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Circulation. 1997;95:1592-1600

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(Circulation. 1997;95:1592-1600.)
© 1997 American Heart Association, Inc.

Articles

Angiotensin AT1 Receptor Inhibition

Effects on Hypertrophic Remodeling and ACE Expression in Rats With Pressure-Overload Hypertrophy due to Ascending Aortic Stenosis

Ellen O. Weinberg, PhD; Min Ae Lee, MD; Marilyn Weigner, MD; Klaus Lindpaintner, MD; Sanford P. Bishop, PhD; Claude R. Benedict, MD, PhD; Kalon K. L. Ho, MD, MSc; Pamela S. Douglas, MD; Edward Chafizadeh, MD; Beverly H. Lorell, MD

From the Charles A. Dana Research Institute and the Harvard-Thorndike Laboratory and the Department of Medicine (Cardiovascular Division) of Beth Israel Deaconess Medical Center and Harvard Medical School (E.O.W., M.W., K.K.L.H., P.S.D., E.C., B.H.L.), Boston, Mass; the Department of Pathology of the University of Alabama at Birmingham (S.P.B.); Brigham and Women's Hospital and Children's Hospital (M.A.L., K.L.), Boston, Mass; and the University of Texas Health Science Center (C.R.B.), Houston.


*    Abstract
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 *Abstract
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 down arrowResults
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Background We tested the hypothesis that long-term administration of the specific angiotensin II subtype 1 (AT1)–receptor blocker BMS-186295 will regress hypertrophy and modify left ventricular angiotensin converting enzyme (ACE) expression in rats with ascending aortic stenosis.

Methods and Results Six weeks after surgery, rats with ascending aortic stenosis were randomized to receive either the AT1-receptor blocker BMS-186295 50 mg·kg-1·d-1 (n=49), amlodipine 2.5 mg·kg-1·d-1 (n=48) as a positive control for systemic vasodilation, or no drug (n=48) and compared with sham-operated rats (n=39). Drug treatment was continued for 15 weeks. Left ventricular ACE mRNA levels were measured by ribonuclease protection assay. The left ventricular/body weight ratio was increased 43% in hearts from rats with untreated left ventricular hypertrophy (LVH) versus control hearts (P<.05). However, there was no difference in either the left ventricular/body weight ratio (2.78±0.08 versus 2.81±0.20 mg/g; P=NS) or myocyte cross-sectional area in the AT1-blocker–treated versus untreated LVH hearts. Amlodipine also showed no effect on regression of hypertrophy. In vivo left ventricular systolic pressure was significantly higher in untreated LVH versus sham-operated rats (193±8 versus 118±4 mm Hg; P<.05), and there was a similar severe elevation of left ventricular systolic pressure in the AT1-blocker– and amlodipine-treated LVH groups (189±9 and 188±16 mm Hg; P=NS versus untreated LVH). In vivo left ventricular end-diastolic pressure was higher in the untreated LVH than in the sham-operated rats (14.8±2.3 versus 7.0±0.5 mm Hg; P<.05). Left ventricular end-diastolic pressure was lower in the AT1-blocker–treated (11.0±1.7 mm Hg) and amlodipine-treated rats (11.5±1.8 mm Hg) and was similar to left ventricular end-diastolic pressure in the sham-operated rats (P=NS). Left ventricular ACE mRNA levels were elevated in untreated LVH rats but were normalized in both the AT1-blocker–treated rats and amlodipine-treated rats.

Conclusions Long-term AT1-receptor blockade did not regress LVH in rats with persistent systolic pressure overload due to ascending aortic stenosis. However, both AT1-receptor blockade and amlodipine improved in vivo left ventricular end-diastolic pressure in association with the normalization of left ventricular ACE mRNA levels.


Key Words: hypertrophy • angiotensin • receptors • stenosis, aortic


*    Introduction
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 up arrowAbstract
 *Introduction
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 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Angiotensin-converting enzyme inhibition has been conclusively shown to improve survival in patients with advanced heart failure1 and to attenuate the progression of LV remodeling in patients with asymptomatic LV dysfunction2 and in patients3 and experimental animals after infarction.4 5 Regression of LVH in response to ACE inhibition has also been observed in experimental animals with long-term pressure overload6 7 8 9 and in humans with hypertension-induced pressure-overload hypertrophy.10 11 Recent studies from our laboratory using rats with ascending aortic stenosis12 13 and by others in experimental animals with postinfarction hypertrophic remodeling14 15 demonstrated the presence of an increase in cardiac ACE message levels and activity resulting in an increased capacity for local cardiac conversion of angiotensin I to angiotensin II.

