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Am J Physiol Heart Circ Physiol 288: H2637-H2646, 2005. First published January 28, 2005; doi:10.1152/ajpheart.01304.2004
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Modification of sarcolemmal Na+-K+-ATPase and Na+/Ca2+ exchanger expression in heart failure by blockade of renin-angiotensin system

Qiming Shao,1 Bin Ren,1 Vijayan Elimban,1 Paramjit S. Tappia,2 Nobuakira Takeda,3 and Naranjan S. Dhalla1

1Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre and Departments of Physiology, Faculty of Medicine; 2Human Nutritional Sciences, Faculty of Human Ecology, University of Manitoba, Winnipeg, Canada; and 3Aoto Hospital, Department of Internal Medicine, Jikei University, Tokyo, Japan

Submitted 28 December 2004 ; accepted in final form 27 January 2005


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
The activities of both sarcolemmal (SL) Na+-K+-ATPase and Na+/Ca2+ exchanger, which maintain the intracellular cation homeostasis, have been shown to be depressed in heart failure due to myocardial infarction (MI). Because the renin-angiotensin system (RAS) is activated in heart failure, this study tested the hypothesis that attenuation of cardiac SL changes in congestive heart failure (CHF) by angiotensin-converting enzyme (ACE) inhibitors is associated with prevention of alterations in gene expression for SL Na+-K+-ATPase and Na+/Ca2+ exchanger. CHF in rats due to MI was induced by occluding the coronary artery, and 3 wk later the animals were treated with an ACE inhibitor, imidapril (1 mg·kg–1·day–1), for 4 wk. Heart dysfunction and cardiac hypertrophy in the infarcted animals were associated with depressed SL Na+-K+-ATPase and Na+/Ca2+ exchange activities. Protein content and mRNA levels for Na+/Ca2+ exchanger as well as Na+-K+-ATPase {alpha}1-, {alpha}2- and {beta}1-isoforms were depressed, whereas those for {alpha}3-isoform were increased in the failing heart. These changes in SL activities, protein content, and gene expression were attenuated by treating the infarcted animals with imidapril. The beneficial effects of imidapril treatment on heart function and cardiac hypertrophy as well as SL Na+-K+-ATPase and Na+/Ca2+ exchange activities in the infarcted animals were simulated by enalapril, an ACE inhibitor, and losartan, an angiotensin receptor antagonist. These results suggest that blockade of RAS in CHF improves SL Na+-K+-ATPase and Na+/Ca2+ exchange activities in the failing heart by preventing changes in gene expression for SL proteins.

cardiac sarcolemma; Na+-K+-ATPase isoforms; cardiac gene expression; congestive heart failure; angiotensin-converting enzyme inhibitors

THERE IS AMPLE EVIDENCE TO suggest that different isoforms of Na+-K+-ATPase are colocalized with Na+/Ca2+ exchanger in the sarcolemmal (SL) membrane and that these proteins are intimately involved in the regulation of Ca2+ movements in cardiomyocytes (24, 32). Although inhibition of SL Na+-K+-ATPase has been demonstrated to promote Ca2+ influx through the stimulation of Na+/Ca2+ exchange in the SL membrane, Na+/Ca2+ exchanger has been implicated in both Ca2+ influx and Ca2+ efflux processes in the myocardium. Several investigators have reported that SL Na+-K+-ATPase activity is depressed in different types of heart failure in humans (22, 27, 33, 34, 36, 39) as well as in animal models including genetic cardiomyopathy (19), hypertension (28), and chronic myocardial infarction (MI) (9, 35). A wide variety of alterations in gene or protein expression of different Na+-K+-ATPase isoforms have also been observed in the hypertrophied (3, 4) and failing hearts (19, 22, 34, 36, 39). On the other hand, some investigators have shown increased expression or activity of Na+/Ca2+ exchanger at late stages of human heart failure (11, 20, 29, 31, 38), whereas others (15, 34) have failed to detect such changes. Both increased and decreased SL Na+/Ca2+ exchange activities in failing hearts from some animal models have also been reported (10, 13, 25, 26). Because the overexpression of Na+/Ca2+ exchanger in cardiomyocytes from the infarcted heart has been shown to improve contractile dysfunction and enhance both Ca2+ efflux and Ca2+ influx (44), it appears that a depression in the Na+/Ca2+ exchange activity may result in a defect in contractile force development, whereas the increased Na+/Ca2+ exchange activity may tend to increase the heart function.

