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Hypertension Unit, University of Ottawa Heart Institute, Ottawa, Ontario, Canada K1Y 4W7
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Mechanical stretch, ANG II, and
1-receptor stimulation may
contribute to cardiac remodeling after myocardial infarction (MI). Each
of these mechanisms involves different signaling pathways for the
cellular hypertrophic response. All three also activate the
Na+/H+
exchanger. In the present study we evaluated the hypothesis that activation of the
Na+/H+
exchanger is involved in parallel with other signaling mechanisms for
ANG II. Three days before coronary artery ligation, rats were randomly
allocated to no treatment or treatment with amiloride, losartan, or
amiloride and losartan in combination. Four weeks after coronary artery
ligation, left ventricular (LV) function was assessed from in vivo
resting cardiac pressures, hemodynamic responses to cardiac volume and
pressure load, and cardiac remodeling by in vitro pressure-volume
curves and LV and right ventricle (RV) weight. Amiloride and losartan
given alone to a similar extent attenuated the shift of the
pressure-volume curve to the right. This effect was significantly more
pronounced with amiloride and losartan in combination. Each drug alone
to a minor extent improved LV responses to pressure and volume load.
However, with amiloride and losartan in combination, close-to-normal
responses to pressure and volume load were observed. Losartan and
amiloride alone had only a small effect on development of RV
hypertrophy after MI but in combination completely prevented the RV
hypertrophy. Amiloride and losartan appear to be complementary in
prevention of cardiac remodeling and LV dysfunction after MI. This
finding suggests that, besides ANG II, other mechanisms activating the
Na+/H+
exchanger contribute to cardiac remodeling after MI.
amiloride; losartan; left ventricular remodeling; left ventricular failure
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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INCREASES IN DIASTOLIC and, to a lesser extent, systolic wall stress after myocardial infarction (MI) are primary stimuli for left ventricular (LV) remodeling (10). In vitro, stretch of cardiomyocytes results in activation of second messenger systems, including tyrosine kinases, p21ras, mitogen-activated protein kinases, protein kinase C, and phospholipases A, C, and D (10). An increase in activity of the membrane-bound Na+/H+ antiporter by stretch (possibly as the result of protein kinase C activation) increases intracellular pH and free cytosolic Ca2+. These changes are associated with initiation of protein synthesis and resulting hypertrophy of cardiomycytes (10). Blockade of the Na+/H+ antiporter by amiloride prevents the stretch-induced increase in protein synthesis (9). In vivo, blockade of the Na+/H+ antiporter by amiloride or HOE-642 when started before or up to 24 h after coronary artery ligation in rats attenuated cardiac remodeling and improved cardiac function, as indicated by attenuation of LV hypertrophy and dilation and by a significant reduction in LV end-diastolic pressure (LVEDP) and an increase in contractility (7, 20).
In addition to increased hemodynamic load imposed on the heart after an MI, ANG II generated by the circulatory or cardiac renin-angiotensin system (RAS) may potentiate cardiac remodeling (16-18). Stimuli for activation of the circulatory RAS after MI include decreases in blood pressure and increased renal sympathetic tone. Stimuli for activation of the cardiac RAS after MI include increased diastolic wall stress and associated stretch of cardiomyocytes (16, 18) and, possibly, the increase in cardiac sympathetic tone (12). In the heart, ANG II can initiate a hypertrophic response of cardiomyocytes via AT1 receptor-mediated increases in the phospholipid-derived second messenger system (phospholipases A, C, and D), phosphatidic acid, and diacylglycerol and resultant sustained activation of protein kinase C (10, 17, 18). This activation of protein kinase C may in turn signal the hypertrophic response via phosphorylation of regulatory transcription protein(s) or via an activation of the Na+/H+ antiporter (5) with an associated sequence of changes, resulting in hypertrophic responses of cardiomyocytes, as described above. The attenuation of the hypertrophic response and cardiac remodeling after MI by blockers of the RAS is consistent with the involvement of ANG II in cardiac remodeling after MI (11, 14).
