© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
Role of superoxide anion in the pathogenesis of cytokine-induced myocardial dysfunction in dogs in vivo1
aThe Research Institute of Angiocardiology, Kyushu University School of Medicine, Fukuoka, Japan
bThe Department of Physiology, Tokai University School of Medicine, Isehara, Japan
* Corresponding author. Fax: +81-92-642-5374. E-mail address: shimo@cardiol.med.kyushu-u.ac.jp (H. Shimokawa)
Received 13 July 1998; accepted 16 October 1998
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Abstract |
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Objective: Although studies in vitro have implicated oxygen-derived free radicals as possible mediators of inflammatory cytokine-induced cell injury, the role of the radicals in the cytokine-induced myocardial dysfunction in vivo remains unclear. The present study was designed to address this point in our novel canine model of cytokine-induced myocardial dysfunction in vivo. Methods: Studies were performed in mongrel dogs, in which microspheres (MS, 15 µm in diameter) with and without interleukin-1β (IL-1β) were injected into the left main coronary artery (control and IL-1β group). Left ventricular ejection fraction (LVEF) was evaluated by echocardiography for 1 week. Results: Immediately after the intracoronary injection of MS (106/kg), LVEF equally decreased to approximately 30% in both the control and IL-1β group. While LVEF rapidly recovered within 2 days in the control group, it remained depressed in the IL-1β group until day 7 (p<0.0001 vs. control group). Pretreatment with OPC-6535 (an inhibitor of superoxide production) before (2 mg/kg IV) and 1 and 2 days after IL-1β MS application (1 mg/kg IV) prevented the IL-1β-induced myocardial dysfunction. Superoxide production in the myocardium was significantly higher in the IL-1β group than in the control group at day 2 (p<0.01), and OPC-6535 significantly suppressed the IL-1β-induced superoxide production (p<0.01). An HPLC assay showed that nitrotyrosine, a marker of the formation of peroxynitrite by superoxide anion and nitric oxide, was present in the myocardium treated with IL-1β but not in that with control MS. OPC-6535 abolished the IL-1β-induced formation of myocardial nitrotyrosine. Conclusion: These results indicate that superoxide anion and the resultant formation of peroxynitrite may substantially be involved in the pathogenesis of the cytokine-induced myocardial dysfunction in dogs in vivo.
KEYWORDS Cytokines; Free radicals; Heart failure; Myocytes; Nitric oxide
See Editorial of this article by Bkaily et al. (pages 576–577) in this issue.
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1 Introduction |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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Oxygen-derived free radicals (OFRs) have been implicated in the pathogenesis of myocardial injury (e.g. reperfusion injury [1, 2] and stunned myocardium [3]), reperfusion arrhythmias [2, 4, 5], myocardial inflammation [1], and atherosclerosis [6]. OFRs include superoxide anion (O2–), hydrogen peroxide (H2O2), and hydroxyl radical (·OH). Superoxide anion is known to react with nitric oxide (NO) to form an even more toxic species, peroxynitrite (ONOO–) [7, 8]. Peroxynitrite has been proposed to cause cell injury in a number of pathophysiological conditions in vitro [7, 8]. Inflammatory cytokines participate in the regulation of the early-phase response to inflammation and are well known to induce superoxide production [9–11] and inducible NO synthase (iNOS) expression [12, 13]. However, the role of the superoxide anion in the cytokine-induced cell injury in vivo remains to be fully understood.
We recently developed a canine model of cytokine-induced myocardial dysfunction in vivo, in which long-term treatment with interleukin-1β (IL-1β), a major inflammatory cytokine, causes sustained myocardial dysfunction [14]. IL-1β has been shown to have a similar negative inotropic effect to tumor necrosis factor-
[15, 16]. In this model, we injected the microsphere-bound IL-1β into the left coronary artery in order to selectively treat the heart with the cytokine without causing any direct systemic effect of the cytokine. In this model, it was shown that neutralizing antibody against IL-1β prevented the myocardial dysfunction, indicating that the dysfunction was triggered by IL-1β [14]. In addition, inhibition of iNOS activity by aminoguanidine markedly ameliorated the IL-1β-induced myocardial dysfunction, demonstrating that iNOS-derived NO plays a role in the pathogenesis of the cytokine-induced myocardial dysfunction [14]. However, it remains unclear whether or not overproduction of superoxide anion also contributes to the myocardial dysfunction induced by IL-1β in vivo.