We16 17 recently showed that long-term ACE inhibition regressed LVH, normalized survival, and improved LV diastolic and systolic function in rats in which a severe persistent elevation of LVSP was maintained by ascending aortic stenosis. Multiple studies18 19 20 21 22 showed that angiotensin II can stimulate myocardial cell hypertrophy as well as growth of the cardiac interstitium. In immature myocardial cells, the induction of hypertrophic growth by passive stretch appears to be mediated by AT1 signaling and can be inhibited by administration of AT1-receptor antagonists.23 24 AT1 receptors are also present in LV myocardium from adult normal and hypertrophied rat hearts.25 26 These observations have led to the speculation that increased cardiac ACE expression and concomitant activation of the AT1 receptor are critical for the maintenance of hypertrophy independent of the reduction of LV load.

Therefore, we speculated that the beneficial effects of long-term ACE inhibition on hypertrophic remodeling, which we have observed in rats with ascending aortic stenosis16 17 and which have been observed in other models of hypertrophy,4 5 6 7 8 9 are related to the specific mechanism of an attenuation of AT1-receptor signaling. In the present study, we tested the hypothesis that long-term treatment with the specific AT1-receptor blocker BMS-186295 would regress hypertrophy and modify LV ACE mRNA levels via a feedback regulation in rats with persistent LVSP overload due to ascending aortic stenosis. The effects of the vasodilator amlodipine were also studied as a positive control for the mild systemic vasodilator effects of AT1-receptor blockade.


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
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Preparation of Animals
Ascending aortic stenosis was created in weanling rats (body weight, 60 to 70 g; age, 3 to 4 weeks) by use of a tantalum clip (Weck, Inc) of 0.58-mm internal diameter placed on the ascending aorta via a thoracic incision.16 17 27 Six weeks after aortic banding, rats with aortic stenosis were randomized to receive either treatment with no drug (LVH group, n=48), the AT1 blocker BMS-186295 (50 mg·kg-1·d-1, n=49), or the calcium channel blocker amlodipine (2.5 mg·kg-1·d-1, n=48) added to the drinking water. The doses of the AT1 blocker and amlodipine were selected from a 2-week pilot dosing trial (n=6 rats per group) to achieve a comparable and sustained mild reduction of systolic tail-cuff pressure of <=10 mm Hg. Furthermore, this dose of AT1 blocker prevented the vasopressor response to 10-6 mol/L angiotensin II infusion (n=3). Sham-operated rats served as age-matched controls (n=39). Drug or no drug treatment continued for 15 weeks, beginning 6 weeks after banding.

Survival and In Vivo Measurements
Animals were monitored daily, and deaths were recorded. Body weights and in vivo blood pressures were measured weekly by the tail-cuff method (Narco Biosystems).16 At the end of the 15-week treatment period, rats from each group were randomly selected for measurements of echocardiographic assessment of LV mass as previously reported in detail by our laboratory.17 28 In vivo LV pressure was measured as previously described by our laboratory.16 27

Perfusion Technique
At the end of the 15-week treatment period (21 weeks after aortic banding), 13 untreated, 15 AT1-blocker–treated, and 9 amlodipine-treated LVH rats and 14 sham-operated control rats were killed, and the isolated hearts underwent hemodynamic evaluation with the use of the isovolumic (balloon–in–left ventricle) buffer-perfused rat heart preparation described in detail elsewhere.12 13 16 17 27 LV filling curves were generated at three different perfusate calcium concentrations (0.6, 1.5, and 3.0 mmol/L) as previously described.16 After hemodynamic evaluation, hearts were rapidly removed from the perfusion apparatus, and the right and left ventricles were dissected and weighed.

