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(Hypertension. 1995;26:150-155.)
© 1995 American Heart Association, Inc.
Articles |
Nifedipine Prevents Renal Injury in Rats With Chronic Nitric Oxide Inhibition
Presented in part at the 26th Congress of the American Society of Nephrology, Boston, Mass, November 14-17, 1993, and published in abstract form (J Am Soc Nephrol. 1993;4:520).
From the Renal Division, Department of Clinical Medicine, University of São Paulo (Brazil) School of Medicine, and Department of Pharmacology, State University of Campinas (Brazil) School of Medicine.
Correspondence to Roberto Zatz, MD, PhD, Laboratório de Fisiopatologia Renal, Av. Dr. Arnaldo, 455, 3-s/67, 01246-903 São Paulo SP, Brazil.
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Abstract |
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Abstract Chronic nitric oxide inhibition promotes hypertension, renal dysfunction, and renal injury by unclear mechanisms. We examined the effects in this model of concomitant treatment with the calcium channel blocker nifedipine. Six adult male Munich-Wistar rats received 0.025% nifedipine in chow. Six untreated rats served as controls. Fifteen days later, renal function was evaluated in anesthetized rats before and after a bolus injection of the nitric oxide inhibitor N
-nitro-L-arginine methyl ester
at 3 mg/kg IV. Renal vasoconstriction and systemic hypertension induced
by the inhibitor were similar in untreated and nifedipine-treated rats.
In a second protocol, eight rats received the nitric oxide inhibitor in
their drinking water at 2.6 mmol/L. Eight additional rats also received
nifedipine as above. At day 15, rats given the nitric oxide inhibitor
exhibited systemic hypertension and renal vasoconstriction.
Simultaneous nifedipine lowered blood pressure slightly without
ameliorating renal hemodynamics. Tail-cuff pressure rose continuously
in rats receiving the nitric oxide blocker, reaching 171±7 mm Hg at
30 days, but remained at 143±3 mm Hg in rats also given nifedipine.
At this stage, rats treated with the nitric oxide inhibitor exhibited
extremely variable plasma renin activity, tuft collapse in 10.1±2.2%
of the glomeruli, and renal interstitial fibrosis. Simultaneous
nifedipine treatment normalized the dispersion of plasma renin
levels, while preventing renal morphological abnormalities. These
results suggest that in the chronic nitric oxide inhibition model,
sustained operation of voltage-sensitive calcium channels is not
essential for renal vasoconstriction but contributes to systemic
hypertension and plays a pivotal role in the development of renal
structural injury.
Key Words: nitric oxide • channel blockers, calcium • kidney • blood pressure • nephritis, interstitial • kidney glomerulus
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Introduction |
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Chronic inhibition of nitric oxide (NO) synthesis leads to progressive hypertension associated with severe renal vasoconstriction and glomerular and renal interstitial injury.1 2 3 The mechanisms underlying the hemodynamic and structural changes encountered in this model have not been established. A possible direct effect of NO inhibitors on cellular mechanisms leading to vasoconstriction is yet to be demonstrated, and evidence obtained in this laboratory and elsewhere suggests that the vascular effects of NO inhibition may be mediated at least in part by circulating vasoconstrictors such as angiotensin II (Ang II), catecholamines, and endothelin.1 3 4 5
A large body of evidence shows that vasoconstrictors act largely by promoting calcium entry into smooth muscle cytosol through plasmalemmal voltage-sensitive calcium channels (VSCCs).6 7 8 9 Accordingly, calcium channel blockers (CCBs) have been shown to effectively antagonize the mechanical effects of vasoconstrictors in vascular smooth muscle6 8 and mesangial cells.10 Previous studies suggest that acute CCB administration partially reverses hypertension and renal vasoconstriction11 associated with the chronic NO inhibition model. However, the possible salutary effect of persistent VSCC blockade in the hemodynamic and renal structural abnormalities elicited by NO inhibition has not been examined.
In the present study, we investigated whether chronic administration of a CCB, nifedipine, prevents the hemodynamic response to acute NO blockade as well as the progressive hypertension and renal parenchymal injury associated with chronic NO inhibition.