A third mechanism contributing to progressive remodeling of the LV
after MI is an increase in cardiac sympathetic tone (13). The signaling
pathway for 1-receptor-mediated
cellular hypertrophy appears to involve phospholipase C,
diacylglycerol, and protein kinase C as well as activation of the
Na+/H+
antiporter (10, 22). However, whether
1-receptor-mediated effects of
cardiac sympathetic tone contribute to LV remodeling after MI has not
yet been assessed.
Thus all the stimuli that have been identified to contribute to progressive LV remodeling after MI may involve stimulation of the Na+/H+ exchanger. To what extent the activation of the Na+/H+ exchanger reflects a common final pathway for all stimuli or one of the parallel mediating mechanisms has not been studied. In other words, it is unknown whether combined inhibition of, e.g., the RAS and the Na+/H+ antiporter is more effective than either blockade alone in attenuating cardiac remodeling after MI.
In the present study we therefore assessed in rats the effects of the AT1 receptor blocker losartan and the Na+/H+ antiporter blocker amiloride alone and in combination on cardiac remodeling and cardiac function after MI. On the basis of the above concepts, we expected that amiloride and losartan would complement each other and that amiloride + losartan would result in more complete blockade of cardiac remodeling after MI associated with beneficial effects on cardiac function.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals, treatments, and coronary artery ligation.
Male Wistar rats (200-250 g body wt, 6-7 wk of age; Charles
River Breeding Laboratories, Montreal, PQ, Canada) were housed two per
cage, given food (Charles River rodent chow with 120 µmol Na+/g food) and water ad libitum,
and kept on a 12:12-h light-dark cycle. After an acclimatization period
of 
5 days, an occluder was placed around the left coronary artery.
Treatment with losartan or amiloride started 3 days before the actual
coronary artery occlusion. Rats were randomized into specific groups,
for practical reasons, in two sets of experiments. In
experiment 1, rats were randomized to
sham-untreated, MI-untreated, MI + losartan (15 mg · kg
1 · day1)-treated,
or MI + losartan (15 mg · kg1 · day1) + amiloride-treated (~4
mg · kg1 · day1)
groups. In experiment 2, rats were
randomized to sham-untreated, MI-untreated, or MI + amiloride (~4
mg · kg1 · day1)-treated
groups. Doses for losartan and amiloride treatment were derived from
previous studies (7, 15, 19), with the bioavailability related to the
route of administration taken into account. In both experiments,
amiloride was administered via the drinking water (30 mg/l), and
losartan was administered once daily by subcutaneous injection.
1 · day1
sc for 5 days markedly inhibited pressor responses to ANG II at 1, 4, and 7 h after dosing and still exerted substantial blockade after 24 h.
Resting mean arterial pressure was ~100-105 mmHg in control rats
and 85-90 mmHg in losartan-treated rats
(P < 0.01). To ensure a high degree
of AT1 receptor blockade
throughout the 24-h dosing interval, for the actual experiments, the
dose of losartan was further increased to 15 mg · kg1 · day1.
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Resting cardiac hemodynamics. On the day of the study, rats were anesthetized with halothane-oxygen, and one PE-50 catheter filled with heparinized saline (100 U/ml) was inserted into the LV via the right common carotid artery and another into the right external jugular vein. Catheters were exteriorized on the back of the neck. After 4 h of recovery from anesthesia, LVEDP and LV peak systolic pressure (LVPSP) were assessed in conscious, unrestrained rats after a 30-min acclimatization period, as previously described (3). Heart rate was calculated from the LVPSP and LVEDP curves.
Responses of cardiac hemodynamics to pressure load.
Changes in LVEDP, LVPSP, and heart rate in response to phenylephrine
infused at the rate of 4, 8, 12, 16, and 24 µg · kg1 · min1
for 1 min each were recorded.
