 receptor an-
tagonist may have an additive cardioprotective ef-
fect in heart failure, because these 2 agents could
**
200
150
100
50
*
ꢀ+
0
Sham
MI
**
Ena
**
Los
B
1200
1000
800
600
400
200
0
**ꢀꢀ++
Sham
MI
Ena
Los
Fig. 3 - Levels of angiotensin II (A) and aldosterone (B) in heart
perfusion. Values are the mean SE (Sham no.=8; MI no.=7;
MI+Ena no.=7; MI+Los no.=6; respectively). *p<0.05 vs sham-
operated rat; **p<0.01 vs sham-operated rat; °p<0.05 vs MI;
°°p<0.01 vs MI; +p<0.05 vs enalapril; ++p<0.01 vs enalapril. Ang
II: angiotensin II; Ena: enalapril; Los: losartan; MI: myocardial
infarction; Sham: sham–operated rat.
tissues by pre-wash out and adrenalectomy in their
ex vivo cardiovascular perfusion experiments. Here,
according to their methods, we proved that aldos-
terone in ex vivo cardiovascular perfusate was in-
creased 24 weeks after MI induced heart failure,
which was identified by the increase of LVEDP. In-
deed, increased cardiac expression of angioten-
sinogen, ACE and AT1 receptor proteins, ACE activ-
ity and Ang II content has been previously described
in infarcted hearts (11, 16). The harmful effects of al-
dosterone in heart failure include magnesium loss,
blockade of norepinephrine uptake by the my-
ocardium, sympathetic activation, parasympathetic
inhibition, myocardial ischemia, and myocardial fi-
brosis (4). Takeda et al. (17) observed that cerebral
hemorrhage was significantly higher in the patients
with aldosterone-producing adenoma when com-
pared to the essential hypertension group. Pozzan
et al. (18) believed that cardiomegaly was related to
both hyperaldosteronism and hypertension.
Many clinicians have assumed that ACEIs would
block both Ang II and aldosterone. However, there
is data to suggest that plasma aldosterone may “es-
cape” blockade and that Ang II plasma levels may
rebound despite the use of an ACEI in patients with
heart failure, hypertension, and acute MI (1-3, 19).
466

Enalapril and losartan vs cardiovascular aldosterone
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artery, while the AT1 receptor blocker losartan did
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ACKNOWLEDGEMENTS
This study was supported by the National Nature and Science
Foundation of China (39870812 and 39870331) and the Nature
and Science Foundation of Guangdong Province (980235). The
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