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Methods |
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Adult male Munich-Wistar rats (n=134) obtained from an established colony at the University of São Paulo and weighing 239 to 295 g were used in this study. Rats received standard chow (22% protein) and tap water ad libitum. All experimental procedures were in accordance with our institutional guidelines.
Study 1: Effect of Previous Nifedipine Treatment on Hemodynamic
Response to Acute NO Inhibition
For determination of whether acute NO inhibition still promotes
vasoconstriction when VSCCs are blocked, six rats received standard
chow to which nifedipine (Sigma Chemical Co) was added at 0.025% by
weight. This dose was shown to block the in vivo and in vitro effects
of the dihydropyridine agonist Bay K8644 (see below). After 2 weeks of
treatment, the rats were anesthetized with thiobutabarbital (100 mg/kg
body wt IP) and placed on a temperature-controlled surgical table.
Rectal temperature was monitored with a thermistor and maintained at
37±0.5°C. The femoral artery was cannulated with PE-50 tubing for
determination of baseline arterial hematocrit and subsequent periodic
collection of systemic blood samples as well as for continuous
monitoring of mean arterial pressure (MAP) by a Statham P23Db pressure
transducer connected to a chart recorder (model A8200, Anamed
Instruments). After tracheotomy, the jugular veins were catheterized
with PE-50 tubing for infusion of homologous plasma and
[14C]inulin. Physiological solution containing
14C-tagged inulin (2 µCi/mL) was infused at the rate of
1.5 mL/h throughout the experiment. As described previously, rats
received a continuous infusion of homologous plasma to replace surgical
losses.12 An amount of plasma equivalent to 1% body
weight was given over approximately 45 minutes, followed by an infusion
of 0.5 to 1.0 mL/h for the remainder of the experiment. The left ureter
was catheterized with PE-10 tubing. Approximately 2.5 hours after
anesthesia, urine was collected during 25 to 35 minutes for
determination of flow rate and inulin clearance. Whole-kidney
filtration fraction (FF) was determined by simultaneous collection of
blood samples from the femoral artery and renal vein and
measurement of the respective 14C activities in a
scintillation counter (Beckman Instruments) to calculate inulin
extraction. Blood was obtained from the renal vein with a sharpened
glass micropipette (approximately 40 µm OD). Renal plasma flow (RPF)
was calculated as GFR/FF, where GFR is glomerular filtration
rate. Total renal vascular resistance (RVR) was estimated by
MAP(1-Ht)/RPF, where Ht is arterial hematocrit.
In a second experimental period, we reassessed renal and systemic
hemodynamic parameters 30 minutes after a bolus intravenous injection
of the NO inhibitor
N-nitro-L-arginine methyl ester
(L-NAME), dissolved in saline, at 3 mg/kg. A group of six
weight-matched previously untreated rats underwent an identical
experimental protocol.
Study 2: Effect of Simultaneous Nifedipine Treatment on Renal
Hemodynamic and Structural Consequences of Chronic NO Inhibition
To ascertain whether simultaneous blockade of VSCCs would
prevent the functional and structural consequences of chronic NO
blockade, four rat groups were studied: (1) C (n=23), rats receiving no
drug therapy; (2) C+NIF (n=23), rats receiving 0.025% nifedipine mixed
with chow; (3) NAME (n=27), rats receiving 2.6 mmol/L L-NAME in
drinking water, corresponding to a daily intake of approximately 65
mg/kg; and (4) NAME+NIF (n=27), rats receiving L-NAME and
nifedipine simultaneously as described above. Fifteen days after
these treatments were initiated, 7 rats of group C, 7 of group C+NIF, 8
of group NAME, and 8 of group NAME+NIF were anesthetized and prepared
for functional studies as described above. The remaining rats were
followed up to 4 weeks, with weekly evaluation of blood pressure by a
tail-cuff method.13 At the end of this period, 8 rats of
group C, 8 of group C+NIF, 7 of group NAME, and 7 of group NAME+NIF
were anesthetized with 50 mg/kg IP pentobarbital sodium, and the
kidneys were perfusion-fixed in situ with Dubosq-Brazil solution after
a brief washout with saline. After fixation, two midcoronal slices of
each kidney were embedded in paraffin, and 2- to 3-µm-thick sections
were stained by the periodic acid–Schiff reaction for examination
under light microscopy. Additional sections were stained with Masson's
trichrome for better visualization of the extracellular matrix. Renal
tissue was examined in a blinded fashion under light microscopy at
x160 magnification. At least 300 glomeruli were examined for each rat.
