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(Hypertension. 1995;25:437-442.)
© 1995 American Heart Association, Inc.

Articles

Cardiovascular Changes by Long-term Inhibition of the Renin-Angiotensin System in Aging

Felipe Inserra; Luis Romano; Liliana Ercole; Elena M.V. de Cavanagh; León Ferder

From the Institute of Nephrology, Jewish Hospital, Buenos Aires, Argentina.

	Abstract

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Abstract We studied four groups of 20 female mice to evaluate the long-term effect of an angiotensin-converting enzyme on myocardium and vessels during the natural process of aging. Three groups received enalapril in water from weaning to 24 months of age (group A, 20 mg/L; group B, 10 mg/L; group C, 5 mg/L); group D served as a control. Animals surviving after 24 months were killed, and morphometric studies were performed. Total corporal weight was higher in animals receiving enalapril. Cardiac weight relative to total body weight was lower in the treated groups than in the control group. Cardiac morphometric studies showed lower myocardiosclerosis in animals receiving angiotensin-converting enzyme inhibitor (groups A through D, respectively, 0.9±0.6%, 1.1±0.2%, 1.03±0.1%, and 9.5±4.3%; P<.01, groups A, B, and C versus D). The number of mitochondria per myocardiocyte was higher in the groups receiving enalapril (A through D, respectively, 85±7, 85±6, 83±8, and 58±8; P<.01, groups A, B, and C versus D). At the vascular level, vessel diameters were not significantly different between the groups receiving angiotensin-converting enzyme inhibitor and the control group, whereas differences were seen in arterial tunica media thickness (wall-lumen ratio) (groups A through D, respectively, aorta: 0.13±0.02, 0.11±0.02, 0.12±0.01, 2.81±0.35; intrapulmonary: 0.9±0.43, 0.6±0.41, 0.8±0.46, 1.9±0.51; intracerebral: 2.18±0.46, 2.29±0.45, 2.46±0.43, 3.30±0.41; intrarenal: 2.28±0.46, 2.73±0.48, 2.70±0.51, 3.23±0.41; intracariaciac: 2.27±0.44, 2.59±0.41, 2.80±0.43, 3.68±0.47; P<.001, groups A, B, and C versus D). No significant differences in blood pressure were found among the groups. We conclude that cardiovascular changes in aging may be altered by angiotensin-converting enzyme inhibitors.

Key Words: aging • heart • sclerosis • blood vessels • angiotensin-converting enzyme inhibitors • renin- angiotensin system

	Introduction

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Among the phenomena that characterize aging are myocardiosclerosis and changes in the vasculature,¹ which may be accelerated by high arterial blood pressure.^{2 3} Data also indicate that myocardiosclerosis occurs when left ventricular hypertrophy develops after the size of the ventricle increases.⁴ Angiotensin-converting enzyme (ACE) inhibition prevents or reverses left ventricular hypertrophy⁵ and myocardial sclerosis in animals and humans⁶ as well as a variety of other conditions.^{4 7} Furthermore, recent animal experiments have shown that ACE inhibition reduces the incidence of arrhythmia and myocardial contractile dysfunction caused by ischemia and reperfusion.^{8 9} Likewise, in acute myocardial infarction, ACE inhibition reduces mortality and postischemic myocardial dysfunction.¹⁰ Finally, angiotensin II (Ang II) can alter vascular structure (muscular hypertrophy and arteriosclerosis) either by a hemodynamic effect and/or as a growth factor,¹¹ acting through muscle protein synthesis stimulation.¹²

It is known that renin-angiotensin inhibition prevents vascular hypertrophy in a variety of experimental models.^{13 14} Recently, we found that long-term (from the time of weaning) inhibition of Ang II production with enalapril in aging mice leads to a decrease in heart weight, myocardiosclerosis, and glomerular sclerosis compared with control mice. In addition, the number of mitochondria in myocardiocytes and hepatocytes was greater in mice receiving enalapril, and they had a significantly lower mortality.¹⁵ In the face of these findings, we decided to further evaluate the effects of ACE inhibition on the histology and morphology of the heart and vasculature in the same mouse model of aging.

	Methods

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We used 80 CFI female mice (obtained from the Centro de Investigaciones Médicas Albert Einstein, Buenos Aires, Argentina). Three experimental groups (n=20 each) received enalapril maleate in their drinking water immediately after weaning (between 15 and 20 days of age): group A received 20 mg/L; group B, 10 mg/L; and group C, 5 mg/L. Group D (n=20) acted as control.

