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(Circulation. 1997;95:245-251.)
© 1997 American Heart Association, Inc.
Articles |
Beneficial Effects of Amlodipine in a Murine Model of Congestive Heart Failure Induced by Viral Myocarditis
A Possible Mechanism Through Inhibition of Nitric Oxide Production
the Departments of Cardiovascular Medicine (W.Z.W., A.M., T.Y., T.S., I.O., S.M., Y.S., H.S., S.S.) and Anatomy and Development Biology (W.Z.W., K.S.), Kyoto University, Kyoto, Japan.
Correspondence to Akira Matsumori, MD, The 3rd Division, Department of Internal Medicine, Faculty of Medicine, Kyoto University, 54 Kawaracho, Shogoin, Sakyo-ku, Kyoto, 606 Japan.
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Abstract |
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Background Although calcium channel blockers have not been shown to be beneficial for the treatment of patients with heart failure, a recent clinical trial demonstrated a favorable effect of amlodipine on the survival of patients with heart failure resulting from nonischemic dilated cardiomyopathy. We investigated the effects of amlodipine on a murine model of congestive heart failure induced by the M variant of encephalomyocarditis virus (EMCV).
Methods and Results Four-week-old male DBA/2 mice were inoculated with EMCV and administered amlodipine, diltiazem, or vehicle PO for 2 weeks. The heart weight–to–body weight ratio and the histopathological grades of myocardial lesions were significantly lower and survival was significantly increased in the amlodipine-treated group (P<.01, P<.05, and P<.05, respectively) than in the control group. In vitro, amlodipine added to murine J774A.1 macrophages concomitant with EMCV inhibited nitrite formation in a concentration-dependent manner, but diltiazem did not. Furthermore, NG-monomethyl-L-arginine, an inhibitor of NO synthesis, decreased myocardial lesions significantly in this murine model. Immunohistochemistry revealed that the number of cells stained with antibody against an inducible NO synthase decreased significantly in the amlodipine-treated group compared with that in the control group (P<.01).
Conclusions Amlodipine appears to have a protective effect against myocardial injury in this animal model of congestive heart failure. The therapeutic effect of amlodipine may be in part resulting from inhibition of overproduction of NO.
Key Words: myocarditis • heart failure • endothelium-derived factors
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Introduction |
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The therapeutic effects of calcium channel blockers on congestive heart failure are controversial. Diltiazem, a first-generation calcium channel blocker, has been reported to be associated with an increased number of cardiac events and increased risk of congestive heart failure, and it was conclusively demonstrated to involve a hazard in the Multicenter Diltiazem Postinfarction Trials.1 2 More recently, however, amlodipine, a novel calcium channel blocker, was shown to improve the exercise capacity of patients with mild-to-moderate heart failure in a double-blind, placebo-controlled clinical trial,3 and it produced a favorable effect on the survival of patients with heart failure resulting from nonischemic dilated cardiomyopathy in the PRAISE Trial.4 In contrast, few experimental data regarding the effects of amlodipine in the treatment of congestive heart failure have been reported, and the mechanism of action of amlodipine on heart failure has not been clarified.
Recent evidence suggests that oxygen free radicals play an important role in the pathogenesis of viral myocarditis.5 NO, a gaseous free radical, is generated in a large quantity from L-arginine by stimulated endothelial cells, activated macrophages, and other cell types.6 7 8 NO is considered to have an important role in the pathogenesis of a variety of inflammatory and immunological disorders.9 Some evidence suggests that calcium channel blockers can inhibit NO production induced by lipopolysaccharide.10 11 These results imply that amlodipine may be an effective agent in countering congestive heart failure resulting from viral myocarditis as a result of an action in the removal of overproduced NO.
The purpose of the present study was to examine the effects of amlodipine on a murine model of congestive heart failure induced by EMCV and its inhibitory effects on the NO production in the monocyte/macrophage cell line induced by EMCV, J774A.1. The myocardial dilatation and hypertrophy that develop in the chronic stage in our animal model resemble those seen in dilated cardiomyopathy; thus, the model may be considered appropriate to study the effects of amlodipine.
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Methods |
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All experiments were performed in accordance with the "Guidelines for Animal Experiments of Kyoto University."