Responses of cardiac hemodynamics to volume load. After stable hemodynamic status had been reestablished (30-40 min after the pressure load), changes in LVEDP, LVPSP, and heart rate in response to volume expansion by intravenous infusion of 5% dextrose over 30 s at 0.33, l.0, and 3.0 ml/100 g body wt at 15-min intervals were recorded.
In vitro assessment of passive pressure-volume curves.
After the assessments described above, rats were killed by intravenous
injection of 2 M KCl (1 ml/animal), the chest cavity was opened, and
the heart was excised. To avoid fluid accumulation and variable
compressive force on the interventricular septum, the RV was dissected
along its septal insertion from the remaining ventricular mass. A
double-lumen catheter was inserted into the LV, with one end connected
to a Harvard infusion pump and the other to a pressure transducer. The
atrioventricular groove was ligated, and the ventricle was compressed
manually to expel blood and create a negative pressure of 
5
mmHg, which was taken as a zero volume. Saline (0.9%) was then infused
into the LV at the rate of 0.68 ml/min, and the pressure was recorded
continuously over a pressure range of 5 to 30 mmHg. Two to three
reproducible passive pressure-volume curves were obtained within 10 min
after cardiac arrest. Ventricular volumes were determined at pressures of 0, 2.5, 5, 10, 15, 20, and 30 mmHg from the passive pressure-volume curve. The pressure-volume curve is linear from 0 to 2.5 mmHg and
exponential thereafter. The slope of the pressure-volume relationship between 2.5 and 30 mmHg was therefore compared on a logarithmic scale
by use of the least-squares linear regression method.
Measurement of the infarct size. After the assessment of RV and LV weight, infarct size was determined according to Chien et al. (2). For this determination, four to five incisions were made in the LV so that the LV tissue could be placed flat. The circumference of the entire LV and the visualized infarcted area, as judged from epicardial and endocardial sides, was outlined on a clear plastic sheet. The difference in weight between the two marked areas on the sheet was used to determine the infarct size. The degree of tissue edema was assessed from the dry-to-wet weight ratio for LV and RV. Dry weights were obtained after the tissue was placed in an oven at 90°C for 24 h.
Statistical analysis. Values are means ± SE. One-way ANOVA was performed to determine effects of treatments on various parameters after myocardial infarction. When F ratios were significant, Duncan's multiple-range test was used as a post hoc test for locating the differences between the means of different groups. Least-squares linear regression analysis was used to compare the changes in LVEDP in relation to LVPSP induced by phenylephrine infusion and for differences in passive pressure-volume curves in vitro.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Cardiac anatomy.
Four weeks after coronary artery ligation, the infarcted myocardium was
~40% of the LV in untreated animals. Treatment with losartan and
amiloride alone or in combination had no significant effect on the
infarct size (Table 1). LV weight had
increased 4 wk after MI by 10-20% compared with sham-operated
animals (significant in 1 experiment only). Losartan alone or in
combination with amiloride tended (not significant) to inhibit the
increase in LV weight (Table 1). In contrast, at 4 wk after MI, RV
weight had increased significantly compared with rats subjected only to
sham surgery (Fig. 2). Whereas losartan and
amiloride given alone did not attenuate this increase in RV weight, in
combination they resulted in complete prevention of RV hypertrophy
(Fig. 2). The dry-to-wet weight ratios for LV and RV were similar in
all groups (data not shown).
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In vivo central hemodynamics. LVPSP showed minimal or no decreases after MI. Treatment with losartan decreased LVPSP compared with untreated animals after MI. Amiloride given alone or in combination with losartan had no effect on LVPSP (Table 1).
Resting LVEDP increased significantly after MI (Fig. 3). Treatment with losartan or amiloride alone had only a small (not significant) effect on this rise in LVEDP (Fig. 3). In contrast, amiloride and losartan in combination significantly attenuated the rise in LVEDP (Fig. 3).
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Hemodynamic responses to volume overload.
Volume overload increased LVEDP in a dose-related manner (Fig.
