From the Department of Physiology and Biophysics, Faculty of Medicine,
Technion-Israel Institute of Technology, Haifa, Israel (S.B., K.G., Z.A.,
A.H., J.W.), and Department of Cardiovascular Pharmacology, SmithKline Beecham
Pharmaceuticals, King of Prussia, Pa (R.R.R., G.Z.F.).
Correspondence to Joseph Winaver, MD, Department of Physiology and Biophysics, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Efron St 1, POB 9649, Haifa 31096, Israel. E-mail winaver{at}tx.technion.ac.il
The recent advancements in identification and cloning of the Ang II
receptor subtypes AT1 and
AT2 and the understanding that
physiological actions of Ang II are mediated
largely through activation of the AT1 receptor
subtype have prompted the development of highly selective nonpeptide
AT1 receptor
antagonists.16 17 These potent
agents, of which losartan (DuP 753) was the first to be
studied, are of importance as research tools to probe the specific
contribution of Ang II to the pathophysiological
evolution of CHF, as well as novel therapeutic alternatives to ACE
inhibitors. Initial studies with losartan in
patients and experimental models of CHF have indicated a beneficial
effect of this AT1 receptor
antagonist in augmenting cardiac index and reducing left
ventricular preload, systemic vascular resistance, and
pulmonary capillary pressure.18 19 20 21
However, there is a clear paucity of information on the effects of the
drug on the kidney, since only limited data are available on the renal
actions of this class of drugs in experimental and neurohormonal
CHF.22 23 24
In the present study we evaluated the effects of eprosartan, a
nonbiphenyl tetrazole Ang II antagonist with potent renal
vasodilatory activity,25 26 in rats with
aortocaval (A-V) fistula, an experimental model of CHF. Previously, we
demonstrated that this model is characterized by renal manifestations
and neurohumoral changes that closely mimic those observed in patients
with severe CHF.6 27 28 Moreover, we have shown
that renal retention of salt and water in this experimental model is
largely dependent on the degree of activation of the
RAAS.6 In addition, rats with A-V fistula develop
severe eccentric cardiac hypertrophy as a result of volume
overload.27 29 30 In view of these
characteristics, it was of interest to study the effects of eprosartan
on renal function and cardiac hypertrophy in this
experimental model of heart failure.
Acute Studies
Effects of Eprosartan on Renal Hemodynamics and
Mean Arterial Pressure
Effects of Eprosartan on Renal Regional Blood Flow
Effects of Eprosartan on Renal Clearance Parameters
Chronic Studies
Effects of Eprosartan on Daily Sodium Excretion
In the second approach (late treatment protocol), a preselected group
of rats with decompensated heart failure and avid sodium retention was
subjected to eprosartan treatment. In these rats (n=8), daily sodium
excretion in the first 6 postoperative days was <100 µmol/24
hours. Previously, we reported that this subgroup develops symptoms of
severe congestion and usually succumbs to the condition within 8 to 12
days.6 Thus, on the sixth day after the operation
these rats were lightly anesthetized, and an osmotic minipump,
loaded with eprosartan, was inserted into their peritoneal cavity
through a small incision made in the abdominal wall. The animals were
then returned to their metabolic cages, and daily
measurements of urinary volume and sodium concentration were obtained
for 7 additional days.
Effects of Eprosartan on Cardiac Hypertrophy:
Comparison With ACE Inhibition
Chemical Analysis
Statistical Analysis
Effects of Eprosartan on Renal and Intrarenal Hemodynamics
The beneficial effects of eprosartan on RBF and RVR are also reflected
in Figure 2
Effects of Eprosartan on Renal Clearance Parameters
Chronic Studies
Figure 3B
Effects of Eprosartan on Cardiac Hypertrophy:
Comparison With ACE Inhibition
The findings of the present study are therefore important in 2 main
aspects. First, they lend further support to the concept that Ang II,
acting through its AT1 receptor subtype, plays a
major role in the pathogenesis of renal dysfunction and cardiac
hypertrophy in heart failure. Second, they provide evidence
that direct blockade of the AT1 receptor may be
used as an effective approach to counteract the detrimental actions of
Ang II on the kidney and cardiac muscle in heart failure. Thus, this
newly developed group of pharmacological blockers may find increasing
use in the future as an additional or alternative therapy to the
well-characterized ACE inhibitors.
