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(Hypertension. 2001;37:1273.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Effect of Antihypertensive Therapy on Renal Artery Structure in Type 2 Diabetic Rats With Hypertension
From the Department of Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark.
Correspondence to Alluru S. Reddi, MD, PhD, Department of Medicine, UMDNJ-New Jersey Medical School, 185 South Orange Ave, Newark, NJ 07103. E-mail reddias{at}umdnj.edu
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Abstract |
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Abstract—We have previously demonstrated that antihypertensive treatment with doxazosin (DZN), an
-adrenergic blocker, and lisinopril
(LIS), an ACE inhibitor, reverse glomerular
sclerosis in corpulent spontaneously hypertensive rats with type 2
diabetes. In this study, we examined the effects of the above-mentioned
antihypertensive drugs alone and in combination on the structure of
interlobular and arcuate arteries in these rats. Both male and
female rats aged 6 months were treated with antihypertensive drugs for
16 weeks. Various structural parameters were evaluated by
light microscopy, with the use of digital image analysis, in
kidney sections stained with periodic acid–Schiff. Systolic
blood pressure was significantly lower in treated than in untreated
rats. Untreated diabetic rats had a significantly higher media/lumen
ratio (smaller luminal diameter) of both arteries compared with the
ratio in treated rats (for interlobular artery, 0.72±0.06 [no
treatment], 0.49±0.03 [DZN treatment], 0.54±0.06 [LIS
treatment], and 0.52±0.04 [combination therapy],
P<0.05 to <0.001 for
no treatment versus treatment; for arcuate artery, 0.66±0.11
[no treatment], 0.40±0.02 [DZN treatment], 0.39±0.04 [LIS
treatment], and 0.40±0.03 [combination therapy],
P<0.05 for no treatment versus
treatment). Antihypertensive treatment caused significant increases in
total arterial cross-sectional area, internal and external
diameters, luminal and medial cross-sectional area, and medial
thickness in both interlobular and arcuate arteries. The
improvement in arterial structure after antihypertensive
treatment was due to remodeling and growth of the vessels. Both DZN and
LIS were equally efficacious, and combination therapy had no additive
or synergistic
effect.
Key Words: kidney • arteries • hypertension, experimental • diabetes mellitus • rats, inbred SHR • adrenergic receptor blockers • angiotensin-converting enzyme inhibitors
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The kidney plays an important role in the development and regulation of blood pressure in human subjects and in animals.1 Several renal functional abnormalities, including an increase in renal vascular resistance, have been demonstrated in the normotensive offspring of hypertensive parents.2 The role of the kidney in the development of hypertension in humans3 4 and animal models5 6 7 has been convincingly demonstrated by kidney transplantation studies. In humans, kidney transplants from normotensive donors to patients with kidney failure due to essential hypertension resulted in normotension after 4.5 years of follow-up.3 The most convincing evidence has come from animal studies in which the kidneys from spontaneously hypertensive rats (SHR) were transplanted into normotensive rats, resulting in hypertension in the recipients.5 6 Thus, these studies point to a renal defect in the pathogenesis of essential hypertension.
The renal defect seems to reside in the
preglomerular resistance arterioles. Vascular
cast8 9 10
and
morphometric10 11 12
studies have demonstrated a significant reduction of afferent
arteriolar luminal diameter in SHR compared with normotensive
Wistar-Kyoto rats. Also, the volume density of arterial
wall, the wall/lumen ratio, and wall thickness of the arcuate
and interlobular arteries were significantly greater in SHR than in
Wistar-Kyoto rats.13
Treatment of SHR with an ACE inhibitor (ACE-I),
lisinopril (LIS) or captopril, caused larger afferent
arteriolar luminal diameter than that found in untreated
SHR.10 14 Also,
ACE-Is were found to have beneficial effects on the structure of
nonrenal vascular beds not only in
nondiabetic15 16
but also in
streptozotocin-diabetic17 18
rats. In the latter group of rats, renal vascular
hypertrophy was also prevented by
perindopril.19 It has been
well established that type 2 diabetes causes accelerated
atherosclerosis20
and that superimposed hypertension further aggravates the atherogenic
potential in both diabetic and nondiabetic human
subjects.21 ACE-Is have been
shown to improve endothelial dysfunction in patients
with coronary
atherosclerosis22
and in diabetic patients with microvascular disease, particularly
nephropathy.23
However, to the best of our knowledge, the effects of ACE-Is or other
antihypertensive drugs on renal vascular structure, particularly
vessels other than glomerular capillaries, in type 2
diabetic patients with hypertension or animals with both diabetes and
hypertension had not been studied. The purpose of the present study
was to examine the effect of an 1-adrenergic
blocker, doxazosin (DZN), on the structure of interlobular and
arcuate arteries in type 2 diabetic rats with hypertension.