At 15 to 20 days of age, cardiovascular development is morphologically complete. In 80% of the animals, the foramen ovale was anatomically and functionally closed, and the ductus arteriosus was collapsed, which allowed good hemodynamic function.

Animals were observed until the age of 24 months. Those surviving were killed with pentobarbital (4 mg/kg IP). The day before death, blood pressure was measured by tail plethysmography and recorded with an IITC model 20 amplifier (Life Science Laboratory). Peripheral blood was drawn by puncture of the abdominal aorta to obtain serum sodium and potassium levels, which were determined by flame photometry. After blood sampling, the thoracic aorta was catheterized. Normal saline solution was perfused followed by Bouin's solution to distend and fix vascular structures. Total body, hepatic, and cardiac weights were measured, and ratios were established between hepatic and cardiac weights and total body weight. Only animals surviving more than 18 months were used for the morphometric analysis and histological studies (group A, n=17; group B, n=16; group C, n=17; group D, n=9) because from this age on, they could be considered old adults; in this way, homogeneous results could be maintained.

Cardiac, lung, hepatic, renal, and cerebral tissues were fixed in 10% formalin. Renal tissue was additionally fixed in Bouin's solution over 3 hours. Tissue samples were placed in Histoplast, and histological sections were stained with hematoxylin-eosin and Masson's trichrome.

Myocardial fragments were fixed in 2% glutaraldehyde and embedded in epoxy resin (Epon 812); an ultramicrotome (LKB) was used for tissue cuts, which were stained with uranyl acetate and lead citrate for electron microscopy (Zeiss M109).

Morphometric analyses were carried out in aorta, coronary, renal, pulmonary, and cerebral arteries; these analyses included vessel diameter and the portion of that diameter occupied by tunica media in the aorta or by muscle tissue in the coronary, renal, cerebral, and pulmonary arteries. Twenty histological sections of each organ were made, and 10 vascular structures per histological section were analyzed using the Wagervood method,¹⁶ according to the formula %MT=TAD, where MT is the medial tunica and TAD the total arterial diameter.

The percentage of myocardiosclerosis was determined with a 100-point Zeiss ocular integrator plate II.¹⁷

Mitochondrial counts in cardiac muscle cells were performed according to the method of Tashiro et al.¹⁸ Eight electron photomicrographs of cell cross sections were taken and magnified x5000. Each photomicrograph was printed on paper and magnified x2.5, for a total magnification of x12 500. Total area measured varied from 1244 to 2074 µm². A sheet of transparent acetate and a grid (similar to the ocular integrator used in optical microscopy) were placed over each photograph.

Results were statistically analyzed by ANOVA and Scheffé's test of contrast.

	Results

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Table 1 summarizes body, cardiac, and hepatic weights in the four groups. Body weights in the treated groups were significantly higher than the mean body weight in the control group D (P<.01, A, B, and C versus D; Table 1). Cardiac weights did not differ among the groups, but the hepatic weights of the mice in groups A, B, and C were significantly greater than those in group D (P<.01, A, B, and C versus D; Table 1). When cardiac weight as a percentage of body weight was evaluated, the ratio was lower in groups A, B, and C versus D (P<.01). However, hepatic weight as a percentage of body weight was not significantly higher in the treated groups compared with the control group.

View this table: [in this window] [in a new window]   Table 1. Body, Cardiac, and Hepatic Weights and Ratios

Serum potassium levels were significantly higher in groups A, B, and C compared with group D, but there was no difference noted in serum sodium (Table 2).

View this table: [in this window] [in a new window]   Table 2. Blood Pressure and Serum Potassium and Sodium

Light microscopy showed significant differences in the myocardium. In control animals, an increase in intrafibrillar fibroconnective tissue was found (Fig 1). By contrast, in treated animals, no significant sclerosis was observed (Fig 2). Morphometrically, significant myocardiosclerosis was found in the treated groups compared with the control group (Fig 3) (groups A through D, respectively, 0.9±0.6%, 1.1±0.2%, 1.03±0.1%, and 9.5±4.3%; P<.001, groups A, B, and C versus D). Electron microscopy showed differences in the number of mitochondria in myocardiocytes in the treated groups versus control animals (Fig 3) (groups A through D, respectively, 85±7, 85±6, 83±8, and 58±8; P<.01, groups A, B, and C versus D).