The purpose of the present study was thus to examine whether or not superoxide anion is involved in the pathogenesis of the cytokine-induced myocardial dysfunction in our canine model in vivo. For this purpose, we used OPC-6535, a novel inhibitor of superoxide production [17], as a pharmacological tool to prevent the superoxide production in vivo.
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2 Methods |
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2.1 Animal preparation
The present study was reviewed and approved by the Committee of the Ethics on Animal Experiments in the Kyushu University School of Medicine and according to The Law (No. 105) and Notification (No. 6) of the Japanese Government.
Adult healthy mongrel dogs of both sexes, weighing from 9 to 18 kg, were sedated with ketamine hydrochloride (10 mg/kg IM) and anesthetized with pentobarbital sodium (25 mg/kg IV). Each dog was intubated and mechanically ventilated with room air mixed with oxygen in the supine position. Lactated Ringer solution was administered continuously at a rate of 5 ml/kg/h intravenously to compensate for evaporative fluid losses. A fluid-filled catheter connected to the pressure transducer was advanced into the left ventricle via the left carotid artery for continuous measurement of blood pressure, heart rate and left ventricular end-diastolic pressure (LVEDP). The jugular vein was also cannulated for intravenous administration of drugs and blood sampling.
2.2 Preparation of IL-1β-bound microspheres
One hundred million of colored polyethylene microspheres (MS) (E-Z Trak Co., Los Angeles, USA), which bind the amino residues of protein including cytokines, were centrifuged at 3000 rpm for 5 min. After the supernatant was separated, MS were added to 5 ml of 80% ethanol and suspended in 2 ml of 5 mol/l NaOH solution for 5 min. After centrifugation at 3000 rpm for 5 min, the above procedure was performed twice. MS were added to 5 ml of 80% ethanol and resuspended in 2 ml of 1 mol/l Tris solution for 5 min. After centrifugation at 3000 rpm for 5 min, the above procedure was performed twice. After the addition of 5 ml of 80% ethanol, MS were resuspended in 2 ml of 0.1 mol/l NaHCO3 solution for 5 min. After centrifugation at 3000 rpm for 5 min, MS were resuspended in 2 ml of 0.1 mol/l NaHCO3 solution with 0.1 mg of human recombinant IL-1β. MS were allowed to bind with IL-1β at room temperature overnight. The IL-1β-bound MS were resuspended with 0.2 ml of canine serum for 2 h to coat their remaining surface to avoid any non-specific adsorption. The control MS were also coated in a similar manner with canine serum so that they do not cause any non-specific effects [14]. The IL-1β-bound MS were finally washed and resuspended at 4°C. The molecules of IL-1β were connected to the surface of MS and the final concentration of IL-1β was approximately 1 µg/106 MS/ml. The present technique is based on the industrial one to bind a cytokine to polystylenes, and the stability of the cytokine is almost 100%. All of the above preparations were performed under sterile conditions [14].
2.3 Injection of microspheres
IL-1β was chemically bound to MS with a diameter of 15 µm at a concentration of 1 µg/106 MS as described above. After a Kifa coronary catheter was inserted into the left main coronary via the right carotid artery, IL-1β-bound MS (IL-1β group) or control MS (control group) were injected under fluoroscopy at a dose of 106 MS/kg [14]. We have previously confirmed that IL-1β bound to MS remained in the myocardium by more than 70%, one week after the IL-1β-bound MS injection [14].
2.4 Drug administration
Animals were randomly assigned to the treatment with either control MS (n=13), IL-1β-bound MS (n=14), or IL-1β-bound MS plus OPC-6535, (6-[2-(3,4 diethoxyphenyl)-thiazol-4yl]-pyridine-2-carboxylic acid), an inhibitor of superoxide production (Otsuka Pharmaceutical Co., Tokyo, Japan) (OPC-6535 group, n=12) [17]. OPC-6535 was administered before MS injection (2 mg/kg IV), and at day 1 and day 2 after MS injection (1 mg/kg IV). The present dose of OPC-6535 was determined based on a preliminary study in vitro and in vivo (data not shown). Peripheral venous blood samples were collected for measurement of plasma concentration of OPC-6535 by an HPLC assay immediately after, and 1, 2, 4 and 7 days after the MS injection (the drug administration at day 1 and day 2 was performed after blood sampling).
