(Hypertension. 1996;27:245-250.)
© 1996 American Heart Association, Inc.
Articles |
Effects of Amlodipine on Glomerular Filtration, Growth, and Injury in Experimental Hypertension
From the Department of Medicine, Brown University and Rhode Island Hospital, Providence (L.D.D., E.T.), and the Departments of Medicine (P.A.R.) and Pathology (J.C.H., H.F., R.I.L.), New York University Medical Center, New York.
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Abstract The objective of this study was to determine whether the calcium antagonist amlodipine could slow the progression of chronic renal disease. We examined the effects of amlodipine on kidney structure and function in two experimental models of hypertension. In the first study, adult, male Munich Wistar rats underwent uninephrectomy and were given weekly injections of desoxycorticosterone and 1% saline for drinking. Rats ingested normal chow or chow containing amlodipine for 8 weeks. The drug reduced systemic blood pressure, but glomerular filtration rate, kidney weight, proteinuria, and morphological evidence of glomerular injury were not affected. In the second study, male spontaneously hypertensive rats underwent uninephrectomy at 5 weeks of age and were followed for 6 months, during which they received no therapy or amlodipine. The drug dose was determined in preliminary studies to be the highest dose not associated with marked growth retardation. Again, although systemic blood pressure was significantly reduced by amlodipine, proteinuria and the prevalence of glomerulosclerosis were similar in amlodipine-treated and control spontaneously hypertensive rats. Micropuncture studies revealed that glomerular pressure remained elevated in amlodipine-treated spontaneously hypertensive rats. Kidney weight and glomerular volume were also similar in amlodipine-treated and control rats. Amlodipine also failed to inhibit platelet aggregation. Therefore, antihypertensive therapy with amlodipine fails to reduce glomerular pressure in spontaneously hypertensive rats as well as glomerular size and injury in spontaneously hypertension rats and desoxycorticosterone-salt hypertension. Although other dihydropyridine calcium antagonists have been found to reduce experimental glomerular injury, these data suggest that amlodipine may not prevent hypertensive nephrosclerosis.
Key Words: hemodynamics • calcium channel blocker • hypertrophy • glomerular sclerosis • rats, inbred SHR • mineralocorticoid
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Introduction |
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Because glomerular filtration rate declines progressively in chronic forms of renal disease, most kidney patients eventually require dialysis or transplantation. Recent studies in rats1 2 3 and humans4 5 suggest that the rate of decline in renal function can be significantly reduced by antihypertensive therapy. However, all agents may not be equally effective in preventing kidney damage.6 In particular, controversy exists regarding the effects of calcium antagonists on progressive renal injury, and both positive3 7 and negative8 results have been reported.
In previous studies, we developed the DOC-salt–treated hypertensive rat6 9 and the uninephrectomized SHR as models of progressive renal failure.2 3 10 In both models, rats develop severe systemic hypertension, proteinuria, and progressive glomerulosclerosis. Glomerular injury is associated with increases in PGC9 10 and Vg.3 9 In DOC-salt rats, administration of the calcium antagonist nifedipine reduces Vg and lessens glomerulosclerosis.6 In uninephrectomized SHR,3 nifedipine also reduces PGC, Vg, and morphological evidence of glomerulosclerosis. In the present study, we examined the effect of a new, longer-acting dihydropyridine calcium antagonist, amlodipine, on glomerular injury in DOC-salt rats and uninephrectomized SHR. Our study suggests that even structurally similar calcium blockers such as amlodipine and nifedipine can have markedly different effects on glomerular morphology and function.
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Methods |
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Animals
All studies were performed in rats in accordance with applicable portions of the Animal Welfare Act (PL 99-158 as amended) and the guidelines prescribed in Department of Health and Human Services publication No. 85-23 Guide for the Care and Use of Laboratory Animals, National Institutes of Health implementing instructions, and were approved by the animal use and care committee of our institution. Laboratory animals were housed in the New York University animal facility, which has an approved General Assurance Statement of Compliance with US Public Health Service guidelines.