In addition to depressed SL Na+/Ca2+ exchange, previous studies from our laboratory have demonstrated a marked reduction in SL Na+-K+-ATPase activity in hearts failing due to MI (9, 10). Both the steady-state levels of mRNA and protein content were increased for the Na+-K+-ATPase {alpha}3-isoform and decreased for the {alpha}2-isoform without any changes for the {alpha}1- and {beta}1-isoforms in the infarcted heart (35). Although such alterations in gene and protein expressions as well as Na+-K+-ATPase activity in the failing heart can be seen to be associated with changes in the molecular structure and composition of the SL membrane (SL remodeling), no information concerning the mechanism of SL remodeling in hearts failing due to MI has appeared in the literature. Because the renin-angiotensin system (RAS) is activated in heart failure due to MI (8, 14), it is possible that its blockade may prevent SL remodeling in the infarcted hearts. This view is based on our observations that the MI-induced changes in protein and gene expression as well as activities for both sarcoplasmic reticulum and myofibrils were prevented by blockade of the RAS (14, 37, 40). The present study was therefore undertaken to test the hypothesis that treatment of infarcted animals with imidapril, an angiotensin-converting enzyme (ACE) inhibitor (37, 40), will improve SL Na+-K+-ATPase and Na+/Ca2+ exchange activities by preventing changes in the SL gene and protein expressions.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Experimental model. Animals used in this study were handled according to the guidelines of the Canadian Council of Animal Care, and the experimental protocol was approved by the Animal Care Committee of the University of Manitoba. MI was induced in male Sprague-Dawley rats (175–200 g) by occlusion of the left coronary artery as described previously (14, 37, 40). Sham-operated animals were treated in the same way except that the artery was not ligated. Rats were divided randomly into four groups after the surgery: sham untreated (sham), sham plus imidapril (sham + IMP), MI, and MI plus imidapril (MI + IMP). Imidapril (1 mg/kg, daily, unless indicated in the text) was given by gastric gavage for a period of 4 wk starting at 3 wk after the coronary occlusion. The selection of this dose of imidapril was based on our previous studies (37, 40) showing optimal beneficial effects on hemodynamic changes in this experimental model. Sham and untreated MI animals were given water by gavage to minimize the effects of stress due to daily drug administration through this route. In some experiments, imidapril treatment was carried out for 8 or 12 wk starting at 3 wk after the coronary artery was occluded. To demonstrate whether the effects of imidapril are due to blockade of the RAS, 3-wk infarcted animals were also treated with and without enalapril (10 mg·kg–1·day–1), an ACE inhibitor, or losartan (20 mg·kg–1·day–1), an ANG II receptor antagonist, for 4 wk. It is pointed out that infarct in this experimental model has been shown to be fully healed at 3 wk and clinical signs of congestive heart failure, such as ascites and dyspnea, begin to appear at 4 wk after occlusion of the coronary artery. Thus all drug treatments were started at 3 wk (unless indicated in the text) after MI was induced to examine whether these drugs prevented the heart failure-induced changes in SL activities. The anesthetized rats were hemodynamically assessed and the hearts were surgically removed. The left ventricle (LV) (including septum) was dissected, weighed, and frozen in liquid N2. Scar tissue from the infarcted LV was also separated and weighed; the remaining viable tissue was used for analysis. As indicated previously (14, 37, 40), the animals with small (~10%) scarring were excluded from this study. The status of RAS was assessed by monitoring the plasma level of ANG II (46) as well as plasma and LV ACE activities (16), whereas oxidative stress was evaluated by measuring LV malondialdehyde (MDA) as well as thiobarbituric acid-reactive substance, reduced glutathione, and oxidized glutathione contents (7, 21).

Hemodynamic measurements. The animals were anesthetized with an injection of a mixture of ketamine (60 mg/kg) and xylazine (10 mg/kg). A microtip pressure transducer (model PR-249; Millar Instruments, Houston, TX) was advanced to the LV through the lumen of the carotid artery, and different hemodynamic changes were monitored as described earlier (14, 37, 40). Various parameters such as heart rate, LV systolic pressure (LVSP), LV end-diastolic pressure (LVEDP), maximal rate of pressure development (+dP/dt), maximal rate of pressure decay (–dP/dt), and mean arterial blood pressure (MAP) were recorded by a computer program (Acknowledge 3.1, Harvard Apparatus, Saint-Laurent, Quebec, Canada).

