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Research Centre, Hôpital Sainte-Justine, and Department of Obstetrics and Gynecology, Université de Montreal, Montreal, Quebec, Canada H3T 1C5
Submitted 21 December 2002 ; accepted in final form 24 March 2003
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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sodium supplement; renin-angiotensin-aldosterone system; preeclampsia
Hypertensive disorders of pregnancy such as preeclampsia are the most
common medical complications of pregnancy. They remain a major cause of
maternal and perinatal morbidity and mortality worldwide and affect
5–10% of all pregnancies. Several pathophysiological mechanisms
have been proposed for preeclampsia, such as defective placentation
(2), alteration of
immunological responses (38),
or genetic defects (40).
Compared with normal pregnancy, preeclampsia is characterized by maternal
hypertension, decreased circulatory volume, proteinuria, and reduced
activation of RAAS (11). Other
manifestations such as an increase in maternal vascular tone, enhanced
platelet aggregation, and reduced uteroplacental blood flow are observed
(24). These coupled to
disturbed renal functions can bring intrauterine growth restriction or worsen
perinatal outcome. Moreover, as it has been observed that the vascular
reactivity to ANG II is greatly enhanced in preeclampsia compared with that of
normal pregnancies, it is believed that preeclampsia is a vasoconstricted
condition (15).
To try unravelling the physiological mechanisms of decreased blood pressure in pregnancy and, by the mean, the pathophysiological ones implicated in preeclampsia, animal models (for a review, see Ref. 30) have been investigated. These include inhibition of nitric oxide (NO) synthesis (45) and reduction of the uterine perfusion (1). However, although providing valuable information on cardiovascular regulatory mechanisms, these models are sometimes not specific to the pregnant condition and occasionally are associated with fetal mortality. Modifications of sodium intake have been shown to modulate RAAS activity (12, 31). It is well known that reduction of sodium intake increased RAAS activity. However, this maneuver did not modify the decrease in blood pressure observed during rat pregnancy (31). On the opposing side, high-sodium intake during pregnancy induces reduction in PRA and aldosterone (12). Such alteration of activity of RAAS can provide a valuable avenue to modify the reduction of blood pressure associated with the end of pregnancy in the rat. Of course, we are aware that there is no indication in the literature that the incidence of preeclampsia is increased by high-salt intake or, in the opposite, that low-salt intake prevents the development of gestational hypertension (13, 35). However, in the rat, salt restriction during gestation was associated with reduction in circulatory volume and reduced fetal growth (31). The purpose of the present study was not to find some links between high-salt diet and preeclampsia but only to alter the renin-angiotensin system.
We thus attempted to reduce the activity of RAAS by giving salt supplements to pregnant rats for the last week of gestation. The aim of this study was to define a possible link between RAAS and blood pressure during pregnancy and study the effects of salt supplementation on 1) plasma electrolytes, creatinine, and hematocrit; 2) urinary volume, electrolytes, and proteins; and 3) fetal and placentas weight and plasma sodium. Fetal length was also measured to better characterize fetal growth. Because ANG II receptors were shown to be modulated by sodium intake (33), the expression of subtypes of these receptors (AT1 and AT2) was also measured in the kidneys, involved in water and electrolyte homeostasis, and in the placenta, responsible for fetomaternal exchanges.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Experiments were performed on female Sprague-Dawley rats (Charles River Canada; St. Constant, Quebec) weighing between 225 and 250 g, and they were bed with a known fertile male in the animal room. Day 1 of pregnancy was established when spermatozoa were found in morning vaginal smears. Nonpregnant rats were picked up randomly through the estrous cycle and paired with pregnant ones. All animals were housed under controlled light (6 AM–6 PM) and temperature (21 ± 3°C). They were fed a normal diet containing 0.23% NaCl (Teklad global 18% protein rodent diet, Harlan Teklad; Montreal, Quebec, Canada). Control animals (pregnant and nonpregnant) had tap water during all the treatment period. The experimental groups received 0.9 or 1.8% NaCl solution as a beverage for 7 days, starting on day 15 of experimentation, corresponding to the last week of gestation. At the end of treatment (day 22 of gestation, term = day 23), the animals were decapitated (9–9:30 AM), and trunk blood was collected for hormones and electrolytes analyses. Kidneys and placentas were rapidly removed from the animal and snap frozen in liquid nitrogen. This study was approved by the local Animal Care Committee, which is accredited by the Canadian Council on Animal Care.