Studies in DOC-Salt Hypertensive Rats
Description of
Groups
Studies were performed in two groups of male Munich Wistar rats
with initial weights of 225 to 250 g. All rats underwent a right
nephrectomy under pentobarbital (50 mg/kg IP) anesthesia
via a flank incision. Rats were given weekly subcutaneous injections of
DOC acetate (25 mg) in peanut oil and 1% saline for drinking. Rats
ingested either normal chow (CON, n=9) or chow containing amlodipine
(AM, n=9) in a concentration that delivered a daily dose of
approximately 10 mg/kg body wt. This dose was identified in preliminary
studies as one that significantly reduced systolic BP in this
model. Because amlodipine may be light sensitive, rats were housed in
covered cages and fresh chow was provided daily.
Study
Design
Rats were followed with weekly determinations of weight and
biweekly determinations of awake systolic BP and protein
excretion rate. After 8 weeks, glomerular filtration rate
was determined by inulin clearance, and the kidney was perfusion fixed,
weighed, sectioned, and examined for morphological evidence of
glomerular injury.
Studies in SHR
Study Design
Six groups of SHR
that underwent right nephrectomy under
pentobarbital (50 mg/kg IP) anesthesia via a flank incision
at 6 weeks of age were studied. CON rats were fed standard rat chow
(Purina Mills, Inc) containing 23% protein and given tap water to
drink. AM rats were fed identical chow, except that amlodipine (50
mg/kg body wt) was added to the chow before pelleting. This dose was
derived from preliminary studies in which it was found to be the
highest dose not associated with marked growth retardation of the rats.
Lower doses failed to reduce BP effectively. All rats had free access
to tap water. A CON (n=9) and AM (n=11) group of rats were
followed for
6 months, with monthly determinations of 24-hour urinary protein
excretion rate and awake systolic BP made during the first 5
months.
Protein Excretion and BP Measurements
Rats
were placed in metabolic cages, and urine was
collected for 24 hours. Protein concentration was measured by
precipitation with 3% sulfosalicylic acid, and turbidity was
determined by measurement of absorbance at 595 µm with a
spectrophotometer (Spectronic 501, Milton Roy). Awake systolic
BP was measured at 4-week intervals with a photoelectric tail-cuff
device (model 29, IITC Inc) attached to a recorder (model SE 120,
IITC Inc). For each rat, the value recorded represented
the mean of four to six measurements obtained at a single time.
Inulin Clearance Study
Rats were anesthetized with
thiobutabarbital (100 mg/kg
IP). A polyethylene catheter (PE-50) was inserted into the femoral
artery, and mean arterial pressure was measured by a
Statham P23B pressure transducer connected to a recorder (model 7A,
Grass Instruments). A tracheostomy was then performed, and polyethylene
catheters were inserted into both jugular veins and the left ureter for
infusion of test substances and collection of urine. To compensate for
surgical losses and specimens drawn, all rats received an
intravenous infusion of isoncotic rat plasma of 10 mL/kg
body wt at a rate of 0.1 mL/min, followed by a sustained infusion of
plasma at a rate of 0.5 mL/h. The rats also received a 0.5-mL
intravenous bolus of inulin (10 g/100 mL) in saline
followed by an infusion of 1.0 mL/h. After a 45-minute equilibration
period, two timed urine collections of 15 minutes each were made. At
the midpoint of each collection, 100 µL blood was collected in
microhematocrit tubes.
At the conclusion of the clearance study, the kidneys were fixed in situ by perfusion for 5 minutes at the measured BP with 1.25% glutaraldehyde in 0.1 mol/L cacodylate buffer. The kidney was excised and weighed. Inulin concentrations were determined by the anthrone method,9 and inulin clearance was calculated by the standard formula.
Morphological Studies
Two coronal sections of tissue were embedded in paraffin for
light microscopy. Sections 3 µm thick were stained with
hematoxylin-eosin and periodic acid–Schiff. The incidence of
glomerulosclerosis was quantitatively assessed
in a blinded fashion by one observer (H.F.). In each rat, 150 to 200
glomeruli were examined. The percentage of glomeruli with
glomerulosclerosis was calculated for each rat
by dividing the number of abnormal glomeruli by the total number
examined.