Preparation of cardiac SL membrane. SL membrane was isolated from sham and MI with or without imidapril treatment according to the method employed earlier (9, 10). The SL protein was measured by Lowry's method and the protein yield was calculated as described earlier (10). Determination of marker enzyme activities (9, 10) in SL fractions from control and experimental hearts showed minimal but equal (2–3%) amount of cross contamination with other subcellular organelles. The purification factor for the SL preparation was calculated by measuring the ratio of ouabain (1 mM)-sensitive Na+-K+-ATPase activities in SL and homogenate according to the method described elsewhere (9, 10).

Measurement of total Na+-K+-ATPase activity. Estimation of Na+-K+-ATPase activity was carried out by a previously described method (10) with some modification. Briefly, 10 µg of SL vesicle were preincubated at 37°C with (in mM) 1.0 EGTA-Tris (pH 7.4), 5 NaN3, 6 MgCl2, 100 NaCl, 10 KCl, and 2.5 phosphoenolpyruvate (PEP) plus 10 IU/ml pyruvate kinase. Phosphoenolpyruvate and pyruvate kinase were used as an ATP-regenerating system to maintain the concentration of ATP in the incubation medium. The reaction for measuring the total ATPase activity was started by adding of 0.025 ml of 80 mM Tris-ATP, pH 7.4, and terminated after 10 min with 0.5 ml of ice-cold 12% trichloroacetic acid. Mg2+-ATPase activity was estimated as the difference between the activities with and without Mg2+ (in the absence of Na+ and K+) in the medium. All measurements were carried out in duplicate. Na+-K+-ATPase activity was calculated as a difference between the total ATPase and Mg2+-ATPase activities.

Na+-dependent Ca2+ uptake measurement. Na+-dependent Ca2+ uptake measurement was carried out by a method described in detail elsewhere (9). Briefly, 5 µl of SL vesicle (1.5 mg/ml; 7.5 µg protein/tube) preloaded with NaCl-MOPS buffer at 37°C for 30 min were rapidly diluted 50 times with Ca2+ uptake medium containing 140 mM KCl, 20 mM MOPS, 0.4 µM valinomycin, and 0.3 µCi 45Ca2+, pH 7.4. After an appropriate time span, the reaction was stopped by adding ice-cold 0.03 ml of the stopping solution containing (in mM) 140 KCl, 1 LaCl3, and 20 MOPS, pH 7.4. Radioactivity was measured with a Beckman LS 1701 scintillation counter. In parallel with these samples, nonspecific Ca2+ uptake was measured by placing the Na+-loaded SL vesicles in Ca2+ uptake medium containing 140 mM NaCl instead of KCl. Na+-dependent Ca2+ uptake activity was calculated by subtracting the nonspecific Ca2+ uptake value from the total Ca2+ uptake activity.

SDS-PAGE and Western blot assay. SL membrane was diluted to a concentration of 2.0 mg/ml with 0.25 M sucrose and 10 mM histidine buffer. The relative Na+-K+-ATPase protein was run on 10% minigel with a 4% stacking gel by SDS-PAGE according to the method used previously (19). The proteins separated by SDS-PAGE were then electroblotted to polyvinylidene difluoride membranes (Millipore, Bedford, MA) and incubated for 1 h at room temperature with monoclonal anti-Na+-K+-ATPase antibodies [{alpha}1-subunit mouse IgG (1:10,000), polyclonal {alpha}2-subunit rabbit IgG (1:2,000) and {beta}1-antibodies (1:2,000) (Upstate Biotechnology, Lake Placid, NY) and polyclonal anti-Na+/Ca2+ exchanger antibody (1:1,500; Swant Swiss Antibodies, Bellinzona, Switzerland)]. The membranes were subsequently incubated for 1 h with secondary antibody (biotinylated anti-rabbit IgG antibody 1:1,000 for {alpha}1-subunit and 1:3,000 for {alpha}2-, {alpha}3- and {beta}1-subunits; Amersham Biosciences, Baie d'Urfe, Quebec, Canada). The membranes were incubated with strepdavidin conjugated horseradish peroxidase (1:5,000; Amersham Biosciences) in Tris-buffered saline containing 0.1% Tween 20 for 30 min at room temperature. The bands were detected by chemiluminescent technique using the ECL kit (Amersham Biosciences), and the chemilumigrams were developed on ECL-Hyperfilm (Amersham Biosciences) to visualize Na+-K+-ATPase bands. Gels were stained with Coomassie blue after blotting, and blots were stained with Ponceau S solution to ensure uniform protein loading in all groups. The bands were analyzed by the model GS-670 Imaging Densitometer (Bio-Rad Laboratories, Mississauga, Ontario, Canada) with the Image Analysis Software (version 1.0). The values were expressed as a percentage of sham control values.