Virus Stock
The M variant of EMCV was used. The virus stock was prepared as described previously12 13 and had a titer of 1x107 PFU/mL determined by plaque assay using FL (human amnion) cells. The virus stock was stored at -70°C until use.
Chemicals and Reagents
RPMI was obtained from Life Technologies. MTT was purchased from Wako Pure Chemical Industries. Amlodipine was a gift from Pfizer Pharmaceuticals. Diltiazem was a gift from Tanabe Chemical Co. L-NMMA was a gift from Otsuka Pharmaceutical.
Experimental Congestive Heart Failure and Drug Administration
A well-established murine model of congestive heart failure following EMCV myocarditis was used.12 14 A total of 131 four-week-old DBA/2 male mice were purchased from Japan SLC. The mice were inoculated with 10 PFU of EMCV intraperitoneally. The day of virus inoculation was defined as day 0 in the following studies. The mice were observed daily, and after viral inoculation, they were randomly assigned to several groups.
Calcium Channel Blocker Treatment
Calcium channel blockers were orally administered daily to three groups: two consisted of 25 mice each and the third, the control group, consisted of 27 mice. Amlodipine was administered at a dose of 1, 3, or 10 mg/kg; diltiazem was administered at 60 mg/kg; and the control mice were administered an equal volume of distilled water. Mice from each group were randomly assigned to be killed at day 5 (n=5), 7 (n=10), or 14 (surviving mice) after infection to determine myocardial virus titer (day 5) and histopathological changes (day 7).
L-NMMA Treatment
Two groups of 12 mice each received either sterile distilled deionized water alone or that containing 50 mmol/L L-NMMA. Histopathological changes were determined on day 7. For the immunohistochemical study, three groups of 10 mice received distilled water alone, 2.25% L-arginine in drinking water, or amlodipine (10 mg·kg-1·d-1).
Histopathological Examination
Hearts obtained from infected mice were divided into two parts along the long axis. One part was fixed in 10% formalin, embedded in paraffin, stained with hematoxylin and eosin, then observed by microscopy at x200 magnification. Myocardial lesions, including cell necrosis and cellular infiltration, were graded by two observers who were unaware of the treatment group. Histopathological grades were evaluated as follows: 0, no lesions; 1+, lesions involving <25% of the myocardium; 2+, lesions involving 25% to 50% of the myocardium; 3+, lesions involving 50% to 75% of the myocardium; and 4+, lesions involving >75% of the myocardium (Fig 1
).
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Immunohistochemical Staining for iNOS and Macrophages
Frozen sections that were 4 µm thick were thawed on gelatin-coated slides, air dried, and fixed in acetone (10 minutes, -20°C). Nonspecific binding sites were blocked by incubation PBS containing 10% normal goat serum or normal rabbit serum (30 minutes, room temperature) before the addition of the primary antibody (rabbit anti-murine iNOS polyclonal antibody [UBI] or rat F4/80 anti-murine monocytes/macrophages monoclonal antibody [BMA]) (diluted in PBS/0.1% BSA) (overnight, 4°C). Subsequently, the sections were washed three times for 10 minutes with PBS/0.05% Tween 20 and incubated with affinity-purified, biotinylated goat anti-rabbit IgG or biotinylated rabbit anti-rat IgG (Zymed Laboratories) (1 hour, room temperature). They were washed again and overlaid with preformed streptavidin/biotin/peroxidase complex for 1 hour at room temperature. After a final wash, the labeling was visualized with 3,3'-diaminobenzidine and 0.05% H2O2 in acetate buffer (50 mmol/L, pH 5.1). When the first-step antibody was replaced by preimmune serum of an unrelated isotype-matched control antibody, no staining was obtained. Optimal antibody concentrations were determined in several series of pilot experiments. The sections were counterstained with methyl green (Sigma) and mounted.
Immunohistochemical Assay
On day 5, an immunohistochemical study was performed as described previously.15 Briefly, the number of iNOS-positive cells of heart tissue in the infected control group, L-arginine–treated group, and amlodipine-treated group were counted blindly by two observers in six random fields at x400 magnification (within a 1-mm2 grid). The results were then averaged for each group.
