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1 Département de Physiologie et Pharmacologie Clinique, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5014, Institut Fédératif de Recherche 39, Faculté de Pharmacie, 69373 Lyon Cedex 08; and 2 Institut National de la Santé et de la Recherche Médicale Unité 80, Hôpital Edouard Herriot, 69437 Lyon Cedex 03, France
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The present work aimed to assess, in
Lyon hypertensive (LH) rats, whether an early and prolonged inhibition
of the renin-angiotensin system (RAS) could result in a blood pressure
(BP) lowering and nephroprotection that persist after its withdrawal.
Male LH rats received orally from 3 to 12 wk of age either an
angiotensin-converting enzyme inhibitor perindopril at the doses of 0.4 and 3 mg · kg
1 · day1 or an
AT1 receptor antagonist losartan at the dose of 10 mg · kg1 · day1. BP,
histological changes in the kidney, and urinary protein excretion were
examined during and 10 wk after cessation of the treatments. Both
perindopril and losartan decreased BP, prevented renal lesions, and
limited urinary protein excretion. After cessation of the treatment, BP
returned to the level of never-treated LH rats in rats having received
3 mg · kg1 · day1 of
perindopril while it remained slightly lower in those treated with 0.4 mg · kg1 · day1 of
perindopril or with losartan. This lack of marked persistent antihypertensive effect contrasted with a durable decrease in urinary
protein excretion and improvement of the renal histological lesions. In
conclusion, it is possible to separate the BP-lowering effects of RAS
blockade from those on glomerulosclerosis and urinary protein excretion.
angiotensin-converting enzyme; AT1 receptor antagonist; glomerulosclerosis
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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IN LYON
GENETICALLY HYPERTENSIVE (LH) rats, as well as in spontaneously
hypertensive rats (SHR), a blockade of the renin-angiotensin system
(RAS) fully prevents the development of hypertension and much of the
accompanying target-organ damages (15, 16). Interestingly, several studies showed that, in young SHR, an early and short-term blockade of RAS induced decreases in blood pressure (BP) and
improvements in vascular and renal function that persisted after
treatment withdrawal (4, 6, 8, 13, 24). When the blockade
was induced in adult SHR, such persistent effects were either modest or
absent (13, 20, 26). In addition, it is noteworthy that the long-lasting BP decrease observed after blockade seems specific of
the RAS blockade, as it is not observed with vasodilators, 
-blockers, or calcium antagonists (4, 8, 24). A likely explanation is that an early and brief increase in RAS activity may be
sufficient to allow the development of a stable hypertension. Such an
hypothesis is favored by the observation that plasma renin is increased
in young hypertensive rats and thereafter reduced in adult animals
(23, 27). However, the observation that in LH rats
captopril given from conception to weaning was devoid of persistent
effects on BP after its cessation (7) argues against this
hypothesis. Nevertheless, because in LH rats the RAS was never blocked
during the period of fast rise of BP (4 to 10 wk of age), we thought it
of interest to determine whether a blockade of the RAS using an
angiotensin-converting enzyme (ACE) inhibitor or an AT1
receptor antagonist during this period might induce a BP decrease and a
renoprotection that persist after treatment withdrawal.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals. Fifty male LH rats (28) were used. They were housed two to three per cage under controlled conditions (temperature: 21 ± 1°C; humidity: 60 ± 10%; lighting: 8-20 h) and fed a standard rat chow containing 0.3% sodium (Elevage UAR A03, Villemoisson-sur-Orge, France) and tap water ad libitum. The studies were conducted in accordance with our institutional guidelines for animal care.
Experimental protocols.
