(Hypertension. 1999;34:865-871.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Long-Term Nitric Oxide Synthase Inhibition in Rat Pregnancy Reduces Renal Kallikrein
From the Center for Medical Research (S.P.S., J.F.V., A.G., P.R.) and the Departments of Obstetrics and Gynecology (S.P.S.) and Pediatrics (P.R.), School of Medicine, and the Department of Physiology (C.P.V.), Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.
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Abstract |
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Abstract—This study was performed to test the hypothesis that long-term nitric oxide synthase (NOS) inhibition during pregnancy may alter the predominance of the vasodilator kallikrein system. Sprague-Dawley rats were treated with the competitive inhibitor of NOS N
-nitro-L-arginine (L-NNA, 50
mg · kg-1 · d-1, dissolved in
water) from days 7 to 21 of pregnancy. Rats were studied before
treatment (day 5), at days 11, 17, and 21 of pregnancy (during
treatment), and at postpartum days 7 and 21 (after the drug was
withdrawn at delivery). Each group (n=5 to 8) had its corresponding
control group (C) that received only vehicle. Additional rats were
treated with NG-nitro-L-arginine
methyl ester (L-NAME) alone or with an excess of
L-arginine. At each study day, we measured blood pressure,
collected urine overnight, obtained blood samples, and processed the
kidneys for conventional histology and immunohistochemistry. In L-NNA
rats, fetal and placental weights were reduced at days 17 and 21. Blood
pressure was higher at days 17 and 21, returning to normal after
L-NNA was removed. Urinary kallikrein activity was lower at days 11 and
17 (L-NNA=1147±213 and C=2317±146 nmol/16 h,
P<0.001). Plasma renin activity was reduced at day 21
(L-NNA=9.6±2.1 and C=25.9±5 ng · mL-1 ·
h-1, P<0.05) and remained lower at
postpartum day 7. L-NNA rats exhibited glomerular lesions
and tubular atrophy, particularly of connecting tubules that displayed
reduced kallikrein staining. Tubulointerstitial
infiltrating macrophages (ED1+) were also observed. Renal
lesions were present as early as day 11 and persisted at day 7
postpartum. L-NAME rats exhibited similar alterations that were
attenuated with an excess of L-arginine. We postulate that
the reduction in renal kallikrein may contribute to the
hemodynamic alterations described in this model.
Key Words: pregnancy • nitric oxide • plasma renin activity • renal kallikrein • renal lesions • macrophages
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Introduction |
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Normal pregnancy is characterized by a marked stimulation of the renin-angiotensin system (RAS), which causes renal water and sodium retention and increases plasma volume.1 2 In turn, plasma volume expansion allows a sustained elevation in cardiac output and, indirectly, in uterine blood flow, conditions necessary for normal fetal growth. Despite the rise in blood volume and the activation of the vasoconstrictor RAS, blood pressure decreases during pregnancy2 because of a marked reduction in peripheral vascular resistance associated with a predominance of vasodilator, such as kallikrein and nitric oxide (NO), over vasoconstrictor substances.3 Thus, systemic vasodilatation would initiate the series of hemodynamic changes that are important for fetal growth. Consistent with such a possibility, in normal pregnant rats we have demonstrated a rise in urinary kallikrein activity that precedes the increase in plasma renin activity (PRA).4 In addition, in conditions associated with a limited plasma volume expansion, such as idiopathic fetal growth restriction5 and preeclampsia,6 and in underweight mothers,7 we have demonstrated a significant reduction in urinary kallikrein activity.
