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Hypertension. 1995;26:321-326

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(Hypertension. 1995;26:321-326.)
© 1995 American Heart Association, Inc.

Articles

Contribution of Systemic Blood Pressure to Myocardial Remodeling in Uremic Rats

Bruno Fabris; Renzo Carretta; Fabio Fischetti; Riccardo Candido; Mario Calci; Maurizio Castellano; Moreno Bardelli; Luciano Campanacci

From the Institute of Medicina Clinica, Cattinara Hospital, University of Trieste, and Cattedra di Medicina Interna, University of Brescia (M. Castellano) (Italy).

Correspondence to Bruno Fabris, MD, Università di Trieste, Istituto di Medicina Clinica, c/o Ospedale di Cattinara, 34149 Trieste, Italy.


*    Abstract
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 *Abstract
down arrowIntroduction
 down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Abstract Left ventricular hypertrophy with diffuse intermyocardiocytic fibrosis is a feature of uremia. The role of blood pressure and/or other cardiovascular uremic risk factors in cardiac remodeling is still uncertain. To determine the extent to which improvement of kidney function and the control of uremia-related risk factors are associated with a reduction of myocardial injury, we evaluated the effect of dietary protein restriction or the angiotensin-converting enzyme inhibitor lisinopril on cardiac structure in remnant kidney rats. One week after subtotal nephrectomy, Wistar rats were allocated to receive drinking water solution (group 1), 5 mg/kg per day lisinopril (group 2), or a low-protein diet (6%) (group 3) for 12 weeks. Groups 2 and 3 showed a comparable efficacy in preventing the expected rise in creatininemia, urinary protein excretion, and glomerulosclerosis. However, hypertension development was prevented only in group 2. Groups 1 and 3 developed a significant (P<.01) increase in left ventricular weight (2.45±0.1 and 2.5±0.5 mg/g body wt, respectively) compared with group 2 (1.9±0.06 mg/g body wt). Cardiac hydroxyproline concentration was also lower in group 2 compared with group 1 (2.07±0.16 versus 2.73±0.17 mg/g left ventricular weight, P<.05) but not compared with group 3 (2.59±0.19 mg/g left ventricular weight). The effect of angiotensin-converting enzyme inhibition on left ventricular mass and intracardiac collagen content appeared to be dissociated from anemia, sympathetic activity, and hyperlipidemia. There was a close relationship between systolic pressure and left ventricular mass; however, no relationship between the degree of cardiac fibrosis and systolic pressure could be determined. Compared with other uremia-related risk factors, control of systemic blood pressure is an essential component of the prevention of left ventricular hypertrophy, and the limitation of interstitial fibrosis may occur by a mechanism other than blood pressure control.


Key Words: hypertension, experimental • uremia • hypertrophy • fibrosis • angiotensin-converting enzyme inhibitors


*    Introduction
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 up arrowAbstract
 *Introduction
down arrowMethods
 down arrowResults
 down arrowDiscussion
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Cardiac disease is the leading cause of death in dialysis patients.1 Enlargement of the heart and left ventricular hypertrophy are the most consistent findings in both clinical2 3 and experimental4 uremia. Morphological studies indicate that the increment in myocardial mass is caused by muscle hypertrophy and a disproportionate accumulation of fibrillar collagen in the interstitial space.5 6 This finding is considered a major determinant of pathological hypertrophy and may lead to ventricular dysfunction and symptomatic heart failure.7 Many factors have been implicated in the pathogenesis of uremia-associated cardiac hypertrophy, but it is still uncertain to what extent uremic myocardial remodeling can be explained by hypertension, anemia, lipid disorders, sympathetic overactivity, electrolyte imbalance, or other factors.4 8

To determine the contribution of systemic blood pressure (BP) elevation to cardiac remodeling in uremia compared with other related risk factors, we studied the effect of improving renal function with or without lowering systemic BP in remnant kidney rats by administering the angiotensin-converting enzyme (ACE) inhibitor lisinopril or by exploiting the beneficial effect of a low-protein diet on kidney function. We chose an ACE inhibitor because these agents have been shown to be comparable to a low-protein diet in ameliorating the progression of renal damage.9 In addition, several lines of evidence suggest that angiotensin II may act as a growth promoter in left ventricular hypertrophy,10 11 12 and ACE inhibitors have been demonstrated to reverse left ventricular hypertrophy and prevent myocardial fibrosis in genetic and acquired hypertension.13 14 15 Consequently, we specifically sought to determine whether the control of systemic hypertension and/or other uremia-related cardiovascular risk factors could be associated with the prevention of myocardial injury and whether long-term ACE inhibitor treatment could hinder the pathological remodeling of the myocardial interstitium in rat remnant kidney.