Isolation of total RNA and Northern blot analysis. Total RNA was isolated from LVs of sham control and experimental animals with or without imidapril treatment by using the guanidinium thiocyanate method (5). The final RNA pellet was suspended in sterile distilled water containing 0.1% diethyl pyrocarbonate and stored at –70°C. Twenty micrograms of total RNA were denatured at 65°C for 10 min and size fractioned on a 1.2% agarose gel containing 1.2 M formaldehyde. The blotted samples were transferred onto nylon membranes (Schleicher & Schuell; Keene, NH), UV cross-linked, and hybridized to randomly primed cDNA probes. The membranes were washed with standard saline citrate and 0.1% SDS at 42°C for 20 min and exposed to Kodak X-Omat-AR film using an intensifying screen at –70°C. After autoradiography, the individual mRNA bands were quantitated by using a GS-670 densitometer (Bio-Rad Laboratories). The optical density of each of the Na+-K+-ATPase isozymes as well as Na+/Ca2+ exchanger bands was divided by the GAPDH band optical density. The relative level of these messages in each sample was calculated as a percentage of the mean value of the corresponding message level in the sham control group.

Statistical analysis. The data are presented as mean ± SE. Differences between the control and experimental groups were evaluated statistically by ANOVA followed by Newman-Keul's test; a P value of <0.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
General characteristics and hemodynamics. In one set of experiments, sham control and 3-wk infarcted animals were treated with or without imidapril (1 mg·kg–1·day–1) for a period of 4 wk. The infarcted animals showed an increase in both left and right ventricular weights; these changes were attenuated by imidapril treatment without any effect on the scar weight (Table 1). Hemodynamic evaluations of the infarcted animals revealed an increase in LVEDP and a decrease in both +dP/dt and –dP/dt. Alterations in these parameters were also attenuated by imidapril treatment (Table 1). No changes in LVSP, heart rate, or MAP were evident between the control and experimental groups. It should also be noted from Table 1 that the treatment of sham control animals with imidapril had no effect on the general characteristics or hemodynamic parameters. These observations are in agreement with our previous results in this experimental model with or without imidapril treatments (37, 40).


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  		Table 1. General characteristics and hemodynamics of sham and infarcted rats with or without IMP treatment for 4 wk starting at 3 wk after coronary artery occlusion

 
SL Na+-K+-ATPase activity and protein content. The results in Fig. 1 show that Na+-K+-ATPase activity, unlike Mg2+-ATPase activity, in SL preparations from infarcted animals was markedly depressed and this effect was attenuated by imidapril treatment. The results in Fig. 2 show that protein contents for {alpha}1-, {beta}1- and {alpha}2-isoforms of SL Na+-K+-ATPase were decreased, whereas those for {alpha}3-isoform were increased in the infarcted heart. Furthermore, the depressions in protein contents for {alpha}1- and {alpha}2-isoforms were greater than that in the {beta}1-isoforms indicating differential alterations in protein expressions of Na+-K+-ATPase isoforms in the failing heart. All of these changes in Na+-K+-ATPase isoforms were prevented by treatment of the infarcted animals with imidapril (Fig. 2). It is also pointed out that no changes in protein contents for Na+-K+-ATPase isoforms were evident on treating sham control animals with imidapril.



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  		Fig. 1. Sarcolemmal Na+-K+-ATPase and Mg2+-ATPase activities in sham and experimental animals with or without imidapril (IMP) treatment. IMP was given orally (1 mg/kg, daily) for 4 wk starting at 3 wk after coronary occlusion. Each value is a mean ± SE of 5 animals in each group. MI, myocardial infarction. *P < 0.05 compared with sham control; #P < 0.05 compared with MI.

