(Hypertension. 2001;37:1268.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Comparative Effects of Selective T- and L-Type Calcium Channel Blockers in the Remnant Kidney Model
From the Departments of Medicine (K.A.G., A.K.B.) and Pathology (M.P.), Loyola University Medical Center and Hines Veterans Administration Hospital, Maywood; and Department of Preventative Medicine, Rush-Presbyterian St. Luke’s Medical Center (G.L.B.), Chicago, Ill.
Correspondence to Karen A. Griffin, MD, Loyola University Medical Center, Section of Nephrology, 2160 S First Ave, Maywood, IL 60153.
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Abstract |
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Abstract—We have previously reported that the dihydropyridine L-type calcium channel blockers (CCBs) have an adverse impact on glomerulosclerosis (GS) in the remnant kidney model despite significant blood pressure (BP) reduction, because of the concurrent deleterious effects on renal autoregulation. The effects of the CCB mibefradil, which is
10-fold more selective for T- than
L-type channels, were compared with the L-type selective amlodipine.
One week after 5/6 ablation, rats were left untreated or received
mibefradil or amlodipine. Systolic BP was monitored by
continuous radiotelemetry. At 7 weeks, proteinuria and percent GS were
quantitated. Average BP was significantly and comparably reduced after
mibefradil (141±3 mm Hg) and amlodipine (143±5 mm Hg)
compared with untreated rats (188±5 mm Hg). Despite the
reduction in BP, proteinuria and percent GS in the mibefradil- or
amlodipine-treated groups were not significantly different from those
in the untreated rats. Excellent correlations were observed between BP
and GS in each group (r=0.74 to
0.85, P<0.02). However, the
slope of the relationship between GS and BP (increase in percent
GS/mm Hg increase in average BP) was made significantly steeper by
both mibefradil (2.7+0.6) and amlodipine (1.9+0.6) as compared with
untreated rats (0.7±0.2;
P<0.01). Thus, at any given BP
elevation, greater GS was seen in mibefradil- and amlodipine-treated
rats as compared with untreated rats. Additional studies performed at 3
weeks after renal ablation showed that the ability to autoregulate
renal blood flow, already impaired in untreated rats, was essentially
abolished by both mibefradil and amlodipine, thus providing an
explanation for the shift in the slope of the relationship between BP
and GS. These data indicate that CCBs with selectivity for either the
T- or L-type calcium channel fail to protect against GS despite
significant BP reductions because of the similar adverse effects on
renal autoregulation and BP transmission.
Key Words: glomerulosclerosis • nephrectomy • hypertension, experimental • telemetry • blood pressure • autoregulation
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Introduction |
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The rat remnant kidney (RK) model (produced by right nephrectomy and infarction of two thirds of the left kidney) has been extensively used to investigate the mechanisms responsible for the progressive nature of human renal disease.1 2 3 The model is characterized by hypertension and the development of proteinuria and progressive glomerulosclerosis (GS) of the initially normal remnant nephrons with time.1 2 3 Substantial evidence indicates that preglomerular vasodilation and an impairment of the normally protective renal autoregulatory mechanisms lead to an exaggerated transmission of systemic hypertension and barotrauma to the renal microvasculature and resultant GS.2 3 4 5 We have previously shown that the dihydropyridine calcium channel blockers (CCBs) cause a further impairment of the already impaired renal autoregulation in this model and fail to provide renoprotection despite substantial BP reductions.6 7 The slope of the relationship between blood pressure (BP) and GS becomes significantly steeper in the dihydropyridine CCB-treated rats (increase in percent GS/mm Hg increase in average systolic BP) such that greater GS is observed at any given BP increase compared with untreated controls. Mibefradil, a CCB antihypertensive agent with significant antiproliferative activity and a 10-fold greater selectivity for T- compared with L-type calcium channels,8 has been recently reported to provide renoprotection in several models.9 10 11 The present studies compare the relative effects of mibefradil with those of the dihydropyridine CCB amlodipine on radiotelemetrically monitored systemic BP, renal autoregulation, and GS in the RK model.