Morphometric Studies
Morphometric
measurements of Vg were made in the
same kidney sections examined for morphological changes. Slides stained
with hematoxylin-eosin were examined with the Zeiss Interactive
Digital Analysis System (ZIDAS, Carl Zeiss Inc), and
calculations were made based on standard stereological principles, as
reviewed by Elias et al.11 For determination of
Vg, the mean cross-sectional tuft area was
obtained by tracing the outlines of capillary tufts of approximately 75
glomeruli per rat. In this method, it is assumed that the glomerulus is
spherical and that the glomerular tuft cross-sectional
areas represent random sections through a population of spheres
that are distributed in a statistically predictable pattern. The area
of each section depends on the diameter of the sphere and the distance
of the section from the center of the sphere. From the mean
cross-sectional area (Ag), Vg can be
calculated by the equation
Vg=B/k(Ag)3/2, where B=1.38,
the shape coefficient for spheres; and k=1.1, the size distribution
coefficient.
Additional groups of CON and AM rats underwent platelet studies 2 weeks after nephrectomy or micropuncture measurements of glomerular pressure 5 weeks after nephrectomy. At this point, sustained hypertension has developed, and the hemodynamic response to nephrectomy is complete; however, neither proteinuria nor morphological evidence of kidney damage is present.10
Platelet Studies
Studies were performed on platelets obtained from 44 CON and
48 AM uninephrectomized SHR. Platelet aggregation was performed in
a four-channel aggregometer (Monitor IV Plus, Helena Laboratories)
by the use of minor modifications of methods previously
described.12 Rats were anesthetized with
thiobutabarbital (100 mg/kg IP). The lower aorta was exposed via a
midline incision and cannulated. Arterial blood was drained
directly into plastic tubes containing heparin (final concentration, 10
U/mL) in phosphate-buffered saline (pH 7.4) with or without 3.8%
sodium citrate (9:1, vol/vol). Platelet-rich and
platelet-poor plasmas were prepared by differential
centrifugation; platelet counts were determined by
hemocytometer; and platelet-rich plasma was diluted with
platelet-poor plasma to achieve a final platelet count of
200 000/mL. In each experiment, aggregation was induced by various
concentrations in a random order of collagen (0 to 20 mg/mL) or ADP (0
to 200 mmol/L) in an alternating sequence of platelet-rich
plasma samples from either CON or AM rats. Aggregation was quantified
as previously described by determining the area under the curve of
light transmission from 0 to 5 minutes by use of digital planimetry on
a ZIDAS digitizing tablet. Each curve was measured three times. To
facilitate comparisons between individual experiments, all data were
expressed as percentages of the maximal aggregation observed in each
experiment.
Micropuncture Studies
Micropuncture
studies were performed in rats at 11 weeks of age.
Rats were anesthetized with 100 mg/kg thiobutabarbital and
prepared in the standard fashion for micropuncture.2 A
tracheostomy was performed, and polyethylene catheters were inserted
into the jugular veins, femoral artery, and ureter for infusion of
solutions and collection of samples. The kidney was exposed via a
subcostal incision, placed on a Lucite holder, and illuminated with a
fiber-optic light. All rats received an initial infusion of
isoncotic plasma equal to 10 mL/kg body wt followed by a sustained
infusion of plasma at approximately 0.5 mL/h adjusted to maintain a
stable hematocrit. Hydraulic pressure in cortical tubules was measured
directly with the servo-null micropipette technique.10
Systemic protein concentration was determined by refractometry and
plasma oncotic pressure calculated with the Landis-Papenheimer
equation. Mean PGC was estimated as the sum of the
stop-flow pressure and the plasma oncotic pressure, as described by
Allison et al.13
Statistics
Statistical analysis of
glomerulosclerosis data was performed by the
Kruskal-Wallis test (
2 approximation) and for all
other data by one-way unpaired t test. Statistical
significance was defined at a value of P<.05. Data are
reported as mean±SE.