Also, the effect of DZN was compared with that of LIS, an ACE-I, and
the possibility that a combination of these 2 drugs was superior to
either of them administered alone was
tested.
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Methods |
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Animals
A total of 33 male and female corpulent SHR were used in the study. These rats were initially obtained from Dr Carl T. Hansen (United States Department of Agriculture, Beltsville, Md). In our laboratory, we selectively inbred those rats with plasma glucose levels >12 mmol/L and urine albumin >10 mg/d. After 4 generations of inbreeding, both male and female rats aged 24 weeks were randomly divided into 4 groups and allocated to various regimens as follows: 9 rats on DZN (32 mg/100 mL) in tap water, 7 rats on LIS (7 mg/100 mL) in tap water, 8 rats on both DZN and LIS in the above dosages, and 9 rats on tap water. These dosages were selected on the basis of dose response in lowering blood pressure in these rats. DZN and LIS were first dissolved in distilled water and made up to the required volume with tap water. Water was changed daily for all groups of rats. The daily consumption of DZN and LIS was 12.30±0.87 and 4.57±0.26 mg (mean±SEM), respectively. Drug treatment was continued for 16 weeks. All groups of rats were fed Purina rodent chow 5001 ad libitum with the following composition by weight: 23.4% protein, 10% total fat, 49% carbohydrate, and 17.6% minerals (ash and vitamins). The energy provided was 4.00 kcal/g. The protocol was approved by the Institutional Animal Care and Use Committee (University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark).
Blood Pressure and Plasma Glucose
Systolic blood pressure was determined in
conscious rats by the tail-cuff method at the start and every 4 weeks
until euthanasia. Blood glucose was determined from tail bleeding at
the start and every 4 weeks by the glucose oxidase method with the
reagents supplied by Sigma Chemical Co.
Morphometry of Interlobular and
Arcuate Arteries
At the end of the study, each rat was
anesthetized with pentobarbital (5 mg/100 g), and the kidneys
were excised and fixed in 10% neutral formalin. Coronal sections of
the kidney (2 µm thick) were stained with periodic acid–Schiff and
examined by light microscopy in a blind fashion for various
characteristics of the
artery.10 Measurements of
various parameters were performed by digital image
analysis. The interlobular artery was identified as a single
muscular artery within the inner cortex and, at times, lying close to
the glomerulus. Arcuate arteries were identified along the
corticomedullary junction and surrounded by
tubules. Arteries that were not sectioned transversely (ie, wall
thickness was asymmetrical) were excluded from the study. Therefore, 2
to 5 arteries from each animal were evaluated. Images of the arteries
at x400 magnification (interlobular arteries) or at x200
magnification (arcuate arteries) were digitized and saved. The
digitized images were then projected on the computer screen and
analyzed at a resolution of 768x493 pixels. The total
cross-sectional area (CSAtot) of the artery,
defined as the cross-sectional area of the lumen plus the vessel wall,
was determined by manually outlining the external circumference of the
vessel on the image screen by using the cursor, and the area was
automatically calculated by the computer. Then, the luminal
cross-sectional area (CSAlum) was determined by
giving pseudocolor to the luminal image, and the area was calculated by
the computer. The short and long internal diameters of the vessels
(IDshort and IDlong),
defined as the shortest and longest distances between the 2
perpendicular lines across the vessel from one adluminal side of
the internal elastic lamina to the other, were measured.
The medial cross-sectional area (CSA) of the vessel was
calculated as CSA
=(CSAtot-CSAlum)x(IDshort/IDlong).
The external diameter (ED) was determined as
ED=2x(CSAtotxIDshort/IDlong/
)1/2.
Medial thickness was determined as
(ED-IDshort)/2, and the media/lumen ratio was
determined as
(ED-IDshort)/2/IDshort.
The remodeling and growth indices, expressed as percentages, were calculated from the equations derived by Heagerty et al24 ; values from untreated rats were compared with those from treated rats. Remodeling is defined as realignment of preexisting tissue material; growth index is defined as the addition of tissue material onto either the luminal or adluminal side of the blood vessel.
Statistical Analysis
Multiple-group comparisons were analyzed by
1-way ANOVA. Statistical significance among groups was evaluated by the
post hoc Tukey test. Results are expressed as mean±SEM; a value of
P<0.05 was considered
significant.
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Results |
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General information involving various groups of rats has been reported in a previous publication.25 At the end of the present study, there were no significant differences either in body or kidney weights (mean±SEM) among various groups of rats (body weights were 371±42 g [no treatment], 315±38 g [DZN], 354±31 g [LIS], and 393±34 g [DZN+LIS]; kidney weights were 2.68±0.32 g [no treatment], 2.66±0.39 g [DZN], 2.40±0.23 g [LIS], and 2.86±0.25 g [DZN+LIS]). Systolic blood pressures (mean±SEM) were significantly lower in treated groups (176±2 mm Hg [no treatment], 137±2 mm Hg [DZN], 113±2 mm Hg [LIS], and 115±2 mm Hg [DZN+LIS]), and plasma glucose levels (mean±SEM) were as follows: 21.06±0.97 mmol/L (no treatment), 15.81±0.93 mmol/L (DZN), 19.33±2.31 mmol/L (LIS), and 17.38±1.10 mmol/L (DZN+LIS).