The experimental model used in the present study, rats with A-V
fistula, is characterized by several features that closely mimic the
pathophysiological consequences of CHF in patients.
In particular, this model displays the characteristic neurohumoral
activation of heart failure, with increased sympathetic activity,
activation of the RAAS, high circulating levels of the atrial
natriuretic peptide, and rapid development of severe
eccentric cardiac hypertrophy due to volume
overload.6 27 30 32 The renal manifestations in
this model include marked decrease in RBF with a selective decline in
cortical perfusion, decreased GFR, and a tendency to avid retention of
salt and water by the kidney that may lead to extracellular volume
expansion and edema formation.6 28 Previous
studies in these rats, as well as in dogs with A-V fistula, have
suggested that the alterations in renal handling of sodium in this
model are highly dependent on the increased activity of the
RAAS.6 32 35 Indeed, activation of the RAAS is
considered to play a major role in the pathogenesis of the deranged
renal hemodynamics and augmented tubular sodium
reabsorption in CHF.1 8 35 Ang II contributes
significantly to the decrease in renal perfusion and the diminished GFR
through its vasoconstrictor effect on the efferent and afferent
arterioles as well as by promoting mesangial
contraction.8 Although Ang II may be important in
maintaining GFR in the initial stages of heart
failure,4 in more advanced states GFR tends to
decrease as a result of the Ang II–mediated intense afferent
arteriolar vasoconstriction and diminished ultrafiltration
coefficient.7 8 The findings of the present
study demonstrate that removal of the influence of Ang II by eprosartan
resulted in a marked improvement in renal hemodynamics
and GFR in rats with CHF. Furthermore, as shown by the measurements of
renal regional blood flow, eprosartan preferentially increased renal
cortical perfusion. This restoration of blood flow to the renal cortex,
an area mostly involved in filtration, could be an additional mechanism
by which eprosartan caused the elevation in GFR. However, despite this
impressive increase in RBF and GFR, acute administration of eprosartan
was not associated with a comparable increase in sodium excretion. This
could be related to the concomitant decrease in MAP caused by the drug,
which apparently counteracted its potential natriuretic
action. Indeed, when eprosartan was administered for 7 days through
osmotic minipumps, the natriuretic properties of the drug
became manifest. The ability of eprosartan to increase sodium excretion
in rats with CHF when administered on a chronic basis is apparently due
to a combination of several potential mechanisms. These include the
favorable action of the drug on renal hemodynamics and
GFR, its ability to antagonize the direct action of Ang II on tubular
sodium reabsorption, and lastly, the potential effect of the drug on
aldosterone secretion. Of interest was the observation that
the natriuresis evoked by eprosartan in rats with decompensated CHF
became significantly elevated over pretreatment value only on day 4 of
treatment and later. Taken together with the lack of
natriuretic action in the acute studies, despite the
prominent hemodynamic effect of the drug, these
findings might suggest that the natriuretic effect of the
drug is not related to its action on renal
hemodynamics. Rather, the chronic effects of eprosartan
could be mediated mainly by antagonizing the action of Ang II on
tubular sodium reabsorption or its effect on aldosterone
release. However, since plasma levels of the drug were not measured in
the present study, we cannot rule out the possibility that this
delayed natriuretic response may be related to other
factors, eg, delivery of the drug by osmotic minipumps.
Initial reports alluding to the therapeutic benefits of Ang II
antagonists in heart failure have dealt primarily with
their cardiovascular effects rather than the kidney.