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Results |
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DOC-Salt Model
Data from the studies performed in rats with DOC-salt hypertension are shown in Table 1
and Figs 1 and
2. Rats in both groups gained a similar amount of weight
from the time of nephrectomy to time of death. As expected, average
values for awake systolic BP (Fig 1) and mean
arterial BP (Table 1) were elevated in DOC-salt rats and
reduced by amlodipine throughout the study. As shown in Fig 2,
there
was a trend toward greater proteinuria in the AM rats; however, there
was marked heterogeneity in protein excretion rates in
this group, so the difference was not statistically significant. By the
8th week after nephrectomy, protein excretion rate in the CON rats had
increased to a mean that was virtually identical to that seen in CON
rats. Despite the reduction in BP, inulin clearance, morphological
evidence of glomerular injury, and kidney weight were not
altered by amlodipine administration.
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, n=9) and AM (
, n=9)
DOC-salt rats.
Systolic pressure was significantly lower in the AM group
throughout the study. *P<.02 vs amlodipine.
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Studies in Uninephrectomized SHR
Long-term Study
There were no significant differences in body weight between the
groups at any time during the study. At the conclusion of the study,
CON rats weighed 394±7 g and AM rats 404±9 g. Mean values for
awake
systolic BP are shown in Fig 3. BP was markedly
reduced by amlodipine at every time point throughout the study. The
effect of amlodipine on 24-hour urinary protein excretion is shown in
Fig 4. Proteinuria increased with time in both groups.
Surprisingly, proteinuria in AM rats significantly exceeded that
observed in CON rats at 4 and 5 months after uninephrectomy. Inulin
clearance was similar in the two groups, averaging 0.033±0.007 mL/s in
CON and 0.038±0.004 mL/s in AM rats. These values indicate that
glomerular filtration rate had not declined significantly
in either group by the time of death.
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, n=11)
uninephrectomized
SHR. Systemic BP was significantly lower in the treated group
throughout the study. *P<.01 vs amlodipine. UNX indicates
uninephrectomy.
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Morphological and
Morphometric Data
Glomerular lesions in uninephrectomized SHR were
mainly sclerotic, consisting of increases in both mesangial
matrix and basement membrane material. Glomerular lesions
were predominantly global in distribution, although segmental lesions
were also observed. Both superficial and deep nephrons were affected. A
complete description of the morphological changes observed in glomeruli
of uninephrectomized SHR has been published
elsewhere.2 3
A minority of glomeruli were abnormal in both groups, averaging
2.6±0.8% of glomeruli in CON versus 4.1±0.8% in AM rats. These
values were not significantly different. Therefore, as assessed by
either protein excretion rate or glomerular morphology,
amlodipine failed to reduce the severity of glomerular
damage in these rats. Morphometric studies indicated that amlodipine
failed to inhibit renal growth in uninephrectomized SHR. Mean values
for kidney weight and Vg were 3.14±0.10 g and
2.27±0.14x106 µm3,
respectively, in CON rats versus 3.17±0.13 g and
2.86±.013x106 µm3 in AM rats. These
values were not significantly different.
Micropuncture Studies
Mean values for weight, hematocrit,
mean arterial
pressure, PGC, proximal tubular pressure, efferent
arteriolar pressure, the glomerular
transcapillary hydraulic pressure difference, and the
plasma protein concentration at the time of micropuncture are shown in
Table 2. As was the case for awake systolic
pressure, arterial pressure in anesthetized AM rats
was significantly reduced compared with CON rats. Despite this
35–mm Hg reduction in perfusion pressure, PGC and 
P
values remained elevated in AM rats.
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Platelet Studies
Amlodipine had no significant effect on
platelet aggregation,
regardless of whether studies were performed in the presence or absence
of extracellular calcium.
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Discussion |
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Studies in animals have suggested a general hypothesis to explain the progressive nature of renal disease. According to this theory, progressive kidney damage is caused by one or more adaptations of the kidney to a partial loss of function. At first, these adaptations appear to be beneficial because they tend to return total kidney function toward normal; however, in the long term, they cause nephron damage. Then, as additional units are injured secondarily, more extreme adaptations develop in those that remain until all nephrons are destroyed.