Morphological Examination and Tissue Morphometry
Morphological evaluation was performed on perfusion-fixed tissues from six animals from each group: sham, aortic-banded untreated, aortic-banded AT1-blocker–treated, and aortic-banded amlodipine-treated rats. Methods were modified from those previously reported.16 29 Briefly, the hearts were removed from deeply anesthetized animals and retrogradely perfused through the ascending aorta at 80 to 100 mm Hg pressure with the use of gravity flow with saline followed by modified Karnofsky fixative (2% glutaraldehyde and 2% paraformaldehyde in phosphate buffer) for 5 minutes. Horizontal short-axis sections through the mid-left and right ventricles were dehydrated through an ethanol series, embedded in paraffin sectioned at 5-µm thickness, and stained with hematoxylin and eosin, Gomori's aldehyde fuchsin trichrome, and picric acid sirius red F3BA. Additional LV long- and short-axis sections were embedded in glycol methacrylate, sectioned at 1-µm thickness, and stained with silver to stain the glycocalyx and other matrix substances. Quantitative analysis was accomplished by light microscopy with a video-based image-analyzer system. Collagen volume percent was quantitatively evaluated at low power (x1 objective, x30 video-screen magnification) for large focal scars and perivascular collagen and at high power (x10 objective, x300 video-screen magnification) for interstitial collagen. Endocardial and epicardial halves of the LV myocardium were examined by use of the picrosirius red–stained sections and a 540-nm (green) filter to provide contrast of the collagen with the background. Using digitized images collected by the video camera, we determined the volume percent collagen on a single low-power field for the entire cross section of the LV inner and outer halves or for 20 to 30 randomly selected fields at high power in each transmural half, and the mean value was calculated for each animal. Myocyte cross-sectional area was quantitated in the 1-µm methacrylate sections stained with silver by digitizing a minimum of 100 myocyte cross-sectional areas. All myocytes were measured in subendocardial and subepicardial regions judged to be cut normal to the long axis of the cells by the nearly round shape of perfused capillaries in the region. All morphometric measurements were performed in a blinded manner. Results are presented as the mean±SEM values computed from the average of individual measurements obtained from each region of each heart.

Plasma Norepinephrine, Renin Activity, and ACE Activity
Neurohormonal measurements were performed as previously described by our laboratory16 in 9 sham-operated rats and in 7 untreated, 14 AT1-blocker–treated, and 12 amlodipine-treated LVH rats at the end of the 15-week trial period. Plasma norepinephrine was determined by a radioenzymatic assay with the use of the enzyme carbachol-O-methyl transferase.30 Plasma renin activity was measured by a standard radioimmunoassay method modification from Sealy and Laragh.31 ACE activity was measured with a radiometric assay (Ventrex Laboratories) that used radiolabeled [3H]Hip-Gly-Gby, which is converted by ACE to [3H]hippuric acid.32 33

Ribonuclease Protection Assay of ACE mRNA
Total RNA was isolated from frozen LV tissue by the guanidinium/cesium chloride method. LV tissue was analyzed from 8 untreated, 8 AT1-blocker–treated, and 7 amlodipine-treated LVH rats as well as 6 sham-operated rats. Labeled riboprobes were generated using MAXIscript In Vitro Transcription kit (Ambion) and 32P-{alpha}-UTP. Labeled RNA was separated from unincorporated nucleotides by spin chromatography (Chromaspin-100, Clontech). The rat ACE probe was derived from clone pRace622, which after linearization with Ava II yielded a 250-bp fragment. The rat ß-actin probe was derived from clone pSKrBac and yielded a 150-bp fragment after linearization with Xho I. Fifty µg of total RNA was hybridized to 1x105 cpm of ACE cRNA and 1x104 cpm of ß-actin cRNA and then treated with RNase A/RNase T1 according to the protocol for the RPA II kit (Ambion). After RNase inactivation and precipitation of the protected fragments, the samples were separated on a 5% polyacrylamide gel. The gel was exposed to a phosphorimager screen (Molecular Dynamics) overnight, and hybridization signals were quantified with Image Quant software (Molecular Dynamics). ACE mRNA levels were normalized to ß-actin mRNA.

Statistical Analysis
All values are expressed as mean±SEM. Survival during the 15-week trial was analyzed by standard Kaplan-Meier analysis comparing each treatment group with the untreated LVH group by use of the log-rank test and {chi}2 analysis.16 34 Statistical analysis of differences between the sham-operated group and the untreated, AT1-blocker–treated, and amlodipine-treated LVH groups was done by ANOVA comparison or ANOVA for repeated measures where appropriate and Fisher's exact test or Student's t test for post hoc analyses of noncontinuous and continuous variables, respectively. Statistical significance was accepted at the level of P<.05.