Glomeruli exhibiting global collapse were identified according to
criteria described previously3 and detailed in
"Results." The frequency of collapsed glomeruli was expressed as
a percentage of the total number of glomeruli examined. For assessment
of the extent of interstitial expansion, the fraction of renal cortex
occupied by interstitial tissue staining positively for collagen was
quantitatively evaluated in Masson-stained sections by a point-counting
technique14 in 25 consecutive microscopic fields examined
at a final magnification of x320 under a 100-point ocular grid. In 8
additional rats of group C, 8 of group C+NIF, 12 of group NAME, and 12
of group NAME+NIF, also followed for 30 days, 400-µL blood samples
were obtained from a tail vein for determination of plasma renin
activity (PRA) by an enzymatic technique15 adapted for
small samples.
In Vivo and In Vitro Assessment of VSCC Blockade
For confirmation of whether the nifedipine dose used in this
study afforded effective blockade of VSCCs in smooth muscle, four rats
received nifedipine treatment for 2 weeks as described above. On the
morning of the experiment, rats were anesthetized with 100 mg/kg IP
thiobutabarbital. The left femoral artery was cannulated with PE-50
tubing, and blood pressure was monitored by a Statham P23Db pressure
transducer connected to a chart recorder (model A8200, Anamed
Instruments). The right jugular vein was also catheterized with PE-50
tubing. After a 45-minute stabilization period, rats received a bolus
injection of Bay K8644, 25 mg/kg IV in saline, used here as a specific
indicator of VSCC activity. Four rats receiving no previous treatment
received Bay K8644 as described above and served as controls.
To assess VSCC inactivation directly in vascular tissue, we used a cascade system for the superfusion of vascular tissue.16 Seven rats receiving nifedipine as described above for 7 days were killed by exsanguination under anesthesia with 60 mg/kg IP sodium pentobarbital. The thoracic cavities were opened and thoracic aortas removed and placed in Krebs' solution. The vessels were cleared of adipose tissue, and the endothelial layer was removed mechanically to avoid interference by endothelium-derived vasoactive factors. Effective removal of the endothelial layer was confirmed by abolishment of the relaxation induced by acetylcholine (1 µmol/L) in tissues precontracted by norepinephrine (3 µmol/L). The aortic strips were suspended in a cascade16 and continuously superfused with oxygenated (95% O2/5% CO2) and warmed (37°C) Krebs' solution at 5 mL/min. Tissue responses (tension, 1 g) were detected with auxotonic levers17 attached to heart/smooth muscle transducers (Harvard Apparatus) and displayed on a multichannel pen recorder (model WTR 381, Watanabe). After a 60-minute equilibration period, Bay K8644 was injected into the system as a single bolus (10 to 30 µL). Norepinephrine and the thromboxane agonist U46619 were injected in the same manner as positive controls. Responses to Bay K8644, U46619, and norepinephrine were tested in the manner described above in aortic strips obtained from seven age-matched controls receiving no previous drug treatment.
Drugs and Solutions
Bay K8644 (stock solution, 1 mmol/L in 40% ethanol) was
obtained from Bayer AG. L-NAME, norepinephrine, and nifedipine were
purchased from Sigma Chemical Co. U46619 was kindly provided by Dr John
Pike (Upjohn Co). The composition of the Krebs' solution was (mmol/L)
NaCl 118, NaHCO3 25, glucose 5.6, KCl 4.7,
KH2PO4 1.2,
MgSO4 · 7H2O 1.17, and
CaCl2 · 6H2O 2.5.