Kallikrein, through kinin formation, stimulates the NO–NO synthase
(NOS) pathway, which is also activated in pregnancy. The plasma
level, metabolic production, and urinary excretion
of guanosine 3',5'-cyclic monophosphate (cGMP), the urinary excretion
and plasma levels of the stable NO metabolite nitrate, and the
expression and activity of different NOSs are increased in gravid
animals.8 9 10 Long-term administration of NOS
inhibitors, such as
N-nitro-L-arginine
(L-NNA) and
NG-nitro-L-arginine
methyl ester (L-NAME), to gravid rats causes sustained hypertension,
reduced plasma volume, intrauterine growth retardation, proteinuria and
thrombocytopenia, and renal morphological abnormalities that resemble
those observed in women with preeclampsia.11 12 13 14 15
These observations led us to evaluate the hypothesis that long-term NOS inhibition during pregnancy may alter the predominance of the vasodilator kallikrein-kinin system (KKS), either by increasing renin or decreasing renal kallikrein, thus contributing to the hemodynamic alterations described in this model. In consequence, we explore the time course of the changes on PRA, urinary kallikrein activity, and renal levels of renin and kallikrein as assessed by immunohistochemistry, associated with NOS inhibition in pregnant rats.
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Methods |
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Experimental Design
A total of 86 virgin Sprague-Dawley rats, weighing 230 to 260 g, were used and maintained at the Center for Medical Research animal care facilities, under constant temperature (24°C) in a 12-hour light/dark cycle, with free access to standard rat chow and water. All procedures were performed in accordance with the institutional and international guidelines for animal welfare.
Rats in estrous phase were mated overnight with fertile males, and day 0 of pregnancy was determined by the presence of spermatozoa in vaginal smears. Following a protocol previously described,14 on day 7 of gestation the rats were randomly assigned to either a control group or an experimental group that received 50 mg · kg-1 · d-1 of L-NNA dissolved in tap water.
Control and experimental groups were studied on days 11, 17, and 21 of pregnancy. Baseline values were obtained in another group of rats at day 5 of pregnancy, before randomization. Additional rats from both groups were allowed to deliver spontaneously and were studied on days 7 and 21 postpartum, after the drug was withdrawn at delivery. Five to 8 animals in each group per study day were used. Systolic blood pressure was measured by tail-cuff plethysmography,14 and rats were individually placed in metabolic cages with free access to food and water from 5 PM to 9 AM On the following day, between 10 AM and 12 noon, the rats were weighed and anesthetized with pentobarbital sodium (40 mg/kg). Blood samples obtained from the abdominal aorta were placed in tubes containing either liquid EDTA or sodium heparin. An aliquot was used for microhematocrit determination, the remaining samples were centrifuged at room temperature, and the plasma was frozen for later determinations of PRA and creatinine. The kidneys were rapidly removed for morphological analysis (see below). Maternal net body weight (after removal of all major organs), litter size, and weights of individual fetuses and placentas were recorded. In postpartum rats, the number and weight of the pups were registered. Urine was measured, divided into aliquots, frozen, and subsequently used for determinations of sodium, protein, creatinine excretion, and kallikrein activity.
To determine the specificity of the lesions, additional rats (n=6 per group) received the NOS inhibitor L-NAME (50 mg · kg-1 · d-1), alone or associated with an excess of L-arginine (2.7 g · kg-1 · d-1), or received the inactive stereoisomer D-NAME (50 mg · kg-1 · d-1), from days 7 to 21 of pregnancy. Experimental and control groups were studied on day 21 of pregnancy according to the same protocol as described above.
Hormonal and Biochemical Measurements
Kallikrein activity was determined by the amidase method using
the synthetic substrate
DL-Val-Leu-arginine-p-nitroanilide.4 16
PRA was determined by radioimmunoassay of generated
angiotensin I under control conditions. The concentration
of urinary sodium was measured by flame photometry (IL 343).
Colorimetric reactions were used to determine plasma
and urine levels of creatinine (Beckman
Autoanalyzer). Urinary protein concentration was determined by
Bradford's method (Bio-Rad protein assay).
