1 The Third Department of
Internal Medicine, To investigate the
role of increased polyol pathway activity and hemodynamic deficits in
the pathogenesis of diabetic retinopathy in non-insulin-dependent
diabetes mellitus (NIDDM), Otsuka Long-Evans Tokushima fatty (OLETF)
rats, an animal model of human NIDDM, were given water with or without
30% sucrose and some of them were fed laboratory chow containing
0.03% cilostazol, an anticoagulant, or 0.05%
[5-(3-thienyl)tetrazol-1-yl] acetic acid monohydrate (TAT),
an aldose reductase inhibitor, for 8 wk. Long-Evans Tokushima Otsuka
(LETO) rats were used as nondiabetic controls. The peak latencies of
oscillatory potentials of the electroretinogram in sucrose-fed OLETF
rats were significantly prolonged compared with those in OLETF rats
without sucrose feeding and LETO rats. There was a marked increase in
platelet aggregability and a significant decrease in erythrocyte
2,3-diphosphoglycerate in sucrose-fed OLETF rats. Cilostazol
significantly improved these parameters without changes in retinal
levels of sorbitol and fructose. TAT, however, ameliorated all of these
parameters. These findings confirm that the sucrose-fed OLETF rat is a
useful animal model of retinopathy in human NIDDM and suggest that
cilostazol improved diabetic retinopathy by modifying vascular factors,
not by altering polyol pathway activity.
Otsuka Long-Evans Tokushima fatty rats; cilostazol; platelet
aggregation; red blood cell 2,3-diphosphoglycerate; polyol pathway; [5-(3-thienyl) tetrazol-1-yl] acetic acid monohydrate
DIABETIC RETINOPATHY is a serious medical complication
of diabetes mellitus without available and effective medical therapy for its prevention. A variety of hypotheses concerning the etiology of diabetic retinopathy, which is extremely complex, have been proposed, including factors such as metabolic, endocrine, and hemodynamic abnormalities. The hemodynamic factors, including platelet
aggregation and red blood cell 2,3-diphosphoglycerate (RBC 2,3-DPG),
appear to have a complex etiology and, in fact, may be caused
secondarily by some of the metabolic changes. Rheological abnormalities
are likely to contribute to the reduction of the retinal blood flow,
and the consequent retinal hypoxia has been suggested to be a major
factor in the pathogenesis of diabetic retinopathy. Various
vasodilators have been reported to have a therapeutic effect on
experimental diabetic neuropathy (3). In our previous study (15), a
vasodilatory and anticoagulant agent, cilostazol (23), prevented the
development of diabetic neuropathy with a concomitant increase in
endoneurial blood flow and a decrease in platelet aggregation activity,
which suggests that cilostazol may possess an efficacy of preventing
diabetic retinopathy. On the other hand, increased polyol pathway
activity, which has been a leading metabolic contender for the
pathogenesis of diabetic complications, has been recently considered to
link to other pathogenic factors, especially vascular factors (3, 4,
30). Moreover, inhibition of polyol pathway hyperactivity is known to
improve electroretinographic abnormalities in both animals (16, 19, 20,
26) and humans (1) and may possibly delay and/or prevent the
development of diabetic retinopathy.
Diabetic retinopathy has been studied in animal models of
insulin-dependent diabetes mellitus (IDDM) (6, 10, 19, 20, 26) but not
in those of non-insulin-dependent diabetes mellitus (NIDDM). Clinical
and pathophysiological characteristics of retinopathy in NIDDM would
differ from those in IDDM, because neuropathological features of
diabetic neuropathy in NIDDM are not consistent with those in IDDM
(27). Therefore, it is very important to establish a useful animal
model of NIDDM to study the pathogenesis of diabetic retinopathy.
Otsuka Long-Evans Tokushima fatty (OLETF) rats established as an animal
model of human NIDDM by Kawano et al. (17) develop diabetic neuropathy
by sucrose administration (15, 22). Thus sucrose-fed OLETF rats would
be a suitable animal model to investigate the pathogenesis of diabetic
retinopathy in NIDDM.