Statistics
One-way ANOVA with four preplanned pairwise comparisons
according to the Bonferroni method18 was used for
analysis of differences among groups regarding chronic
administration of L-NAME and/or nifedipine. PRA values were log
transformed before statistical analysis. Student's paired
t test was used for analysis of the effects of acute
L-NAME administration.
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Results |
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Effects of Nifedipine on In Vivo and In Vitro Responses to Vasoconstrictors
Acute intravenous injections of the dihydropyridine agonist Bay K8644 raised blood pressure by 40±5 mm Hg in untreated rats, whereas in rats chronically treated with nifedipine, the blood pressure elevation was only 9±2 mm Hg. Bay K8644, the thromboxane mimetic U46619, and norepinephrine elicited dose-dependent contractions in aortic strips obtained from untreated rats. In aortic strips obtained from rats pretreated with nifedipine, the vasoconstrictor responses to norepinephrine and U46619 were indistinguishable from control (Fig 1). However, the vasoconstrictor response to Bay K8644 was abolished in five aortic strips and attenuated by approximately 80% in the remaining two aortic strips obtained from these rats (Fig 1).
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Study 1
Table 1 shows the effect of acute L-NAME treatment
in untreated rats and rats previously treated with nifedipine. As
shown previously,19 acute NO inhibition markedly elevated
MAP (151±3 versus 106±2 mm Hg before treatment, P<.05)
and RVR (25.3±1.5 versus 12.8±0.4 mm Hg/[mL/min] before treatment,
P<.05) in untreated rats. In rats chronically treated with
nifedipine, basal renal hemodynamic parameters were similar to
those observed in rats given no previous treatment. Acute L-NAME
administration to nifedipine-treated rats promoted similar variations
in blood pressure (151±3 versus 106±2 mm Hg before treatment,
P<.05) and RVR (25.0±1.5 versus 13.9±0.8
mm Hg/[mL/min] before treatment, P<.05) as in previously
untreated rats.
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Study 2
Table 2 shows renal and systemic hemodynamic
parameters obtained in rats receiving oral L-NAME and/or nifedipine for
15 days. Body and left kidney weights were comparable among groups,
although body weight was slightly reduced in group NAME+NIF (262±7
versus 288±3 g in group C+NIF, P<.05). As shown
previously,1 2 3 chronic NO inhibition promoted marked
hypertension in group NAME (157±5 versus 109±3 mm Hg in untreated
controls, P<.05). Nifedipine treatment had no effect on
blood pressure in group C+NIF compared with group C (114±4 mm Hg,
P<.05 versus untreated controls) and lowered blood pressure
only slightly in group NAME+NIF (141±5 mm Hg, P>.05
versus NAME and P<.05 versus C+NIF). Chronic L-NAME
treatment lowered GFR in group NAME (1.01±0.03 versus 1.35±0.08
mL/min in untreated controls, P<.05). Chronic nifedipine
treatment had little effect on GFR in group C+NIF (1.29±0.04 mL/min,
P>.05 versus untreated controls). Likewise, simultaneous
nifedipine therapy failed to improve GFR in group NAME+NIF (0.94±0.06
mL/min, P>.05 versus group NAME). Parallel results were
obtained regarding FF, RPF, and RVR.
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As reported previously,1 3 histological examination of renal parenchyma disclosed two main modalities of renal parenchymal injury: (1) glomerular collapse (Fig 2), consisting of a severe reduction in tuft size and a uniform collapse of the capillary loops with no adhesion to Bowman's capsule, and (2) interstitial expansion (Fig 3), consisting of focal expansion of interstitial tissue, with infiltration by fibroblasts and deposition of a collagen-like material, frequently in association with tubular atrophy and vacuolization. Glomerular segmental areas of sclerosis or necrosis were also encountered, albeit much less frequently than glomerular collapse or interstitial expansion.
