(Hypertension. 1997;30:1054-1061.)
© 1997 American Heart Association, Inc.
Articles |
Angiotensin Blockade Improves Cardiac and Renal Complications of Type II Diabetic Rats
From the Department of Pharmacology (S.K., A.H., K.M., S.Y., H.I.) and the First Department of Pathology (H.W.), Osaka City University Medical School, Osaka, Japan.
Correspondence to Shokei Kim, MD, Department of Pharmacology, Osaka City University Medical School, 1-4-54 Asahimachi, Abeno, Osaka 545, Japan.
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Abstract |
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Abstract Using Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a new model of human non–insulin-dependent diabetes mellitus (NIDDM), we examined the role of local angiotensin II in cardiovascular and renal complications of NIDDM. OLETF rats were orally given cilazapril (an angiotensin-converting enzyme inhibitor, 1 or 10 mg/kg), E4177 (an angiotensin AT1 receptor antagonist, 10 mg/kg), or vehicle for 26 or 40 weeks (from the age of 20 to 46 or 60 weeks). Cardiac mRNAs were measured by Northern blot analysis, and the thickening of the coronary arterial wall and the degree of perivascular fibrosis were determined by an image analyzer. Cilazapril or E4177 did not significantly affect body weight or plasma glucose and insulin levels of OLETF rats, indicating the minor effects on diabetes itself. However, both drugs significantly and similarly prevented coronary microvascular remodeling (the increase in wall thickening and perivascular fibrosis in coronary arterioles and small coronary arteries) in OLETF rats, and they were associated with the suppression of cardiac transforming growth factor-ß1 expression. Both drugs suppressed not only the increase in left ventricular weight but also the downregulation of cardiac
-myosin heavy chain expression in OLETF rats.
Glomerulosclerosis and glomerular
hypertrophy in OLETF rats were improved by cilazapril and
E4177 to a comparable extent. These results, taken together with the
fact that OLETF rats show normal plasma renin levels, support that the
AT1 receptor is involved in the pathogenesis of cardiac and
renal complications in NIDDM.
Key Words: diabetes mellitus • diabetic nephropathy • angiotensin-converting enzyme inhibition • receptors, angiotensin II • insulin resistance • transforming growth factor
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Introduction |
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Both diabetes and hypertension are major risk factors in the pathogenesis of atherosclerotic cardiovascular and renal diseases.1 2 3 4 5 NIDDM and hypertension are closely interrelated diseases, and patients with NIDDM often have hypertension.1 3 Therefore, the detailed investigation into the effects of antihypertensive drugs on diabetic complications is clinically very important. Accumulating clinical or experimental evidence supports that the renin-angiotensin system plays an important role not only in hypertension but also in the development of various cardiovascular6 7 8 9 and renal diseases.10 Previous studies on diabetic patients3 11 and streptozotocin-induced diabetic rats12 13 show that ACE inhibitor can significantly retard the progression of diabetic renal disease, thereby supporting the possible involvement of the renin-angiotensin system in diabetic nephropathy. However, in contrast to the evidence for the beneficial effect of ACE inhibitor on diabetic nephropathy, the effect of ACE inhibitor on cardiovascular complications of diabetes remains to be elucidated. Furthermore, the mechanism of diabetic cardiovascular disease is poorly understood because of the scarcity of suitable animal models of diabetes.
OLETF rats are a newly developed model of human NIDDM.14 Very recently, we have characterized cardiac and renal lesions in OLETF rats and have found that OLETF rats develop not only glomerulosclerosis but also cardiac complications, thereby indicating that OLETF rats are a useful model to study the pathogenesis of cardiac and renal complication in NIDDM.15
In the present study, we investigated the long-term effects of ACE inhibitor on cardiac and renal complications of OLETF rats and compared them with those of the angiotensin AT1 receptor antagonist. We have obtained evidence that the local AT1 receptor is involved in cardiac complications as well as nephropathy in NIDDM rats.
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Methods |
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Drugs
Cilazapril, an ACE inhibitor, was a gift from Nippon Roche, Ltd. E4177, a specific and potent nonpeptide AT1 receptor antagonist, was provided by Eisai Co, Ltd.16 17
Animals
All procedures were in accordance with institutional guidelines
for animal research. Male OLETF rats and LETO rats were kindly supplied
by the Tokushima Research Institute (Otsuka Pharmaceutical). LETO rats
are the genetic control of OLETF rats. All rats were kept under
controlled temperature (23±2°C) and humidity (55±5%) with a
12-hour light/dark cycle. They were fed standard laboratory chow
(Oriental Kobo) and given tap water ad libitum.