Only a few studies have provided data on the renal effects of this
class of drugs in this cardiovascular
disorder.22 23 36 In a model of ovine heart
failure, acute administration of losartan was able to maintain
GFR and urinary sodium excretion despite a fall in renal perfusion
pressure.22 Likewise, in dogs with CHF due to
rapid atrial pacing, chronic administration of TVC-116, a biphenyl
tetrazole Ang II antagonist, prevented the decrease in GFR,
renal plasma flow, and sodium excretion.36 Also,
acute administration of losartan was found to improve the
natriuretic response to atrial natriuretic
peptide in rats with A-V fistula.23 The
present study indicates that eprosartan is another Ang II
antagonist that is highly effective in preserving renal
function in heart failure. Taken together with the previous data, our
findings suggest that the favorable effects of these agents on the
cardiovascular system in CHF may be mediated, in part,
by improving renal function and promoting salt and water excretion,
thus unloading the failing myocardium.
Finally, of interest and of no less importance was the observation on
the effects of eprosartan on cardiac hypertrophy in
experimental heart failure. Our data demonstrate that early treatment
with the drug significantly attenuated and actually prevented the
increase in cardiac muscle mass in this experimental model of CHF.
Previous studies have suggested that in addition to the mechanical
stress exerted on the myocardium as a result of Ang
II–mediated increased afterload, activation of the local
(intracardiac) RAAS may play a crucial role in inducing cardiac
hypertrophy and remodeling in
CHF.37 38 This growth activity is thought to
involve upregulation of cardiac ACE and is the result of Ang
II–induced expression of growth factors in myocytes as well as
increased formation of connective tissue by fibroblasts and mesenchymal
cells. Indeed, rats with A-V fistula are characterized by increased
myocardial expression of renin mRNA and ACE mRNA in proportion to the
severity of cardiac dysfunction.39 Moreover, ACE
inhibitors have been found to be effective in retarding
left ventricular hypertrophy in rats with CHF
induced by coronary ligation10 and in
preventing ventricular enlargement in patients with left
ventricular dysfunction after myocardial
infarction.12
Initial studies with the Ang II antagonist losartan
indicated that early treatment with the drug reduced cardiac
hypertrophy and inhibited myocardial collagen deposition
after myocardial infarction in rats.40
Interestingly, Ruzicka et al30 reported that only
the Ang II antagonist losartan, but not the ACE
inhibitor enalapril, was able to effectively reduce the
development of overload-induced cardiac hypertrophy in a
model similar to that used in the present study. This discrepancy
occurred despite a comparable systemic hemodynamic
effect of both drugs and was attributed to increased cardiac Ang II
generation by pathways resistant to ACE
inhibition.30 The findings of the present
study lend further support to the latter report by demonstrating the
higher efficacy of eprosartan, compared with ACE inhibition, in
limiting the progress of cardiac hypertrophy in response to
volume overload. Our findings also indicate that delayed administration
of eprosartan, ie, after cardiac enlargement became established, did
not result in regression of the hypertrophic response to volume
overload. However, this interpretation should be taken with caution
since drug administration in the chronic protocols lasted for no more
than a week, a period that might have been too short to note regression
of preformed remodeling of the cardiac muscle. Certainly, a more
prolonged treatment is necessary before the potential clinical
implications of this finding can be assessed.
In summary, the present study demonstrates that the
nonpeptide AT1 receptor antagonist
eprosartan is highly effective in improving renal
hemodynamics, promoting sodium excretion, and
attenuating cardiac hypertrophy in rats with experimental
heart failure induced by A-V fistula. Selective blockade of the
AT1 receptor may therefore be viewed as an
additional important and efficient therapy in CHF.
Received January 22, 1998;
first decision February 10, 1998;
accepted May 7, 1998.
© 1998 American Heart Association, Inc.
