Relevance of Blockade of Cardiac and Circulatory Angiotensin-Converting Enzyme for the Prevention of Volume Overload–Induced Cardiac Hypertrophy
Background Angiotensin-converting enzyme (ACE) inhibitors show major differences in their affinity for cardiac and other tissue ACEs, and their effects on tissue ACE range from minimal to nearly complete blockade. Angiotensin II taken up from the circulation or generated in the heart may mediate the cardiac hypertrophic response to increased cardiac load. Thus, differences between the ACE inhibitors regarding their effects on cardiac ACE may determine their effects on prevention or regression of cardiac hypertrophy.
Methods and Results In the present study, we assessed the effects of ACE inhibitors with low (enalapril) and high (quinapril) affinity for cardiac tissue ACE on prevention of volume overload–induced cardiac hypertrophy in relation to their hemodynamic effects. Both blockers were equipotent for circulatory ACE as assessed from the pressure response curve to angiotensin I. Both blockers partially (and similarly) prevented the increase in left ventricular end-diastolic pressure by aortocaval shunt. However, only quinapril prevented or attenuated the development of right ventricular hypertrophy and left ventricular hypertrophy and dilation.
Conclusions The present findings further stress the involvement of the renin-angiotensin system as a trophic stimulus in the development of cardiac hypertrophy in this model. Moreover, the low affinity of enalapril for cardiac ACE appears to lead to continuous angiotensin II generation in the heart and can thus explain the failure of enalapril to attenuate hypertrophic response of the heart induced by shunt despite decreasing cardiac volume overload.
Angiotensin II may contribute to the development and maintenance of cardiac hypertrophy via its hemodynamic effects as well as trophic effects on cardiomyocytes.1 2 3 4 5 6 In addition to uptake of angiotensin II from the circulation, angiotensin II can be generated in the heart.7 Thus, inhibition of tissue angiotensin-converting enzyme (ACE) may contribute to the beneficial effects of ACE inhibitors on the prevention/regression of cardiac hypertrophy in different models of cardiac volume/pressure overload.3 4 5 Although blockade of the plasma ACE by different ACE inhibitors differs mostly in its duration,8 ACE inhibitors show major differences in their affinity for different tissue ACEs, and their effects on tissue ACE range from minimal to nearly complete blockade.8 9 In doses equipotent for plasma ACE (as assessed from the decrease in plasma ACE activity), enalapril shows only minimal (20% decrease in ACE activity) and short (lasting for approximately 1 hour) inhibition of cardiac ACE compared with modest inhibition of cardiac ACE (by approximately 40% to 60%) after lisinopril and fosinopril lasting for approximately 8 hours and to nearly complete blockade of the cardiac activity persisting for 24 to 48 hours after zofenopril or captopril.8 A similar inhibition (by approximately 90%) of plasma ACE at 5 hours after a single (oral) dose of enalapril and quinapril was accompanied by a minimal (approximately 10% decrease) effect of enalapril on cardiac ACE but marked inhibition (62%) of cardiac ACE by quinapril.9 These large differences in the affinity for different target tissue ACEs between ACE inhibitors may affect the outcome of treatment of different cardiovascular diseases.
Cardiac hypertrophy induced by volume overload after aortocaval shunt can be prevented by the angiotensin II receptor blocker losartan.10 This effect appears to be only in part related to the decrease in cardiac preload and afterload by losartan, since the ACE inhibitor enalapril showed similar hemodynamic effects but failed to prevent cardiac hypertrophy.10 These data suggested that an activated circulatory and/or cardiac renin-angiotensin system (RAS) (as assessed from increases in plasma and cardiac renin activity10 ) indeed contributes to the remodeling of the heart.10 The failure of enalapril might be explained by its low affinity for cardiac tissue ACE, resulting in continuous generation of angiotensin II in the heart and stimulation of growth of cardiomyocytes.
In the present study, we assessed the effects of doses equipotent for circulatory ACE (as assessed from the pressure-response curve to angiotensin I) of ACE inhibitors with low (enalapril) and high (quinapril) affinity for cardiac tissue ACE on prevention of volume overload–induced cardiac hypertrophy in relation to their hemodynamic effects.
Animals and Treatment
Male Wistar rats weighing 200 to 225 g were obtained from Charles River Breeding Laboratories. Rats were housed two per cage, given food and water ad libitum, and kept on a 12-hour light-dark cycle. After an acclimatization period of at least 3 days, they were randomized into six groups: control, control plus enalapril, control plus quinapril, shunt, shunt plus enalapril, and shunt plus quinapril. Treatment with enalapril (250 mg/L in drinking water4 6 10 ) and quinapril (200 mg/L in drinking water11 ) started 3 days before the shunt/sham surgery and continued for 1 week. Aortocaval shunt was induced by an 18-gauge needle as described by Garcia and Diebold.12 Control (treated and untreated) animals were subjected to similar surgical procedure with the exception of puncturing the big vessels. One week after the shunt/sham surgery, central hemodynamics and cardiac anatomy were assessed.