Tissue Processing and Immunohistochemistry
Kidney slices 3 mm thick, including cortex, medulla, and
papilla, were fixed by immersion in Bouin's solution for 24 to 48
hours at room temperature, dehydrated, embedded in Paraplast, serially
sectioned at 7-µm thickness, and mounted on glass slides until
immunohistochemistry was performed. In addition, the tissue sections
were studied with conventional staining, such as hematoxylin-eosin and
periodic acid–Schiff (PAS). Immunohistochemical staining for renal
kallikrein and renin was performed according to the
peroxidase/antiperoxidase (PAP) method as previously
described.17 Briefly, the tissue sections were dewaxed,
rehydrated, and rinsed in 0.05 mol/L Tris-phosphate-saline buffer, pH
7.6, and incubated overnight with rabbit antiserum raised against rat
tissue kallikrein (1:5000) or against renin (1:5000) at 22°C. The
second antibody (goat anti-rabbit IgG, 1:20), and the corresponding PAP
complex (1:150) were applied for 30 minutes each
at 22°C. The immunoperoxidase reaction was visualized by incubating
sections in 0.1% (wt/vol) 3,3'-diaminobenzidine and 0.03% (vol/vol)
hydrogen peroxide. The antisera and PAP complex were diluted in Tris
buffer containing 0.25% (vol/vol) Triton X-100 and 0.7% (wt/vol)
-carrageenan. To characterize the interstitial
infiltrate, additional sections were incubated with ED1, a mouse
monoclonal antiserum raised against rat monocytes and
macrophages (1:400). The second antibody (rabbit anti-mouse)
was used at a dilution of 1:400, and the third (goat anti-rabbit) was
diluted 1:20. The PAP complex was used as above. Controls for the
immunostaining procedure were prepared by omission of
the first antibody or by its replacement with preimmune serum. All
sections were counterstained with hematoxylin and then dehydrated,
cleared with xylene, and coverslipped.
Quantitative Morphology
The tissue samples from all groups were coded and studied
independently by 2 expert observers (S.P.S. and J.F.V.) in a blinded
fashion. One section selected at random was used for each rat (5 to 8
rats per group), and at least 4 fields per section were studied. To
estimate the intensity of the immunostaining at the
cellular level, the observers made a single ordinal ranking (0 to 3),
with 0 being absent, 1 being very faint yet distinguishable, 2 being
moderate staining, and 3 the strongest staining. The comparison
of staining intensity was done at a first antibody dilution of 1:5000.
If any difference was observed, further dilutions of the first antibody
were done until the staining disappeared.18 The tissue
sections were observed and photographed on a Nikon Optiphot
microscope, with a Nikon Microflex UFX IIA photographic system (Nikon
Corp).
Source of Antisera and Chemicals
L-NNA, L-NAME, D-NAME, L-arginine,
DL-Val-Leu-arginine-p-nitroanilide,
-carrageenan, Triton X-100, 3,3'-diaminobenzidine, and Tris were
purchased from Sigma Chemical Co; Paraplast was purchased from Monoject
Scientific; and the PAP complex was from Cappel. Rabbit antiserum
against kallikrein was obtained from our
laboratory17 ; the renin antibody was a gift from Dr
François Alhenc-Gelas, INSERM U367, Paris, France; and a
monoclonal antibody against macrophages (ED-1) was purchased
from Serotec. The goat anti-rabbit IgG and the rabbit anti-mouse IgG
were from Cappel.
Statistical Analysis
All data were expressed as arithmetic mean±SEM. Within each
study day, we analyzed differences between the group means by
an unpaired 2-tailed Student's t test, with a significance
level of 95%, using the computer program Stat View II (Abacus Concepts
Inc).
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Results |
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Net maternal weight at term (day 21 of pregnancy) was similar in both groups, whereas hematocrit values were higher in rats treated with L-NNA. No significant differences in creatinine clearance, urine volume, and urinary protein and sodium excretion were observed. Litter size was similar in both groups, and fetal and placental weights were significantly lower in L-NNA rats (Table). On day 17 of pregnancy, fetal weights (Control, 0.76±0.02 and L-NNA, 0.64±0.03 g, P<0.01) and placental weights (Control, 0.29±0.01 and L-NNA, 0.24±0.01 g, P<0.01) were also reduced. In contrast, no difference in pup weights was observed at postpartum days 7 (Control, 11.9±0.5 and L-NNA, 11.3±0.9 g) or 21 (Control, 35.7±1.8 and L-NNA, 38.2±2.2 g). However, litter size was significantly reduced in L-NNA rats compared with controls at postpartum days 7 and 21 (Control, 10.2±0.6 and L-NNA, 6.2±0.7, P<0.01). L-NNA dams allowed to deliver spontaneously did not show any difference in gestational length from control rats.