The electroretinogram (ERG) provides a reliable means of evaluating
retinal function and also provides early warning of retinal abnormalities before ophthalmoscopically visible alterations are detectable in diabetes (31). Damage of the Müller (glial) cells of the retina due to diabetes occurs before the retinal blood vessels
are affected (28), and the B wave of the ERG is known to be related to
Müller cell function (21). Changes in the peak latencies of
oscillatory potentials are more significant than those of the B wave
amplitude in rats with early diabetes (18).
The present study was conducted to investigate the role of increased
polyol pathway activity and hemodynamic deficits in the pathogenesis of
diabetic retinopathy in NIDDM. Sucrose-fed OLETF rats were treated with
cilostazol or an aldose reductase inhibitor, [5-(3-thienyl)tetrazol-1-yl] acetic acid monohydrate (TAT)
(11, 16), for 8 wk. The effects of these two agents on oscillatory potentials of the ERG, free sugar, and polyol content in the retina, platelet aggregation, and the RBC 2,3-DPG levels were compared.
Animals.
Five-week-old male OLETF and Long-Evans Tokushima Otsuka (LETO) rats as
nondiabetic controls (15, 17) (Tokushima Research Institute, Otsuka
Pharmaceutical, Tokushima, Japan), weighing 130-140 g and
120-130 g, respectively, were used in this study. They were housed
in the animal facility for 25 wk before use; they were kept in a clean
room at 23 ± 1°C and a relative humidity of 50 ± 10%, with
a 12:12-h light-dark cycle and 12 changes of fresh air per hour. They
were allowed free access to rat chow (CA-1, Clea, Tokyo, Japan) and tap
water. After 25 wk, the OLETF rats were randomly divided into four
groups of nine rats each and the LETO rats into two groups of nine rats
each, as shown in Fig. 1. One OLETF group
and one LETO group were allowed free access to laboratory chow and
plain water, and the other three OLETF groups and the other LETO group
were allowed free access to water containing 30% sucrose (Katayama
Chemical, Tokyo, Japan) for 8 wk. Of the three OLETF groups given
sucrose, one group was allowed free access to laboratory chow, one
group received chow containing 0.03% cilostazol and one group received
chow containing 0.05% TAT.
ABSTRACT
Top
Abstract
Introduction
Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References
METHODS
Top
Abstract
Introduction
Methods
Results
Discussion
References
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Fig. 1.
Design of present study. LETO, Long-Evans Tokushima Otsuka; OLETF,
Otsuka Long-Evans Tokushima fatty; TAT,
[5-(3-thienyl)tetrazol-1-yl] acetic acid monohydrate.
Measurement of ERG. The rats were adapted to darkness for at least 20 min and then anesthetized by the intraperitoneal injection of a mixture of 50 mg/ml ketamine (Ketalar 50; Sankyo Pharmaceutical, Tokyo, Japan), 25 mg/ml xylazine (Seructal; Bayer Japan, Tokyo, Japan), and physiological saline (10:1:11) at a dose of 0.2 ml/100 g body weight. The ERG was done by the method of Segawa et al. (26), as described in our other studies (14, 16). Monocular recordings were obtained with the pupil maximally dilated by instillation of Mydrin P (Santen Pharmaceutical, Osaka, Japan). Photic stimulation was delivered from a xenon lamp (3G21-P, San-ei, Tokyo, Japan) at an intensity of 1 J, with a 20-s interstimulus interval. Using a contact lens-type electrode, the ERG was amplified (AVB-10, Preamplifier, Nihon Koden, Osaka, Japan) with a time constant of 0.3 s and displayed on an oscilloscope (VC-10, Nihon Koden). Groups of five potentials were summated using a signal averager (DAT-1100, Nihon Koden) that also provided a recording (WX 2400 X, Y-recorder, Graphtec, Tokyo, Japan) of the averaged ERG. The peak latency was measured as the interval between stimulus onset and the peak of the corresponding oscillatory potentials, and the latencies were designated as O1, O2, O3, and O4, in order of superimposition on the B wave, as described previously (14, 16, 26).
Determination of retinal sorbitol and fructose.