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Methods |
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Studies were conducted in male Sprague-Dawley rats (body weight 225 to 300 g) fed a standard (25%) protein diet (Purina) and synchronized to a 12:12 hours light (6:00 AM to 6:00 PM) and dark (6:00 PM to 6:00 AM) cycle. All rats received food and water ad libitum throughout the study.
Radiotelemetry
The rats were anesthetized with
intraperitoneal sodium pentobarbital (45 mg/kg) and
subjected to 5/6 renal ablation (right nephrectomy and ligation of
all but 1 posterior extrarenal branch of the left renal artery) and
prepared for telemetric monitoring of BP (Data Sciences, International)
at the time of the renal ablation surgery as previously
described.12 13
Systolic blood pressure (SBP) in each animal was recorded
at 10-minute intervals for 7 weeks with each BP measurement
representing the average of 50 to 60 individual BP readings
during a 10-second interval (heart rate in rats is 300 to 360 bpm).
Tail-vein blood samples were obtained at 3 days for measurement of
serum creatinine (SCr) as an index
of the degree of renal mass
reduction.5 At 7 days, the
rats were randomly assigned to the untreated group or received either
Mibefradil (0.1% in chow; 30 mg ·
kg-1 · d-1)
or amlodipine (200 mg/L; 30 mg · kg-1
· d-1) in drinking water. At 7 weeks,
24-hour urine collections for protein excretion were obtained, after
which glomerular filtration rate (GFR) (inulin clearance)
and renal blood flow (RBF; Transonic Systems, Inc) were measured under
anesthesia (IV sodium pentobarbital 40 mg/kg) as described
previously.5 14 At
the conclusion of these studies, the rats were killed and the kidneys
were harvested for morphological studies.
To determine if their antihypertensive effects were
synergistic, additional rats (n=3 each) received either amlodipine (100
mg/L) or mibefradil (0.065% in chow) and were given the other CCB 1
week later. BP was reduced by another 10 mm Hg, but all 6 rats
died within 2 to 7 days after developing severe
bradycardia.
Autoregulatory Studies
After renal ablation, the rats were followed for 3
weeks without radiotelemetry. Tail-vein SCr was
obtained at 3 days to stratify for renal mass reduction. At 7 days,
the rats were randomly assigned to the untreated (n=11), mibefradil-
(n=13), or amlodipine-treated groups (n=9). At 3 weeks, inulin
clearance and RBF were measured (vide supra). Autoregulatory studies
were then performed using aortic miniclamps positioned above and below
the left renal artery to raise or lower renal perfusion pressure (RPP)
as previously
described.5 6 7 14
The RBF was allowed to stabilize for 1 to 2 minutes at each pressure
before RBF measurements were made.
Morphological Methods
The RKs were perfusion-fixed in situ and 3-µm
transverse sections stained with hematoxylin and eosin and periodic
acid-Schiff were evaluated in a blinded fashion by standard
morphological methods as previously
described.5 6 7 12 13
At least 100 glomeruli in each animal were examined, and the severity
of glomerular injury was expressed as the percentage of
glomeruli exhibiting lesions of GS.
Analyses, Calculations, and
Statistics
SCr, inulin, and urinary
protein (quantitative sulfosalicylic-acid method) were measured as
previously
described.5 6 7 12 13
GFR was calculated using standard formulae. Autoregulatory index (AI)
was calculated as follows: AI=
[(RBF2 -RBF1 )/RBF1 ]/[(RPP2 -RPP1 )/RPP1 ].5 6 7 14 .
An AI of 0 indicates perfect autoregulation, whereas an AI of 1
indicates the vessels act as passive conduits for blood flow. All
results are expressed as mean±SE. Statistical analysis was
performed using ANOVA followed by Student-Newman-Keuls
test.15 Linear regression
analysis was used to calculate the slopes and intercepts of the
relationship between BP and GS in each
group.15 A
P<0.05 was considered
statistically significant.