Physiological Measurements
Systolic blood pressure was measured as previously described (36) by the indirect tail-cuff method (50–001 rat tail blood pressure system; Harvard Apparatus, St-Laurent, Quebec, Canada) in unanesthetized rats. The animals were trained for blood pressure measurement on day 7 to 11 of experimentation. Systolic blood pressure was then recorded for day 12 to 22. Body weight was measured on day 1 and daily from day 12 to the end of treatment. Water and food intake were recorded every day from day 12. Placental weight, fetal weight, as well as fetal length (nose-rump length) were determined on day 22.
Sample Collection and Analysis
On day 20, rats were housed in individual metabolic cages for collection of 24-h urine samples. Urinary volume was determined, and an aliquot was used to measure the concentrations of sodium and potassium and the amount of proteins excreted per 24 h. On day 22, the animals were decapitated. The first blood sample (0.5 ml) was drawn into heparin sodium vacutainer tubes (Becton Dickinson; Franklin Lakes, NJ), and an aliquot was used for hematocrit measurement. After centrifugation at 3,000 rpm for 20 min at 4°C, plasma was stored at -80°C for hormone measurements. The second sample was drawn into heparin lithium vacutainer tubes (Becton Dickinson), centrifuged, and used for determination of plasma electrolytes and creatinine. Sodium and potassium were measured with specific electrodes, total calcium by colorimetric reaction, and creatinine by an enzymatic colorimetric test. Fetuses were also decapitated, and trunk blood was pooled to measure sodium concentration.
Hormonal Measurements
PRA was determined indirectly by radioimmunoassay of ANG I generated during a 2-h incubation period (17). The antibody used was purchased from Peninsula Laboratories (Belmont, CA). Plasma aldosterone and corticosterone measurements were obtained directly from plasma with commercial radioimmunoassay kits (aldosterone: Intermedico, Montreal, Quebec, Canada; corticosterone: Medicorp, Montreal, Quebec, Canada) Cross-reactivity of aldosterone antibody with progesterone is <0.007%.
RNA Isolation
Total cellular RNA in the frozen kidney and placenta was extracted by a modification of the method of Chomczynski and Sacci (10) using TRIzol Reagent (Life Technologies). Final RNA pellets were dissolved in an appropriate volume of 100% deionized formamide (Amresco; Solon, OH) and stored at -20°C. RNA concentration was determined from absorbance measurement at a wavelength of 260 nm, integrity of samples was determined by the 260-to-280-nm ratio, and quality was verified by ethidium bromide fluorescence.
RNAse Protection Assay
Probe preparation. A 182-base DraI fragment excised from
pcDNAI plasmid (kindly provided by Dr. Kathy Griendling, Emory University,
Atlanta, GA) was used for the preparation of a high-activity RNA antisense
probe for the AT1 receptor. A 215-base
HindIII-XbaI fragment excised from pcDNAI/Amp plasmid (gift
from Dr. Gaétan Guillemette, Université de Sherbrooke,
Sherbrooke, Quebec, Canada) was cloned into the multiple cloning sites of the
Bluescript vector, linearized with PvuII, and used for the
preparation of a high-activity RNA antisense probe for the AT2
receptor. A 334-base fragment of 
-actin gene (Ambion RNA; Austin, TX)
was used as an internal control. The antisense probes were prepared by
transcription in vitro with the Ambion Maxiscript technique (Ambion RNA) in
the presence of T7 polymerase for AT2, SP6 polymerase for
AT1 and -actin, and [
-32P]UTP (Perkin-Elmer
Life Sciences; Boston, MA) and washed with 75% ethanol-25% sodium acetate.