*    Results
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 up arrowIntroduction
 up arrowMethods
 *Results
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Blood Pressure, Heart Rate, and Body Weight
Treatment with both the AT1-receptor blocker BMS-186295 and the vasodilator amlodipine resulted in a modest reduction in systolic tail-cuff pressure of {approx}8 mm Hg compared with the untreated LVH rats (Fig 1Down). This effect on arterial blood pressure occurred immediately after initiating treatment and was stable and sustained throughout the treatment period. Heart rates and body weights were similar in the LVH groups that received no treatment, AT1-receptor blockade, and amlodipine and in the sham-operated control group, as shown in Table 1Down.



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  		Figure 1. Tail-cuff blood pressure measurements in rats with aortic stenosis during 15 weeks of treatment with an AT1 blocker (LVH/AT), amlodipine (LVH/Ca), or no drug (LVH). Values are mean±SE.


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  		Table 1. LVH and Right Ventricular Hypertrophy

Plasma Norepinephrine Levels and Renin Activity
As shown in Table 2Down, plasma norepinephrine and epinephrine levels and circulating ACE activity levels were similar in the sham-operated control group and the LVH groups. Plasma renin activity was also similar in the sham-operated control group, the untreated LVH group, and the amlodipine-treated LVH group, which corroborates our previous observation16 that the ascending aortic stenosis model is not characterized by the elevation of circulating plasma renin activity at this stage in its natural history. Consistent with the positive feedback of AT1-receptor blockade on plasma renin activity, a fourfold elevation of plasma renin activity was measured in the LVH group treated with AT1-receptor blockade compared with the untreated LVH group (Table 2Down).


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  		Table 2. Plasma Renin Activity, ACE Activity, and Plasma Norepinephrine Levels

In Vivo Ventricular Function
Measurements of in vivo LVSP are shown in Fig 2Down. In vivo LVSP measured at the end of the 15-week treatment period was 193±8 mm Hg in the untreated LVH rats versus 118±4 mm Hg in the sham-operated control rats (P<.05). LVSP was also markedly elevated in the AT1-blocker–treated LVH group (189±9 mm Hg) and the amlodipine-treated group (188±16 mm Hg) and was similar to the untreated LVH group (P=NS). These data suggest that the magnitude of the severe elevation of LVSP in the ascending aortic–banded rats was not modified by treatment with either the AT1-receptor blocker or amlodipine. In vivo LVEDP was higher in the untreated LVH rats than in the sham-operated control group (14.8±2.3 versus 7.0±0.5 mm Hg; P<.05). In vivo LVEDP was 11.0±1.7 mm Hg in the AT1-blocker–treated rats and 11.5±1.8 mm Hg in the amlodipine-treated LVH rats and did not differ statistically from the sham-operated control group (P=NS).



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  		Figure 2. In vivo LVSPs (top) and LV diastolic pressures (bottom) measured in intact animals at the end of the 15-week treatment period. Sham indicates sham-operated control group; LVH, untreated LVH group; LVH/AT, AT1-blocker–treated LVH group; and LVH/Ca, amlodipine-treated group. Values are mean±SE.

Echocardiographic Measurements
Echocardiographic measurements were obtained in nine untreated, nine AT1-blocker–treated, and seven amlodipine-treated LVH rats and in seven sham-operated control rats that were randomly selected at the conclusion of the trial. The untreated LVH rats exhibited a 40% increase in LV mass compared with sham-operated control rats (1.52±0.12 versus 1.09±0.06 g; P<.05). However, calculated LV mass was similar in the AT1-blocker– and amlodipine-treated LVH rats (1.32±0.08 and 1.41±0.12 g, respectively) and comparable to the untreated LVH group (P=NS).

Effects of AT1-Receptor Blockade on LVH
LV weight was 43% higher (1.70±0.05 versus 1.19±0.04 g; P<.05) and LV weight/body weight was 48% higher (2.70±0.08 versus 1.82±0.06 mg/g; P<.05) in the untreated LVH group than in the sham-operated control group. The present study showed that there was no effect of treatment with either AT1-receptor blockade or amlodipine on the magnitude of hypertrophy in the rats with ascending aortic stenosis (Table 1Up). Right ventricular weight did not differ significantly between any of the groups (Table 1Up).