Virus Titers of Murine Hearts
Hearts obtained from infected mice on day 5 were weighed and homogenized in 2 mL of EMEM (Nissui Pharmaceutical Co) and then centrifuged at 1500g for 15 minutes at 4°C. Then, the virus titer of the supernatant (0.1 mL) was assayed by FL-plaque assay. Briefly, FL cells were grown to confluent monolayer on six-well plates (Corning) in 4 mL of EMEM supplemented with 10% FCS at 37°C in 5% CO2. The wells were washed with PBS three times. The samples were diluted to 1:10 with EMEM, and 0.1 mL of the diluted samples was inoculated onto the FL cell monolayer followed by incubation for 1 hour with occasional shaking. The wells were then overlaid with 4 mL of EMEM supplemented with 2% FCS and 1% methylcellulose and incubated at 37°C in 5% CO2 for 30 hours. At the end of incubation, the wells were fixed with acidified methyl alcohol and stained with crystal violet, and the plaques were counted. Values are given as the mean of duplicate experiments. The myocardial virus titer was expressed as log10 PFU/mg of heart.
Nitrite Production
J774A.1, a mouse monocyte/macrophage cell line, was obtained from the Japanese Cancer Research Resources Bank and maintained in RPMI containing 10% FBS, penicillin (100 U/mL), streptomycin (100 U/mL), and amphotericin B (25 µg/mL). Nitrite production, an indicator of NO synthesis, was measured as described previously.16 Briefly, the cells were seeded onto 96-well culture plates at 2x105 cells/well. EMCV was infected at an MOI of 1. The same concentration of EMCV exposed to UV irradiation for 30 minutes was added to cells as an inactivated virus control. Amlodipine (10-7 to 10-5 mol/L) and diltiazem (10-7 to 10-5 mol/L) were added simultaneous with EMCV to the cells. The final volume in each well was 200 µL. After a 36-hour incubation, 100 µL of medium was sampled from each well, and 100 µL of Griess reagent (1% sulfanilamide and 0.1% naphthylethylenediamide in 5% phosphoric acid) was added, and the absorbance at 540 nm (A540nm) was then measured with a Molecular Devices microplate reader (Labsystems). Nitrite concentrations were calculated by comparison with the A540nm of standard solutions of sodium nitrite prepared in culture medium.
Cell Viability
To measure the cell viability of J774A.1 cells after infection with EMCV and addition of calcium channel blockers, we assessed the cell respiration by measuring the mitochondria-dependent reduction of MTT to formazan. The MTT reduction assay was performed as previously described.17 Briefly, a 10-µL volume of a stock MTT solution (5 mg/mL in PBS) was added to each well containing J774A.1 cultures after removal of medium for nitrite analysis. After a 4-hour incubation at 37°C in 5% CO2, 100 µL of acid-isopropanol/0.04N HCl was added to each well to stop the reaction. Quantification of MTT reduction was performed by measuring A570nm against a 620-nm reference with the use of a microplate reader.
Statistical Analysis
Survival was analyzed using Kaplan-Meier survival tests. Statistical analyses of all other data were performed with one-way ANOVA. Values are given as mean±SD. Results were considered significantly different at a value of P<.05.
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Results |
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Percent Survival
On day 14, although 4 of 12 mice (33%) survived in the infected control group, 7 of 10 mice (70%) in the amlodipine (10 mg/kg)-treated group and 5 of 10 mice (50%) in the diltiazem (60 mg/kg)-treated group survived (Fig 2A
). The survival in the amlodipine group was significantly higher than that in the infected control group from day 10 through 14 (P<.05). The infected control group receiving no treatment began to die on day 5 after EMCV inoculation, and the majority of the deaths occurred from day 5 through day 7. The diltiazem-treated group also began to die on day 5, and the majority of the deaths occurred between day 9 and 11. However, there was no significant difference in the survival at day 14 between the diltiazem-treated group and the control group. Mice were also administered amlodipine at 1 or 3 mg/kg. However, there was no significant difference in the survival among amlodipine (1 or 3 mg/kg)-treated groups and the control group (Fig 2B). Thus, amlodipine appears to show beneficial effects in a dose-dependent manner mainly at an early stage after viral infection.