2.5 Echocardiography
Left ventricular ejection fraction (LVEF) was evaluated by echocardiography using an echocardiogram (SSH-65A Toshiba Medical Co., Tokyo, Japan) on the experimental day under conscious conditions before MS injection and under anesthesia after MS injection, and thereafter under conscious conditions on days 1, 2, 4 and 7 [14].
2.6 Histology and myeloperoxidase assay
On day 2 or day 7, after measuring the hemodynamics as described above, the animals were killed by intravenous injection of an excess dose of pentobarbital sodium. The part of the left ventricle was quickly removed, flash frozen in liquid nitrogen, and then stored at –80°C for later analysis. The rest of the heart was washed and fixed in 6% formalin for at least 24 h. The heart was sliced into transverse sections. Histological samples were taken from each section and stained with hemotoxylin and eosin.
As a specific enzymatic marker of neutrophil infiltration into the myocardium, the activity of myeloperoxidase (MPO) was determined in myocardial tissue, using the method similar to that described by Bradley et al. [18]. Briefly, frozen myocardial tissue samples were homogenized in 0.5% hexadecyltrimethyl ammonium bromide, solubilized in 50 mmol/l potassium phosphate buffer at pH 6.0 using a Physcotron NS-600 tissue homogenizer (Niti-On, Japan) for 10 s, four times at 7000 rpm. Homogenates were freeze–thawed three times and sonicated twice to disrupt the cells, and centrifuged at 4°C for 30 min at 15 000 rpm. The supernatant was added to 0.167 mg/ml o-dianisidine dihydrochloride (Sigma), and 0.005% hydrogen peroxide in 50 mmol/l phosphate buffer at pH 6.0. The change in absorbance was measured spectrophotometrically at 490 nm. MPO activity was normalized using human MPO as a standard [18].
2.7 Measurement of superoxide production
The method for measurement of superoxide production in the myocardium on a lucigenin-chemiluminescence assay was essentially similar to that described previously [19]. Briefly, the frozen myocardium was ground to a fine powder and weighed exactly. One ml phosphate-buffered saline (pH 7.4 and PO2 190–200 mmHg) containing 1 mg lucigenin in a test tube was placed in the measuring chamber of a luminescence reader (BLR-301, Aloka Co., Tokyo, Japan). After the background chemiluminescence was measured for 3 min, the myocardium powder was added into the tube. The chemiluminescence was monitored for 10 min. To test the specificity of the light producing reaction, Tiron (10 mmol/l), a non-enzymatic scavenger of superoxide anion [20], was also added to the IL-1β-treated myocardium before the chemiluminescence measurement. Chemiluminescence data were expressed as counts/minute/mg wet tissue weight (cpm/mg).
We confirmed in a preliminary study the validity of our chemiluminescence assay technique, as the chemiluminescence intensity linearly increased with increasing myocardium content in the normal canine heart (data not shown).
2.8 Detection of nitrotyrosine formation
Nitrotyrosine formation in the myocardium was measured by an HPLC assay as described previously [21]. Briefly, reaction of the superoxide anion with NO generates peroxynitrite, which can decompose to products that nitrate aromatic amino acids. Such nitro-aromatics may be a marker of peroxynitrite-mediated damage in vivo. We evaluated the ratio (%) of nitrotyrosine to tyrosine.
2.9 Statistical analysis
Results are expressed as mean±SEM. Regarding the MPO activity, superoxide production, and nitrotyrosine, the mean of those values in the myocardium perfused by the left anterior descending and circumflex coronary arteries was used.
To analyze the time course of LVEF and of other variables, we first tested differences in the entire time course with an ANOVA for repeated measures, and if significant difference was noted, post-hoc comparisons were performed to compare the variable at each time point by Fisher’s PLSD test. The relationship between myocardial nitrotyrosine concentrations and LVEF was analyzed by a single-variable linear regression analysis. A p value of <0.05 was considered to be statistically significant.