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
 down arrowDiscussion
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Study Protocol
Three groups of male Wistar rats with initial weights of 245 to 265 g were studied for 12 weeks. All rats underwent ether anesthesia and were subjected to 5/6 renal ablation by removal of the right kidney and infarction of approximately two thirds of the left kidney by ligation of two or three branches of the left renal artery. Before abdominal closure, the left kidney was inspected and the pattern of infarction noted. Only those rats with clearly delineated infarction of two thirds of the kidney were included in the remainder of the study.

Rats were housed in groups of three per cage in an air-conditioned, light-controlled environment and allowed free access to tap water. One week after 5/6 nephrectomy the rats were randomly allocated to one of three groups. Group 1 (n=15) received no specific therapy and was maintained throughout the experimental period on standard rat chow containing approximately 24% protein by weight. Group 2 (n=14) was treated with 5 mg/kg per day lisinopril (Zeneca SpA). Rats in group 3 (n=16) received no antihypertensive therapy but were subjected to a low-protein diet containing 6% protein by weight (Altromin-Rieper). Food was provided ad libitum. At 2-week intervals systolic BP was measured in conscious, restrained, preheated rats by tail-cuff plethysmography. Rats were then placed in individual metabolic cages for 24 hours, and urine was collected for measurement of total urinary protein. The day after the metabolic study a venous blood sample was also taken with rats under ether anesthesia and centrifuged; the serum was frozen for later analysis of creatinine, cholesterol, and triglycerides.

After 11 weeks of treatment microhematocrit was measured. After death by decapitation the chest and abdomen were opened, and the heart and renal tissues were rapidly excised, rinsed with 0.9% saline solution, and weighed. Atria were divided from ventricles, and each ventricle was weighed separately. The left ventricles were then cut into two parts at the equator and stored at -70°C. The upper sections were used for catecholamine measurements, and determination of myocardial hydroxyproline was performed in the lower sections. The remnant kidney was immersed in Duboscq Brazil fixative solution for evaluation of glomerulosclerosis.

The procedures followed in this study were in accordance with institutional guidelines for experimental animal research.

Biochemical Determinations
Serum creatinine was determined by an autoanalyzer technique. Total cholesterol and triglyceride levels were determined in whole serum by an enzymatic colorimetric method (SGM) with the use of an autoanalyzer (Hitachi 737). Proteinuria was assessed by measurement of 24-hour total urinary protein excretion with the Coomassie dye binding technique.16

Left ventricular collagen content was measured by determining left ventricular hydroxyproline concentration. After the left ventricles had been dried for 24 hours, the specimens were hydrolyzed in 6N hydrogen chloride solution at 120°C. After resolution in a buffer at pH 7.0, p-dimethylaminobenzaldehyde (Ehrlich's reagent) was added to form a complex with hydroxyproline. Hydroxyproline concentration was measured by spectrophotometric analysis at a wavelength of 560 nm.17

Cardiac norepinephrine content was measured by high-performance liquid chromatography with electrochemical detection as previously reported.18 Briefly, frozen left ventricles were homogenized with a polytron device in 10 mL ice-cold buffer solution (0.1 mol/L Tris-HCl, pH 7.4) containing dihydroxybenzylamine as internal standard. The suspension was then centrifuged for 30 minutes at 10 000g (4°C). Norepinephrine was extracted from 1 mL of supernatant on alumina, and 80 µL of the final eluate was injected into a cation-exchange chromatographic column.

Assessment of Renal Morphology
Two midcoronal sections 3 to 5 mm thick from each kidney were stained by the periodic acid–Schiff method and examined by light microscopy. Glomerulosclerosis was semiquantitatively graded from 0 (absent) to 4 (global hyalinosis) by two independent observers. Grades 1/4 through 4/4 were assigned when the glomerular area involved was 25%, 50%, 75%, and 100%, respectively. One hundred or more glomeruli were examined from each pair of sections, and the extent of glomerulosclerosis was estimated as the percentage of sclerotic area over the total glomerular area.19

Statistical Analysis
Data are reported as mean±SEM. Comparisons among different rat groups over the study period were performed by ANOVA and subsequent Scheffé's test. Parameters within one group at different time points were compared by ANOVA for repeated measures. Linear regression analysis was used for testing two variable relationships. STATVIEW 512 software for the Apple Macintosh computer was used. A value of P<.05 was required for significance.