Although a number of adaptations of damaged kidneys have been associated with progressive renal failure in animals, a large body of evidence implicates two specific alterations as important in this process: (1) an increase in PGC and (2) compensatory kidney growth. PGC is high in experimental diabetes14 and in models characterized by systemic hypertension and reduced renal mass.9 14 15 Furthermore, maneuvers that reduce PGC lessen damage.1 2 3 14 15 For example, angiotensin-converting enzyme inhibitors have been consistently shown1 2 3 to reduce PGC and glomerular injury in a variety of settings. Less constant effects on glomerular pressure have been observed with other antihypertensive agents, including calcium antagonists. Anderson16 found that these drugs reduced glomerular pressure when given acutely to rats with hypertension consequent to a reduction in renal mass. On the other hand, Pelayo et al17 found no reduction in glomerular pressure when rats with remnant kidneys were chronically treated with verapamil. We examined the effects of chronic administration of the dihydropyridine nifedipine to rats with remnant kidneys,18 DOC-salt hypertensive rats,6 or uninephrectomized SHR.3 Although systemic hypertension was either entirely prevented or markedly ameliorated in all three models, glomerular pressure declined only in uninephrectomized SHR. Nevertheless, administration of the drug was associated with a reduction in glomerulosclerosis in all three studies. These findings suggest that calcium antagonists can reduce renal injury but that this effect does not depend on alterations in glomerular perfusion. Rather, it was linked to inhibition of renal growth, assessed morphometrically by analysis of kidney weight and Vg.
Because both the size and perfusion of surviving nephrons generally increase in damaged kidneys, it has been difficult to assess the independent contributions of glomerular hypertension and hypertrophy to injury. For example, maneuvers such as dietary protein restriction19 20 or antihypertensive therapy with angiotensin-converting enzyme inhibitors,20 which were initially felt to lessen glomerular injury by reducing glomerular pressure, also inhibit renal growth. In fact, it may be that injury is most severe when both glomerular hypertrophy and hypertension are present.
Yoshida et al21 compared two groups of rats in which renal excretory function was diminished by five sixths. Both groups underwent infarction of two thirds of one kidney; however, in one group the contralateral kidney was removed, and in the other it was left in situ but its ureter was diverted to drain into the peritoneal cavity. Glomerular hypertension was present in both groups; however, hypertrophy developed only when one kidney was completely removed. Severe injury was also limited to this group. Meyer and Rennke22 compared the effects of 50% reductions in renal mass produced by uninephrectomy or by segmental infarction. Hypertrophy developed in both groups; however, only infarcted rats had glomerular hypertension. As in the study of Yoshida et al,21 injury was observed only in the group in which glomerular hypertension and hypertrophy coexisted.
Salt intake also has a major effect on kidney size and compensatory renal growth. We23 reported that salt restriction reduced glomerular size and injury in uninephrectomized SHR despite persistent elevation in glomerular pressure. Similar observations have been made in rats with remnant kidneys.24 25 In this model, the beneficial effect of the low salt diet is significantly abrogated when its antihypertrophic effect is blocked by simultaneous administration of an androgen.24 In addition to salt restriction, antihypertensive agents may also inhibit renal growth and lessen glomerular injury by this mechanism. Like nifedipine, verapamil has been found to suppress compensatory renal growth after uninephrectomy26 and glomerulosclerosis7 in the remnant kidney model without reducing glomerular pressure.17 Similarly, Yoshida et al20 suggested that the beneficial effects of enalapril and of the combination of hydralazine, hydrochlorothiazide, and reserpine on glomerular structure in remnant kidney rats resulted from inhibition of glomerular growth. Taken together, these studies provide convincing evidence that glomerular damage is promoted when renal growth is stimulated.