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Systolic blood pressure was significantly higher in L-NNA rats at days 17 and 21 of gestation; this difference disappeared postpartum, after the drug had been withdrawn. PRA was reduced in L-NNA rats on days 21 of pregnancy and 7 postpartum. L-NNA treatment suppressed the fall in blood pressure as well as the marked increase in PRA observed normally at day 21. In L-NNA rats, urinary kallikrein activity was significantly reduced on days 11 and 17 of pregnancy, attaining normal values thereafter (Figure 1).
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) and in rats
that received L-NNA 50 mg · kg-1 ·
d-1 from days 7 to 21 of pregnancy (•). Values are
mean±SEM. *P<0.05; **P<0.01;
***P<0.001 vs control rats.At day 21 of pregnancy, rats treated with L-NAME had a rise in blood pressure similar to that of L-NNA rats (128±7.4 mm Hg) and also exhibited reduced fetal weight (5.0±0.2 g). Pregnant rats treated with D-NAME or L-arginine did not exhibit an increase in blood pressure (100±6.1 and 98±3.5 mm Hg, respectively) or a reduction in fetal weight (5.4±0.07 and 5.6±0.05 g, respectively) compared with control rats.
Morphological Study
Representative morphological features of renal
sections from control and L-NNA–treated rats are shown in Figure 2, A through H. Tissues from sections 2A
through 2F and 2H were obtained at day 21 of pregnancy, whereas section
2G was obtained at postpartum day 7. Figure 2A shows normal
glomeruli and tubules from a control pregnant rat. Figure 2B
shows a section from an L-NNA rat, depicting dilatation of some tubules
and flattening of the tubular epithelium. Kallikrein
immunostaining was observed exclusively in the
connecting tubule cells of the distal nephron (Figure 2C and 2D)
and was reduced in L-NNA rats at both days 17 and 21 of pregnancy
(Figure 2D). Comparison of staining intensity was done at a
first antibody dilution of 1:5000. Five of 8 control rats exhibited the
maximum staining, scoring +++, and 3 had moderate staining (++). Three
of 6 L-NNA rats exhibited faint staining, scoring +; 2 had moderate
staining, scoring ++; and only 1 had maximum staining (+++). Further
dilution of the first antibody showed that the kallikrein staining
disappeared in L-NNA kidneys at a dilution of 1:80 000, whereas in
control kidneys, it persisted even at a dilution of 1:160 000.
Compared with control rats (Figure 2C), the
kallikrein-containing cells from L-NNA rats were smaller (Figure 2D), although the cross-sectional area of the cells was not
measured. No differences in renin staining were observed; at a dilution
of 1:5000, all sections from both groups displayed the maximum
intensity and were ranked as +++ (Figure 2E and 2F). Kidneys
from L-NNA rats exhibited interstitial cellular
inflammatory infiltration, particularly at postpartum day 7. The
infiltration was predominantly monocytes-macrophages (ED1+)
(Figure 2G). Tubular and glomerular alterations were
observed as early as day 11 of pregnancy (4 days with NOS inhibition).
At this time, some glomeruli were hypercellular and Bowman's capsule
was thickened. These lesions progressed until day 21 of pregnancy, when
segmental areas of hyalinization, segmental fibrinoid necrosis of the
glomerular tuft, and cellular vacuolization were observed.
In addition, intraglomerular mitosis was also observed
(Figure 2H). Some tubules exhibited the presence of eosinophilic
intraluminal material, as well as thickening of basal membrane,
containing PAS-positive material. These changes were decreased at
postpartum day 7 and were undetectable at postpartum day 21 (data not
shown). Similar alterations were observed with the administration of
L-NAME, another inhibitor, and were attenuated with the
administration of an excess of L-arginine. Rats treated
with D-NAME did not exhibit renal alterations (data not shown).