Cellular RNA (25 µg) was incubated at 65°C for 10 min with the
antisense probes (100,000 counts/min for AT1 and AT2,
15,000 counts/min for -actin) in a 5x PIPES buffer (200 mM
1,4-piperazine diethanesulfonic acid, pH 6.4, 2 M NaCl, and 5 mM EDTA) and
100% deionized formamide. After denaturation of RNA at 85°C for 5 min, the
hybridization was performed overnight at 47°C. Nonhybridized RNA was
digested by RNAse T1/A (RNAse cocktail from Ambion RNA) in a buffer containing
1 M Tris · HCl (pH 1.5), 0.5 M EDTA, and 0.3 M NaCl for 1 h at
30°C. After treatment with 20% SDS and 10 mg/ml proteinase K for 15 min at
37°C, the hybridized RNA was purified by phenol-chloroform extraction,
precipitated in 100% ethanol, and resuspended in 10 µl of electrophoresis
buffer containing 80% deionized formamide, 1 mM EDTA, 0.1% bromophenol blue,
0.1% xylene cyanol, and 0.1% SDS. Preparations were denatured at 85°C for
5 min and then separated by electrophoresis in a 5% acrylamide-7 M urea gel at
40 W. After electrophoresis, the gel was fixed for 15 min in 10% methanol-5%
acetic acid and dried for 1 h. The dried gel was exposed to X-ray film (Fuji
medical X-Ray film, Fuji Photo Film; Tokyo, Japan) with intensifying screens
at -80°C for 1–7 days. Relative intensities of AT1,
AT2, and -actin bands were determined by analysis of the gel
with Scion Image computer software (National Institutes of Health). The
steady-state mRNA levels of AT1 and AT2 were expressed
in arbitrary units and standardized by comparison with hybridization results
obtained from the housekeeper gene -actin.
Statistical Analysis
Systolic blood pressures were compared in each group with stable pretreatment values by ANOVA for repeated measurements (GraphPad Prism; GraphPad Software). Body weight, plasma and urine parameters, RAAS activity, fetal parameters, and expression of ANG II receptors were performed using a one-way ANOVA to assess the impact of 0.9 and 1.8% sodium supplement compared with their control groups (BMDP, BMDP statistical software). All results are expressed as means ± SE. P < 0.05 was considered to represent significant difference.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Figure 1 illustrates the effects of sodium supplementation on blood pressure in nonpregnant (Fig. 1A) and pregnant (Fig. 1B) rats from day 12 to day 22 of the experiment. Before the sodium supplement (day 12 to 14), systolic blood pressure was similar in all groups of rats. Sodium supplements (0.9 or 1.8%) did not affect systolic blood pressure in nonpregnant rats. However, pregnant rats receiving 0.9% NaCl supplement did not show the expected decrease of blood pressure observed in control pregnant rats. Pregnant rats on 1.8% sodium supplement had a significant increase in blood pressure compared with the pretreatment period and pregnant control.
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Maternal Body Weight Gain, Food, and Water Intake
Weight gain in the first 14 days of the experiment was not statistically different between animals randomly chosen to receive normal salt diet or salt supplementation and averaged 10 ± 2 and 53 ± 2 g in nonpregnant and pregnant rats, respectively. During this period, all animals received normal diet and tap water. As shown in Table 1, during sodium (0.9 or 1.8%) supplements (day 15 to 22), water and sodium intake was increased in nonpregnant rats, but food intake was reduced by 14% in the group receiving 1.8% sodium supplement, accompanied by a decreased in body weight. Sodium intake was calculated from the water and food intake and was increased 10- and 20-fold with 0.9% and 1.8% salt water, respectively. In pregnant rats, water intake was increased only by the 0.9% sodium supplement. In the 1.8% sodium-supplemented group, food intake was decreased by 44% and this is accompanied by an absence of body weight gain. Sodium intake was increased by 12- and 17-fold by 0.9% and 1.8% salt water, respectively.
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Urinary Parameters on Day 20
Water intake and urinary volume were measured on day 20 to calculate water balance. For each animal, this was calculated by subtracting the quantity of urinary volume from the quantity of water drunk during 24 h. As shown in Table 2, sodium supplements (0.9 or 1.8%) increased water intake and urinary volume in nonpregnant rats. Water balance was not different between the sodium-supplemented rats and their controls. In pregnant rats, water intake was increased only by the 0.9% salted water. Both supplements induced an increased urinary volume. This resulted in a negative water balance in pregnant rats on 1.8% supplement compared with their controls. Sodium supplement (0.9 or 1.8%) induced an increased sodium urinary excretion in both nonpregnant and pregnant rats. In pregnant rats, 1.8% sodium supplement induced a decreased potassium excretion. Urinary protein loss was not different in nonpregnant groups. However, pregnant rats receiving 1.8% sodium supplement showed a 40% increased urinary protein excretion in their 24-h urine compared with the control pregnant rats.