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Body Weight, Heart Weight, and Heart Weight–to–Body Weight Ratio
Although the body weights were similar in the three groups (amlodipine 10 mg/kg group, 18.3±0.9 g; diltiazem group, 17.4±1.0 g; control group, 16.4±0.9 g) (Fig 3A), the heart weight was significantly lower in the group treated with amlodipine (10 mg/kg) (85±3 versus 111±7 mg in the control group, P<.05) (Fig 3B). Therefore, the heart weight–to–body weight ratio in mice administered amlodipine (10 mg/kg) (4.7±0.2) was significantly (P<.01) lower than that in the infected control group (6.9±0.7). In the diltiazem group, the heart weight (98±6 mg) and heart weight–to–body weight ratio (5.8±0.6) were not significantly different from those in the control group (Fig 3C).
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Histopathological Examination
Fig 4 shows the pathological grades in each group. The cellular infiltration score and the myocardial necrosis score in the infected control group were 2.3±0.7 and 2.2±1.4, respectively. The cellular infiltration score in the amlodipine (10 mg/kg)-treated group (1.2±0.9) was significantly lower than that in the control group (P<.05). Similarly, the myocardial necrosis score in this group (1.1±0.8) was significantly less severe than that observed in the control group (P<.05). The cellular infiltration score and the myocardial necrosis score of the diltiazem group were 2.0±0.9 and 1.8±1.6, respectively, and there were no significant differences between the diltiazem group and control group (Fig 4).
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Myocardial Virus Titers
The results for myocardial virus titers studied on day 5 were similar in the three groups (Fig 5): the titer was 2.6±1.7 log10 PFU/mg of heart tissue in the infected control group, 2.3±1.6 log10 PFU/mg in mice administered diltiazem at 60 mg·kg-1·d-1, and 2.3±2.0 log10 PFU/mg in mice administered amlodipine at 10 mg·kg-1·d-1. Viral replication in the heart was not influenced by both drugs.
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Effects of Calcium Channel Blockers on Nitrite Production
The nitrite concentration in culture medium of unstimulated cells was 0.46±0.07 µmol/L (n=10), whereas that of J774A.1 cell line stimulated with 1 MOI of EMCV was 1.42±0.14 µmol/L (n=10) and that of inactivated virus–stimulated cells was 0.58±0.10 µmol/L (n=10). Amlodipine at 10-7, 10-6, and 10-5 mol/L inhibited the EMCV-stimulated accumulation of nitrite in a dose-dependent fashion (1.16±0.09, P<.01 versus EMCV stimulated; 0.91±0.08, P<.01; 0.83±0.07 µmol/L, P<.01, respectively), but diltiazem at the same concentrations did not (1.42±0.1, 1.38±0.112, and 1.39±0.138 µmol/L, respectively) (Fig 6). At concentrations of 10-7 to 10-5 mol/L, neither amlodipine nor diltiazem inhibited cellular respiration. At concentrations of 
10-4 mol/L, however, both drugs inhibited nitrite formation and cellular respiration (data not shown).
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Effect of L-NMMA In Vivo
The cellular infiltration score and the myocardial necrosis score in the infected control group were 2.2±0.6 and 1.7±1.0, respectively. The cellular infiltration score in the L-NMMA (50 mmol/L)–treated group (1.1±0.9) was significantly lower than that in the control group (P<.05). Similarly, the myocardial necrosis score in this group (1.0±0.9) was significantly lower than that observed in the control group (P<.05) (Fig 7).
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Immunohistochemistry
On day 7 of infection, iNOS-positive cells were found mainly in the areas near the myocardial lesion, colocalized with numerous macrophages as determined by staining of consecutive tissue sections (Fig 8). iNOS-positive macrophages appeared to be distributed diffusely throughout the tissue. In addition, iNOS immunostaining was seen in the endothelium-like cells (Fig 8). iNOS-positive cells were not found in noninfected murine heart tissue (data not shown).
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There was an increase in the number of iNOS-positive cells in the L-arginine–treated group compared with the infected control group (P<.05), but there was a marked decrease in the amlodipine-treated group compared with the infected control group (P<.01) (Fig 9).