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Table 3 shows the frequency of glomerular collapse and extent of interstitial expansion at 30 days of L-NAME and/or nifedipine treatment. The frequency of collapsed glomeruli was negligible in untreated controls and in rats treated with nifedipine alone (0.2±0.2% and 0.2±0.1%, respectively). As expected, L-NAME treatment was associated with a high frequency of collapsed glomeruli in group NAME (10.1±2.2%, P<.05 versus untreated controls). Concomitant nifedipine treatment prevented the appearance of glomerular collapse in group NAME+NIF (0.7±0.2%, P<.05 versus NAME and P>.05 versus C+NIF). Percent interstitial area was not affected by treatment with nifedipine alone (2.4±0.1% in group C+NIF versus 3.1±0.4% in group C, P>.1). Chronic NO inhibition was associated with an expansion of interstitial area in group NAME (8.5±1.1%, P<.05 versus C). Simultaneous treatment with nifedipine largely prevented interstitial expansion in group NAME+NIF (4.6±0.6%, P<.05 versus NAME, P>.05 versus C+NIF).
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Fig 4 shows the time course of tail-cuff pressure in rats receiving chronic treatment with L-NAME and/or nifedipine. A steady elevation of tail-cuff pressure was evident in rats given L-NAME alone, reaching 171±7 mm Hg after 30 days of treatment. Although rats simultaneously receiving nifedipine were also hypertensive, tail-cuff pressure did not rise with time, reaching 143±3 mm Hg at 30 days. Nifedipine had little influence in rats not receiving L-NAME. Fig 5 shows PRA values in the various groups. No statistically significant difference was observed among groups. However, mean PRA was numerically higher in group NAME compared with control (10.0±2.7 ng Ang I/mL per hour versus 4.9±0.5 in controls, P>.05). Of note, group NAME rats exhibited a striking dispersion of individual PRA values (range, 1.9 to 32.2 ng Ang I/mL per hour compared with 3.2 to 7.6 in control), as previously described in association with this model.1 Nifedipine treatment reduced both mean PRA values (6.1±0.6 versus 3.4±0.5 ng Ang I/mL per hour in group C+NIF) and dispersion (range, 4.2 to 9.2 ng Ang I/mL per hour versus 1.5 to 5.4 in group C+NIF).
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), control rats
chronically treated with nifedipine (
), rats treated with
N
), and rats treated simultaneously with L-NAME and
nifedipine (
). All differences were significant at 15 and 30
days, except for the comparison between untreated controls and
nifedipine-treated controls.
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Discussion |
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Previous studies from this laboratory and elsewhere11 20 showed that in rats with chronic NO blockade, acute treatment with the CCB verapamil partially reversed hypertension and renal vasoconstriction, suggesting that VSCCs may in part mediate these hemodynamic abnormalities. In the present study, we used nifedipine in an attempt to prevent the marked elevation of systemic blood pressure and RVR associated with acute L-NAME treatment.19 Although prior nifedipine treatment afforded effective VSCC inhibition, the renal and systemic hemodynamic responses to acute L-NAME infusions were similar in untreated and nifedipine-treated rats, suggesting that VSCC activation is not a prerequisite for the acute vascular effects of NO inhibition. However, these findings do not necessarily exclude a role for extracellular calcium in this process, because several cell types can adapt to chronic depletion of calcium stores by opening alternative, as yet undefined pathways to allow extracellular calcium into the cytosol.21 22 23
In view of its poor efficacy in blocking the acute renal effects of L-NAME, chronic nifedipine treatment would be expected to be equally innocuous in the prevention of the severe functional and structural abnormalities associated with chronic NO inhibition. Simultaneous nifedipine treatment did fail to prevent the pronounced renal vasoconstriction, hypofiltration, and hypoperfusion associated with chronic L-NAME treatment. However, nifedipine therapy prevented the continuous rise of blood pressure characteristically observed in L-NAME–treated rats, indicating that VSCCs contribute at least in part to the development of hypertension in this model. The mechanisms underlying this effect are unclear. Nifedipine could lower peripheral resistance by directly lessening the sustained vasoconstriction induced by L-NAME treatment, although smooth muscle cell adaptations such as mentioned above might counteract this effect. In addition, VSCC inactivation may have limited hypertension by preventing glomerular tuft collapse, the most common type of renal injury in this model.1 3 Meyer and