View larger version (178K): [in this window] [in a new window]   Figure 1. Photomicrograph shows myocardium of control mouse with sclerosis (asterisk) and fibrillar hypertrophy (Masson's trichrome, original magnification, x70).

View larger version (166K): [in this window] [in a new window]   Figure 2. Photomicrograph shows myocardium of enalapril-treated mouse without sclerosis (Masson's trichrome, original magnification x70).

View larger version (31K): [in this window] [in a new window]   Figure 3. Bar graphs show percentage of myocardiosclerosis and number of mitochondria. EM indicates enalapril maleate. *P<.001, **P<.01, groups A, B, and C vs D.

As shown in Table 3, no differences were found in the diameter of studied vessels (aorta, intrapulmonary, intracerebral, intrarenal, and intramyocardial).

View this table: [in this window] [in a new window]   Table 3. Diameters of Medium Layers of Aorta, Intrarenal, Intramyocardic, Intracerebral, and Intrapulmonary Vessels

There was significantly less muscle in all of the vessels examined in the treated animals compared with the control animals (Fig 4). The percentage of tunica media in the aorta in groups A through D, respectively, was 0.13±0.02, 0.11±0.02, 0.12±0.01, and 2.81±0.35; the percentage of muscular layer in intrapulmonary arteries was 0.9±0.43, 0.6±0.41, 0.8±0.46, and 1.9±0.51 (Fig 5); the percentage of muscular layer in intracerebral vessels was 2.18±0.46, 2.29±0.45, 2.46±0.43, and 3.30±0.41; the percentage of muscular layer in intrarenal vessels was 2.28±0.46, 2.73±0.48, 2.70±0.51, and 3.23±0.41; and the percentage of muscular layer in intramyocardial vessels was 2.27±0.44, 2.59±0.41, 2.80±0.43, and 3.68±0.47 (Fig 6).

View larger version (126K): [in this window] [in a new window]   Figure 4. Top, Photomicrographs show aorta of control mouse with increased muscular tunica (left) and aorta of enalapril-treated mouse with normal muscular tunica (right). Bottom, Photomicrographs show pulmonary artery of control mouse (arrow) with increased muscular tunica (left) and pulmonary artery of enalapril-treated mouse with normal muscular tunica (right). (Hematoxylin and eosin, original magnification x70.)

View larger version (22K): [in this window] [in a new window]   Figure 5. Bar graphs show percentage of muscular layer of the aorta and intrapulmonary vessels. EM indicates enalapril maleate. *P<.001, groups A, B, and C vs D.

View larger version (30K): [in this window] [in a new window]   Figure 6. Bar graphs show percentage of muscular layer of intramyocardium and intracerebral and intrarenal vessels. EM indicates enalapril maleate. *P<.001, groups A, B, and C vs D.

For all tunica media or muscular layer values, the difference in percentages related to the wall-lumen ratio between groups A, B, and C versus D was significant (P<.001), whereas differences among the treated groups A, B, and C were not significant.

	Discussion

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Following development and differentiation, long-term inhibition of the renin-angiotensin system for life in mice can alter the changes normally seen in both the heart and blood vessels during the aging process. Long-term inhibition of the renin-angiotensin system was confirmed in the present studies by the change in the serum potassium-sodium ratio in the enalapril-treated mice (Table 1) and by the effect of ACE inhibition on the juxtaglomerular apparatus, as we previously demonstrated in the same model.¹⁹

Several reports have demonstrated an effect of Ang II on the vascular wall. In cell cultures, smooth muscle cells of vessels hypertrophy when exposed to Ang II.^{20 21} In animal models, inhibition of the renin-angiotensin-aldosterone system protects against the structural changes in the vasculature caused by high blood pressure.²² Moreover, there is evidence that this protection is independent of the effects of ACE inhibition on blood pressure because the effects do not correlate with pressure changes and are similar in both normal and hypertensive animals.¹³ Likewise, Kakinuma et al¹⁴ found that ACE inhibitors modify the vascular changes seen during experimental chronic renal failure, which was also independent of blood pressure. These authors suggested that bradykinin might play a role.²³

In the present study, the control mice developed cardiovascular pathological changes that are seen as part of the normal aging process. Those mice receiving the ACE inhibitor enalapril at various doses had significantly fewer changes in all the vessels studied (aorta, renal, cardiac, cerebral, and pulmonary arteries) primarily because of a decrease in the age-related increase in arterial smooth muscle tissue. Since the vessel diameter was similar in the groups receiving enalapril compared with the control mice, the wall-diameter ratio of the vessels was lower in the ACE-inhibited mice. Of special interest is the fact that the findings also were noted in the pulmonary arteries, which supports the concept that the vascular effects of aging are independent of blood pressure per se, strongly suggesting an action of ACE inhibitors independent of their effects on blood pressure. This suggestion is strengthened by the lack of any difference in blood pressure between the treated and control mice. The low enalapril dose used and the fact that the mice were not hypertensive explain the lack of blood pressure variation in the treated compared with the control mice.