Experimental Protocol
Twenty-week-old OLETF rats were divided into four groups: (1) a
vehicle (saline)-treated group (control), (2) a cilazapril (1
mg/kg per day)-treated group, (3) a cilazapril (10 mg/kg
per day)-treated group, and (4) an E4177 (10 mg/kg per
day)-treated group. The age-matched LETO rats were treated with
vehicle. Vehicle or each drug in a volume of 2 mL/kg was given orally
to rats by gastric gavage in the morning once a day. Blood pressure of
OLETF and LETO rats was periodically measured by the tail-cuff method
with a sphygmomanometer (Riken Kaihatsu PS-8000) before and throughout
drug treatment. For measurement of urinary protein and albumin
excretion, rats were individually housed in metabolic cages
and urine was collected for 24 hours.
To examine the effects of cilazapril and E4177 on left ventricular weight and mRNAs, the treatment was carried out for 26 weeks (from 20 to 46 weeks of age). After the treatment, rats were decapitated and the heart was rapidly excised. The left ventricle was immediately separated from the right ventricle and the atria and was weighed, frozen in liquid nitrogen, and stored at -80°C until the extraction of total RNA.
To examine the effects of cilazapril and E4177 on cardiac and renal morphology, rats were given vehicle or drug for 40 weeks (from 20 to 60 weeks of age), and cardiac and renal histological examinations were performed as described below.
Northern Blot Analysis of Cardiac mRNAs
Total RNA extraction and the subsequent Northern blot
hybridization were carried out as previously described in
detail.18 19 For the detection of - and ß-MHC mRNAs,
the sequences of oligonucleotide probes used were
5'-TTGTGGGATAGCAACAGCGA-3' for -MHC and 5'-GTCTCAGGGCTTCACAGG-3' for
ß-MHC.19 For the detection of TGF-ß1 and GAPDH mRNAs,
the probes used were a 1.0-kb HindIII-Xba I
fragment of rat TGF-ß1 cDNA20 and a 1.3-kb
Pst I-Pst I fragment of rat GAPDH
cDNA.21 The detailed method of Northern blot
analysis with oligonucleotide probe or cDNA
probe, including the prehybridization, hybridization, and washing of
the membranes and the subsequent autoradiography, has
been previously described in detail.18 19
Histological Examination
OLETF rats, orally given vehicle, cilazapril (1 or 10
mg/kg per day), or E4177 (10 mg/kg per day) for 40 weeks
(from 20 to 60 weeks of age) as described above, and age-matched
vehicle-treated LETO rats were anesthetized with pentobarbital
sodium (50 mg/kg IP). The heart and the kidney were preperfused
with phosphate-buffered saline (pH 7.4) and rapidly fixed by the
perfusion of 10% formalin in 0.1 mol/L phosphate buffer (pH
7.4) from a catheter inserted into the left ventricle under constant
pressure (100 mm Hg). The heart and the kidney were rapidly
removed and were again fixed in 10% phosphate-buffered formalin for 24
hours and embedded in paraffin. Paraffin slices (4 µm thick)
from each heart and kidney were stained with hematoxylin-eosin or Azan
and with hematoxylin-eosin or periodic acid-Schiff (PAS), respectively.
All histological examinations were carried out by a
pathologist (H.W.) in a blinded manner.
Thickening of coronary arterial wall and the degree of perivascular fibrosis were assessed according to the method of Numaguchi et al.22 All Azan-stained sections were carefully scanned with an Olympus light microscope connected to the image-analysis system IPAP (Sumika Technos Corp), and all microscopic images were measured at a magnification of x100. The transsectional images of the small arterioles with diameters <100 µm and small coronary arteries with diameters of 100 to 300 µm were examined. The areas, encircled by tracing the outer border of the media and the inner border of the lumen, were calculated to determine the total vascular area and the luminal area, respectively, and the total area of the vessel wall was calculated as the difference between these two areas. Thickening of the coronary arterial wall was determined as the wall-to-lumen ratio (the area of the vessel wall divided by the total area of the vessel lumen). The area of perivascular fibrosis (the area of fibrosis immediately surrounding the blood vessel) was calculated and corrected for the total area of the blood vessel. In each heart, more than 13 arterioles (diameter <100 µm) and 4 to 8 small coronary arteries (diameter of 100 to 300 µm) were examined, and averaged values in each size of blood vessel were used for analysis.