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Results |
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Radiotelemetry Studies
Table 1 shows that the initial body weight, SCr, and 24-hour urine protein excretion for the 3 groups were not significantly different from each other. Similarly, the SCr at 3 days was not significantly different between the groups, indicating comparable renal mass reduction in all groups. The final body and kidney weights, GFR, and RBF at 7 weeks were also not significantly different among the 3 groups.
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Figure 1 illustrates the course of the weekly averages of
SBP after 5/6 renal ablation in untreated animals and in the 2
groups treated with CCBs. For the first 7 days after renal ablation and
before the initiation of antihypertensive therapy, the BP was similar
in the 3 groups. By contrast, the average SBP during the final 6 weeks
in both the mibefradil- (141±3 mm Hg) and the amlodipine-treated
groups (143±5 mm Hg) was significantly lower than that of the
untreated group (188±5 mm Hg) as well as in comparison to the
average pretreatment
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SBP during the first week (P<0.001). But, these BP parameters were not different between amlodipine- and mibefradil-treated rats.
The protein excretion rate (mg/24 hours) and the percent
glomeruli that exhibit GS in the RKs of these 3 groups after 7 weeks
of radiotelemetry are presented in
Figure 2. There was no statistically significant difference
in proteinuria and GS between the mibefradil- and amlodipine-treated
groups or compared with the untreated rats, although the
amlodipine-treated rats tended to show greater GS than
mibefradil-treated rats (6/9 amlodipine-treated rats, but only 3/11
mibefradil-treated rats exhibited 
50% GS).
Figure 3 shows the relationship between the average SBP and
GS in individual animals of each group. A strong and direct
relationship was observed within each group with the correlation
coefficients (r) ranging
between 0.74 to 0.85, P<0.01.
However, the slopes of the relationship between GS and BP (percent
increase in GS/mm Hg increase in average BP) were significantly
different in mibefradil- and amlodipine-treated rats compared with the
untreated control rats
(P<0.01) but were not
significantly different from each other. Although the mean GFR was not
significantly different between the groups, a significant correlation
was present between percent of GS and GFR in individual animals
(r=0.63,
P<0.01,
n=32).
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Autoregulatory Studies
Basal body weight, SCr, and
SCr at 3 days were not significantly different
between the groups or as compared with the rats undergoing
radiotelemetry studies (data not presented). However, body
weight at 3 weeks in the amlodipine group (237±14.5 g) was
significantly lower than in the untreated (307±18.7 g) or the
mibefradil group (280±8.7 g;
P<0.05). However, no
significant differences between the groups were present for RBF and
GFR (mL · min-1 ·
kg-1) measured at the ambient arterial
pressure (AP): untreated (26.0±3.8 and 2.5±0.3), mibefradil-
(23.8±1.8 and 2.9±0.4), and amlodipine-treated (20.6±2.1 and
1.8±0.3), respectively. Ability to autoregulate RBF was impaired in
all groups; ie, there were significant changes in RBF with each change
in RPP in all groups
(Figure 4). However, as shown by a comparison of the
calculated autoregulatory indices, the impairment was significantly
greater in both the amlodipine- and mibefradil-treated rats compared
with untreated rats (<0.01). The differences in autoregulatory indices
between amlodipine and mibefradil were not statistically
significant.