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Discussion |
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The rationale for the use of calcium channel blockers in patients with chronic heart failure lies in their vasodilator action, anti-ischemic effect, and capacity to reduce left ventricular diastolic dysfunction and in the observation of their effect in preventing progression of myocardial dysfunction in animals with cardiomyopathy. Despite initial studies reporting improvement of the hemodynamic profile with nifedipine, further evaluation revealed variable results, with deterioration of patient hemodynamics.18 19 20 21 22 23 24 25 Longer-term controlled studies in which the symptoms and clinical status were evaluated demonstrated progression of chronic heart failure in the patients within the first 8 weeks of nifedipine therapy. Although diltiazem has a lesser myocardial depressant effect and its short-term use is associated with less frequent hemodynamic and clinical deterioration, long-term exposure to the drug in a large group of patients with chronic heart failure resulted in an increased incidence of cardiac events, with progression of heart failure and death.26 27 28 The use of verapamil in a similar patient cohort disclosed the loss of its demonstrated protective effect in patients with clinical evidence of heart failure.29 The use of other calcium channel blockers such as nisoldipine, felodipine, and nicardipine resulted in no change or deterioration of clinical status, which did not seem to be prevented by the concomitant use of ACE inhibitors.30 31 32 33
The mechanism responsible for the clinical deterioration associated with calcium antagonists in heart failure is probably multifactorial. Immediate hemodynamic deterioration as reported by some investigators21 22 23 24 is most likely resulting from the negative inotropic effect of these drugs. Reported clinical deterioration despite hemodynamic improvement29 31 may suggest activation of unfavorable neurohormonal mechanisms34 ; activation of the sympathetic nervous system, the renin-angiotensin system, and vasopressin has been documented with nifedipine24 and nisoldipine.31 A third potential mechanism for clinical deterioration with calcium antagonists in chronic heart failure may be an increase in blood volume as shown by an increase in body weight35 and decrease in hematocrit.25 35
A recent study of the use of amlodipine, a dihydropyridine calcium channel blocker, demonstrated a significantly more marked improvement in exercise time and symptoms, and these favorable changes were associated with a significant reduction in the serum norepinephrine level.3 The more recent clinical trial, PRAISE, disclosed that long-term treatment with amlodipine was not associated with adverse effects on survival or an increase in the combined risk of mortality and life-threatening cardiovascular events.4 The effect of amlodipine appeared to depend on the cause of heart failure. Amlodipine did not improve the morbidity and mortality of patients with heart failure resulting from ischemic heart disease. In contrast, 45% reduction in the risk of death by the use of amlodipine on the survival of patients with heart failure resulting from nonischemic dilated cardiomyopathy has been reported.4
To clarify the effect of calcium channel blockers on congestive heart failure, we investigated the effects of amlodipine and diltiazem in a murine model, and we focused on the influence of NO production. There are few animal models of congestive heart failure suitable for the evaluation of methods of therapeutic intervention. In our murine model of congestive heart failure,12 13 cellular infiltration and myocardial necrosis appear and become prominent in the acute stage of myocarditis, and the surviving mice subsequently develop severe congestive heart failure. This murine model is useful in the investigation of the effects of drugs on congestive heart failure as well as on acute myocarditis.5 14 36 37 38 In this study, amlodipine increased survival at and after day 5, the stage at which the majority of deaths were caused by myocardial damage; the effect was also seen at the stage of congestive heart failure. Amlodipine reduced myocardial damage without a significant effect on viral replication in the heart. Therefore, the effects of amlodipine may result from an altered inflammatory responses or immunomodulating effect during the early stage. Verapamil, another calcium channel blocker, is also known to be an immunomodulator.39 However, verapamil has not produced a significant improvement in survival, although it has been found to be effective in improving histopathological lesions.39
In the in vitro study, our data demonstrated that infective EMCV induces NO production in a murine macrophage cell line but inactivated EMCV did not. The amount of NO produced by EMCV infection was approximately threefold that of untreated or treated macrophages with inactivated EMCV. Amlodipine inhibited the NO production induced by EMCV in a concentration-dependent manner. Our data imply that the NO production is closely related to EMCV infection. Because the virus did not seem to be the direct cause of the induction of the production of NO, the mechanisms of the NO production by EMCV may be the result of increased production of cytokines. We recently reported that the levels of interleukin-1 and tumor necrosis factor–
are increased in patients with myocarditis.40 Macrophages may generate NO in response to cytokines that are induced by EMCV infection. To clarify the mechanism of the effects, we performed a series of related studies. (1) In the in vivo study, an inhibitor of NO synthesis, L-NMMA, ameliorated myocardial damage in our animal model as assessed histologically. (2) In heart tissue, there is enhanced NO production in response to EMCV infection, and the iNOS is produced by various cells, including macrophages. (3) An immunohistochemical study showed that the number of iNOS-positive cells was markedly decreased by treatment with amlodipine but increased by treatment with L-arginine compared with the infected control group.