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Discussion |
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The present study shows that NOS inhibition in pregnant rats produces a significant reduction in urinary kallikrein activity and in renal kallikrein immunostaining, associated with renal morphological abnormalities, high blood pressure, reduced PRA levels, and reduced fetal weight. These functional and morphological alterations seem to be a consequence of NOS inhibition rather than the effect of L-NAME or L-NNA per se, for several reasons. First, they were observed with the use of 2 different inhibitors (L-NNA and L-NAME); second, they were attenuated with the administration of an excess of substrate (L-arginine); and third, they were not observed when the inactive stereoisomer D-NAME was administered.
An interesting finding of our study is that NOS inhibition in pregnant rats reduced urinary kallikrein activity and renal kallikrein immunostaining. The KKS is known to be activated in normal pregnancy, and reduced urinary kallikrein activity has been demonstrated in pregnant women with fetal growth restriction or preeclampsia,5 6 conditions characterized by a reduced plasma volume expansion and increased total peripheral vascular resistance. The renal KKS seems to participate in complex events such as regulation of blood pressure and control of the extracellular volume, sodium and water excretion, renal vascular resistance, and renin release.19 Several findings provide anatomic and functional frameworks for a role of the KKS in the hemodynamic events in the kidney. Among them, (1) immunohistochemical studies demonstrate an anatomic relationship between kallikrein-containing tubules and the juxtaglomerular apparatus20 21 ; (2) kallikrein is observed in the basolateral membrane of connecting tubule cells,22 and Madin-Darby canine kidney distal tubule cells transfected with rat kallikrein cDNA secrete kallikrein into both the apical and basolateral poles,23 suggesting that renal kallikrein can reach the circulation; and (3) there is evidence for renal kinins as mediators of the amino acid–induced renal hyperperfusion and hyperfiltration in the rat.24 Furthermore, kinins contribute to the control of renin secretion.25
Previous studies have shown that L-NAME partially or completely blocks glomerular filtration rate and renal plasma flow responses to amino acid infusion in rats, suggesting that NO is a downstream modulator of the actions of kinin on the glomerulus.26 The reduced urinary kallikrein activity observed in the present study may be caused directly by NOS inhibition or may be a consequence of the morphological alterations observed in the connecting tubule cells. In nonpregnant rats, a 3-week treatment with L-NAME increased hepatic kininogen and renal kallikrein mRNA levels.27 In the same study, the use of HOE-140, a bradykinin B2-receptor antagonist, produced a greater rise in blood pressure in L-NAME–treated rats, suggesting that an increased activity of the KKS plays a protective role in this model of hypertension. Several factors may account for this apparently contrasting result. First, in our study we gave the NOS inhibitor for only 2 weeks, a period of time in which no significant changes in the components of the KKS were observed in the study by Chao et al.27 Second, the interaction between the NO-NOS pathway and the KKS may be different in pregnant animals. And third, it cannot be ruled out that the stimulation of the KKS reported in that study27 was caused by the increment in blood pressure, which was >200 mm Hg after 3 weeks of L-NAME treatment and not a direct effect of NOS inhibition. In our study, the highest blood pressure observed was within the normal range for virgin rats (134 mm Hg) and presumably did not activate compensatory mechanisms. We were surprised to find that urinary kallikrein activity was within the normal range on day 21 of pregnancy, despite continuous administration of L-NNA and decreased renal kallikrein immunostaining. Because kallikrein excretion in control pregnant rats had returned toward nonpregnant values, we could speculate that NOS inhibition attenuates the pregnancy-induced rise in kallikrein but has no effect on basal kallikrein. Alternatively, the ratio of active to total kallikrein may have increased to overcome the reduction in renal kallikrein synthesis observed in this model. This possibility was not investigated in the present study. Independently of the mechanism that caused reduced renal kallikrein synthesis, this change may contribute to the rise in blood pressure and the reduction in plasma volume expansion described previously in this model.14
Inhibition of NO formation substantially attenuated the stimulatory effect of pregnancy on PRA. The reduced PRA levels are in keeping with previous studies in pregnancy14 and in nonpregnant conditions.28 29 30 Because L-NNA administration increases blood pressure, thus withdrawing sympathetic activity (both renin inhibitory signals), the lower PRA levels may be an indirect consequence of the hemodynamic changes induced by NOS inhibition. Decreased PRA levels have also been observed in pregnancies associated with reduced plasma volume expansion, such as in idiopathic fetal growth restriction and in preeclampsia.5 6 It is interesting to note that this difference in PRA between the control and L-NNA groups was not accompanied by substantial changes in renal immunostaining at the juxtaglomerular apparatus. This paradox of low PRA levels without apparent changes in renal renin has been described in a model of experimental diabetes31 and can be explained by the fact that the immunohistochemical technique is less sensitive to detecting small changes in renin content than is PRA.