Morphology and Quantitative Morphometry
Routine light microscopy revealed a subjective slight increase in LV myocardial fibrosis in all LVH groups relative to controls, consisting of multifocal increase in interstitial connective tissue surrounding individual myocytes (Fig 3Down). There was a moderate increase in perivascular collagen but no significant increase in replacement-type fibrosis resulting in large areas of solid scar tissue. Active inflammation was absent; markers of apoptosis were not examined. LV myocyte cross-sectional area was significantly greater in the untreated LVH group than in the sham-operated control group (Fig 4Down; Table 3Down). However, there was no reduction in myocyte cross-sectional area in response to treatment with either AT1-receptor blockade or amlodipine compared with the untreated LVH group (Table 3Down). Quantitative assessment of the volume percent of collagen was performed in both the subendocardial and epicardial regions of the left ventricle. The increase in volume percent collagen found at low power (Table 3Down) was due to an increase in perivascular collagen. The volume percent of interstitial collagen in the subendocardial region in the untreated banded group, the AT1-blocker–treated group, and the amlodipine-treated groups was significantly greater than in the control group, whereas in the subepicardial region, only the amlodipine-treated group had a slight increase in collagen volume percent.



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  		Figure 3. Perfusion-fixed myocardial tissues from the LV subendocardial region of animals from the sham-operated (Sham) (A), LVH untreated (B), LVH AT1-blocker–treated (C), and LVH amlodipine-treated (D) groups. Connective tissue, appearing black, is increased in the interstitial space in multifocal areas of all three aortic stenosis groups (B, C, and D) compared with the sham-operated animals. Picrosirius red stain. Bar in A=100 µm; magnification is the same in all.



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  		Figure 4. Perfusion-fixed subendomyocardial tissue embedded in glycol methacrylate and stained with silver as used for measurement of cross-sectional area. A, Sham-operated control animal; B, animal with untreated aortic stenosis. Myocyte cross-sectional area is greater in the banded animals than in controls, as quantitatively presented in Table 3Up. Bar in A=50 µm; A and B at same magnification.


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  		Table 3. LV Morphometry

Survival
Survival was significantly reduced in the untreated group of rats with ascending aortic stenosis (LVH group) compared with age-matched controls. During the 15-week treatment period, 11 of 48 animals died in the untreated LVH group (23%) compared with none of the age-matched, sham-operated control group (P<.005). The Kaplan-Meier analysis (Fig 5Down) demonstrated no significant improvement in survival in the LVH group randomized to treatment with the AT1-receptor blocker BMS-186295, in which 5 of 49 animals died, compared with the untreated LVH group (P=.11). There was also no improvement in survival in the LVH group randomized to treatment with the vasodilator amlodipine, in which 9 of 48 animals died, compared with the untreated LVH group (P=.70).



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  		Figure 5. Kaplan-Meier survival curves for the group with untreated aortic stenosis (LVH), the AT1-blocker–treated aortic stenosis group (LVH/AT), and the amlodipine-treated aortic stenosis group (LVH/Ca). AT1 blocker, amlodipine, or no drug was administered for 15 weeks beginning week 6 after aortic banding through week 21 after aortic banding.

Isolated Heart Studies: Diastolic Pressure-Volume Relations and Contractile Function
In the isolated perfused hearts, coronary flow rate per gram was similar in the sham-operated control group and the untreated, AT1-blocker–treated, and amlodipine-treated LVH groups (17.9±0.7, 16.9±0.7, 16.6±0.7, and 15.9±0.3 mL·min-1·g-1; P=NS). The relation between LVEDP versus balloon volume is shown in Fig 6Down. The diastolic pressure-volume relation was significantly shifted upward and to the left in the untreated LVH hearts compared with the sham-operated control group (P<.05), indicating a decrease in LV diastolic chamber distensibility. Diastolic distensibility was not improved in the LVH groups treated with AT1-receptor blockade or amlodipine, as shown in Fig 6Down. The dose-response relation between LV systolic developed pressure per gram of left ventricle and perfusate calcium concentrations was examined at identical LV diastolic balloon volumes in the hypertrophied hearts, in which the diastolic pressure-volume relations were similar. Fig 7Down shows that the capacity to increase LV systolic function in response to an increase in perfusate calcium was not improved in the LVH hearts with AT1-receptor blockade or amlodipine compared with the untreated LVH group.