 


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  		Fig. 2. A typical Western blot showing sarcolemmal protein contents for Na+-K+-ATPase {alpha}1-, {alpha}2-, {alpha}3- and {beta}1-isoforms as well as Na+/Ca2+ exchanger (top) and bar graphs of protein contents for Na+-K+-ATPase {alpha}1- and {beta}1-isoforms in left ventricles (LVs) from sham and experimental animals with or without IMP treatment (A–D). Relative protein contents were determined by immunoblotting assay with monoclonal anti-Na+-K+-ATPase {alpha}1, {alpha}2, {alpha}3, and {beta}1 as well as Na+/Ca2+ exchanger antibodies. IMP was given orally (1 mg/kg, daily) for 4 wk. Bands for {alpha}1-, {alpha}2- and {alpha}3-isoforms were located at 110 kDa, whereas those for {beta}1-isoform of Na+-K+-ATPase and Na+/Ca2+ exchanger were located at 55 and ~120 kDa, respectively. Values are means ± SE of 6 experiments in each group. *P < 0.05 compared with sham control; #P < 0.05 compared with MI group.

 
Steady-state mRNA levels for Na+-K+-ATPase isoforms. The data in Figs. 3 and 4 indicate that mRNA levels for {alpha}1-, {beta}1-, and {alpha}2-isoforms were depressed, whereas that for {alpha}3-isoform was increased in the failing heart. The depression in mRNA level for {beta}1-isoform was greater than those for the {alpha}1- and {alpha}2-isoforms; the pattern of such alterations was different from that observed for protein expression. Likewise, the increase in mRNA level for {alpha}3-isoform (Fig. 4) is greater than the corresponding increase observed for the protein content of {alpha}3-isoforms (Fig. 2) in the infarcted heart. It can also be seen from Fig. 4 that the steady-state levels for mRNA for different Na+-K+-ATPase isoforms were not affected by treatment of sham control animals with imidapril.



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  		Fig. 3. Typical Northern blot of mRNA for sarcolemmal Na+-K+-ATPase {alpha}1-, {alpha}2-, {alpha}3- and {beta}1-isoforms as well as Na+/Ca2+ exchanger in left ventricles of sham and experimental animals with or without IMP treatment. In contrast to other Na+-K+-ATPase isoforms, the {alpha}2-isoform showed 2 bands; these were combined for densitometric analysis. GAPDH mRNA and 18S levels were used as internal standards for correcting the loading variation in each RNA sample. Ethidium bromide staining of 28S and 18S rRNA is also shown.

 


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  		Fig. 4. A–D: bar graphs showing ratio of the Northern blot density for sarcolemmal Na+-K+-ATPase {alpha}1, {alpha}2, {alpha}3, or {beta}1 mRNA and GAPDH mRNA from sham and experimental left ventricles with or without IMP treatment. IMP was given orally (1 mg/kg, daily) for 4 wk. Values are means ± SE of 6 experiments in each group. *P < 0.05 compared with sham control; #P < 0.05 compared with MI group.

 
SL Na+/Ca2+ exchanger and its protein and gene expression. Figure 5 shows that the Na+-dependent Ca2+ uptake activity in SL vesicles was decreased in the failing heart and this change was prevented by imidapril treatment. Both Western and Northern blots for Na+/Ca2+ exchanger in the sham control and imidapril treated groups are shown in Figs. 2 and 3, respectively. The analysis of these blots indicate that protein content and steady-state mRNA level for Na+/Ca2+ exchanger were decreased in the failing heart (Fig. 5). These alterations in the infarcted group were attenuated by imidapril. On the other hand, treatment of sham control animals with imidapril did not alter protein content or mRNA level for Na+/Ca2+ exchanger significantly.



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  		Fig. 5. Sarcolemmal Na+-dependent Ca2+ uptake activity (A), protein content for Na+/Ca2+ exchanger (B), and the ratio of the Northern blot density for sarcolemmal Na+/Ca2+ exchanger and GAPDH mRNA (C) in left ventricles from sham and experimental animals with or without IMP treatment are shown. Na+/Ca2+ exchange activity in sarcolemmal preparations was measured for 2 s. IMP was given orally (1 mg/kg, daily) for 4 wk. Values are means ± SE of 5 experiments in each group. *P < 0.05 compared with sham control; #P < 0.05 compared with MI group.