4). Moderate and marked volume overload
resulted in significantly larger increases in LVEDP in the MI-untreated
than in the sham-operated rats (Fig. 4). Losartan and amiloride each
alone caused some (not significant) attenuation of this increase
compared with the MI-untreated groups. Only losartan and amiloride in
combination significantly attenuated the extent of rise in LVEDP in
response to volume load compared with the MI-untreated groups (Fig. 4).
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Hemodynamic responses to pressure overload.
Phenylephrine increased LVPSP in a dose-related manner (Fig.
5). In MI-untreated rats this increase was
significantly attenuated. This attenuation was improved
(P < 0.05) only by losartan and amiloride in combination (Fig. 5). Increases in LVEDP by pressure overload were markedly higher in MI-untreated rats relative to the
increases in LVPSP. Losartan had no effect on the extent of increases
in LVEDP relative to increases in LVPSP. Amiloride caused a modest but
significant improvement, whereas amiloride and losartan in combination
more clearly improved the response in LVEDP to pressure overload (Fig.
6).
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In vitro pressure-volume relationship.
MI resulted in a significant shift of the pressure-volume curve to the
right compared with sham-operated animals (Fig.
7). Amiloride and losartan given alone to a
similar extent attenuated the shift of the pressure-volume curve to the
right caused by MI. Treatment with losartan and amiloride in
combination further moved the pressure-volume curve toward that in
sham-operated animals (Fig. 7). Combined treatment, however, did not
completely normalize the pressure-volume relationship in vitro (Fig.
7).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In the present study we assessed the effects of losartan and amiloride alone or in combination on cardiac remodeling and LV function after MI and found that 1) the shift of the LV pressure-volume curve to the right after MI is significantly more attenuated with amiloride and losartan in combination than with either drug alone, 2) this effect on LV remodeling by the combined treatment is associated with LV function (as assessed from LVEDP at rest and in response to volume and pressure overload) superior to that in rats treated with amiloride or losartan alone, and 3) amiloride and losartan only in combination prevent RV hypertrophy after MI.
Effects of MI on cardiac anatomy and LV function. Consistent with many previous studies (7, 11, 14, 15, 19, 20), coronary artery ligation resulted in a clear shift of the LV pressure-volume curve to the right, with a modest increase in LV weight and clear RV hypertrophy. An increase in LV end-diastolic wall stress as assessed from the increase in LVEDP is a major factor in LV remodeling after MI. Although LVPSP tended to decrease after MI, LV systolic wall stress may still increase as the result of progressive dilation of the LV during the remodeling process (6). The more pronounced RV hypertrophy after MI is likely related to progressive LV failure, resulting in increases in RV systolic and diastolic wall stress. LV function decreased after MI, as reflected by an increase in resting LVEDP to ~15 mmHg, indicating the development of heart failure of moderate severity. In addition, volume loading caused two- to threefold larger increases in LVEDP as did pressure overload by phenylephrine. The increase in LVEDP in response to a rapid intravenous infusion depends on several factors, such as LV diastolic and systolic function, the venous capacitance bed, and afterload. LVPSP decreased during volume load but more in MI than in control rats, possibly reflecting more marked sympathetic withdrawal via the cardiopulmonary reflex in the MI rats because of the higher filling pressures. Cardiac output was not measured in the present study, and one can therefore not exclude that the same volume load caused different degrees of actual cardiac volume overload; i.e., venous return may have been higher in MI than in control rats because of venous constriction in the MI rats.
Phenylephrine caused a smaller increase in LVPSP in MI than in control rats (Fig. 5). This may reflect less arterial vasoconstriction, e.g., because of higher sympathetic tone and increased1-receptor occupancy in MI
compared with control rats. In addition, decreased myocardial
contractility likely impaired the ability of the LV to generate higher
LVPSPs with increasing afterload. Indeed, at similar increases in
LVPSP, LVEDP increased substantially more in MI than in control rats,
likely reflecting impaired pump ability in MI rats becoming more
prominent at higher afterloads.