*    Results
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 *Results
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Systemic BP
Systolic BP for the three groups is shown in Fig 1. In untreated rats 5/6 nephrectomy resulted in the development of systemic hypertension within 2 weeks after ablation. BP in these rats increased to 159±4.3 mm Hg after 2 weeks (P<.001) and continued to rise slowly over the course of the experiment, reaching a mean of 165±3.8 mm Hg at 12 weeks (P<.001). In the lisinopril-treated group systolic BP remained significantly lower (P<.001) than that of untreated rats during the treatment period. In contrast, reduction of dietary protein intake in group 3 had no significant effect on BP elevation.



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  		Figure 1. Line graph shows sequential values for systolic pressure (mean±SEM) for the three rat groups. Blood pressure was controlled only in rats treated with lisinopril. Group 1 indicates control; group 2, lisinopril (5 mg/kg per day); and group 3, low-protein diet (6% by weight). *P<.001, group 2 vs groups 1 and 3.

Renal Function and Structure
In the control group serum creatinine concentration rose continuously over the study period. After the initiation of lisinopril and low-protein treatments, serum creatinine fell slightly. The treated groups had significantly lower serum creatinine levels than the control group during the treatment period. At the 12-week end point rats treated with lisinopril or a low-protein diet had serum creatinine levels of 106.1±3.8 and 121.1±5.6 µmol/L, respectively. Both values were significantly less (P<.01) than the 148.5±5.8 µmol/L of untreated rats at the same stage (Table 1).


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  		Table 1. Hematocrit and Renal Parameters

Rats treated with either lisinopril or a low-protein diet had higher hematocrit values (P<.03) than untreated rats (Table 1).

Assessment of 24-hour total urinary protein excretion confirmed that all three groups had similar levels of proteinuria at the beginning of the study (Table 1). Untreated rats developed progressive glomerular injury as manifested by increasing proteinuria throughout the study period. In marked contrast early institution of lisinopril treatment or a low-protein diet maintained proteinuria at low levels (P<.01) in groups 2 and 3 (Table 1). Histological study revealed that proteinuria reflected development of glomerular injury. Untreated group 1 rats had a significantly higher (P<.01) percentage of sclerotic area at 12 weeks compared with groups 2 and 3 (Table 1). Nephroprotection in the low-protein group occurred independently of systemic BP control.

Heart Structure and Ventricular Norepinephrine Content
The ratio of left to right ventricular weights (Table 2) and left ventricular weight normalized to body weight (Table 2 and Fig 2A) were significantly higher in control and low-protein diet rats compared with lisinopril rats. Right ventricular weight normalized to body weight was similar in all groups (Table 2). Left ventricular hydroxyproline concentration per gram of left ventricular wet weight as a measure of left ventricular collagen was also lower (P<.05) in rats treated with lisinopril (2.07±0.16 mg/g left ventricular weight) compared with control rats (2.73±0.17 mg/g left ventricular weight) but not in those treated with a low-protein diet (2.59±0.19 mg/g left ventricular weight) (Fig 3A). The degree of ventricular hypertrophy was closely related to the level of arterial pressure (r=.79, P<.001; Fig 2B). In contrast, no relationship was found between cardiac collagen content and systolic BP (r=.24, Fig 3B). Cardiac levels of norepinephrine are shown in Fig 4. No difference in left ventricular norepinephrine concentration was observed among the groups after treatment. Body weight (grams) evaluated at the end of the study did not differ among the three groups (Table 2).


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  		Table 2. Body Weight and Heart Weight Measurements



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  		Figure 2. A, Bar graph shows left ventricular mass for different experimental groups. For values in each group, see Table 2. *P<.01, group 2 vs groups 1 and 3. B, Scatterplot shows correlation between left ventricular mass and systolic pressure in the three rat groups. Groups are as defined in Fig 1 legend. BW indicates body weight.



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  		Figure 3. A, Bar graph shows left ventricular hydroxyproline (L.V. OH-proline) concentration for the different experimental groups. *P<.05, group 2 vs groups 1 and 3. B, Scatterplot shows correlation between left ventricular hydroxyproline content and systolic pressure in the three rat groups. Groups are as defined in Fig 1 legend.