The contents of sorbitol and fructose in the retina were determined by
gas-liquid chromatography, as described previously (15). Under diethyl
ether (Katayama Chemical), the retinas were removed and blood was
obtained from the abdominal aorta at 3-5 h after administration of
the final food containing cilostazol or TAT. The retinas were weighed
immediately and frozen at 70°C until the sorbitol and
fructose contents were determined.
Assessment of platelet aggregation. Before removal of the retinal tissues, blood was collected from the abdominal aorta under anesthesia and 4.5 ml of it were mixed with 1.0 ml of 3.8% trisodium citrate. A platelet suspension was prepared according to the method described previously (8, 15). Briefly, the citrated blood was centrifuged at 120 rpm for 10 min at room temperature. The upper portion of the supernatant was taken as platelet-rich plasma and recentrifuged at 1,100 rpm for 10 min at room temperature, after which the resultant platelet pellet was suspended in modified Tyrode's balanced salt solution (TBSS, pH 7.35) containing 0.35% bovine serum albumin without calcium and magnesium. The platelet concentration was measured with a Celltac MEK-5108 (Nihon Koden) and was adjusted to 300,000/mm3 with modified TBSS. Then 100 µl of this platelet suspension were placed in an NBS Hematracer 601 (Niko-Bioscience, Tokyo, Japan) and 2.0 µM ADP-induced platelet aggregation was measured by turbidimetry with constant stirring at 1,000 rpm. ADP was dissolved in modified TBSS with calcium and magnesium. Deionized distilled water was used as a substitute for platelet-poor plasma, and the largest percent difference in light transmittance between this water and the platelet sample was used as an indicator of platelet aggregation.
Measurement of RBC 2,3-DPG. Blood obtained from the abdominal aorta was treated with 0.6 mM HClO3 to precipitate protein and then was centrifuged at 3,000 rpm for 10 min. The supernatant was neutralized with 2.5 mM KCO3 and again centrifuged at 3,000 rpm for 10 min. The final supernatant was assayed enzymatically for 2,3-DPG using a 2,3-DPG ultraviolet test kit (Boehringer Mannheim, Mannheim, Germany). The hematocrit was simultaneously measured with microhematocrit tubes centrifuged at 15,000 rpm for 5 min, and the 2,3-DPG concentration was expressed in micromoles per milliliter of RBCs, as described previously (24, 28).
Measurement of serum glucose, triglycerides, and insulin. Untreated blood obtained from the abdominal aorta was centrifuged at 3,000 rpm for 10 min, after which aliquots of serum were tested as described previously (11, 13). Triglycerides was measured by enzymatic methods (Determiner TG-S, Kyowa Medex, Tokyo, Japan). Serum insulin was measured by a radioimmunoassay (Insulin Riabeads, Dainabot, Tokyo, Japan), and serum glucose was determined using an autoanalyzer (Enzyme Electrode Analyzer AS 200, Toyo Jozo, Tokyo, Japan).
Drugs and other chemicals. Cilostazol and TAT were kindly provided by Otsuka Pharmaceutical (Tokushima, Japan) and Wakamoto Pharmaceutical (Tokyo, Japan), respectively. The other reagents and enzymes used in this study were purchased from Sigma Chemical (St. Louis, MO) or Wako Pure Chemical Industries.
Statistical analysis. Results are expressed as the means ± SE. Differences between experimental groups were investigated by analysis of variance, and the significance of differences between groups was assessed by Scheffé's S-test. A probability value <0.05 was taken to indicate significance.
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RESULTS |
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Body weight, serum glucose, serum triglycerides, and serum insulin. The changes in body weight as well as serum glucose, triglycerides, and insulin levels for all groups are shown in Table 1. At the beginning of the experiment, the OLETF rats were heavier than the LETO rats. After administration of sucrose for 8 wk, however, OLETF rats showed significant weight loss, whereas LETO rats showed no changes.
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Effect of cilostazol and TAT on ERG.
There were no significant differences in the peak latency of each
oscillatory potential (O1,
O2,
O3, and
O4) among all of the experimental
groups. However, sucrose administration tended to prolong that in OLETF
rats, and significant prolongation of the summated peak latency
[(O1 + O2 + O3 + O4)] was observed in
sucrose-fed OLETF rats. This prolongation in sucrose-fed OLETF rats was
reduced by treatment with cilostazol or TAT, neither of which had any
effects on the peak latencies of oscillatory potentials in control
OLETF rats.