Scientific Contributions
Effects of Eprosartan on Renal Function and Cardiac Hypertrophy in Rats With Experimental Heart Failure
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Abstract—Activation of the
renin-angiotensin system may contribute to the derangement
in renal and cardiac function in congestive heart failure. The
present study evaluated the effects of eprosartan, a selective
angiotensin II receptor antagonist, on renal
hemodynamic and excretory parameters and on
the development of cardiac hypertrophy in rats with
aortocaval fistula, an experimental model of congestive heart failure.
Infusion of eprosartan (1.0 mg/kg) in rats with aortocaval fistula
produced a significant increase (+34%) in total renal blood flow and a
sustained decrease (-33%) in the calculated renal vascular
resistance. These effects on renal hemodynamics were
more pronounced than those observed in sham-operated control rats and
occurred despite a significant fall (-12%) in mean
arterial blood pressure. Moreover, eprosartan caused a
preferential increase in renal cortical blood perfusion and
significantly increased glomerular filtration in rats with
congestive heart failure. Chronic administration of eprosartan (5.0
mg/kg per day for 7 days through osmotic minipumps inserted
intraperitoneally on the day of operation) resulted
in a significant enhancement of urinary sodium excretion compared with
nontreated rats with heart failure. Moreover, administration of
eprosartan to salt-retaining rats with congestive heart failure
resulted in a progressive increase and ultimate recovery in urinary
sodium excretion. Finally, early treatment with eprosartan blocked the
development of cardiac hypertrophy in rats with aortocaval
fistula to a larger extent than the angiotensin-converting
enzyme inhibitor enalapril. These findings emphasize the
importance of angiotensin II in mediating the impairment in
renal function and induction of cardiac hypertrophy in
heart failure and further suggest that angiotensin II
receptor blockade may be a useful treatment of these consequences in
severe cardiac failure.
Key Words: angiotensin II • angiotensin antagonist • fistula, aortocaval • hypertrophy • renal circulation • hemodynamics • rats
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Activation of the
renin-angiotensin-aldosterone system (RAAS) is
considered an important reaction and one of the earliest compensatory
neurohumoral responses to the decrease in pumping capacity of the
failing myocardium in congestive heart failure
(CHF).1 2 3 Although this mechanism may prove to
be beneficial in the early stages of CHF, continuous activation of the
system may become detrimental to cardiac and renal
function.4 Angiotensin II (Ang II)
plays a major role in this maladaptive response by promoting systemic
vasoconstriction and increasing the abnormal loading conditions in the
failing heart. In addition, Ang II, by virtue of its growth-promoting
properties, may contribute to the development of cardiac
hypertrophy as a result of a direct action on cardiac
myocytes.5 Numerous studies have also indicated
that activation of the RAAS is involved in mediating the deranged renal
function in heart failure.1 6 7 The kidney
appears to be uniquely sensitive to the vasoconstrictor action of Ang
II, mainly in the efferent and afferent arterioles as well as on
glomerular mesangial
cells.8 In addition, Ang II increases tubular
reabsorption of sodium, both by direct action on the nephron and by
augmenting aldosterone release.1 9
The resultant renal hypoperfusion and the avid salt and water retention
by the kidney may promote circulatory congestion and edema formation,
which imposes a further circulatory overload on the failing
myocardium. On the basis of these maladaptive responses of
Ang II, one can envision that blocking the formation of the peptide may
improve myocardial function in CHF. Indeed,
angiotensin-converting enzyme (ACE) inhibitors
have revolutionized the clinical approach to patients with CHF, and the
efficacy of these agents in improving cardiac performance and
increasing life expectancy in severe heart failure is well
established.10 11 12 13 However, it is also known that
some of the cardiovascular effects of ACE
inhibitors are mediated through their action on the kinin
system, since they can be blocked by concomitant administration of
bradykinin antagonists.14 15 Thus,
other mechanisms not related directly to Ang II blockade may contribute
to the beneficial actions of these drugs in heart failure.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Experiments were conducted on a local strain of male Wistar rats
weighing 280 to 380 g that were maintained on a standard rat diet
(containing 0.5% to 0.6% NaCl) and water ad libitum. CHF was induced
by creating an arteriovenous fistula between the abdominal aorta and
inferior vena cava according to the method of Stumpe et
al,31 as adapted in our
laboratory.6 27 32 In short, the abdominal aorta
and inferior vena cava were exposed through a midabdominal
incision under halothane anesthesia, and an anastomosis was
surgically created in the common wall of the 2 vessels (1.0 to 1.2
mm OD, side to side). After surgery, the animals were allowed to
recover and were then transferred into individual metabolic
cages for daily measurements of urinary sodium and water excretion.