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3 Results |
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3.1 Time course of LVEF after MS injection
Fig. 1 shows the time course of LVEF evaluated by echocardiography after MS injection for 1 week. The injection of IL-1β-bound or control MS caused a comparable degree of decrease in LVEF in both groups (36±2% vs 31±3%). LVEF in the control group rapidly recovered to the baseline levels within 2 days, whereas in the IL-1β group the myocardial dysfunction was sustained until day 7 (Fig. 1). Administration of OPC-6535 before MS injection did not alter systemic arterial pressure, heart rate or left ventricular pressure (data not shown). OPC-6535 completely prevented the IL-1β-induced sustained myocardial dysfunction in vivo (Fig. 1). OPC-6535 alone did not alter the recovery of LVEF in the control group (n=2, data not shown).
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3.2 Plasma concentration of OPC-6535
The plasma concentration of OPC-6535 (µg/ml) immediately after, and 1, 2, 4, and 7 days after the MS injection was 16.3±2.1 (n=12), 12.0±2.5 (n=12), 9.3±3.2 (n=11), 2.9±1.1 (n=6), and 0.23±0.13 (n=6), respectively. When expressed in molar concentration, the plasma concentration of OPC-6535 (x10–5 mol/l) at those five points was 4.4±0.6, (n=12), 3.2±0.7 (n=12), 2.5±0.9 (n=11), 0.8±0.3 (n=6), and 0.06±0.04 (n=6), respectively. (The effective concentration of OPC-6535 to inhibit the superoxide production by canine neutrophils in vitro is >10–5 mol/l.)
3.3 Hemodynamics
Hemodynamic variables in the three groups are shown in Table 1. There was no significant difference in mean aortic pressure or heart rate among the three groups at any experimental period. However, LVEDP was significantly elevated in the IL-1β group on day 2 compared with the control group. OPC-6535 prevented the IL-1β-induced elevation of LVEDP on day 2.
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3.4 WBC counts and CPK-MB levels
White blood cell count in peripheral blood was significantly greater in the IL-1β group than in the control group on day 2 (Table 2). Such increase was prevented in the OPC-6535 group on day 2. Plasma creatine phosphokinase-MB (CPK-MB) levels peaked on day 1 in all the three groups and there was no significant difference in the levels among the three groups (Table 2).
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3.5 Neutrophil infiltration in the myocardium
Histological examination showed that the IL-1β-treated myocardium but not the normal myocardium had an intense neutrophil infiltration on day 2 (Figs. 2 and 3
). However, the treatment with OPC-6535 had no inhibitory effect on the neutrophil infiltration induced by IL-1β (Figs. 2 and 3).
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Similarly, neutrophil-specific MPO activity was two times greater in the IL-1β group than in the control group on day 2 (Fig. 4). Although the MPO activity tended to be reduced in the OPC group compared to the control group on day 2, the difference in the MPO activity between the two groups was not statistically significant (Fig. 4).
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3.6 Superoxide production in the myocardium
Superoxide production was about three times higher in the IL-1β group than in the control group on day 2 (Fig. 5). The treatment with OPC-6535 almost abolished the IL-1β-induced superoxide production on day 2 to the levels seen in the control group or to those acutely achieved by Tiron, a scavenger of superoxide anion (Fig. 5).
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3.7 Nitrotyrosine formation in the myocardium
The concentrations of nitrotyrosine were significantly higher in the IL-1β group than in the control group on both day 2 and day 7 (Fig. 6). OPC-6535 abolished the IL-1β-induced nitrotyrosine formation on both day 2 and day 7 (Fig. 6).
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Nitrotyrosine is a stable substance [22]. In the present study, there was no significant increase in the myocardial nitrotyrosine concentrations from day 2 to day 7, which suggests that no significant amount of nitrotyrosine was formed between day 2 and day 7. Thus, in animals that were followed-up until day 7, LVEF on day 2 was analyzed with the nitrotyrosine levels on day 7. There was a significant positive linear relationship between myocardial superoxide production and nitrotyrosine concentrations (r=0.43, p<0.01). Furthermore, there also was a significant inverse linear relationship between myocardial nitrotyrosine concentrations and LVEF on day 2 (Fig. 7).
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4 Discussion |
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The novel findings of the present study were that (a) superoxide production and the resultant formation of peroxynitrite may play an important role in the pathogenesis of the cytokine-induced myocardial dysfunction in vivo, and (b) neutrophil infiltration per se or subsequent increase in MPO activity in the myocardium may not play a primary role in the cytokine-induced myocardial dysfunction. To the best of our knowledge, this is the first report that demonstrated the important role of the superoxide anion in the pathogenesis of the cytokine-induced myocardial dysfunction in vivo.