Glomerular sclerosis was assessed in PAS-stained renal sections by a semiquantitative score (grades 0 to +4), as described23 24 : grade 0, no sclerosis of glomerulus; grade 1, sclerosis of up to 25% of glomerulus; grade 2, sclerosis of 25% to 50% of glomerulus; grade 3, sclerosis of 50% to 75% of glomerulus; and grade 4, sclerosis of more than 75% of glomerulus. More than 50 glomeruli were analyzed in kidney sections of each rat. The average glomerular tuft volume (Vg) on the same sections was calculated according to the method of Weibel.24 25 The mean cross-sectional area (Ag) was measured by using a video micrometer (VM-30, Olympus). From Ag, Vg can be calculated by the following equation: Vg=B/k (Ag)3/2, where B=1.38, the shape coefficient for spheres, and k=1.1, the size distribution coefficient.25
Oral Glucose Tolerance Test
At 20, 31, and 59 weeks of age, an oral OGTT was performed on
rats fasted for 16 hours before the test. Glucose (2 g) solution was
given orally to rats, and blood samples were collected before and 30,
60, and 120 minutes after the administration of glucose by puncture of
the external jugular vein (20 weeks of age) or from the tail vein (31
and 59 weeks of age).
Miscellaneous Measurement
Plasma glucose was determined by the glucose oxidase method.
Urinary protein and albumin concentrations were measured with
an A/G-B test (Wako Pure Industries, Ltd) and an enzyme-linked
immunosorbent assay, respectively. Plasma insulin levels were
determined by a radioimmunoassay kit (Amersham Japan).
Statistics
The data are expressed as mean±SEM. The data on blood
pressure, urinary protein and albumin, and plasma glucose
responses were analyzed by two-way ANOVA, and the differences
between each group at each time point were determined by the
least-squares means test (SuperANOVA, Abacus Concepts). Comparisons of
body weight, cardiac and renal weights, cardiac mRNA, the wall-to-lumen
ratio, perivascular fibrosis, glomerular sclerosis index,
and Vg were performed by one-way ANOVA, followed by
Duncan's multiple range test. Differences were considered
statistically significant at a value of P<.05.
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Results |
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Effects of Cilazapril and E4177 on Blood Pressure, Urinary Protein, and Albumin Excretion of OLETF Rats
As shown in Fig 1
, blood pressure of
OLETF rats was slightly but significantly higher than that of LETO rats
throughout 10 to 60 weeks of age. Cilazapril or E4177 (10 mg/kg
per day) lowered blood pressure of OLETF rats to a slight but
significant extent throughout the treatment. The hypotensive effects of
10 mg/kg cilazapril and E4177 were significantly greater than 1
mg/kg cilazapril. Blood pressure was similar between 10
mg/kg cilazapril-treated and 10 mg/kg E4177-treated
groups.
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P<.05,
*P<.01 vs V (vehicle-treated OLETF rats).
As shown in Fig 2, urinary protein
and albumin excretions of LETO rats were less than 0.02
g/d and 0.001 g/d, respectively, until 60 weeks of age.
On the other hand, urinary protein and albumin excretions in
OLETF rats were significantly increased with age and were much larger
than in LETO rats during 30 to 60 weeks of age. Cilazapril
significantly prevented the increase in urinary protein and
albumin excretions of OLETF rats in a dose-dependent manner
throughout the treatment. E4177 had beneficial effects similar to
cilazapril.
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Body Weight, Left Ventricular Weight, and Kidney Weight
of LETO and OLETF Rats Subjected to Vehicle or Drug Treatment for
26 Weeks
As shown in the Table, body weight
of vehicle-treated 46-week-old OLETF rats was significantly greater
than in the LETO rats of the same age (P<.01) and was not
significantly different from that of the cilazapril- or E4177-treated
group. Left ventricular weight of OLETF rats was greater
than that of LETO rats (P<.01) and was significantly
decreased by treatment with cilazapril (1 or 10 mg/kg) or E4177.