Sham-operated rats served as controls.
Six to 7 days after the operation, rats were
anesthetized by intraperitoneal injection
of thiobutabarbital (Inactin) (100 mg/kg, RBI), placed on a
thermoregulated table (37°C), and prepared for
hemodynamic and renal clearance
measurements.6 28 After tracheotomy, polyethylene
tubes (PE-50) were inserted into the left carotid artery and right
jugular vein for blood pressure monitoring, blood sampling, and
infusion of the various solutions. The urinary bladder was then
catheterized by PE-50 through a suprapubic incision for timed urine
collections. A solution of 0.9% saline was infused
intravenously by a syringe pump, at a rate equal to 1.0%
to 1.5% of body weight per hour, throughout the experiment. After a
60-minute equilibration period, the following experimental protocols
were performed.
Measurements of total renal blood flow (RBF) were performed by
an ultrasonic flowmeter (model T206, Transonic Corp) with the use of an
ultrasonic flow probe (type 1RB) placed around the midportion of the
left renal artery, as previously described.28
Arterial blood pressure was continuously monitored with a
pressure transducer (model 156PC05GWL, Microswitch) connected to the
arterial line. Data of RBF and mean arterial
pressure (MAP) were continuously recorded by a computerized data
acquisition system with the use of Labtech Notebook software. Renal
vascular resistance (RVR) was calculated by the standard formula
(RVR=MAP/RBF). In preliminary experiments we evaluated the effects of
incremental doses of the drug (0.3, 1.0, and 3.0 mg/kg) on MAP and RBF
in rats with CHF. On the basis of these experiments, the dose of 1.0
mg/kg was chosen for assessment in the present study. After surgery
and equilibration, baseline measurements were obtained for 30 minutes.
Eprosartan, dissolved in 20%/80% ethanol/saline mixture, was then
injected intravenously at a dose of 1.0 mg/kg over a
5-minute period to control (n=6) and CHF (n=6) rats.
Hemodynamic recordings were obtained for an
additional 60 minutes after administration of the drug.
For measurements of renal regional blood flow, the left kidney
was exposed in control (n=6) and CHF rats (n=6) and placed in a
Plexiglas holder with warm mineral oil (37°C) poured on the surface
of the kidney at frequent intervals. Cortical and medullary blood flow
(CBF and MBF, respectively) were measured simultaneously by
laser-Doppler flowmetry with a dual-channel flowmeter
(model 4001, Master Perimed AB) with 2 needle probes (Periflux 411), as
previously described.33 Calibrated probes were
placed perpendicular to the surface of the cortex and inserted into the
outer medulla at a depth of 4 to 5 mm. Recordings of 30
seconds were obtained at 5-minute intervals during the baseline period.
Eprosartan was then administered as described in the previous protocol,
followed by 2 minutes of continuous recordings and then at
5-minute intervals for an additional 60 minutes. Regional blood flow
was calculated in perfusion units (PU) by multiplying the velocity by
the concentration of the moving blood cells and expressed as percent
change from baseline value.