Effects of cilostazol and TAT on retinal sorbitol and fructose levels. The sorbitol and fructose levels in the retina are shown in Table 3. Sucrose administration caused a marked elevation of the sorbitol and fructose levels in OLETF rats but had no effect on any of these parameters in LETO rats. TAT treatment significantly decreased the elevated retinal sorbitol and fructose levels in sucrose-fed OLETF rats, whereas cilostazol failed to reduce them. Neither TAT nor cilostazol had any significant effects on sorbitol and fructose levels in control OLETF rats.
Effects of cilostazol and TAT on platelet aggregation and RBC 2,3-DPG level. The effects of sucrose administration and treatment with cilostazol or TAT on ADP-induced platelet aggregation and the RBC 2,3-DPG level are shown in Table 4. Sucrose administration caused a significant increase in platelet aggregation and a marked reduction in the RBC 2,3-DPG level in OLETF rats, but these effects were not observed in LETO rats. Although neither cilostazol nor TAT affected platelet aggregation or the RBC 2,3-DPG level in control OLETF rats, treatment with either cilostazol or TAT significantly inhibited the changes of these two parameters in sucrose-fed OLETF rats. However, the inhibitory effect of cilostazol on platelet hyperaggregability appeared more prominent than that of TAT.
Correlations between hematological changes and the ERG oscillatory
potentials.
The correlations between the sum of peak latencies of oscillatory
potentials in ERG [(O1 + O2 + O3 + O4)] and platelet aggregation, the RBC 2,3-DPG level, or retinal polyol content were calculated in
OLETF rats (Table 5). There were significant correlations between the
sum of peak latencies of oscillatory potentials and platelet
aggregation as well as the RBC level of 2,3-DPG. However, the sum of
peak latencies does not significantly correlate with retinal sorbitol
and fructose content.
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DISCUSSION |
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In the present study, OLETF rats were used as a model of human NIDDM in which the peak latencies of the oscillatory potentials of the ERG were not significantly prolonged compared with those in LETO control rats. However, it was clearly shown that administration of sucrose to OLETF rats for 8 wk worsened the ERG, whereas there was no change in sucrose-fed LETO rats as a model of nondiabetic controls. These changes in sucrose-fed OLETF rats were accompanied by a significant increase in platelet aggregation and a marked decrease in the RBC 2,3-DPG level. In addition, the anticoagulant cilostazol significantly reversed all these parameters observed in sucrose-fed OLETF rats, even though this drug had no effect on the retinal levels of sorbitol and fructose. On the other hand, the aldose reductase inhibitor TAT significantly reversed all these changes, including the increased retinal levels of sorbitol and fructose.
Most experimental studies on diabetic retinopathy have employed animal
models of IDDM, with typical ones being rats with
streptozotocin-induced diabetes (10, 19, 20, 26) and dogs with
alloxan-induced diabetes (6). In contrast, there have been no studies
on diabetic retinopathy using animal models of NIDDM. OLETF rats were
established by Kawano et al. (17) as an animal model of human NIDDM,
which develop kidney changes similar to those of humans and also
diabetic neuropathy by sucrose administration (15, 22). However,
diabetic retinopathy has not yet been investigated using this model.
The plasma glucose level of male OLETF rats becomes higher than that of
LETO rats from 18 wk of age (17). At 24 wk, the elevation of plasma
glucose with oral glucose loading is marked in OLETF rats compared with
LETO rats, and the plasma insulin level is also higher in OLETF rats.
These responses of OLETF rats to oral glucose loading became
significantly more abnormal over time until 65 wk of age (17). As shown
in Table 2, there were no differences in
the peak latencies of the ERG oscillatory potentials at
O1, O2,
O3,
O4 and
(O1 + O2 + O3 + O4) between LETO and OLETF control rats at 38 wk of age. However, sucrose administration to OLETF rats
prolonged peak latencies of each oscillatory potential at O1,
O2,
O3, and
O4 and caused significant prolongation
of the summated peak latencies of oscillatory potentials
[
(O1 + O2 + O3 + O4)]. Thus the present
findings suggest that the resistance of OLETF rats to the development
of diabetic retinopathy may be related to the slight elevation of serum
glucose and the mild changes in hyperglycemia-induced metabolic
abnormalities.