Kidney weight of OLETF rats, which was much greater than LETO rats
(P<.01), was not significantly decreased by cilazapril or
E4177.
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Left Ventricular MHC and TGF-ß1 mRNA Levels of LETO
and OLETF Rats Subjected to Vehicle or Drug Treatment for 26
Weeks
As shown in Fig 3, left
ventricular ß-MHC mRNA levels in 46-week-old OLETF rats
were 1.3-fold higher than the same age of LETO rats
(P<.05). On the other hand, -MHC mRNA levels in OLETF
rats were decreased to 71% of those in LETO rats (P<.01).
Cilazapril and E4177 at a dose of 10 mg/kg significantly
prevented the decrease in -MHC gene expression in OLETF rats,
although these drugs did not affect the upregulation of ß-MHC
expression in OLETF.
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As shown in Fig 4, left
ventricular TGF-ß1 mRNA levels in OLETF rats were
1.5-fold higher than in LETO rats (P<.01). The increased
expression of TGF-ß1 was significantly suppressed by 10 mg/kg
cilazapril and E4177.
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Effects on Thickening of Coronary Arterial Wall
and Perivascular Fibrosis in OLETF Rats
Figs 5 and 6 show the data on thickening of
coronary arteries and perivascular fibrosis in 60-week-old LETO
and OLETF rats subjected to vehicle or drug treatment for 40 weeks. The
wall-to-lumen ratios in coronary arterioles (internal diameters
<100 µm) (Fig 6A) and in small coronary arteries
(internal diameters of 100 to 300 µm) (Fig 6B) of
vehicle-treated OLETF rats were 1.9- and 1.4-fold, respectively,
greater than in LETO rats. However, the wall-to-lumen ratios in
arterioles and small coronary arteries of OLETF rats treated
with cilazapril at 1 or 10 mg/kg and E4177 were significantly
smaller than those of vehicle-treated OLETF rats and were similar to
those of LETO rats.
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The degrees of perivascular fibrosis in coronary arterioles
(Fig 6C
) and small coronary arteries (Fig 6D) of
vehicle-treated OLETF rats were also larger compared with LETO rats.
There was no significant difference in the degree of perivascular
fibrosis of arterioles and small coronary arteries among LETO
rats and OLETF rats treated with 10 mg/kg cilazapril and
E4177.
Effects of Cilazapril and E4177 on Glomerular Sclerosis
and Hypertrophy of OLETF Rats
As shown in Figs 7 and 8, the glomerular sclerosis
index in vehicle-treated OLETF rats was significantly greater compared
with LETO rats. Treatment with cilazapril (1 and 10 mg/kg) and
E4177 significantly prevented
glomerulosclerosis of OLETF rats. The average
glomerular tuft volume (Vg) of OLETF rats was
also greater than that of LETO rats. Both cilazapril (1 and 10
mg/kg) and E4177 significantly prevented the increase in
glomerular tuft volume in OLETF rats.
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Oral Glucose Tolerance Test and Plasma Insulin Levels
As shown in Fig 9, plasma glucose
responses of 20-, 31-, or 59-week-old LETO rats in the OGTT were within
the normal ranges. On the other hand, 20-week-old OLETF rats already
showed diabetes, as indicated by a plasma glucose response in the OGTT
(Fig 9A). Before the start of the treatment (at 20 weeks of age),
plasma glucose responses were comparable among the four groups of OLETF
rats. As shown in Fig 9B and 9C, plasma glucose responses in
cilazapril- and E4177-treated groups were similar to those in
vehicle-treated group, except for lower plasma glucose concentrations
at 60 minutes in cilazapril (10 mg/kg)-treated and E4177 (10
mg/kg)-treated groups at 31 weeks of age and higher plasma
glucose at 120 minutes in the E4177-treated group at 59 weeks of
age.
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At 60 weeks of age (after 40 weeks of the treatment), the fasting plasma insulin concentrations of vehicle-treated OLETF rats (9.90±1.15 ng/mL), which were higher than those of LETO rats (4.32±0.35 ng/mL) (P<.05), were not different from those of OLETF rats treated with cilazapril (1 mg/kg; 7.81±0.81 ng/mL), cilazapril (10 mg/kg; 9.65±1.80 ng/mL), and E4177 (10 mg/kg; 11.98±2.62 ng/mL).