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  		Figure 4. Bar graph shows left ventricular norepinephrine content for the three rat groups. There was no statistical difference among groups. Groups are as defined in Fig 1 legend. LVW indicates left ventricular weight.

Serum Lipids
In the control group after subtotal nephrectomy, plasma cholesterol rose from 1.98±0.14 to 3.18±0.2 mmol/L (P<.001) and plasma triglycerides from 0.73±0.05 to 1.25±0.1 mmol/L (P<.003) over a period of 12 weeks.

After 11 weeks of treatment in the lisinopril and low-protein diet groups, serum cholesterol and triglyceride values were significantly lower (P<.01) than the serum lipid levels of the untreated group (Fig 5).



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  		Figure 5. Bar graphs show serum cholesterol (A) and triglycerides (B) for the three rat groups 12 weeks after subtotal nephrectomy. *P<.01, groups 2 and 3 vs group 1. Groups are as defined in Fig 1 legend.


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
Subtotal nephrectomy is a well-studied model of chronic progressive renal disease. Previous investigations20 21 22 have demonstrated that after subtotal nephrectomy in the rat, a syndrome of mild hypertension and progressive renal damage develops with reduction of glomerular filtration, increased proteinuria, and glomerulosclerosis. Moreover, experimental uremia is known to cause cardiac hypertrophy with interstitial fibrosis.5 6

The present study confirmed comparable efficacy of dietary protein restriction and ACE inhibitor treatment in reducing the progression of renal failure in the remnant kidney.9 All three indexes of renal disease (serum creatinine concentration, urinary protein excretion, and histological score of glomerular injury) were blunted by lisinopril and a low-protein diet. In the dietary protein restriction group, renal structure and function were preserved despite persistent mild systemic hypertension. Micropuncture studies have demonstrated that both dietary protein restriction9 21 and converting enzyme inhibitors9 23 markedly reduce mean glomerular capillary hydraulic pressure in the remnant kidney. Accordingly, our data further support the notion that systemic BP is of less relevance in determining glomerular injury than glomerular hypertension.9 21 24

In recent years several abnormalities of myocardial function in uremia have been recognized.2 25 26 The term "uremic cardiomyopathy" has been proposed, but it is not universally accepted because of the difficulty in separating the various mechanisms involved in cardiac dysfunction in experimental and clinical uremia.4 27 28 The significant regression of left ventricular hypertrophy that occurs after renal transplantation29 suggests that factors related to renal insufficiency are the probable cause of cardiovascular alterations during end-stage renal disease. One of the objects of the current study was to determine whether the development of cardiac hypertrophy in experimental rats with renal insufficiency could be prevented by the control of systemic hypertension and/or other cardiovascular uremic risk factors. Heart weight was not significantly affected by a low-protein diet despite an appreciable efficacy in preventing the expected rise in creatininemia, urinary protein excretion, and glomerulosclerosis after 3 months of treatment. In contrast, left ventricular weight was significantly lower in rats treated with lisinopril compared with controls. The anticardiohypertrophic effect of lisinopril appeared to be dissociated from anemia, sympathetic activity, and lipid disorders. Rats treated with either dietary protein restriction or antihypertensive therapy had higher final hematocrit values than untreated rats. Therefore, although anemia has been suggested as a possible factor responsible for increased heart weight,26 30 the current study does not support this theory. Some authors31 have suggested that cardiac hypertrophy in hemodialysis patients could be due to sympathetic overactivity. However, in our study left ventricular norepinephrine levels were not different among the three rat groups. These findings, in accordance with those of Rambausek et al,4 suggest that the increase in heart weight can be dissociated from ß1- and {alpha}1-adrenoceptor stimulation.

Hyperlipidemia has also been suggested as a possible mechanism involved in the increase of myocardial fiber mass because it is a major cause of accelerated atherogenesis.32 33 In this condition the loss of aortic elasticity and thus of arterial compliance increases the load imposed by the vasculature on the left ventricle.34 35 Consequently, one would expect the reduction in serum lipid concentration to lead to an improvement in arterial compliance with a decreased left ventricular load and eventually a favorable effect on cardiac hypertrophy. However, in the present study both treatments had a favorable effect on cholesterol and triglyceride plasma levels, but the development of cardiac hypertrophy was prevented only in the lisinopril group.