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  		Figure 6. Relation between LVEDP vs balloon volume as an index of LV diastolic chamber distensibility. Sham indicates sham-operated control group; LVH, untreated LVH group; LVH/AT, AT1-blocker–treated LVH group; and LVH/Ca, amlodipine-treated group. Values are mean±SE.



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  		Figure 7. Relation between LV developed pressure per gram (LV DevP/g) vs perfusate calcium concentration (mmol/L) in untreated LVH group (LVH), AT1-blocker–treated group (LVH/AT), and amlodipine-treated group (LVH/Ca) at an identical LV preload (balloon volume of 0.2 mL). Values are mean±SE.

LV ACE mRNA Levels
Steady-state levels of LV ACE mRNA were measured by ribonuclease protection assay and expressed as densitometric units normalized to ß-actin. Despite similar elevation of in vivo LVSP in the three LVH groups, LV ACE mRNA levels were lower in both AT1-blocker–treated and amlodipine-treated LVH hearts (0.026±0.002 and 0.028±0.003 densitometric units) than in untreated LVH hearts (0.041±0.007 U; P<.05) and were similar to levels in the sham-operated control group (0.026±0.003 U). As shown in Fig 8Down, linear regression analysis showed a significant correlation between ACE mRNA levels and in vivo LVEDP (r=.75; P=.0001) and no correlation with LVSP (r=.04; P=NS). There was also no correlation between ACE mRNA levels and LV weight/body weight (r=.29; P=NS).



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  		Figure 8. Linear regression relation between LV ACE mRNA levels and in vivo LVEDP (left) and ACE mRNA levels and LVSP (right) among the aortic-banded rats. {bullet}, No treatment; {circ}, AT1 blocker; and {blacktriangleup}, amlodipine. ACE mRNA levels were highly correlated with LVEDP. There was no correlation with LVSP or left ventricular weight/body weight (not shown).


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
The beneficial effects of long-term ACE inhibition on hypertrophic remodeling have been attributed to the inhibition of cardiac ACE activity and secondary reduction of AT1 activation. Thus, the aim of the present study was to test the hypothesis that long-term AT1-receptor blockade would promote regression of hypertrophy in rats with established hypertrophy and persistent severe elevation of LVSP due to aortic banding. The dose of the specific AT1-receptor blocker BMS-186295 was selected to achieve a small but detectable reduction in systemic arterial tail-cuff pressure that was sustained throughout the 15-week treatment period. This design strategy was successful and served to provide both (1) a marker of biological activity during long-term oral ingestion of the AT1-receptor blocker and (2) a level of severely elevated LVSP that was comparable to that in rats with untreated aortic stenosis. In addition, animals were randomized to therapy with the calcium channel blocker amlodipine to serve as a positive vasodilator control group with mild equihypotensive changes in arterial blood pressure. The present study demonstrates that long-term systemic AT1-receptor blockade, as well as treatment with the vasodilator amlodipine, did not regress hypertrophy in rats with persistent LVH. However, both treatment with the AT1 blocker and treatment with amlodipine improved LVEDP in association with the normalization of LV ACE mRNA levels.

Angiotensin and Hypertrophy in Immature Myocytes
There is substantial evidence that angiotensin II activation of the AT1 receptor is an autocrine-paracrine signaling pathway that facilitates both angiotensin II and stretch-induced myocyte growth in in vivo preparations of immature myocytes.22 23 24 Activation of the AT1 receptor also appears to facilitate normal cardiac growth during development in immature hearts in vivo35 and to promote the initiation and development of angiotensin II–induced hypertrophy in vivo.20 We36 have shown that angiotensin II directly induces protein synthesis in isolated adult perfused rat hearts. Thus, there is a congruence between the biological effects of AT1-receptor activation on the growth response to pressure overload in immature myocardium and the response to direct angiotensin II stimulation from in vivo and in vitro studies.