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Discussion |
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A growing body of clinical or experimental evidence shows that the renin-angiotensin system participates not only in the pathogenesis of hypertension but also in the development of various cardiac diseases, including cardiac hypertrophy and fibrosis induced by pressure overload,26 hypertension,7 27 28 29 myocardial infarction,30 31 and myocardial ischemia-reperfusion injury.32 Sechi et al,33 who examined the effects of hyperglycemia on cardiac and circulating renin-angiotensin systems in rats with streptozotocin-induced diabetes, found that hyperglycemia leads to an increase in cardiac AT1 receptor density and mRNA levels without altering plasma renin concentrations, which suggests a possible activation of the cardiac renin-angiotensin system in diabetic rats. However, it remains to be determined whether the renin-angiotensin system is involved in the pathogenesis of diabetic cardiac disease. The availability of OLETF rats allowed us to investigate the role of the renin-angiotensin system in diabetic complications.
OLETF rats are a new model of human NIDDM characterized by
late onset of hyperglycemia and the mild and chronic course of diabetes
mellitus.14 Very recently, to characterize cardiac and
renal complications in OLETF rats, we have examined in detail the gene
expression and pathology in OLETF rats at various ages.15
We have found that cardiac expression of TGF-ß1, a growth factor
causing tissue fibrosis,34 35 is significantly enhanced in
the heart of OLETF rats, which is in contrast to no increase in cardiac
TGF-ß1 expression in spontaneously hypertensive rats (SHR), the most
popular model of human hypertension.29 This enhanced
TGF-ß1 expression of OLETF rats is followed by the appearance of
coronary arterial remodeling, which therefore
suggests the contribution of TGF-ß1 in perivascular fibrosis in OLETF
rats.15 Furthermore, OLETF rats are characterized by the
upregulation of cardiac ß-MHC expression and the downregulation of
cardiac -MHC expression, which therefore indicates the shift of
cardiac myocytes to the fetal phenotype in OLETF
rats.15 The enhanced ß-MHC expression is also uniquely
characteristic of OLETF rats, because SHR show decreased -MHC
expression but no increased ß-MHC expression even at the phase of
established hypertension.29 Therefore, in the present
study, we examined the effects of angiotensin blockade on
coronary arterial remodeling and cardiac TGF-ß1
and MHC isoform expressions of OLETF rats.
The present study provided evidence that both cilazapril and E4177 prevented coronary microvascular remodeling (the wall thickening and the increased perivascular fibrosis in arterioles and small coronary arteries) of OLETF rats. Notably, although the hypotensive effect of 1 mg/kg cilazapril in OLETF rats was small and significantly weaker than 10 mg/kg cilazapril and E4177, 1 mg/kg cilazapril completely blocked the thickening of the coronary arterial wall as much as 10 mg/kg cilazapril and E4177. These results, taken together with our recent in vivo findings that AT1 receptor antagonists can directly inhibit cell growth-related gene expression in rat balloon-injured artery,36 support the idea that suppression of thickening of the coronary arterial wall by cilazapril and E4177 is caused at least in part by their direct action rather than by their hypotensive action.
In contrast to the effects on coronary arterial wall thickening, the inhibitory effect of 1 mg/kg cilazapril on perivascular fibrosis of OLETF rats was weaker than 10 mg/kg cilazapril and E4177, which suggests that the mechanism of the perivascular fibrosis might differ from that of arterial wall thickening and that the hypotensive effects of these drugs might lead to the inhibition of perivascular fibrosis. However, interestingly, the inhibition of perivascular fibrosis by 10 mg/kg cilazapril and E4177 was associated with the suppression of cardiac TGF-ß1 expression. Furthermore, we have shown previously that angiotensin II infusion in rats in vivo increases cardiac TGF-ß1 expression, independent of the elevation of blood pressure.19 These findings suggest that the improvement of perivascular fibrosis by cilazapril and E4177 is probably partially explained by the inhibition of TGF-ß1 expression, independent of the hypotensive effect. However, further study is needed to confirm our proposal, because the present study did not allow for the measurement of cardiac TGF-ß1 protein.