In the present study, amlodipine produced a marked fall in BP in both DOC-salt rats and uninephrectomized SHR. The magnitude of the decline in systemic pressure was significant, albeit slightly less than that achieved in our previous studies3 6 of the effects of nifedipine in these models. Unlike nifedipine, amlodipine failed to reduce glomerular injury in these rats. Consistently, amlodipine also did not reduce glomerular pressure or size in uninephrectomized SHR. Although not compared in a single experiment, many aspects of the nifedipine and amlodipine studies were similar, including the species and models examined, the diets used, and the methods used to assess functional and morphological changes in our rats. Taken together, these findings suggest that structurally similar calcium antagonists can have markedly different effects on renal morphology and function that are not closely correlated with changes in systemic BP. However, because we did not anticipate that amlodipine would be less effective than nifedipine in preventing glomerular injury, we did not design our experiment to evaluate differences between the drugs and they were not directly compared in this study. As a result, other factors could account for the differences between the two studies, including drug dose, degree of BP reduction, food intake, or other unknown variables. These questions can be definitively resolved only by another study in which these two agents are directly compared.
The explanation for the failure of amlodipine to inhibit renal growth and injury was not specifically addressed by this study. One possibility, suggested by the observation that systemic BP is quite labile in some models of hypertension,27 is that amlodipine failed to consistently reduce BP in our rats. In fact, BP was measured intermittently, and it is possible that transient elevations in BP might have been missed. However, to our knowledge, there is no direct evidence and little reason to suspect that significant differences in BP lability would exist between rats treated with amlodipine as opposed to nifedipine. In addition, we routinely vary the time of day at which we measure systemic BP. Although not as sensitive as 24-hour BP recording, we have not observed significant differences between pressures measured during the morning and evening hours. Therefore, it seems unlikely that significant, sustained, and unrecognized elevations in BP existed in our rats.
Alternatively, if one assumes that the degree of reduction in systemic BP we observed was accurate and indicative of the extent of blockade of voltage-dependent calcium channels in vascular smooth muscle, then these channels were inhibited to a similar extent in the present and in the previous nifedipine study.3 Logically, the failure of amlodipine to reduce injury might result from a lesser effect of the drug on other tissues, such as the kidney. Of note, although a member of the dihydropyridine family, amlodipine has unique properties that distinguish it from other agents in this class, including nifedipine. As a result of the unique presence of a basic amino side chain on the dihydropyridine ring, amlodipine is positively charged at physiological pH.28 This alters the interactions between amlodipine and both membrane and circulating lipids,29 affecting the volume of distribution, receptor interactions, and pharmacokinetics of the drug. Receptor studies indicate that amlodipine binds to calcium channels not only at the dihydropyridine site but also at the verapamil30 and diltiazem28 sites. The biological consequences of these pharmacological differences are largely unknown; however, in a recent study, subtle differences in diastolic cardiac function were observed between rats treated with amlodipine and those treated with nifedipine.31 These data are consistent with our hypothesis that these drugs may have divergent actions in some tissues.
One additional factor that has been related to progressive kidney damage is coagulation. In SHR,32 administration of heparin to young rats attenuates the rise in BP, suggesting that intravascular thrombosis contributes to the development of hypertension. Morphological studies in the related remnant kidney model33 reveal platelet thrombi occluding glomerular capillaries. In the remnant kidney model, anticoagulant therapy with heparin,34 warfarin,34 or any of a number of antiplatelet agents29 35 lessens injury. Calcium entry is a key event in the platelet aggregation process, and calcium antagonists suppress aggregation in some settings.36 If amlodipine also inhibited platelet aggregation in our rats, this might have reduced glomerular damage. In fact, amlodipine in the dose we administered failed to alter platelet aggregation in vivo, again consistent with its failure to reduce glomerular injury.
In summary, although systemic BP was significantly reduced in DOC-salt rats and uninephrectomized SHR chronically treated with amlodipine, glomerular injury was not avoided. Micropuncture and morphometric studies indicated that neither glomerular pressure nor compensatory kidney growth was reduced by amlodipine. These findings are consistent with a role for glomerular hypertension and hypertrophy in promoting glomerulosclerosis. They suggest that all calcium antagonists may not be equal in their ability to prevent progressive kidney damage. This issue should be further examined in direct comparisons of various agents in individual models of renal disease.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by a grant from Pfizer Laboratories, Inc.
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Footnotes |
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Reprint requests to Dr Lance D. Dworkin, Division of Renal Diseases, Rhode Island Hospital, 593 Eddy St, Providence, RI 02903.
Received September 16, 1994; first decision November 11, 1994; accepted October 25, 1995.
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