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The vertebrate ERG evoked with high-intensity light stimuli exhibits a series of rhythmic, low-amplitude potentials superimposed on the B wave. These rhythmic waves are called the oscillatory potentials (31). Among the various properties of these wavelets, the B wave is physiologically well defined and has been analyzed exhaustively. Although the exact site at which the oscillatory potentials are generated is not yet known, it is possible that the earlier oscillatory peaks arise more proximally within the retina than the later ones, suggesting that the individual oscillatory peaks are likely to have different origins. The first three oscillatory potentials are at the level of the inner plexiform layer, and the neural events may generate the later oscillatory potentials. As shown in Table 2, treatment by both cilostazol and TAT improved the ERG abnormalities in sucrose-fed OLETF rats and completely restored them to the values in OLETF control rats. This effect of TAT seems to be stronger in sucrose-fed OLETF rats than in streptozotocin-induced diabetic rats, in which TAT failed to normalize the prolongation of the peak latencies of oscillatory potentials (16). Thus it is likely that the oscillatory potential abnormalities in sucrose-fed OLETF rats as a model of NIDDM are less severe than those in streptozotocin-induced diabetic rats as a model of IDDM.
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The intake of high dietary sucrose consisting of equimolar concentrations of fructose and glucose has been shown to produce vascular changes (24) and endoneurial edema (25) in nondiabetic rats, and microvascular abnormalities (24) and alterations of Na+-K+-ATPase activity in the impaired nerves of diabetic rats (29) and also abnormalities of nerve functions and blood flow in OLETF rats (15, 22). In addition, a high-fructose diet causes a significant delay of motor nerve conduction velocity with the marked elevation of nerve tissue level of sorbitol and fructose (9) as well as the development of marked retinal morphological changes (10) in streptozotocin-induced diabetic rats. Thus it is not surprising that sucrose administration induced the ERG abnormality in OLETF rats. The data in Tables 3 and 4 suggest that sucrose administration stimulated polyol pathway activity and/or altered hematological properties, resulting in the development of diabetic retinopathy. However, treatment with cilostazol significantly improved the ERG abnormality in sucrose-fed OLETF rats without causing any changes in the retinal sorbitol and fructose levels, whereas a significant decrease of platelet aggregation and an increase in the RBC 2,3-DPG level were observed. Thus it seems unlikely that the effects of cilostazol were related to inhibition of polyol pathway hyperactivity. On the contrary, TAT treatment reversed all these parameters, resulting in the improvement of the ERG abnormality in sucrose-fed OLETF rats. The results obtained in the present study indicate that hemodynamic factors, including rheological elements such as platelet aggregation and the RBC 2,3-DPG level, are important for the development of diabetic retinopathy and also that drugs that ameliorate the rheological abnormality may prevent and/or delay the development of diabetic retinopathy.
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It is well known that vascular factors, including blood rheological properties, are involved in the pathogenesis of diabetic retinopathy. Microcirculatory abnormalities can lead to retinal hypoxia, which in turn leads to metabolical, functional, and finally structural impairment. In fact, our previous report (14) demonstrated that a vasodilatory agent ameliorated the ERG abnormalities in streptozotocin-induced diabetic rats. Thus hypoxia due to platelet hyperaggregability and a reduced RBC 2,3-DPG level may have been the primary cause of impaired retinal function in our sucrose-fed OLETF model, as was the case in a previous study of sucrose-fed diabetic rats with nerve dysfunction (29). Cilostazol is a potent antithrombotic agent that inhibits platelet aggregation and has a vasodilatory action (23). In the present study, the finding that cilostazol significantly reduced ADP-induced platelet aggregation in sucrose-fed OLETF rats suggests that the amelioration of the ERG abnormality with cilostazol treatment was related to improved endoneurial microcirculation. Because TAT inhibits platelet hyperaggregability in diabetic rats (8, 16), the same mechanism may play a role in the effect of this agent on the ERG abnormality.