 
Characteristics of the beneficial effects of imidapril. To test whether the beneficial effects of imidapril in MI-induced heart failure are limited to the time of administration of the drugs, treatment of the infarcted animals with imidapril was started at 3 days of occluding the coronary artery. The results in Table 2 indicate that the hypertrophic response, hemodynamic changes, as well as alterations in SL Na+-K+-ATPase and Na+/Ca2+ exchange activities in the failing hearts were attenuated by imidapril treatment. These data, as well as those given in Table 1 and Figs. 1 and 5, reveal that both early (3 days after MI) and late (3 wk after MI) treatments with imidapril produce beneficial effects. The data in Table 3 show that treatment of the infarcted animals with high doses of imidapril (2 and 5 mg·kg–1·day–1), unlike the treatment with a low dose (0.2 mg·kg–1·day–1), attenuated the depressed SL Na+-K+-ATPase and Na+/Ca2+ exchange activities. Furthermore, treatment of the infarcted animals with imidapril (1 mg·kg–1·day–1) for a period of 8 or 12 wk was also found to partially prevent the MI-induced changes in SL Na+-K+-ATPase and Na+/Ca2+ exchange activities (Table 4). It can also be seen from the results in Tables 3 and 4 that the beneficial effects of imidapril on SL Na+-K+-ATPase and Na+/Ca2+ exchange activities were not confounded by artifacts of the preparation because the SL protein yield, purification factor, and Mg2+-ATPase activity were not affected by imidapril treatment.


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  		Table 2. General characteristics, hemodynamics, and sarcolemmal Na+-K+-ATPase and Na+/Ca2+ exchange activities in infarcted rats with or without IMP treatment for 7 wk starting at 3 days after the coronary occlusion

 

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  		Table 3. Cardiac sarcolemmal Na+-K+-ATPase and Na+/Ca2+ exchange activities in infarcted rats treated with or without different doses of IMP for 4 wk starting at 3 wk after the coronary occlusion

 

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  		Table 4. Cardiac sarcolemmal Na+-K+-ATPase and Na+/Ca2+ exchange activities in infarcted rats treated with or without IMP for 8 or 12 wk starting at 3 wk after the coronary occlusion

 
Mechanisms of the beneficial effects of imidapril. Because RAS is activated (14, 37, 40) and the level of oxidative stress is increased (21, 37) in MI-induced heart failure, it is possible that the beneficial effects of imidapril in heart failure are related to the reduction of RAS activation and oxidative stress. Results in Table 5 show that increased levels of plasma ANG II and plasma, as well as LV ACE activities, are attenuated in the infarcted animals by imidapril treatment. Furthermore, the increased level of MDA and LV oxidized glutathione as well as depressed level of LV reduced glutathione in the infarcted animals are depressed by imidapril treatment (Table 5). These effects of imidapril treatments on different parameters for both RAS activation and oxidative stress suggest the possibility that the beneficial actions of this agent are mediated through such mechanisms.


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  		Table 5. Status of renin-angiotensin system and oxidative stress in sham and infarcted rats with or without IMP treatment for 4 wk starting at 3 wk after the coronary occlusion

 
Effects of treatments with enalapril and losartan. To examine whether the beneficial effects of imidapril on SL Na+-K+-ATPase and Na+/Ca2+ exchanger are simulated by other agents that are known to produce blockade of the RAS, the infarcted animals were treated with enalapril and losartan. The results in Table 6 indicate that the MI-induced increase in heart weight and alterations in cardiac performance as well as changes in SL Na+-K+-ATPase and Na+/Ca2+ exchange activities were attenuated by treatment of the infarcted animals with either enalapril or losartan. It is pointed out that treatment of sham control animals with enalapril or losartan showed no effect on cardiac weight or cardiac performance (data not shown).


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  		Table 6. General characteristics, hemodynamics, and sarcolemmal Na+-K+-ATPase and Na+/Ca2+ exchange activities in infarcted rats treated with or without ENP and LOS for 4 wk starting 3 wk after coronary artery occlusion

 
In vitro effects of imidapril on SL activities. To investigate whether imidapril exerts any direct effect on the SL membrane, the action of this agent on SL Na+-K+-ATPase and Na+/Ca2+ exchange activities was studied under in vitro conditions. The results in Table 7 show no effect of different concentrations of imidapril on SL Na+-K+-ATPase and Na+/Ca2+ exchange activities. Our preliminary results with enalapril and losartan (at 10 µM concentrations) also revealed no action of these agents on the SL activities. It should be pointed out that treatment of control rabbits with enalapril or captopril has been reported to increase the Na+-K+-ATPase activity (18). This observation is in contrast to the results reported in this study showing that the SL Na+-K+-ATPase activity in sham control rats was not affected by treatments with ACE inhibitors or an ANG II receptor antagonist. Such differences in the effects of these drugs may be due to species difference.