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Plasma Electrolytes, Creatinine, and Hematocrit Levels
As shown in Table 3, in nonpregnant animals, sodium supplementation (0.9 or 1.8%) had no effect on plasma electrolytes, osmolality, creatinine, and hematocrit. In pregnant rats, sodium supplementation of 0.9% induced a decrease of 9% in plasma creatinine level, whereas the 1.8% NaCl supplement induced increased plasma sodium and osmolality and decreased plasma potassium and creatinine, as well as an elevation of the hematocrit level.
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RAAS and Corticosterone Levels
Sodium supplements (0.9 or 1.8%) decreased PRA (Fig. 2A) and plasma aldosterone (Fig. 2B) levels in nonpregnant and pregnant rats. Plasma corticosterone levels were increased only in the pregnant animals receiving 1.8% sodium supplement (Fig. 2C).
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Fetal Characteristics
As shown in Table 4, 0.9% sodium supplementation did not affect fetal parameters. However, 1.8% sodium supplement was accompanied by decreased placental weight (19%), fetal weight (10%), and fetal length (5%) compared with control. Plasma sodium concentration was increased in fetuses of mothers receiving 1.8% sodium supplementation. These two supplements of sodium did not affect the number of fetuses.
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mRNA Expression of ANG II Receptors
Sodium supplements (0.9 and 1.8% NaCl) similarly decreased AT1 receptor mRNA steady state in the kidneys of both nonpregnant and pregnant rats (Fig. 3A). We also observed a decrease in AT1 receptor mRNA in the placentas of the dams receiving sodium supplements (Fig. 3B). AT2 mRNA was not detected in these tissues.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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It is well established that a low-sodium diet enhances the activity of RAAS
in nonpregnant and pregnant rats
(31). On the opposite,
high-sodium intake reduces the activity of this system
(12). As expected, we observed
that sodium supplements of 0.9 or 1.8% decreased the activity of RAAS, as
measured by PRA and aldosterone levels. As shown previously
(43), the decreased RAAS
induced by NaCl supplements did not affect systolic blood pressure in
nonpregnant rats. However, in pregnant rats, the 0.9% sodium supplement
prevented the decrease in blood pressure observed in normal pregnancy, whereas
increased systolic blood pressure over pretreatment values was observed with
the 1.8% NaCl supplement. These results suggest that the mechanisms
controlling blood pressure are easily perturbed by high-sodium intake during
pregnancy. In agreement with our results, Milton et al.
(26) demonstrated that 0.9%
saline in drinking water given to pregnant rabbits during the last week of
gestation increased the mean arterial blood pressure compared with that of the
pregnant rabbit on normal NaCl intake. This also corresponds to the finding of
Barron et al. (3), who observed
an increase of arterial pressure in pregnant rats on a high-sodium diet (8%)
but not in nonpregnant rats. Whereas they used a high-sodium chow, we added
sodium in the drinking water. Because pregnant rats on 1.8% of sodium in water
drink around 50 ml of water a day, they ingested around 0.9 g of sodium.
Because pregnant rats eat 23 g of food each day, a diet containing 4%
sodium corresponds to an ingestion of 0.92 g a day. Therefore, in the present
study, the pregnant rats ingest much less sodium than the ones in Barron's
study (3). Moreover, they took
a single measure of blood pressure at day 19 of gestation, whereas we
were documenting it from midpregnancy to term. In a parallel study, we have
also measured contractile response to phenylephrine in the aorta rings of
nonpregnant and pregnant rats on high-sodium intake (K. Auger, A.
Beauséjour, M. Brochu, and J. St-Louis, unpublished observations). We
observed an increased response in aortic rings of pregnant rats on 0.9 and
1.8% sodium supplement compared with pregnant rats on normal water. This
suggested that the decreased sensitivity to vasoconstrictor normally observed
in pregnancy is reversed, and this could explain the absence of decreased
blood pressure. McEniery et al.
(25) demonstrated that
normotensive 18-wk pregnant women receiving a high-sodium diet (300 mmol
sodium per day) for 7–10 days had no blood pressure change compared with
pregnant women on a regular diet. The discrepancy with our results and other
animal studies (3,
26) with those of the women of
McEniery study could be explained by the level of sodium loading. In fact, the
women in McEinery's study consumed 0.11 g Na+ ·
kg-1 · day-1 during midpregnancy, whereas our
rats (on 1.8% NaCl) received 3.29 g Na+ · kg-1
· day-1 at the end of gestation. Both regimens were
administered for 7 days.