Table 1 shows morphometric characteristics of interlobular arteries in untreated, DZN-treated, LIS-treated, and DZN+LIS–treated diabetic rats. As evident, the total arterial area, internal and external diameters, luminal and medial CSAs, and medial thickness were significantly increased in treated compared with untreated rats. However, the media/lumen ratio was significantly lower in treated than in untreated diabetic rats. Similar changes were observed in the characteristics of arcuate arteries (Table 2). There were no significant differences among treated groups.
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Tables 3 and 4 show remodeling and growth indices of interlobular and arcuate arteries, respectively. As evident, all treatment modalities increased both indices in these 2 arteries. However, no significant differences were observed among the treated groups.
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Figures 1 and 2 demonstrate representative photomicrographs of interlobular and arcuate arteries in untreated and treated groups. As shown, the diameters of the lumen and vessels were larger in treated than in untreated rats.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In the present study, we have demonstrated for the first time that the media/lumen ratio is greatly increased in type 2 diabetic rats with hypertension, suggesting reduced luminal diameter of both interlobular and arcuate arteries. Antihypertensive treatment caused a significant increase not only in luminal diameter but also in other characteristics of the vessel, such as total vessel area, internal and external diameters, luminal and medial areas, and medial thickness. The magnitude of these increases was similar in both arteries.
Studies in animals and humans indicate that improvement in luminal diameter is due to remodeling rather than the growth of the vessel after antihypertensive treatment.10 24 This type of structural change associated with antihypertensive therapy has been defined as "eutrophic outward remodeling."26 However, the present study provides evidence of both remodeling and growth after antihypertensive treatment. The observed increases in total vessel area, medial area, and medial thickness support the growth of both interlobular and arcuate arteries after DZN and LIS treatments. However, the present study could not determine whether the growth is due to hyperplasia or hypertrophy. Data shown in Tables 3 and 4 suggest that remodeling also occurred substantially in the structure of both interlobular and arcuate arteries, inasmuch as the media/lumen ratio was found to be greatly reduced in these arteries. This kind of structural change (increases in both luminal diameter and medial thickness) could be termed "hypertrophic outward remodeling,"26 which has been reported in the esophageal veins of rabbits after partial occlusion of the portal vein.27
In streptozotocin-diabetic rats, medial hypertrophy of mesenteric vessels was observed in association with increased mesenteric vessel weight, media/lumen ratio, and ACE activity.17 18 19 These abnormal changes were reversed by perindopril, an ACE-I.19 Although we did not quantify the weight of renal arteries, our data support the observation of improvement in media/lumen ratio by ACE-I treatment.
Kett et al13 failed to observe an improvement in the structure of the interlobular and arcuate arteries of SHR after enalapril treatment, which may be due to the short duration (6 weeks) of treatment. Consistent with the present study, other studies10 14 15 16 17 18 19 28 29 have also shown beneficial effects of the ACE-I on the structure of renal and nonrenal resistance vessels.
Increased sympathetic activity has been reported in
hypertensive animals,30 and
sympathectomy improves trophic changes in blood
vessels.31 32 To
our knowledge, this is the first study to evaluate the effects of DZN,
an 1-adrenergic blocker, on renal vascular
structure in type 2 diabetic rats with hypertension. Similar to LIS,
DZN also had a beneficial effect on renal arteries, and this
observation is consistent with that of a study in which an
ACE-I and sympathectomy were found to be equally
effective in preventing arterial structural changes in
hypertension.33 Also, the
ACE-I and 1-adrenergic blocker were equally
effective in reducing neointimal formation after balloon
injury.34 35 36
It is of interest to note that subantihypertensive doses of moxonidine,
a sympatholytic agent, ameliorated glomerular, tubular, and
vascular damage in subtotally nephrectomized rats with renal
failure.37
In conclusion, the data suggest that the luminal diameter of the interlobular and arcuate arteries was reduced in untreated type 2 diabetic rats with hypertension. Antihypertensive treatment with DZN or LIS increased not only the luminal diameter but also other structural characteristics of both arteries. Both antihypertensive drugs were equally efficacious, and combination therapy was not superior to either DZN or LIS alone.
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Acknowledgments |
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We thank Drs Amos Gona and Arthur Ritter for their critical evaluation of this manuscript.
Received August 22, 2000; first decision September 21, 2000; accepted November 14, 2000.
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References |
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