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Discussion |
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The results of the present study show that despite its differences in relative selectivity for T- versus L-type calcium channels, mibefradil-like amlodipine fails to provide renoprotection in the 5/6 renal ablation model despite substantial BP reduction. This failure likely represents a consequence of its concurrent adverse effects on renal autoregulation in this model, similar to that observed with the dihydropyridine CCBs in this and previous studies.6 7 Normal renal autoregulatory mechanisms, through proportionate vasoconstriction of the preglomerular vasculature, provide the primary protection against systemic hypertension by preventing its transmission to the renal microvasculature.3 16 These protective mechanisms are impaired in RKs and account for their increased vulnerability to hypertensive injury.3 4 5 Both amlodipine and mibefradil essentially abolish this residual renal autoregulatory capacity in the RK model. The further enhancement of BP transmission is expected to result in greater GS at any given BP elevation, which was in fact demonstrated in the present study by the steeper slopes of the relationship between BP and GS in mibefradil- and amlodipine-treated rats compared with untreated rats. Thus, the beneficial effects of BP reduction by these agents are likely counteracted by their simultaneous adverse effects on renal autoregulation, with a resultant inability to provide renoprotection in this model. Such interpretations are supported by the observations that antihypertensives, which are relatively neutral with respect to renal autoregulation such as triple therapy regimens (hydralazine, hydrochlorothiazide, and reserpine) or agents that block the renin-angiotensin system (RAS), confer renoprotection in proportion to the achieved radiotelemetrically measured BP reductions in the 5/6 ablation model.13 17 That CCBs including mibefradil may sometimes have similar adverse effects on renal autoregulation in other models is suggested by their inconsistent ability to provide protection against proteinuria and glomerular injury.18 19 20
The present data, however, do not permit a definitive conclusion as to the degree to which the observed effects of mibefradil on BP and renal autoregulation, at least in the dosage used, are mediated by the blockade of T- versus L-type calcium channels. The mortality observed in rats given combined submaximal doses of amlodipine and mibefradil, similar to that observed in patients, suggests separate and additive cardiac effects.21 However, such an inference may not be equally valid for the BP and renal autoregulatory effects. Although the T-type calcium channels have been demonstrated in the renal vasculature,22 23 their independent role in renal hemodynamics and autoregulation, unlike that for L-type calcium channels,24 25 remains to be established. The observed differences between amlodipine and mibefradil during micropuncture studies11 are suggestive of such a role, but more direct and definitive evidence has yet to be obtained.
The present results are at seeming variance with some recent studies that have examined the relative renoprotective effects of amlodipine and mibefradil in other models of hypertensive renal injury using comparable dosages.10 11 In contrast to the present results, impressive renoprotection was achieved with mibefradil in both the DOCA+salt model in the Wistar rat and the model of accelerated nephrosclerosis in the spontaneously hypertensive rat (SHR) given NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthesis.10 11 However, dissimilar results were obtained with amlodipine in these 2 models. In contrast to the SHR+L-NAME model, amlodipine was ineffective in protecting against proteinuria and GS in the DOCA+salt model, although it did provide protection against vascular damage.10 In the present study, although a trend toward increased GS was observed in the amlodipine-treated rats, the differences were not statistically significant.
The reasons for the differences between the studies are not
readily apparent but several possibilities exist. It is likely that the
models differ in their susceptibility to hypertensive renal damage.