At 3 wk of age, LH rats were randomly divided into four groups. Twelve
LH rats remained untreated and served as controls; the others were
treated orally with losartan (LH-lo; 10 mg · kg1 · day1,
n = 13, Du-Pont Merck Pharmaceuticals, St. Louis, MO),
an AT1 receptor antagonist, or with perindopril (Servier
Laboratories, Neuilly-sur-Seine, France) an ACE inhibitor at a low dose
(LH-lp; 0.4 mg · kg1 · day1,
n = 13) or at a high dose (LH-hp; 3 mg · kg1 · day1,
n = 12). Drugs were given in drinking water, and their
concentration was adjusted weekly according to body weight and water
intake. At 12 wk of age, the animals were placed in individual
metabolic cages. After a 2-day habituation period, 24-h urines were
collected. Urinary sodium concentration was measured by flame
photometry (model 243, ILmeter, Lexington, MA) and urinary protein
excretion by a colorimetric method (29). Then, the right
kidney was removed in half of the rats of each group under halothane
(2% in oxygen) anesthesia to examine the renal histology. The
treatments were stopped at the age of 13 wk. At 21 wk of age, 24-h
urines were collected to measure the urinary sodium and protein
excretion. Between 10 and 21 wk of age, indirect systolic BP (SBP) was
measured each 2 wk (between 9 and 13 h) by tail-cuff
plethysmography (Narco Biosystem, Houston, TX) in conscious preheated
(37°C for 10-15 min) animals. At 22 wk of age, intra-aortic BP
was recorded in freely moving rats through a polyethylene catheter
(PE-10 fused to PE-50) inserted while rats were under anesthesia with
halothane (2% in oxygen) via the left femoral artery in the abdominal
aorta. The catheter was filled with heparinized saline (25 IU/ml),
guided subcutaneously, and exteriorized at the back of the neck. After a 2-day recovery, the arterial catheter was connected to a pressure transducer (Statham P23 ID, Gould, Cleveland, OH) via a rotating swivel
that allowed the animal to move freely. Recordings began 1 h after
connection to the transducer. With the use of our computerized technique (10), 2-h aortic BP curve (between 10 and
12 h) was digitized and processed on-line by a computer (MVME
SYS121, Motorola, Tempe, AZ) to determine and store beat-to-beat values
of SBP and diastolic BP (DBP) as well as of heart rate. Then, all rats
were euthanized with pentobarbital sodium, and the kidneys were
dissected out for histological analysis.
Histological analysis of the kidneys. After removal, kidneys were halved, hemisections fixed in Bouin's solution, and then embedded in paraffin. Standard stainings were applied to 2.5-µm-thick slices: hematoxylin-eosin, periodic-acid Schiff reagent, Masson's trichrome, silver methenamine, and modified May-Grundwald Giemsa stain. Semiquantitative evaluation for glomerular, vascular, tubular, and interstitial lesions was performed in a blinded fashion. The importance of the lesions in each animal was graded from 0 to 3 (0 = normal; 0.5 = minimal; 1 = slight; 2 = moderate; and 3 = severe). The mean of the grades was used to characterize each group of animals.
Statistical analysis. Data are expressed as means ± SE. Comparisons between groups used one-way ANOVA with treatment as factor followed by a Fisher test. Comparison of indirect SBP evolution with age used two-way ANOVA with repeated measures over time. P < 0.05 was considered as significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Effects of RAS blockade.
After 9 wk of treatment, i.e., in 12-wk-old rats, losartan
(LH-lo) and the low dose of perindopril (LH-lp) induced similar decreases in SBP and in urinary protein excretion (Table
1). LH-lp, but not LH-lo, rats exhibited
a lower body weight than untreated LH rats and a larger diuresis than
both untreated and losartan-treated LH rats. The high dose of
perindopril (LH-hp) induced a more marked antihypertensive effect
associated with a further decrease in urinary protein excretion and a
significant increase in both diuresis and natriuresis. When considering
the four groups of rats, the urinary protein excretion was closely related to the SBP level (r = 0.705; n = 50; P < 0.001).
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BP evolution after treatment withdrawal.
Figure 1 shows that SBP rapidly increased
after treatment withdrawal to reach values close to those of
never-treated LH rats. Between 13 and 21 wk of age, SBP remained
slightly lower in LH-lo and LH-lp than in never-treated LH rats (2-way
ANOVA, P < 0.05 for both groups), whereas the SBP of
LH-hp rats exhibited a tendency to overreach that of untreated LH rats.
Intra-aortic BP measurements performed in 22-wk-old rats (Table
2) showed that 10 wk after cessation of
the treatments, losartan and the low dose of perindopril did not have
persistent effects on BP, diuresis, and natriuresis. However, in both
groups, the urinary protein excretion remained significantly lower than
in untreated LH rats. In LH rats having received the high dose of
perindopril, 10 wk after treatment withdrawal, SBP was higher than that
of the LH-lo and LH-lp rats, and the diuresis was larger than that of
untreated LH rats. However, the urinary protein excretion remained
decreased despite the redevelopment of hypertension. At that stage
using the four groups of rats, the urinary protein excretion was no
longer correlated to the SBP level (r = 0.041;
n = 28; not significant).
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Renal lesions.