Effects of amiloride and losartan on changes in LV function and cardiac anatomy caused by MI. In most previous studies, treatment with losartan alone improved parameters of cardiac remodeling and LV dysfunction after MI, such as the shift of the pressure-volume curve (15), RV hypertrophy (8, 15, 19), and the increase in LVEDP (8, 15). In contrast, Capasso et al. (1) did not observe these effects of losartan after treatment for only 1 wk. In the present study, treatment with losartan did significantly inhibit the shift of the pressure-volume curve to the right but otherwise caused only minor improvements. Differences in severity of the heart failure and duration and dose of treatment or (type of) anesthesia may explain some of these different results between studies. Studies on the hemodynamic effects of blockers of the Na+/H+ exchanger are limited. Treatment with amiloride for 4 wk inhibited ventricular remodeling after MI, without affecting LVEDP (7), whereas treatment with HOE-642 for 6 wk did blunt the increase in LVEDP and improved maximal LV pressure development (20). In the present study, treatment with amiloride for 4 wk also blunted cardiac remodeling (i.e., the shift of the pressure-volume curve to the right) but otherwise had only minor effects. To our knowledge, no studies have evaluated the effectiveness of combined AT1 receptor and Na+/H+ exchange blockade. When given in combination, significantly less LV dysfunction was found, the LV pressure-volume curve remained close to control, and RV hypertrophy was completely prevented. Some of these parameters showed an apparent additive effect, others (e.g., RV weight) were only affected by combined treatment.
In addition to mechanical stretch, nonhemodynamic factors, such as the cardiac tissue RAS and cardiac sympathetic activity, have been implicated in the cardiac remodeling after MI (13, 16-18). As described in the introduction, mechanical stretch, ANG II, and1-receptor stimulation may
contribute to cellular hypertrophy after MI. Each of those mechanisms
involves different signaling pathways for signaling the hypertrophic
response, but all three also activate the
Na+/H+
exchanger (5, 9, 10, 22). We hypothesized that activation of the
Na+/H+
exchanger is involved in intracellular hypertrophic signaling for
several stimuli contributing to remodeling after MI, at least in part
in parallel with other mechanisms such as phosphorylation of regulatory
transcription proteins by protein kinase C. Indeed, combined blockade
of AT1 receptors and, therefore,
of the ANG II pathway and the
Na+/H+
exchanger was clearly more effective in inhibiting cardiac remodeling and LV dysfunction after MI than either blockade alone. Several mechanisms may contribute to these more pronounced effects on prevention of LV dilation and LV dysfunction as well as prevention of
RV hypertrophy by combined treatment compared with either drug alone.
First, factors involved in remodeling after MI, including mechanical
stretch, ANG II, and 1-receptor
stimulation, differ in signaling pathways for cellular hypertrophic
response but may involve activation of the
Na+/H+
exchanger as a signaling step. In this regard, the superior effect of
combined treatment is consistent with the concept that more than one
mechanism is indeed involved in cardiac remodeling after MI and
indicates that activation of the
Na+/H+
exchanger is not involved in all pathways signaling intracellular hypertrophic response after MI. In particular, this more pronounced effect of the combination may indicate that in the heart the cellular responses to ANG II do not only depend on the
Na+/H+
exchanger, since the combination otherwise would be as effective as
each alone. In addition, this finding indicates that one of the other
stimuli (e.g., stretch) does involve the
Na+/H+
exchanger. This conclusion assumes that losartan in the dosing regimen
employed completely inhibited AT1
receptor-mediated signaling in the heart. A high degree of blockade was
indeed achieved (Fig. 1), but this does not necessarily indicate full
cardiac blockade. Second, the more pronounced effects on cardiac
remodeling and LV function after MI by amiloride and losartan in
combination may reflect more pronounced effects of combined treatment
on LVEDP per se. Losartan alone significantly decreased LVPSP and
presumably cardiac afterload, but combined treatment did not lower
LVPSP further (Table 1). Thus larger decreases in afterload unlikely contributed to the lower LVEDP and improved LV function on combined treatment. On the other hand, the two treatments combined may have
decreased venous return and, therefore, lowered LVEDP and improved LV
remodeling and LV function. Losartan may decrease venous return by
blunting ANG II-mediated renal effects on
Na+ and water reabsorption and by
venodilation. However, a decrease in venous return would lower cardiac
output, and in rats after MI losartan did not change (21) or tended to
increase cardiac output (19). Amiloride may decrease venous return by
causing natriuresis through its direct renal effect on
Na+ reabsorption. The present
study design cannot exclude that combined treatment decreased preload
sufficiently to prevent RV hypertrophy and improve LV remodeling and LV
function. However, amiloride is generally considered to have only a
mild diuretic effect, and it appears unlikely that this renal effect
could lead to such marked effects on cardiac remodeling after MI.