Rennke24 described similarly collapsed glomeruli in the remnant kidney after 5/6 renal ablation, raising the hypothesis that glomeruli may undergo severe hypoperfusion and even retrograde perfusion from neighboring nephrons. Accordingly, Correa-Rotter and coworkers25 provided evidence that these glomeruli may produce excessive amounts of renin, consistent with our previous finding that their frequency correlates roughly with blood pressure levels and that Ang II inhibition largely prevents hypertension in this model.1 3 In the present study, L-NAME treatment tended to increase PRA at 30 days, although the extreme dispersion of individual values precluded the achievement of statistical significance. These results, similar to those described previously in this laboratory,1 are consistent with the concept that collapsed, underperfused glomeruli may constitute a source of uncontrolled renin production in this model. Further support for this hypothesis is provided by the finding that simultaneous nifedipine treatment lowered both PRA (mean levels and dispersion) and the frequency of collapsed glomeruli in rats receiving chronic L-NAME treatment. The mechanisms whereby VSCC blockade could prevent glomerular collapse are also unclear. Extreme narrowing of the parent afferent arteriole has been demonstrated in association with these collapsed glomeruli in the chronic NO inhibition model.3 The protective effect of chronic nifedipine suggests that adequate operation of VSCCs at the afferent arteriole may be crucial to the development of this process and that adaptive responses to their inactivation are lacking in this particular case. Consistent with this hypothesis is the finding that the afferent arteriole is particularly sensitive to the action of CCBs.26 27 On the other hand, mitigation of systemic hypertension by nifedipine may have directly limited the appearance of collapsed glomeruli, since elevated blood pressure levels may govern the development of renal injury in other experimental models.28 It must be stressed, however, that hypertension of equal or greater severity as that shown in this study is not associated with collapsed glomeruli in models such as renal ablation29 or the Milan hypertensive rat.30
We showed previously that renal interstitial fibrosis is one of the most striking renal structural alterations observed in rats undergoing chronic NO inhibition and that this process is aggravated by concomitant salt overload3 or renal mass reduction.31 In the present study, interstitial fibrosis was evident in rats receiving chronic L-NAME treatment. Simultaneous nifedipine therapy largely prevented renal interstitial expansion in these rats, an effect not attributable to renal hemodynamic alterations. Interstitial expansion in this model may depend at least partially on enhanced cell proliferation, since NO has been shown to act as an antimitogen in several cell types, including fibroblasts,32 smooth muscle cells,33 mesangial cells,34 and leukocytes.35 Several studies indicate that calcium entry through plasmalemmal VSCCs profoundly influences the process of cell proliferation and that CCBs inhibit cell proliferation and inflammation in several cell types, including fibroblasts,36 smooth muscle cells,37 and mesangial cells.38 In addition, chronic CCB treatment was shown to ameliorate renal injury by nonhemodynamic mechanisms in renal ablation39 and deoxycorticosterone acetate–salt hypertension.40 Thus, VSCC blockade by nifedipine treatment in the present study may have prevented L-NAME–induced interstitial expansion by limiting cell proliferation. As in the case of glomerular collapse, cellular adaptive responses aimed at circumventing VSCC blockade were apparently absent or ineffective.
In summary, chronic nifedipine treatment failed to prevent the renal dysfunction resulting from acute or chronic L-NAME treatment. Nevertheless, nifedipine treatment largely attenuated systemic hypertension and arrested renal injury in rats with chronic NO inhibition. The intimate mechanisms linking VSCCs and other plasmalemmal calcium channels to the development of these abnormalities remain to be elucidated.
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Acknowledgments |
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This work was supported by grant No. 92/3496-9 from the São Paulo Foundation for Research Support (FAPESP). During these studies R.Z. was the recipient of a research award (No. 326.429/81) from the Brazilian Council of Scientific and Technologic Development (CNPq). We are thankful to Cláudia Ramos de Sena and Marinete Miristeni dos Santos for expert technical assistance.
Received October 12, 1994; first decision November 16, 1994; accepted February 27, 1995.
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