The RBC 2,3-DPG level was significantly reduced in sucrose-fed OLETF rats and was normalized by both cilostazol and TAT treatments (Table 4). The 2,3-DPG in erythrocytes has a high affinity for hemoglobin and is important in the regulation of oxygen binding. A low level of 2,3-DPG in erythrocytes is observed in patients with diabetic ketoacidosis (5) as well as in rats with streptozotocin-induced diabetes (13). In our previous study, the reduced RBC 2,3-DPG level and decreased sciatic nerve blood flow in diabetic rats were markedly improved by treatment with niceritrol, a peripheral vasodilator and lipid-lowering agent, and these changes were accompanied by a marked increase in the caudal nerve conduction velocity (13). Thus the increased level of RBC 2,3-DPG in cilostazol-treated sucrose-fed OLETF rats might have contributed to the improvement of retinal ischemia and/or hypoxia and retinal dysfunction. The report that nerve degeneration was inversely correlated with the RBC 2,3-DPG level in streptozotocin-induced diabetic rats with genetically determined high and normal RBC 2,3-DPG level (7) indirectly supports this hypothesis, because diabetic neuropathy is related to microvascular disease as is diabetic retinopathy.
It is well known that aldose reductase inhibitors reverse the diminished NADPH and accumulation of NADH caused by hyperglycemia-induced polyol pathway hyperactivity, resulting in the reduction of sorbitol and fructose levels in the tissues. Another site regulated by NAD+-NADH is the glyceraldehyde-3-phosphate dehydrogenase reaction in the cytosolic glycolytic pathway. In the present study using sucrose-fed OLETF rats, NADH may have accumulated due to increased sorbitol dehydrogenase activity secondary to the hyperglycemia-induced activation of aldose reductase, and this may shift the equilibrium of the glyceraldehyde-3-phosphate and 1,3-diphosphoglycerate system toward glyceraldehyde-3-phosphate, resulting in a decrease in 1,3-diphosphoglycerate formation, which leads to the reduction of 2,3-diphosphoglycerate synthesis. The observation that the decrease in the RBC 2,3-DPG level in sucrose-fed OLETF rats was prevented by TAT in our study strongly supports this hypothesis.
As shown in Table 5, there were significant correlations between platelet aggregation or the RBC 2,3-DPG level and the peak latencies of oscillatory potentials in ERG. However, no significant correlations were observed between retinal polyol contents and ERG. Moreover, cilostazol improved retinal dysfunction with no effects on polyol pathway hyperactivity. Although these observations suggest that ischemia and/or hypoxia would directly contribute to the development of retinal damage, the importance of the metabolic changes in the retina related with polyol pathway could not be neglected. The fact that preventive effect of TAT on the abnormalities in ERG accompanied an amelioration of the deficits in vascular factors implicates that ischemic and/or hypoxic changes are based on the increased polyol pathway activity.
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In summary, sucrose administration to OLETF rats caused remarkable hyperglycemia, which increased polyol pathway activity, resulting in not only the accumulation of retinal polyols but also platelet hyperaggregation activity and a decrease in the RBC 2,3-DPG level through the mechanisms described above. The latter would induce ischemia and/or hypoxia in the retina, leading to the abnormal ERG. Treatment with an aldose reductase inhibitor completely prevented this disadvantageous sequence except hyperglycemia, whereas cilostazol ameliorated the abnormalities in ERG by acting vascular factors alone without affecting either hyperglycemia or polyol pathway activity. Therefore, agents such as cilostazol, which improve rheological abnormalities, may have therapeutic values in the treatment of diabetic retinopathy and provide important information on the pathogenesis of this complication, as aldose reductase inhibitors do.
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ACKNOWLEDGEMENTS |
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We thank N. Takeuchi and H. Yamada for assistance with the preparations and the assays.
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FOOTNOTES |
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Address for reprint requests: N. Hotta, The Third Dept. of Internal Medicine, Nagoya Univ. School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466, Japan.
Received 7 February 1997; accepted in final form 24 July 1997.
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