Some possible limitations of the present study should be mentioned.
First, although amiloride is the prototypical
Na+/H+
exchange inhibitor, it is not selective. However, general studies with
more specific amiloride analogs or inhibitors with a different structure confirm results obtained with amiloride (4). Second, in the
present study only global parameters of LV remodeling and LV function
were assessed. Follow-up studies including assessment of cardiac
structure and hemodynamic parameters such as cardiac output and maximal
LV pressure development are needed.
In conclusion, the above data demonstrate the effectiveness of losartan
and amiloride treatment in combination in inhibiting cardiac remodeling
and LV dysfunction after MI compared with each treatment alone. This
finding suggests that activation of the Na+/H+
exchanger by mechanisms other than ANG II contributes to cardiac remodeling after MI.
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ACKNOWLEDGEMENTS |
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This study was supported by Heart and Stroke Foundation of Ontario, Canada, Operating Grant T-3118 and a Medical School Grant from Merck Frosst Canada. F. H. H. Leenen is a Career Investigator of the Heart and Stroke Foundation of Ontario, Canada.
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FOOTNOTES |
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Present address of M. Ruzicka: Dept. of Internal Medicine, University of Ottawa Medical School, Ottawa, ON, Canada K1Y 4W7.
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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: F. H. H. Leenen, Hypertension Unit, Rm. H360, University of Ottawa Heart Institute, 40 Ruskin St., Ottawa, ON, Canada K1Y 4W7 (E-mail: fleenen{at}ottawaheart.ca).
Received 16 December 1998; accepted in final form 24 March 1999.
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METHODS
RESULTS
DISCUSSION
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 Y. Yu, S.-G. Wei, Z.-H. Zhang, E. Gomez-Sanchez, R. M. Weiss, and R. B. Felder Does Aldosterone Upregulate the Brain Renin-Angiotensin System in Rats With Heart Failure? Hypertension, March 1, 2008; 51(3): 727 - 733. [Abstract] [Full Text] [PDF]
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A. Pourdjabbar, T. G. Parker, Q. T. Nguyen, J.-F. Desjardins, N. Lapointe, J. N. Tsoporis, and J.-L. Rouleau Effects of pre-, peri-, and postmyocardial infarction treatment with losartan in rats: effect of dose on survival, ventricular arrhythmias, function, and remodeling Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1997 - H2005. [Abstract] [Full Text] [PDF]
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J. Francis, Y. Chu, A. K. Johnson, R. M. Weiss, and R. B. Felder Acute myocardial infarction induces hypothalamic cytokine synthesis Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2264 - H2271. [Abstract] [Full Text] [PDF]
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R. B. Felder, J. Francis, Z.-H. Zhang, S.-G. Wei, R. M. Weiss, and A. K. Johnson Heart failure and the brain: new perspectives Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2003; 284(2): R259 - R276. [Abstract] [Full Text] [PDF]
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K. Kusumoto, J. V. Haist, and M. Karmazyn Na+/H+ exchange inhibition reduces hypertrophy and heart failure after myocardial infarction in rats Am J Physiol Heart Circ Physiol, February 1, 2001; 280(2): H738 - H745. [Abstract] [Full Text] [PDF]
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, Control; 
, losartan.
* P < 0.05, losartan vs.
control.