Angiotensin and Pressure-Overload Hypertrophy
In contrast, it has not been shown that upregulation of cardiac ACE mRNA expression leading to AT1-receptor activation is critical for the initiation and maintenance of pressure-overload hypertrophy in the adult heart in vivo. Kojima et al24 showed that treatment with an angiotensin II–receptor antagonist prevented the progression of LVH in spontaneously hypertensive rats; however, in that study, treatment with an AT1-receptor antagonist also promoted a decrease in blood pressure. AT1-receptor blockade prevented the development of hypertrophy in rats with abdominal aortic constriction.37 Both ACE inhibition and AT1-receptor blockade have been reported to attenuate hypertrophic remodeling in the rat after large infarcts.38 39 However, speculations regarding any direct effects of AT1-receptor blockade on cardiac growth in these studies were confounded by a large reduction in LVSP37 or arterial blood pressure38 39 in treated animals compared with untreated animals. Similarly, Bruckschlegel et al40 reported that both ACE inhibition and AT1-receptor blockade interfered with the early development of LVH in ascending aortic–banded rats; however, drugs were used at high doses that promoted reductions in systolic arterial pressure sufficient to reduce the pressure gradient across the aortic band. Thus, although occasional studies failed to observe regression of hypertrophy,41 the majority of published studies observed the regression of pressure-overload hypertrophy if systolic loading conditions were modified by either AT1-receptor blockade or ACE inhibition.

Our finding of a failure of systemic AT1 blockade to regress LVH when LVSP remains severely elevated is consistent with recent observations from several laboratories that used different species and adult models of hypertrophic remodeling. Spinale et al42 43 failed to observe an effect of AT1-receptor blockade on cardiac dilatation and function in pacing-induced heart failure. McDonald et al44 examined the relative effects of ACE inhibition and AT1-receptor blockade on hypertrophic remodeling in the dog after transmyocardial DC shock injury. Both zofenopril and ramipril caused a reduction in arterial pressure and attenuated the increase in LV mass and later dilatation; in contrast, the AT1-receptor blocker DuP 532 did not lower arterial pressure and failed to attenuate hypertrophic remodeling.44 In aortocaval-induced cardiac hypertrophy in rats,45 46 both ACE inhibition and AT1-receptor blockade with losartan partially regressed LVH in parallel with changes in LVSP and LV diastolic pressure, suggesting that complex changes in systolic and diastolic load rather than AT1-receptor activation contribute to the maintenance of LVH in this model.

Limitations: Efficacy of AT1-Receptor Blockade
A limitation of the present study is that AT1-receptor blockade and ACE inhibition were not compared directly. It also remains unanswered whether BMS-186295 has the potential to affect hypertrophic remodeling or survival in other animal models or when given at higher doses or for a longer treatment period. This study was designed to achieve systemic AT1-receptor blockade sufficient to cause mild systemic arterial vasodilation. The level of AT1-receptor blockade at the level of the myocyte was not addressed in this or other published trials of long-term in vivo AT1-blocker therapy. A potential limitation of the present study is that AT1-receptor blocking effects may have been attenuated or insufficient during sustained long-term therapy. Arguing against this hypothesis is the observation that the physiological action of mild systemic vasodilation was observed immediately after initiation of therapy and sustained at this level throughout the 15-week treatment period. In addition, there was a robust, fourfold elevation of plasma renin activity in the AT1-blocker group, consistent with the expected feedback upregulation of the renin-angiotensin system in response to AT1-receptor blockade.47 48 These observations provide strong support that a high level of systemic AT1-receptor blockade was achieved in the present study. Alterations in norepinephrine levels must also be considered as an alternate growth-stimulating pathway.18 49 In the present study, there were no differences in norepinephrine levels among the groups.

AT1 Blockade and LV ACE Expression
Recent studies40 47 48 50 showed that long-term treatment with AT1-receptor blockers increases plasma renin activity, which is postulated to cause negative feedback on the gene expression of tissue ACE. In this regard, Schieffer et al39 recently reported that long-term AT1-receptor–blocker therapy in rats after infarction was associated with feedback downregulation of cardiac tissue ACE. Thus, at the tissue level, effects of AT1-receptor blockade may be mediated in part by the reduction of cardiac tissue ACE activity rather than direct interference with AT1-receptor–mediated signaling. A limitation of prior studies is that effects of changes in in vivo loading conditions versus plasma renin activity feedback regulation of ACE expression were not distinguished.