On the day of the study, rats were anesthetized with halothane–nitrous oxide–oxygen, and a PE-50 catheter (Clay Adams) filled with heparinized saline (100 U/mL) was inserted into the left ventricle (LV) via the right common carotid artery and into the right external jugular vein. Catheters were exteriorized on the neck of animals. After a 4-hour recovery period from anesthesia, LV end-diastolic pressure (LVEDP) and LV peak systolic pressure (LVPSP) were assessed in conscious, unrestrained rats after a 30-minute acclimatization period as previously described.13 Heart rate was calculated from the curves of LVPSP and LVEDP recorded at a paper speed of 10 mm/s.
Dose-Response Curve to Angiotensin I
The degree of blockade of plasma and endothelial ACE (in treated compared with untreated control rats) was assessed from the increase in LVPSP in response to angiotensin I (0.01, 0.1, 0.5, 1.0, 5.0, and 10.0 ng/kg body wt per minute IV) immediately after resting hemodynamics were recorded.
At the end of the experiment with animals under pentobarbital anesthesia, the chest cavity was opened and the heart was arrested in diastole by intravenous injection of 1 mol/L KCl, rapidly excised, and placed into ice-cold saline to remain in diastole and to remove the blood. After removal of the atria and great vessels, the ventricles were blotted dry, and the right ventricle (RV) was dissected along its septal insertion from the remainder of the ventricular mass. Subsequently, LV and RV weights were assessed separately. The mass of the LV was then divided by two transverse cuts at one third and two thirds of the length. The middle slice of the LV was used for assessment of the LV wall thickness and internal diameters as previously described by Tsoporis et al.14
Results are expressed as mean±SEM. Differences between groups at a given treatment period were evaluated by ANOVA and Duncan’s multiple-range test. Differences were considered statistically significant if P<.05.
Aortocaval shunt significantly decreased LVPSP compared with control rats (Table⇓). Enalapril and quinapril similarly decreased LVPSP by approximately 10 mm Hg in control rats and had no effects on LVPSP in rats with aortocaval shunt (Table⇓).
Aortocaval shunt significantly increased LVEDP compared with control rats (Table⇑). Enalapril and quinapril did not affect LVEDP in control rats (Table⇑). In contrast, enalapril and quinapril decreased LVEDP in rats with aortocaval shunt by approximately 50% (Table⇑). LVEDP still remained significantly higher in rats receiving either treatment compared with control rats (Table⇑). There were no differences in heart rate between the groups.
Dose-Response Curve to Angiotensin I
Blockade of circulatory ACE by enalapril and quinapril was assessed from the responses of LVPSP to angiotensin I in control treated and untreated rats. As clearly shown in Fig 1⇓, approximately 10-fold higher doses of angiotensin I were required in rats treated with enalapril or quinapril compared with untreated animals. This indicates a similar blockade of the plasma and/or endothelial ACE by enalapril and quinapril.
LV weight increased after 1 week of an aortocaval shunt by 28% compared with control rats (Fig 2⇓). Enalapril and quinapril did not significantly affect LV weight in control rats (Fig 2⇓). In rats that received shunts and enalapril, LV hypertrophy developed similar to that in untreated rats (Fig 2⇓). In contrast, quinapril significantly attenuated the development of LV hypertrophy compared with untreated rats that received shunts (Fig 2⇓).
Aortocaval shunt increased RV weight by 44% compared with control rats (Fig 2⇑). Neither blocker affected RV weight in control rats (Fig 2⇑). Enalapril did not prevent the development of RV hypertrophy in rats that received shunts, and an increase in RV weight by 42% was present in rats with aortocaval shunt receiving enalapril compared with control rats receiving enalapril (Fig 2⇑). In contrast, quinapril nearly completely prevented RV hypertrophy in rats that received shunts compared with (treated and untreated) controls (Fig 2⇑).
LV internal diameter increased by 14% after 1 week of volume overload by an aortocaval shunt (Table⇑). Enalapril and quinapril did not affect LV internal diameter in control rats (Table⇑). In rats that received shunts, enalapril failed to prevent the increase in LV internal diameter, whereas quinapril attenuated LV dilation by approximately 50%.
Aortocaval shunt caused only a small increase in LV wall thickness (Table⇑). Enalapril and quinapril did not affect LV wall thickness in control rats (Table⇑). Quinapril significantly attenuated the increase in LV wall thickness in rats that received shunts compared with enalapril (Table⇑).
Body weights did not differ significantly between the groups at the end of the experiment (control, 292±8 g; control plus enalapril, 295±7 g; control plus quinapril, 289±6 g; shunt, 288±7 g; shunt plus enalapril, 291±5 g; and shunt plus quinapril, 295±7 g).