4.1 Role of superoxide anion in the cytokine-induced myocardial dysfunction in vivo
There is increasing evidence that inflammatory cytokines could induce excessive OFR production in vitro [9–11]. It is well known that OFRs play an important role in the pathogenesis of myocardial injury in a variety of clinical conditions [1–6]. OFRs have been suggested to exert their cytotoxic effect by causing peroxidation of membrane phospholipids, which can result in an increase in membrane fluidity and permeability, and eventually in the loss of membrane integrity [23, 24]. OFRs have also been reported to affect myocardial excitation–contraction coupling and depress the myocardial contractility and cardiac function [3, 25, 26]. However, the in vivo role of OFRs in cytokine-induced myocardial dysfunction remains unclear. We thus examined this point in our new canine model in vivo.
We found that intracoronary injection of IL-1β-bound MS caused sustained myocardial dysfunction for 1 week, and that the superoxide production in the myocardium was about three times higher in the IL-1β group than in the control group on day 2. The novel inhibitor of superoxide production, OPC-6535 [17], completely prevented the myocardial dysfunction and simultaneously reduced the superoxide production and the nitrotyrosine formation to the levels seen in the control group. These results indicate that the superoxide anion and the resultant formation of peroxynitrite may substantially be involved in the pathogenesis of the cytokine-induced myocardial dysfunction in our canine model in vivo.
Natanson et al. [26] previously observed that during the course of continuous infusion with TNF-, cardiac function was first reduced and then normalized in 7–10 days. Although the exact cause for the more sustained myocardial dysfunction in our model is unknown, it is conceivable that the local concentration of inflammatory cytokine was higher in our model.
LVEDP was significantly elevated immediately after MS injection in all three groups. Since there was no statistical difference in the elevation among the three groups, it was likely to be caused by the direct effect of MS embolization (including myocardial ischemia and subsequent small myocardial necrosis as evidenced by the elevated CK-MB values). The difference in LVEDP between the IL-1β group and the control or OPC group was noted only on day 2, which appears to represent the difference in the global LV function as evidenced by LVEF.
4.2 Possible sources of superoxide anion
We used a lucigenin-dependent chemiluminescence method for monitoring the superoxide production in the present study. The specificity of this method has been previously reported [20, 27]. We also confirmed the specificity of this method in the present study, using Tiron, a non-enzymatic scavenger of the superoxide anion [20].
In the cardiovascular system, sites of superoxide production may include myocardial tissue (especially the mitochondria of myocytes injured by ischemia), and the microvascular endothelial cells that possess the enzyme xanthine oxidase and arachidonate metabolism [1, 3]. Furthermore, neutrophils may play a significant role in this respect [28]. In the present in vivo model, we have observed that the neutrophil infiltration, as shown by histological findings and MPO activity, were markedly increased in the IL-1β-treated myocardium. OPC-6535 is not a scavenger of superoxide and is not an inhibitor of xanthine oxidase but inhibits superoxide production primarily by suppressing activation of NADPH oxidase in neutrophils [17]. It is conceivable that the activated neutrophils in the myocardium may be a major source of superoxide production in our model in vivo. Indeed, we have recently demonstrated that the inhibition of neutrophil infiltration by adhesion molecule inhibitors also prevents the IL-1β-induced sustained myocardial dysfunction in our present model in vivo [29]. However, it is unclear what mechanism actually contributed to superoxide production in our model. Further research is needed to elucidate this point.
4.3 Inhibitory effects of OPC-6535 on superoxide production
Two approaches seem to be effective to prevent myocardial injury caused by the superoxide anion. One is to scavenge the superoxide anion, and the other is to inhibit the production of the radical. Various types of scavengers of superoxide anion are known, including superoxide dismutase (SOD), SOD mimetics, and others [30, 31]. By contrast, no drug has yet been developed as an inhibitor of superoxide production.
OPC-6535 is a novel thiazol derivative compound, which has been demonstrated to have a unique profile to potently inhibit superoxide production by neutrophils with NADPH oxidase [17]. We chose this agent in the present study for the following reasons. First, OPC-6535 is an inhibitor rather than a scavenger of the superoxide anion [17]. Second, OPC-6535 directly acts on neutrophils to inhibit superoxide production [17]. As discussed above, the activated neutrophils infiltrating into the myocardium may be a major source of superoxide production in our canine model. Third, OPC-6535 has no direct action on heart rate, left ventricular pressure, coronary blood flow, or myocardial contractility, as shown in the present study, which may enable the elucidation of the role of the superoxide anion.