There is no dose-response effect. It has been shown that enalapril maleate in low doses in the drinking water completely inhibits the serum converting enzyme in female Wistar rats.²⁴ Based on this evidence, we think that responses were similar in all groups at the doses used.

The significantly lower cardiac weight in the present study, along with the significant decrease in the degree of myocardiosclerosis, is similar to that in reports in other experimental models.^{4 7} Inhibition of the renin-angiotensin system prevents postinfarction arrhythmia in models of ischemia and reperfusion^{8 9} and modifies remodeling and cardiac function after myocardial infarction.²⁵ In the same way, inhibition of the renin-angiotensin-aldosterone system could modify cardiac structural changes in a variety of pathological conditions, including those myocardial changes typical of the aging mouse.

The mechanism or mechanisms responsible for the effects of ACE inhibitors on the cardiovascular system are not entirely clear. In addition to hemodynamic effects, ACE inhibitors may function as free radical scavengers. Captopril and other inhibitors with a sulfhydryl group have been shown to be nonspecific antioxidants²⁶ and to strongly inhibit lipidic peroxidation.²⁷ Andreoli²⁷ recently found that oxidative damage seen in renal epithelial and endothelial cells was partially protected at millimolar concentrations of captopril, much higher than obtained with usual therapeutic doses. We have recently found in mouse hepatocytes that this effect of captopril is seen with therapeutic doses.²⁸ Although other researchers have not been able to demonstrate a free radical scavenger effect of enalapril,^{29 30 31} the possibility that the beneficial changes in the heart seen in our mice may be related to this mechanism still must be considered. Furthermore, it is possible that enalapril acted through stimulation of natural mechanisms, offsetting the action of free radicals. We found an increase of cytosolic and mitochondrial superoxide dismutase in the liver of mice treated with enalapril and captopril for 3 months (unpublished data, 1994).

We do not have an explanation for the dramatically greater number of mitochondria in myocardiocytes found in mice chronically receiving enalapril compared with control mice. Aging has been referred to as a "mitochondrial disorder." It is known that mitochondrial DNA regulates the synthesis of various hydrophobic proteins in the inner membrane, which are essential components of cytochromes, cytochrome oxidase, and ATPase.³² If this organelle genome suffers mutations or other alterations with aging, the result will be a progressive loss of the capacity to regenerate the mitochondrial population.³³ This key role played by the mitochondrial genome in aging is compatible with studies showing that mitochondrial DNA is much more sensitive than nuclear DNA to changes associated with aging.³⁴ Other observations that support the genetic-mitochondrial theory of aging include a decreased number of mitochondria³⁵ and a loss of mitochondrial DNA, whereas nuclear DNA is not altered,³⁶ and an increase in the number of catenoid dimers, probably because of errors in mitochondrial genomic replication associated with the aging process.³⁷

As already mentioned, the increase in the number of mitochondria in mice receiving enalapril in different concentrations versus the control group was significant. These differences in the number of mitochondria became evident early (after 6 months of treatment), and we believe that this phenomenon may be partially responsible for the observed effects of enalapril on the myocardium. Other possible mechanisms include a direct effect of the drug; changes in potassium, bradykinin, or prostaglandin levels; or prevention of the production of cellular toxic substances such as lipoperoxides.

In short, a relation could exist among smaller cardiac size, lower myocardiosclerosis, and lower middle vascular layer weight, together with an increase in the number of mitochondria in myocardiocytes and hepatocytes, with lower mortality in mice having received enalapril throughout their entire life. These facts suggest a possibility that the use of ACE inhibitors could alter some of the natural mechanisms of aging.

	Footnotes

 
Reprint requests to Felipe Inserra, Virrey Loreto 3150, Buenos Aires, 1426, Argentina.

Received May 23, 1994; first decision June 29, 1994; accepted October 26, 1994.

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Inserra, F. Articles by Ferder, L. Search for Related Content PubMed PubMed Citation Articles by Inserra, F. Articles by Ferder, L.