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  		Table 7. In vitro study of Na+-K+-ATPase activity and Na+-dependent Ca2+ uptake in normal rat sarcolemma treated with IMP

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
In this study, we have shown that SL Na+-K+-ATPase and Na+/Ca2+ exchange activities are depressed in hearts failing due to MI in rats. These results are in agreement with our earlier reports (9, 10) showing reduced activities of both SL Na+-K+-ATPase and Na+/Ca2+ exchange activities in the infarcted hearts. Depressed SL Na+-K+-ATPase (19) and SL Na+/Ca2+ exchange (26) activities have also been observed in congestive heart failure in genetically determined cardiomyopathic hamsters. A depression in the Na+-K+-ATPase activity can be seen to result in an increase in the intracellular concentration of Na+ in the failing heart and will thus produce an increase in Ca2+ influx through the Na+/Ca2+ exchange system. Such an increase in Ca2+ influx would favor the development of intracellular Ca2+ overload, particularly when the Na+/Ca2+ exchange system, considered to promote Ca2+ efflux under normal conditions (8), is decreased. It should be pointed out that the occurrence of intracellular Ca2+ overload has been well recognized to induce heart dysfunction (8, 33). Although an enhanced Na+/Ca2+ exchange current has been reported in the infarcted rabbit heart (25), a depression in the Na+/Ca2+ exchange current has been observed in the infarcted rat heart (44). Some investigators (13) have shown an increase in the Na+/Ca2+ current but normal Ca2+ transport in cardiomyocytes from infarcted animals, whereas others (6) have reported an increase in the concentration of intracellular Na+ but no changes in Na+-K+ pump function in hearts failing due to aortic insufficiency. Such conflicting results are consistent with the view that alterations in SL Na+-K+-ATPase and Na+/Ca2+ exchange activities are dependent on the stage and type of heart failure (8).

The observed depression in SL Na+/Ca2+ exchange activity as seen in this study may be due to depressed protein content and mRNA levels for Na+/Ca2+ exchanger in the infarcted heart. Experiments in our laboratory have revealed that gene expression for Na+/Ca2+ exchanger in infarcted hearts is decreased at early stages and increased at later stages of heart failure (30, 43); however, the Na+/Ca2+ exchange activity at both early and later stages was depressed in the MI-induced model of heart failure in rats (unpublished data). A decrease in mRNA level for Na+/Ca2+ exchanger has also been reported in the hypertensive heart in the guinea pig (28). On the other hand, an increase (11, 38) or no change in mRNA levels has been observed at the late stages of human heart failure (38). Both enhanced protein expression and Na+/Ca2+ exchange activity have also been reported in the end stage human heart failure (11, 29), and the increased protein expression for Na+/Ca2+ exchanger was suggested to preserve diastolic function (15). In contrast to changes in Na+/Ca2+ exchange, the depression in Na+-K+-ATPase activity in human heart failure has been reported by several investigators (27, 33). In fact, the reduced Na+-K+-ATPase activity in human heart failure has been shown to be due to varying degrees of changes in Na+-K+-ATPase isoforms (27, 34, 39), whereas other investigators (36) have failed to detect any change in the isoforms. Nonetheless, alterations in SL Na+-K+-ATPase activity and protein expression for different isoforms have been reported in cardiac hypertrophy due to pressure overload (3, 4), cardiomyopathic hamsters (19), and other types of failing hearts (23, 28). Our results indicating decreased protein content and mRNA levels for {alpha}1-, {alpha}2- and {beta}1-isoforms, and increased protein content for {alpha}3-isoform in the infarcted heart suggest that changes in protein and gene expressions may account for the observed depression in the SL Na+-K+-ATPase activity. Semb et al. (35) also observed an association of decreased Na+ pump capacity with a decrease and an increase in protein content of {alpha}2-isoform and {alpha}3-isoform, respectively; however, these investigators did not detect any change in the {alpha}1- or {beta}1-isoforms in heart failure due to MI. Although such differences for {alpha}1- and {beta}1-isoforms in these two studies may be due to differences in the degree of heart failure, these data when taken together reflect remodeling of SL membrane with respect to the molecular structure for both Na+-K+-ATPase and Na+/Ca2+ exchange in the failing heart.