In the present study, we observed that LV ACE mRNA levels were elevated in untreated aortic-banded rats compared with sham-operated controls. Although we did not measure ACE activity, we12 13 have previously shown that LV ACE mRNA levels are elevated in this model and are associated with an increase in enzyme levels, tissue ACE activity, and the capacity for intracardiac conversion of angiotensin I to II. A striking and unexpected observation of the present study was that treatment with AT1 blockade as well as treatment with the vasodilator amlodipine completely normalized LV ACE mRNA levels to those of sham-operated controls. This effect is unlikely to be related to feedback regulation by plasma renin activity because plasma renin activity was increased in the AT1-blocker group and was normal in the amlodipine-treated group. Whereas LVSP was severely elevated to a similar magnitude in the three LVH groups, LVEDP was lower in the AT1-blocker–treated and amlodipine-treated aortic-banded rats compared with the untreated LVH rats and was similar to that in the sham controls. It is likely that this was related to mild systemic venodilation with both drugs because no improvement was observed in LV diastolic distensibility in vitro. In the present study, ACE mRNA levels were highly correlated with in vivo LVEDP and not with the extent of hypertrophy or LVSP.

Taken together, these findings demonstrate that LV ACE expression can be dissociated from the magnitude of hypertrophic remodeling and that an increased cardiac ACE expression is not critical for the maintenance of chronic pressure-overload LVH. Second, these data give rise to the speculation that factors related to passive diastolic fiber stretch, rather than the development of elevated systolic pressure during fiber shortening, may modulate the expression of cardiac ACE in vivo as well as in myocytes subjected to passive artificial stretch.23 24

Implications for Therapy
Thus, these lines of evidence suggest that both ACE inhibitors and AT1-receptor blockers have the potential to modify hypertrophic remodeling in the adult heart in association with the reduction of systolic pressure overload. However, systemic AT1-receptor blockade fails to regress hypertrophy when LVSP is severely elevated and comparable to rats with untreated aortic stenosis. The magnitude of LVH relative to age-matched controls was identical to our previous study,16 17 which showed that the ACE inhibitor fosinopril regressed hypertrophy despite persistent elevation of LVSP. These observations suggest that biological actions of ACE inhibitors distinct from the secondary attenuation of AT1-receptor activation merit investigation as pharmacological strategies to modify hypertrophy in the adult heart. ACE inhibitors also inhibit the degradation of bradykinin and other kinins, whose signaling is mediated in part by nitric oxide production,51 which has the potential to modify hypertrophy by abbreviation of the time course and generation of systolic wall stress.52 In addition, Linz and Scholkens53 showed that AT1-receptor blockade was less effective than ACE inhibition in preventing the development of hypertrophy of the aortic-banded rat, whereas a specific ß2-kinin receptor antagonist eliminated the effects of ACE inhibition. This finding is consistent with recent observations that kinins and nitric oxide may suppress cell growth.54 55

In summary, the results of the present study indicate that long-term treatment with AT1-receptor blockade, as well as amlodipine, in rats with persistent severe LVSP overload is not effective in regressing hypertrophy. However, both AT1-receptor blockade and amlodipine treatment normalized LV ACE message levels, correlating with an improvement in LVEDP. Thus, an increase in cardiac ACE expression with secondary AT1-receptor activation is not mandatory for the maintenance of long-term pressure-overload hypertrophy.


*    Selected Abbreviations and Acronyms
 
AT1 = angiotensin II receptor subtype 1
LV = left ventricular
LVEDP = left ventricular end-diastolic pressure
LVH = left ventricular hypertrophy
LVSP = left ventricular systolic pressure


*    Acknowledgments
 
This study was supported in part by NHLBI grant HL-5286401 (Dr Lorell, Dr Weinberg, Dr Lindpaintner, and Dr Douglas), a Pfizer Clinical Investigator Fellowship (Dr Ho), and an educational grant from Bristol-Myers Squibb. The study drug amlodipine was provided by Pfizer Central Research Division. We acknowledge the important contribution of the following investigators to this multidisciplinary study: Soeun Ngoy was responsible for the surgical preparation of the study animals; Farid Fuleihan, MD, was responsible for dosing of the animals; Dorinda George performed the serial tail-cuff blood pressure measurements; Richard Kuntz, MD, assisted Dr Ho with design of the survival trial and performed the actuarial analysis of the survival data.


*    Footnotes
 
Reprint requests to Beverly H. Lorell, MD, Cardiovascular Division, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215.

Guest editor for this article was Suzanne Oparil, MD, The University of Alabama at Birmingham.

Received June 24, 1996; revision received November 14, 1996; accepted November 14, 1996.


*    References
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