To evaluate the acute effects of the drug on
glomerular filtration rate (GFR) and urinary sodium
excretion, additional groups of control (n=7) and CHF (n=7) rats were
prepared as described in previous protocols, with the exception that
the abdominal cavity was not opened. A solution of 2% inulin in 0.9%
saline was continuously infused throughout the experiment. After
surgery and equilibration, 2 baseline periods of 30 minutes each were
obtained. Eprosartan was then administered intravenously,
followed by 3 additional clearance collections. Urine was collected
into preweighed tubes, and urine volume was determined gravimetrically.
Blood samples (0.3 mL) were obtained between each 2 clearance periods
and at the end of the experiment. Plasma was separated by
centrifugation and kept at 4°C until assayed for
inulin and electrolytes.
These studies were designed to evaluate the effects of long-term
administration (7 days) of eprosartan through osmotic minipumps (model
2001, Alzet Pharmaceutical) on urinary sodium excretion and on the
development of cardiac hypertrophy in rats with
experimental heart failure. Eprosartan was dissolved in a solution of
5% sodium bicarbonate (80 mg/mL) and adjusted to a final concentration
sufficient to deliver 5 mg/kg per day for 7 days, according to the
specifications of the manufacturer.
Two experimental approaches were used. In the first approach
(early treatment protocol), osmotic minipumps containing either
eprosartan (n=8 experiments) or vehicle (n=6 experiments) were
implanted into the peritoneal cavity during the creation of the A-V
fistula. Rats with sham operation treated with eprosartan served as a
control (n=5). After the operation the animals were transferred into
metabolic cages, and daily measurements of urinary sodium
excretion were performed for 7 days.
After the completion of the 7 days of eprosartan treatment,
animals from the early and late treatment protocols were killed by
decapitation. Their chest was opened and the heart was removed
instantaneously, placed on absorbent paper to remove excess of blood,
and then weighed to calculate the heart/body weight ratio.
Sham-operated control animals (n=6) served as control. To compare the
effect of eprosartan to that of ACE inhibition, an additional group of
rats with A-V fistula (n=7) was studied. In these rats, the ACE
inhibitor enalapril (Merck & Co) was added to the drinking
water on the day of operation, at a dose of 100 mg/L, and continued for
7 additional days. In preliminary experiments we found that treatment
with this dose for 3 days was sufficient to block the hypertensive and
renal vasoconstrictor effects of bolus injections of
angiotensin I, in a dose range of 100 to 300 ng/kg (data
not shown).
Concentrations of inulin in plasma and in the urine were
measured by the anthrone method.34 Sodium
concentration in plasma and urine was determined by flame photometry
(model IL 943, Instrumentation Laboratories).
One-way ANOVA was used for group comparisons and
repeated-measures ANOVA for comparison of treatment values with
baseline values in each group. The Tukey or Dunnett test was used for
post-ANOVA evaluation, as appropriate. For comparison of the graphs
representing control and experimental groups, 2-way ANOVA
was used. A value of P<0.05 was considered statistically
significant. Data are expressed as mean±SEM.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Acute Studies
Dose-Response Relationships of Eprosartan on MAP and RBF
Table 1
summarizes the data on the effects of incremental doses of eprosartan
on MAP and RBF in rats with A-V fistula. As shown, eprosartan produced
a dose-related decrease in MAP and an increase in RBF when administered
at doses of 0.3 and 1.0 mg/kg. In the higher dose of 3.0 mg/kg, the
drug induced a marked hypotensive response and no increase in RBF. On
the basis of these observations, the dose of 1.0 mg/kg was chosen in
the protocols of the acute studies.
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Table 1. Dose-Related Effects of Eprosartan on Renal
Hemodynamics and MAP in Rats With
CHF
Figures 1 and 2 summarize the data on the acute effects
of eprosartan on renal hemodynamics and intrarenal
distribution of blood flow in rats with CHF and control animals. Rats
with CHF had a significantly lower MAP than control animals (CHF:
111±7 mm Hg; control: 128±3 mm Hg;
P<0.05), and infusion of eprosartan resulted in a further
reduction in MAP in both groups. Baseline RBF was lower in CHF rats
(1.4±0.1 mL/min per 100 g body wt) than in controls (2.8±0.2
mL/min per 100 g body wt; P<0.001). Likewise, RVR was
higher in rats with CHF than in controls (CHF: 26.6±2.1 resistance
units; control: 15.8±0.7 resistance units; P<0.001).