This study has the following major findings. (1) The ACE inhibitor quinapril decreases LVEDP and prevents or attenuates the development of RV hypertrophy and LV hypertrophy and dilation caused by aortocaval shunt. (2) In contrast, enalapril with similar effects on LVEDP fails to prevent remodeling of the heart in response to cardiac volume overload by an aortocaval shunt. These results suggest that the failure of enalapril to prevent or attenuate cardiac hypertrophy in response to volume overload by an aortocaval shunt is related to its low affinity for cardiac tissue ACE.
Effects of an Aortocaval Shunt on Central Hemodynamics and Cardiac Anatomy
As shown previously, the opening of an aortocaval shunt results in cardiac volume overload as reflected by the increase in LVEDP.10 15 16 LVPSP significantly decreases,10 16 likely as the result of a major decrease in total peripheral resistance.10 15 16 RV and LV hypertrophy and dilation develop over a period of approximately 4 weeks, but most of the response is present at 1 week after the shunt.10 15
Effects of Enalapril and Quinapril on Changes in Central Hemodynamics Induced by an Aortocaval Shunt
The doses of enalapril and quinapril used in this study have been shown to nearly completely inhibit plasma ACE activity8 9 and to normalize blood pressure in spontaneously hypertensive or two-kidney, one clip hypertensive rats.6 11 In the present study, dose-response curves to angiotensin I clearly indicate a similar degree of blockade of the plasma and/or endothelial ACE in enalapril- versus quinapril-treated rats. In addition, there are no major differences regarding the affinity of the two blockers for renal ACE.8 9 Enalapril and quinapril blunted the increase in LVEDP by shunt to similar extents. In addition to venodilation17 and improved ventricular relaxation by the two blockers,18 natriuresis and the reduction of the volume expansion caused by a shunt19 could contribute to the attenuation of the increase in LVEDP. Because enalapril has only minimal effects on stroke volume, heart rate, and blood pressure in rats that received shunts,10 improvement in LV diastolic function by enalapril likely contributes to the attenuation of the increase in LVEDP. Whether quinapril causes a similar improvement cannot be answered from our data. The absence of a decrease in LVPSP by the two ACE inhibitors at 1 week after the aortocaval shunt in the present study is consistent with previous studies showing that angiotensin II only plays a role in the maintenance of blood pressure and total peripheral resistance shortly after induction of an aortocaval shunt.20 Overall, there were no differences in hemodynamic effects between the two ACE inhibitors.
Effects of Enalapril and Quinapril on Changes in Cardiac Anatomy Induced by an Aortocaval Shunt in Relation to Their Hemodynamic Effects
In agreement with our previous results,10 in the present study enalapril failed to prevent or attenuate the RV and LV hypertrophy and dilation despite decreasing LVEDP. The ACE inhibitor quinapril, however, significantly attenuated the LV hypertrophy and dilation and nearly completely prevented RV hypertrophy while decreasing LVEDP similarly to enalapril.
In rats that received shunts, the degree of volume overload determines the extent of the cardiac hypertrophic response.10 21 Consistent with the findings of Sadoshima et al1 2 showing that angiotensin II mediates the hypertrophic response of the cardiomyocyte to stretch in vitro, our previous results suggested that RAS acts as a direct trophic stimulus during the development of cardiac hypertrophy in this model.10 First, the plasma and cardiac RAS is activated (as indicated by increases in plasma and RV and LV renin activity) during the development of cardiac hypertrophy after aortocaval shunt.10 Second, a similar attenuation of the increase in LVEDP by enalapril and losartan resulted in blunted hypertrophic response in losartan-treated rats only.10 Third, expanding our previous findings, the results of the present study point to the low affinity for cardiac ACE of enalapril as the explanation for its failure to prevent cardiac remodeling in response to volume overload by an aortocaval shunt. At the same time, these results make the presence in the volume overloaded rat heart of an angiotensin II–forming enzyme resistant to ACE inhibitors unlikely. However, assessment of the effects of enalapril versus quinapril on cardiac angiotensin II and/or ACE activity in this model is necessary for definite conclusions.
This study clearly shows that similar blockade of the plasma and/or endothelial ACE by different ACE inhibitors is relevant for their hemodynamic effects. However, differences in their affinity for cardiac tissue ACE may determine their effect on prevention of cardiac hypertrophy, when the cardiac RAS acts as a trophic factor.
This study was supported by operating grants from the Heart and Stroke Foundation of Ontario and Warner-Lambert Co, Canada. Dr Ruzicka was supported by a research fellowship from the Heart and Stroke Foundation of Canada. Dr Leenen was supported by a career investigatorship from the Heart and Stroke Foundation of Ontario. Enalapril maleate was a generous gift from Merck Sharp & Dohme, Kirkland, Quebec. Quinapril hydrochloride was a generous gift from Parke-Davis, division of Warner-Lambert Co, Ann Arbor, MI.
- Received August 30, 1994.
- Accepted October 30, 1994.
- Copyright © 1995 by American Heart Association
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