Treatment of the infarcted animals with an ACE inhibitor, imidapril, was found to prevent the MI-induced hypertrophic response, alterations in cardiac performance, and depression in the SL Na+/Ca2+ exchange and Na+-K+-ATPase activities. Because imidapril treatment was also found to attenuate the MI-induced changes in gene and protein expressions for Na+/Ca2+ exchange as well as Na+-K+-ATPase isoforms, it appears this drug may prevent remodeling of SL membranes. Imidapril has also been reported to prevent myofibrillar remodeling (40), whereas imidapril and enalapril were found to attenuate remodeling of the sarcoplasmic reticulum (14, 37) in hearts failing due to MI. Because the effects of imidapril on the MI-induced cardiac hypertrophy, heart dysfunction and SL remodeling with respect to Na+/Ca2+ exchange and Na+-K+-ATPase activities were simulated by enalapril and losartan, it is likely that the observed actions of imidapril are due to blockade of the RAS. In fact, the increased levels of plasma ANG II as well as plasma and LV ACE activities indicating the activation of RAS in infarcted animals were attenuated by imidapril treatment. Different agents known to produce blockade of the RAS have also been reported to prevent depression in the Na+-K+-ATPase activity in cardiac hypertrophy due to hypertension (42). In view of marked effects of imidapril on changes in the PKC isoforms in the infarcted heart (41) and the differential regulatory effect of PKC isoforms on the SL Na+-K+-ATPase (2), it is likely that the observed effects of imidapril on SL remodeling are mediated through changes in the PKC activity. The possibility that the beneficial effects of imidapril treatment on SL changes in MI-induced heart failure may be mediated through reduction in the oxidative stress is suggested by attenuation of increased levels of LV MDA and oxidized glutathione as well as depressed levels of reduced glutathione by imidapril. Nonetheless, it remains to be established whether the effects of imidapril on SL remodeling are elicited through the elevated levels of bradykinin (12) or nitric oxide (17). The possible involvement of increased sympathetic activity (1) for SL remodeling in heart failure due to MI needs further investigation.

Although blockade of RAS by different agents has been shown to prevent cardiac remodeling and improve cardiac function in heart failure (8, 14, 37, 40), the present study represents the first report showing attenuation of changes in SL Na+-K+-ATPase and Na+/Ca2+ exchange activities in MI-induced heart failure by treatments with imidapril, enalapril, and losartan. We are also reporting, for the first time, that changes in SL Na+-K+-ATPase and Na+/Ca2+ exchange activities in the infarcted hearts are associated with alterations in gene expressions for Na+-K+-ATPase isoforms and Na+/Ca2+ exchanger. Furthermore, the observations that alterations in protein content and gene expression for Na+-K+-ATPase isoforms and Na+/Ca2+ exchange in heart failure are attenuated by imidapril, an ACE inhibitor, provide new information. Because the MAP was not different in untreated and drug-treated groups, it is unlikely that the observed changes in SL activities, protein contents, and gene expression are due to alterations in the afterload. On the other hand, it can be argued that the observed alterations in SL proteins and gene expression in the untreated and drug-treated experimental animals are due to changes in heart function. However, this may not be the case, because alterations in protein content and gene expression for Na+-K+-ATPase in the failing heart as well as on treatment with imidapril were differential in nature. In addition, changes in SL Na+-K+-ATPase and Na+/Ca2+ exchange activities in untreated and drug-treated infarcted animals were not associated with corresponding changes in the SL Mg2+-ATPase activity. In fact, overexpression of Na+/Ca2+ exchanger in cardiomyocytes from infarcted animals was found to improve contractile function (44). Furthermore, in heterozygous knockout mice, selective reduction of {alpha}2-isoform and depressed Na+-K+-ATPase activity have been shown to result in hypercontractile activity of the heart (27). It should be pointed out that attenuation of SL remodeling by blockade of RAS may not be the only mechanism for the observed improvement in cardiac function because the drugs used in this study have also been shown to affect other subcellular organelles such as the sarcoplasmic reticulum, myofibrils, and extracellular matrix (8, 14, 37, 40). Thus on the basis of the results presented in this study, it is suggested that blockade of RAS may partly account for the attenuation of changes in SL activities, protein content, and gene expression in the failing heart, and this mechanism may be one of several that contribute in explaining the improved cardiac function in MI-induced heart failure.


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This work was supported by a grant from the Canadian Institutes of Health Research and a grant from the Institute of Circulatory and Respiratory Health on Gene Environment Interaction in Heart Failure.


   FOOTNOTES
 

Address for reprint requests and other correspondence: N. S. Dhalla. Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, 351 Tache Ave., Winnipeg, Manitoba, Canada R2H 2A6 (E-mail: nsdhalla{at}sbrc.ca)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
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 REFERENCES
 

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