Administration of the drug resulted in a significant increase in RBF in
both control rats (from 2.8 to 3.6 mL/min per 100 g body wt;
P<0.05) and rats with CHF (from 1.4 to 1.9 mL/min per
100 g body wt; P<0.01). Moreover, when calculated as
percent change from baseline value, the increase in RBF in rats with
CHF was of a significantly higher magnitude and of longer duration than
that observed in control animals (Figure 1). Likewise, eprosartan
caused a more prominent and sustained reduction in RVR in rats with CHF
than in control animals (Figure 1, bottom panel). Thus, the effects of
the Ang II receptor antagonist on renal
hemodynamics were more pronounced and more sustained in
rats with CHF and occurred despite a further decrease in MAP
(
-12%) after administration of the drug.
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Figure 1. Effects of eprosartan infusion on MAP, RBF, and
calculated RVR in control group ( 
) and CHF rats (
). Hatched area
represents the duration of the drug administration. The lines
representing control and CHF groups were significantly
different (by 2-way ANOVA) for each parameter measured.
*Statistically significant compared with baseline value in the same
group.
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Figure 2. Effects of eprosartan on renal CBF (top) and MBF
(bottom) in control group ( ) and in CHF rats (). Data are
expressed as percent change from baseline value. *Statistically
significant compared with baseline value in the same group.
, which depicts the alterations in the intrarenal
distribution of blood flow as evaluated by laser-Doppler
flowmetry. As shown, eprosartan caused a marked and sustained
increase in cortical perfusion (+28%, peak response) in rats with
CHF compared with a significantly lower (+17%) and more transient
response observed in sham-operated controls (Figure 2, top panel). In
contrast, in the medulla the drug produced similar changes in blood
perfusion in both groups, which were not statistically different from
baseline values (Figure 2, bottom panel). These findings suggest that
Ang II blockade caused a preferential increase in CBF and improved
cortical perfusion in rats with heart failure.
The acute effects of eprosartan on GFR and sodium excretion
are summarized in Table 2. As reported
previously,6 27 baseline GFR was significantly
lower in rats with CHF than in control animals (CHF: 0.88±0.13
mL/min; control: 1.79±0.17 mL/min; P<0.05). After
eprosartan, GFR increased significantly in CHF rats (from 0.88±0.13 to
1.62±0.27 mL/min; P<0.05) but not in control rats (Table 2). Likewise, baseline value of fractional sodium excretion was
significantly reduced in rats with CHF (control: 0.63±0.21%; CHF:
0.16±0.06%; P<0.05). Administration of eprosartan
resulted in a significant increase in sodium excretion in control
animals but not in rats with CHF (Table 2).
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Table 2. Effects of Eprosartan on Renal Clearance Parameters
in Control and CHF Rats
Effects of Eprosartan on Daily Sodium Excretion
Figure 3A summarizes the data on the
effects of chronic administration of eprosartan on urinary sodium
excretion in control and CHF rats in which an osmotic minipump,
containing either the drug or vehicle, was inserted
intraperitoneally concomitantly with the operation
(early treatment protocol). Average daily sodium excretion in all
groups before the operation was 1540±54 µmol/24 h (on the
basis of 45 measurements in 15 rats during 3 consecutive days before
the operation). Rats with A-V fistula displayed a sustained decrease in
urinary sodium excretion (days 1 through 6) compared with only a
transient decrease in the first 2 postoperative days in control
animals. Rats with A-V fistula in which eprosartan was administered
through an osmotic minipump displayed a significantly earlier
natriuretic response compared with CHF rats treated with
the vehicle only (Figure 3A). This early "recovery" resulted in
daily sodium excretion values, on days 4 through 7, that were not
different from those observed in the sham-operated control group
treated with the drug.