The present study also clearly demonstrated that OPC-6535 potently inhibits superoxide production in vivo without affecting the neutrophil infiltration or the subsequent increase in myocardial MPO activity [17].
4.4 Role of peroxynitrite in the cytokine-induced myocardial dysfunction in vivo
The superoxide anion is known to react with NO to form an even more toxic agent, peroxynitrite [7, 8]. Peroxynitrite is a highly reactive species capable of oxidizing many organic molecules, and thus could be involved in many pathological processes that are associated with simultaneous overproduction of superoxide anion and NO [7, 8, 22, 32, 33]. Lipton et al. [34] demonstrated that peroxynitrite exerts a cytotoxic effect in isolated cells, whereas neither superoxide anion nor NO causes significant cell damage. Ishida et al. [35] have also shown that peroxynitrite could induce myocardial injury through disturbance of calcium transport systems and thus could impair the functions of contractile proteins.
A major product from the spontaneous reaction of peroxynitrite with proteins is nitrotyrosine, which represents a specific protein modification mediated by peroxynitrite, and thus may be applied as a marker for peroxynitrite [22, 32, 33]. Eiserich et al. [36] recently raised a question about the validity of nitrotyrosine as a specific marker of peroxynitrite formation in vivo. They showed that nitrite (a major endproduct of NO) itself can promote tyrosine nitration in the presence of MPO in polymorphonuclear neutrophils [36]. However, we were unable to detect any peak of chlorotyrosine (data not shown), which should be co-generated with nitrotyrosine in such a nitrite–MPO-related reaction [36]. Thus, at least in our canine model of cytokine-induced myocardial dysfunction, the formation of nitrotyrosine appears to be mediated predominantly by peroxynitrite in vivo.
In this study, we observed that the production of nitrotyrosine was significantly increased in the IL-1β-treated myocardium, and that the inhibition of superoxide production by OPC-6535 almost completely prevented the IL-1β-induced myocardial dysfunction as well as the nitrotyrosine production. We previously showed that inhibition of NO synthesis also exerts the similar cardioprotective effect [14]. Taken together, these results indicate that peroxynitrite, formed by superoxide anion and NO, may play an important role in the IL-1β-induced myocardial dysfunction in vivo.
4.5 Clinical implications
Congestive heart failure (CHF) is a common cardiovascular condition that is increasing in incidence, prevalence, and mortality. Inflammatory heart diseases, such as myocarditis and cardiomyopathy, are one of the major causes of CHF. Cytokines are increasingly recognized as an important factor in the pathogenesis and pathophysiology of myocarditis and cardiomyopathy. Elevated circulating cytokines have been reported in patients with heart failure [37, 38], and various cytokines have been shown to depress myocardial contractility both in vitro and in vivo [39, 40]. However, the detailed mechanisms for the cytokine-induced myocardial dysfunction in vivo have not been elucidated. In the present study, we demonstrated, for the first time, the possible important role of the superoxide anion in the pathogenesis of the cytokine-induced myocardial dysfunction in vivo. We recently observed that TNF- also induces sustained myocardial dysfunction in our canine model (unpublished observation). In the present study, we also showed that OPC-6535, a novel inhibitor of superoxide production, could significantly attenuate the cytokine-induced myocardial dysfunction in vivo. These results may provide a new approach for the treatment of inflammatory cardiovascular diseases, such as myocarditis and myocardial ischemia/reperfusion injury in humans. However, it remains to be elucidated whether or not such cytokine-related inflammatory mechanisms are involved in the pathophysiology of the syndrome of CHF.
Time for primary review 28 days.
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Acknowledgements |
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The authors wish to thank Y. Ohmoto, M. Ikeda, G. Miyakoda, and T. Mori, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan, for cooperation in this study. This work was supported in part by grants from the Japanese Ministry of Education, Science, Sports and Culture, Tokyo, Japan, and by grant-in-aid from the Pfizer Foundation for Cardiovascular Research, Tokyo, Japan.
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Notes |
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1 This work was presented in part at the 70th Scientific Sessions of the American Heart Association, Orlando, Florida, November 9–12, 1997.
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