Rats treated with NOS inhibitors during pregnancy exhibited glomerular, tubular, and interstitial abnormalities. Several studies have shown that NOS inhibition causes a marked increase in the number of abnormal glomeruli in pregnant12 15 and in virgin11 32 rats. Here, we report regression of these lesions after drug removal. Renal changes were present as early as day 11 of pregnancy (4 days of L-NNA treatment), before the onset of increased systolic blood pressure. The mechanisms causing renal injury during chronic NO blockade are under discussion. Previous studies have shown that the NO-NOS system controls both the tone of the glomerular afferent arteriole by modulating its myogenic response and the glomerular hemodynamics indirectly through tubuloglomerular feedback and renin release.33 Therefore, renal alterations may be secondary to intrarenal ischemia or glomerular hypertension and seem not to be caused by the increment in maternal systolic blood pressure. Another possible mechanism contributing to renal damage is the presence of infiltrating macrophages, because in some models of glomerulonephritis, local macrophage proliferation has been associated with the progression of glomerular and tubulointerstitial injury.34 However, macrophage infiltration in the present study was a rather late event, observed mainly at postpartum day 7.
In keeping with previous studies, the present results confirm that NOS inhibition during pregnancy reduces fetal and placental weights (for review, see Reference 3535 ). We have proposed that the mechanisms that cause fetal growth restriction are related to an altered maternal vasodilation, which limits plasma volume expansion and, secondarily, reduces cardiac output and uteroplacental blood flow. A direct role of NO deficiency in placental perfusion may also be involved, because it is well known that the placental villous vascular tree has the ability to both generate and respond to NO.36 Thus, chronically inhibiting the release of NO from placental vessels would result in vasoconstriction and reduced blood flow that indirectly contribute to reduced fetal weight. Surviving pups were capable of catch-up growth, probably favored by the reduction in litter size.
Despite the existence of renal morphological abnormalities and reduced levels of PRA and kallikrein excretion, the present results show no significant changes in diuresis, creatinine clearance, and proteinuria after 2-week L-NNA treatment. Although sodium excretion doubled during NOS inhibition, this difference was not statistically significant. The present results are in disagreement with previous ones that demonstrated increased protein excretion and reduced glomerular filtration rate during NOS inhibition in pregnant rats.12 15 A possible explanation for these differences relates to the fact that in our study, pregnant rats exhibited only a moderate increase in systolic blood pressure that was within the normotensive range for virgin rats, whereas in the previous studies, blood pressure reached much higher values (mean arterial blood pressure of 150 mm Hg).12 Presumably these contrasting results are caused by differences in the dose of the inhibitor used and/or in the route of administration (oral versus intravenous infusion).
In conclusion, the present results demonstrate that long-term NOS inhibition during pregnancy causes reduced renal kallikrein synthesis, associated with renal morphological alterations, increased blood pressure, decreased PRA, and reduced fetal weight. We postulate that the reduction in the vasodilator KKS could contribute to the hemodynamic alterations described in this model by interfering with the normal vasodilator response of pregnancy.
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Acknowledgments |
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This work was partially supported by grant 1.96.0779 from the Fondo Nacional de Desarrollo Científico y Tecnológico (Chile), FONDECYT. The excellent technical assistance of María Alcoholado and Carlos Céspedes is gratefully acknowledged.
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Footnotes |
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Reprint requests to Dr Sofía P. Salas, Center for Medical Research, School of Medicine, Pontificia Universidad Católica de Chile, PO Box 114-D, Santiago, Chile.
Received June 2, 1999; first decision July 1, 1999; accepted July 28, 1999.
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