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Figure 3. A, Effects of chronic eprosartan (Epro)
administration on daily urinary sodium excretion in rats with
experimental heart failure. Hatched area represents the
averaged daily sodium excretion in the last 3 days before operation
(baseline period). Lines representing the
eprosartan-treated and vehicle-treated groups of rats with A-V fistula
are significantly different (by 2-way ANOVA). B, Effect of chronic
administration of eprosartan on urinary sodium excretion in rats with
decompensated heart failure. Data are based on 7 experiments.
Eprosartan-loaded minipumps were inserted
intraperitoneally on day 6 after creation of the
A-V fistula. *Statistically different compared with pretreatment
value. depicts the effects of the drug on urinary sodium excretion
in a preselected group of rats with decompensated CHF that displayed
avid sodium retention (daily urinary sodium excretion <100
µmol/24 h) in the first week after the
operation.6 Administration of eprosartan was
started on the sixth postoperative day and continued for an additional
week (late treatment protocol). As shown, eprosartan treatment resulted
in a progressive increase in urinary sodium excretion, which reached
its peak effect on the fifth day of drug administration and remained
significantly elevated above pretreatment level throughout the
experiment (Figure 3B).
Figure 4 shows the effects of
treatment with eprosartan (early and late treatment protocols) and with
the ACE inhibitor enalapril on the heart/body weight ratio
in rats with experimental CHF. The heart/body weight ratio, an index of
cardiac hypertrophy, increased from 0.34±0.01% in control
rats to 0.49±0.03% in rats with CHF (P<0.001).
Interestingly, early treatment with eprosartan was highly beneficial in
preventing the increase in heart/body weight ratio in rats with CHF
(0.36±0.01%; P=NS compared with control animals). In
contrast, early treatment with enalapril did not prevent the increase
in heart/body weight ratio (0.47±0.03%; P=NS compared with
CHF rats without any treatment). Similarly, in rats with CHF in which
eprosartan was started 1 week after the A-V fistula operation (late
treatment group in Figure 4), the drug did not decrease heart/body
weight ratio (0.55±0.01%). Thus, early but not late administration of
eprosartan was more effective than ACE inhibition in attenuating the
volume overload induced cardiac hypertrophy in rats with
A-V fistula.
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Figure 4. Changes in the heart/body weight ratio (expressed
as percentage), an index of cardiac hypertrophy, in the
various experimental groups. The mean (horizontal line) and individual
values are shown in each experimental group. See text for further
details. Epro indicates eprosartan.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
The present study demonstrated that eprosartan, a highly
specific, nonpeptide AT1 receptor
antagonist, caused a remarkable improvement in renal
function and attenuated the development of cardiac
hypertrophy in rats with experimental heart failure. Thus,
acute administration of the antagonist resulted in a
sustained reduction in RVR associated with a marked increase in total
RBF and in renal cortical perfusion. These beneficial actions of
eprosartan on renal hemodynamics in rats with CHF were
associated with a significant increase in GFR. Moreover, when
administered on a chronic basis, eprosartan induced an impressive
natriuretic response in rats with decompensated CHF and
avid sodium retention. Finally, early treatment with eprosartan was
highly effective in preventing the development of cardiac
hypertrophy, exceeding that produced by ACE inhibition, in
this experimental model of cardiac failure.
Acknowledgments
This study was supported in part by a grant from the Israel
Ministry of Health and awards from the Israel Ministry of Absorption in
Science and from SmithKline Beecham Pharmaceuticals. The authors
acknowledge the expert technical assistance of Eva Shuranyi and Aviva
Kaballa and the secretarial assistance of Ruth Singer.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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