As shown in Fig. 2,
A-D, and summarized in Table
3, histological analysis in 12-wk-old
young LH rats confirmed the existence of the renal lesions previously
described in LH rats (2): focal glomerulosclerosis with
thickening of the capsular basement membrane, arteriolar hypertrophy on
the initial stage, and slight tubular dilatation. Losartan and
perindopril fully prevented the segmental glomerulosclerosis and
arteriolar hypertrophy. However, only losartan and the low dose of
perindopril decreased significantly the tubule dilation.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The present work demonstrates that, despite a full prevention of the development of hypertension in LH rats by perindopril or losartan, the effects of RAS blockade on BP did not persist after cessation of the treatments, whereas, on the contrary, the renoprotection appeared to be longer lasting.
The development of hypertension in LH rats is characterized by two stages, i.e., first a rapid rise in BP from 4 to 10 wk of age, and then a slower elevation. The efficacy of pharmacological blockade of the RAS in LH rats has been previously observed at any stage (15-17), thus suggesting that, despite the low renin secretion seen in adult LH rats (1, 27), high BP in this strain depends on an active RAS. It was repeatedly observed in SHR that the BP decrease induced by RAS blockade persisted for long periods of time after cessation of the treatment, provided that the latter was given in young animals (4, 8, 13, 24). These observations prompted us to test the hypothesis that an early and short-lasting increase in RAS activity could be sufficient to allow for the development of a life-long hypertension in LH rats. Following a protocol used in SHR (31), we previously observed that captopril given from conception to weaning did not exhibit persistent effects after its cessation in LH rats (7). However, it remained possible that the RAS blockade, which in that experiment was stopped at 3 wk of age, did not totally cover the critical phase (between 4 and 10 wk of age) during which the RAS may be crucial for the development of hypertension in LH rats. In the present work using an ACE inhibitor or an AT1 receptor antagonist, we measured the effects of a RAS blockade performed during the period of fast rise in BP and also examined its long-term consequences on BP, urinary protein excretion, and renal histological lesions.
The treatments used markedly decreased the BP of LH rats and fully
prevented the development of glomerulosclerosis while they lowered the
urinary excretion of proteins. However, BP of LH rats started to rise
soon after cessation of RAS blockade so as to reach or even overreach
the level of never-treated, age-matched LH rats. Our observations are
unlikely to be related to the compounds used, because in SHR, marked
persistent effects on BP of RAS blockade were reported using several
drugs, including perindopril at the doses of 0.4 (3) and 3 mg · kg1 · day1 (12,
13) that we used here. The majority of SHR studies have been
done using an indirect tail-cuff method. However, this persistent effect on BP was also observed when BP was measured via an arterial catheter in conscious SHR (4, 13) or by using a
radiotelemetry system (14). The mechanisms underlying the
persistence of the effects of RAS blockade in SHR remain unknown. The
most frequent hypotheses involved the stimulatory effects of ANG II on
various growth factors in the vessels and/or in the kidneys. As a
consequence of an early and prolonged RAS blockade, the decrease in
growth factors may have induced a long-lasting normalization of
vascular structure and reactivity (8, 13, 22, 24). In the
kidneys, key organ in the long-term regulation of fluid volume and BP
(9, 11), this early treatment prevented the development of
renal lesions (21, 32) and ameliorated the renal function
(5, 6). In previous studies (15, 16), we
observed that chronic blockade of the RAS from 3 wk to adult age in LH
rats prevented the development of hypertension, normalized the regional
flows, and ameliorated the renal function.
After cessation of the treatment, the use of LH rats allowed us to clearly differentiate the long-term effects of RAS blockade on BP from those on glomerulosclerosis and protein excretion. This suggests that the period and/or pathways linking ANG II to glomerulosclerosis and urinary protein excretion may differ from those involved in the BP control. Because glomerulosclerosis requires a growth factor-dependent increase in the extracellular matrix formation (19, 21, 30), it is possible that an early and prolonged blockade of the RAS would stop this process. Finally, the present work shows that, at least in terms of glomerulosclerosis and urinary protein excretion, the highest dose of ACE inhibitor used is not more efficient than a lower, less antihypertensive dose. This finding is in close agreement with two other observations, one made in SHR (25) and one in Milan hypertensive rats (18).
In conclusion, the present work demonstrates the lack of marked antihypertensive effect after RAS blockade withdrawal in LH rats. In addition and more importantly, it shows that a short-term and early ACE inhibition or AT1 receptor antagonism can protect from glomerulosclerosis and proteinuria on the long term.
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. Lo, Faculté de Pharmacie, 8 Ave. Rockefeller, 69373 Lyon Cedex 08, France (E-mail: mlo{at}rockefeller.univ-lyon1.fr).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
June 27, 2002;10.1152/ajpregu.00620.2001
Received 11 October 2001; accepted in final form 13 June 2002.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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