The differences in outcome on cardiac hypertrophy of the two therapeutic approaches appear to result from differences in their hypotensive effects. The prevention of increased left ventricular mass after lisinopril treatment occurred with concomitant BP control. Whether the prevention of left ventricular hypertrophy was due to inhibition of circulating angiotensin II and thus reduction of ventricular afterload or to a specific intracardiac effect of ACE inhibition cannot be determined from this study. However, the close correlation between systolic BP and left ventricular weight in rats with renal failure shows that prevention of left ventricular hypertrophy depends on control of systolic BP. Our data, without excluding the possibility that causes other than BP could be involved in left ventricular hypertrophy, suggest that removal of ventricular afterload more than the preservation of kidney function per se or amelioration of other uremia-related risk factors such as anemia and hyperlipidemia is an essential component for the prevention of left ventricular hypertrophy in experimental uremia.

Myocyte growth is but one aspect of the hypertrophic remodeling of the myocardium in uremia. The hallmark of myocardial hypertrophy associated with chronic renal insufficiency is interstitial fibrosis.5 6 This remodeling of the nonmyocyte compartment of the myocardium is considered a major determinant for pathological hypertrophy with heart failure.7 An important additional object of the present study was to determine whether the accumulation of fibrillar collagen in the left ventricle could be hindered by ACE inhibitor treatment. In lisinopril-treated rats the prevention of hypertrophy was associated with a lower cardiac hydroxyproline concentration. In contrast, Mall et al6 found no change in interstitial volume after treatment with an ACE inhibitor in an experimental model of uremia. These conflicting results may be due to the different methods used to evaluate myocardial fibrosis, differences in surgical approach to reduce renal mass, and differences in drug type and dosage. In our study the cardioprotective effect of lisinopril may not have been due to the control of systemic BP alone, as cardiac collagen content was not correlated with systolic BP. In uremic patients5 and animals with experimental uremia (unpublished observations, 1994) intermyocardiocytic fibrosis has been found not only in the pressure-overloaded hypertrophied left ventricle but also in the normotensive nonhypertrophied right ventricle. These findings suggest that myocardial fibrosis is not related to hemodynamic workload but rather to the presence of a trophic circulating substance. Recently, it has been suggested that parathormone can act as a permissive factor in the development of myocardial interstitial fibrosis.36 However, this observation has not been confirmed in clinical studies. Harnett et al8 found the highest prevalence of left ventricular hypertrophy in uremic patients who had parathyroidectomy. In addition, it is of note that in a retrospective postmortem study on uremic patients, Mall et al6 did not find intermyocardiocytic fibrosis in the one patient with primary hyperparathyroidism that they examined.

In uremia the morphological expression of myocardial fibrosis is that of a perivascular and interstitial reactive fibrosis not related to cardiac myocyte necrosis (reparative fibrosis).5 36 A similar pattern in the collagen network remodeling of the heart has been found in the presence of mineralocorticoid excess in both human subjects37 and experimental animals.38 Considering that substantial evidence links the renin-angiotensin-aldosterone system to the hypertension of renal parenchymal disease,39 one could suggest that circulating and myocardial renin-angiotensin systems could be involved in the structural remodeling of the nonmyocyte compartment in uremia. Further studies are necessary to elucidate the mechanisms responsible for fibroblast growth and enhanced collagen synthesis.

Notwithstanding these gaps in our knowledge, it is apparent from the current study that ACE inhibitors can be used to prevent myocardial fibrosis in experimental uremia.

In conclusion, the results of this study suggest that although the beneficial effect on myocardial mass after lisinopril therapy in the uremic rat may have occurred in response to the control of systemic BP, the favorable effect on interstitial fibrosis may occur by a mechanism other than BP control; also, inhibition of local cardiac ACE may contribute. Furthermore, lisinopril may be valuable in preventing cardiac remodeling in end-stage renal disease.


*    Acknowledgments
 
This work was supported by a 60% grant from the Ministero della Università e della Ricerca Scientifica e Tecnologica. The authors would like to thank Drs Annalisa Biagi and Lorenzo Armini for their technical assistance.

Received August 8, 1994; first decision September 21, 1994; accepted April 3, 1995.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 up arrowDiscussion
 *References
 

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Y. Ono, H. Ono, H. Matsuoka, T. Fujimori, and E. D. Frohlich
Apoptosis, Coronary Arterial Remodeling, and Myocardial Infarction After Nitric Oxide Inhibition in SHR
Hypertension, October 1, 1999; 34(4): 609 - 616.
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