Such differences may manifest themselves either as differences in the
BP threshold at which renal damage develops and/or differences in the
slope of the relationship between BP load and renal microvascular
injury. For instance, substantial glomerular injury is
observed at 6 weeks in the 5/6 ablation model even when the
systolic pressures do not exceed 175
mm Hg.5 12 By
contrast, similar injury is only observed in the DOCA+salt or the
SHR+L-NAME model with systolic pressures that are significantly
>200 mm Hg over several
weeks.10 11 It is
possible that such differences reflect differences in the degree to
which BP is transmitted to the renal microvasculature as suggested by
the higher glomerular capillary pressure (PGC)
AP values in the 5/6 ablation
model26 as compared with the
DOCA+salt27 and
SHR+L-NAME15 models. Such
data have important implications for the relative renoprotective
ability of antihypertensive agents in a given model. The degree of BP
reduction necessary to achieve renoprotection may differ between models
depending on the BP threshold for hypertensive renal damage. Thus,
moderate BP reductions may be effective in the DOCA+salt or the
SHR+L-NAME
models,10 11
whereas almost complete BP normalization seems to be necessary in the
5/6 ablation
model.6 7 17
The observation that GS is prevented in RK rats being treated with
dihydropyridine CCBs, if BP is further reduced to
normotensive levels by the addition of another agent, is
consistent with such an
interpretation.28 Similarly,
differences may exist between individual vascular segments (arteries
and arterioles versus glomerular capillaries) and
contribute to the differential effectiveness of amlodipine in
protecting against vascular versus glomerular damage in the
DOCA+salt model.10 Similar
differential effects of antihypertensive agents on vascular versus
glomeruloprotection have sometimes been observed in other
models.29
However, a precise estimate of the ambient BP load is critical for the validity of such distinctions and interpretations. Conventional tail-cuff BP measurements may not allow the detection of relevant differences in the chronic ambient BP load (exposure) within and between experimental groups.6 7 13 17 The fundamental lability of BP in the conscious unrestrained state, which seems to be further exaggerated in models of experimental hypertension,12 30 severely limits the conclusion on the basis of such conventional BP measurements. Even direct intra-arterial BP measurements, if only obtained for a limited period during the course, may not provide an accurate index of the history of BP exposure of the renal vasculature. Similarly, PGC measurements, while having the undoubted merit of providing a direct assessment of BP transmission to the renal microvasculature, nevertheless are limited by providing such data at a single time point and of being compromised by anesthesia-induced activation of neurohormonal systems including the RAS.31 Such activation has the documented potential for independent effects on segmental renal vascular resistances and PGC, and it may account for the often poor correlation between PGC and GS between and within models.1 32
Differential susceptibility to hypertensive renal damage may also stem from the differences in the degree to which individual BP-independent mechanisms contribute to such damage in different models. Such potential mechanisms include the degree of glomerular hypertrophy, activation of the RAS and the NO systems, and relative expression of transforming growth factor-ß among others.1 32 33 Thus, the degree to which such pathogenetic effects can be modulated by the individual antihypertensives, including the CCBs, may represent another source for the observed differences between these models. For instance, the antiproliferative and/or relative renin-suppressive effects of mibefradil compared with amlodipine may account for the differences observed in the DOCA-salt9 10 model. By contrast, the result of RAS blockade in the RK model suggests little contribution of BP-independent mechanisms to GS,17 and despite the potential for differential effects of amlodipine and mibefradil on both hemodynamic and nonhemodynamic mechanisms, no differences were observed with respect to BP, renal autoregulation, and GS between the 2 agents. These data are consistent with the concept that GS in the RK model is primarily dependent on the degree to which the increased BP is transmitted to the renal microvasculature. Pharmacological interventions, such as CCBs, that enhance BP transmission (impair renal autoregulation) may not provide renoprotection proportionate to the BP reduction unless BP is lowered well into the normotensive range.
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Acknowledgments |
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This work was supported in part by National Institutes of Health grant DK-40426; the office of Research and Development (R&D) Medical Research Service, Department of Veterans Affairs (PI to K.A.G.); and a grant from Roche Laboratories, Inc. The authors thank Jennifer Orr and Shilpa Gude for technical assistance and Martha Prado for secretarial assistance.
Received July 13, 2000; first decision August 2, 2000; accepted November 3, 2000.
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K. A. Griffin, I. Abu-Amarah, M. Picken, and A. K. Bidani Renoprotection by ACE Inhibition or Aldosterone Blockade Is Blood Pressure-Dependent Hypertension, February 1, 2003; 41(2): 201 - 206. [Abstract] [Full Text] [PDF]
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 L. L. Cribbs Vascular Smooth Muscle Calcium Channels: Could "T" Be a Target? Circ. Res., September 28, 2001; 89(7): 560 - 562. [Full Text] [PDF]
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