Recent reports indicate that some dihydropyridine calcium channel blockers inhibit the NO production in mouse macrophage cell lines induced by lipopolysaccharide but that nondihydropyridine blockers do not show this effect. The mechanism of action is considered to be inhibition of iNOS, possibly at the transcriptional level.10 11 Our findings also disclosed that amlodipine inhibited the NO production, whereas diltiazem did not. Verapamil, which is a nondihydropyridine calcium channel blocker, also did not inhibit NO production in vitro.10 This may explain the relatively milder effect of verapamil on the murine model of congestive heart failure compared with amlodipine.39
It is well known that iNOS is a type of calcium-independent NO synthase, and it is not clearly understood how amlodipine interferes with the induction of iNOS. This may occur through inhibition of the cytokine production, which mediates the induction of NOS by EMCV, because dihydropyridine calcium channel blockers are reported to inhibit interleukin-1 production in monocytes and the transcription of interleukin-1 mRNA.41 42
The action of NO is a double-edged sword in that it is beneficial as a messenger or modulator and for immunological self-defense43 44 and it is effective against various microbes (viruses, bacteria, and parasites), but during inflammation and in several classic inflammatory syndromes in which NO production is increased, upregulated NO synthesis becomes destructive to the organism itself.45 46 In this condition, the role of NO becomes deleterious.
Recently, the direct effects of proinflammatory cytokines on the contractility of the mammalian heart were reported. Tumor necrosis factor– inhibits myocardial contractility, and this direct negative inotropic effect of cytokines is largely mediated through myocardial NO synthase.47 48 Another study, which was designed to evaluate the role of iNOS on cardiac myocyte cytotoxicity by exposing adult rat cardiac myocytes to either cytokines alone or activated J774 macrophages in coculture,49 revealed increased expression of iNOS in both macrophages and cardiac myocytes. The increased iNOS expression was associated with a parallel increase in myocyte death. The addition of L-NMMA to the culture medium both prevented the NO production and blocked the cytotoxicity.49 On the other hand, induction of NOS activity in the heart was reported in myocardial samples obtained from patients with dilated cardiomyopathy.50 The overproduction of NO may be a common pathophysiological mechanism leading to heart failure.
Our study showed that (1) EMCV induced NO synthesis in both a macrophage cell line and heart tissues of a murine model of congestive heart failure; (2) NO produced by iNOS deteriorated myocardial injury in our model, as has been reported previously47 48 49 ; (3) amlodipine inhibited NO synthesis in both a macrophage cell line and heart tissues of a murine model of congestive heart failure; (4) amlodipine had beneficial effects in the murine model of congestive heart failure; and (5) L-arginine increased the number of iNOS-positive cells in heart tissues of a murine model of congestive heart failure, and L-NMMA ameliorated myocardial damage in our animal model. Taking these findings together with the contributions of other investigators, we conclude that the beneficial effects of amlodipine in this murine model of congestive heart failure may partly result from inhibition of myocardial NO production.
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This work was supported in part by a grant-in-aid for General Scientific Research from the Japanese Ministry of Education, Science and Culture and by a Research Grant from the Japanese Ministry of Health and Welfare. We thank Drs Y. Matoba, T. Hirozane, Y. Furukawa, T. Nakamura, A. Iwasaki, R. Nishio, M. Okada, C. Mori, M. Ishibashi, and T. Takigawa for helping with this work. We also thank C. Murata, T. Nakano, S. Sakai, M. Hasegawa, and Y. Shimohara for assistance with the manuscript.
Received May 13, 1996; revision received July 31, 1996; accepted August 22, 1996.
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