Hajinazarian et al,37 who examined the effects of
captopril on organomegaly in streptozotocin-induced diabetic rats (IDDM
model), found that captopril partially prevents diabetic cardiomegaly
without decreasing cardiac glycogen stores, which suggests that ACE
inhibitor may be a useful agent for the treatment of
cardiomyopathy in IDDM. In the present study,
we showed that cilazapril and E4177 similarly prevented left
ventricular hypertrophy and the downregulation
of -MHC expression of OLETF rats, which suggests that the inhibition
of the renin-angiotensin system may have beneficial effects
on cardiomyopathy in NIDDM as well as in IDDM. On
the other hand, these drugs failed to prevent the upregulation of
cardiac ß-MHC expression in OLETF rats. Therefore, the mechanism of
upregulation of cardiac ß-MHC in OLETF rats was not attributable to
renin-angiotensin system or blood pressure but, rather, to
another factor(s) such as hyperglycemia.
Previous reports12 13 38 show that ACE inhibitor and AT1 receptor antagonist improve nephropathy in streptozotocin-induced diabetic rats. Furthermore, a recent report by the Diabetes Collaborative Study Group shows that ACE inhibitors are more effective in slowing the progression of diabetic nephropathy in patients with IDDM than are other antihypertensive agents.3 11 In contrast to evidence for the usefulness of ACE inhibitors for the treatment of nephropathy in IDDM, it is still unclear whether ACE inhibitors can retard nephropathy in NIDDM. The present study provides evidence that ACE inhibitors and AT1 receptor antagonists can ameliorate the development of albuminuria and glomerulosclerosis in an NIDDM model. Thus, our work provides experimental evidence supporting that angiotensin II blockade may be effective in the treatment of nephropathy in NIDDM patients as well as in IDDM patients.
Although cilazapril and E4177 had similar effects on OLETF rats, the present study does not permit us to conclude that the beneficial effects of these drugs can be completely explained by inhibition of the AT1 receptor. ACE inhibition leads to the inhibition of not only angiotensin II generation but also bradykinin degradation, and bradykinin is shown to inhibit the proliferation of vascular smooth muscle cells and cardiac remodeling.39 Furthermore, investigation on streptozotocin-induced diabetic rats indicates that bradykinin is involved in the renoprotective effects of ACE inhibitor.40 Therefore, it is conceivable that the beneficial effects of cilazapril on cardiac and renal lesions might be mediated in part by increased bradykinin. On the other hand, recent studies41 42 show that AT2 receptor exerts an antiproliferative action on vascular smooth muscle and endothelial cells, counteracting the growth action of AT1 receptor. Furthermore, it has been reported that AT1 receptor is decreased in the kidney of diabetic rats.43 Taken together with the fact that treatment with AT1 receptor antagonists increases plasma angiotensin II levels, it cannot be ruled out that the beneficial effects of E4177 in the present study might be indirectly mediated in part by the enhanced action of AT2 receptor. However, further investigation is needed to demonstrate the possible involvement of bradykinin and AT2 receptor in cardiovascular and renal protections by cilazapril and E4177 in OLETF rats because our present work did not provide any data on bradykinin and AT2 receptor.
Cilazapril and E4177 did not significantly affect body weight, plasma glucose during OGTT, or plasma insulin levels, which indicates therefore that these drugs had minor effects on diabetes itself. However, in the present study, we did not perform detailed studies on insulin sensitivity, and Chen et al44 have reported that both ACE inhibitors and AT1 receptor antagonists can significantly improve glucose metabolism and insulin resistance in fructose-fed rats. Thus, it cannot be completely excluded that the beneficial effect of cilazapril and E4177 in the present study might be attributable in part to the improvement of insulin resistance.
In conclusion, AT1 receptor seems to be involved in the development of coronary microvascular remodeling and nephropathy in OLETF rats. Our experimental work supports the notion that ACE inhibitor and AT1 receptor antagonist may be useful agents for the treatment of not only hypertension but also cardiac and renal complications in NIDDM patients.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by grant-in-aid for scientific research 05770067 from the Ministry of Education, Science, and Culture of Japan. We are grateful to Eriko Gomi for technical assistance and Kazuko Tsukahara for Northern blot analysis.
Received November 18, 1996; first decision January 16, 1997; accepted April 2, 1997.
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