In nonpregnant rats, we observed that the supplement of 1.8% NaCl decreased food intake, accompanied by loss of body weight. This is in agreement with other reports showing that oral hypertonic solution (1.8% saline) reduces food intake in adult rats (22). In parallel to increased sodium and fluid intake, natriuresis and diuresis were also significantly augmented preserving normal water balance. Moreover, we observed decreased AT1 mRNA levels in kidneys of nonpregnant rats receiving sodium supplements (0.9 or 1.8% NaCl). It has been suggested that renal AT1 could be involved in sodium and water reabsorption from the proximal tubules (6). This provides an explanation for the increased sodium and water excretion. Consequently, plasma sodium, potassium, and total calcium, as well as creatinine and hematocrit levels, were not different in all groups of nonpregnant rats, demonstrating that physiological responses to sodium supplements appear to be adequate for maintaining homeostasis.
In pregnant rats, we showed that 0.9% sodium supplement increased water intake but did not affect food intake and body weight gain. However, pregnant rats drinking 1.8% saline did not increase their water consumption. These rats lost more weight because the total body weight at day 22 includes the fetoplacental unit. This is explained by a 44% reduction of food intake compared with control pregnant rats. This reduction in food intake is larger than the reduction observed in nonpregnant rats. It is well established that normal pregnancy in the rat is accompanied by increased sodium appetite and sodium retention (29), and both renal plasma flow and glomerular filtration rate are significantly increased (4). Several studies have shown that increased sodium intake (0.9% saline) leads to important diuresis and natriuresis in adult rats (41) and in pregnant rats (7, 12). In agreement with these, pregnant rats receiving 0.9% sodium supplement showed decreased plasma creatinine, increased diuresis, and natriuresis, which suggests an increased glomerular filtration compared with control pregnant rats. As argued above for nonpregnant rats, decreased AT1 mRNA levels were found in the kidney of pregnant rats receiving 0.9% NaCl. This is in accordance with the increased diuresis and natriuresis observed in this group.
Sodium supplement of 1.8% in water induced increased plasma sodium and corticosterone as well as decreased plasma potassium and creatinine levels and elevated hematocrit. Proteinuria was also observed suggesting that renal function was affected. Increases in diuresis and natriuresis without increase in water intake were observed in pregnant rats receiving 1.8% sodium supplement. This resulted in a negative water balance which, associated with high hematocrit value, is suggestive of decreased circulatory volume and dehydration. According to a mathematical derivation described by Van Beaumont (39), the percent difference between the original and final hematocrit ratios can be used in conjunction with a proportionality factor to estimate the percent change in plasma volume. Thus the increases in hematocrit reflect a significant decrease in plasma volume. It has been shown that intraperitoneal injection of 1.5 M saline solution (8.8% NaCl) to adult male rats induced dehydration (5). However, in our experiment, the suggested dehydration was only observed in pregnant rats on much sodium intake (1.8%), again suggesting that pregnant rats are more sensitive than nonpregnant rats to high-sodium intake.
Sodium supplement of 0.9% NaCl did not affect fetoplacental parameters. However, placental weight, fetal weight, and length were reduced when the dams received the 1.8% NaCl supplement. We suggest that this could be explained by the 44% reduction of maternal food intake and the suspected decrease in blood volume. Indeed, in humans and rats, decrease in maternal plasma volume (31, 32) and reduction of food intake (44) have been associated with decreased fetal growth. We showed a decreased AT1 mRNA in placentas of pregnant rats receiving 1.8% NaCl. This is in agreement with studies on human placenta (21, 23) from pregnancies complicated by preeclampsia and intrauterine growth retardation compared with normal term controls.
Several studies have attempted to prevent and reverse the pregnancy-induced decrease of blood pressure in laboratory animals. For example, Simaan et al. (34) reported that activation of voltage-dependant calcium channels in pregnant rats causes a transient increase in blood pressure. Other studies have provided evidence for a potential role for NO. In fact, endothelial dysfunction is considered an important factor for the induction of gestational hypertension. In pregnant rats, subcutaneous injections of 50 mg/day of a NO synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) from day 17 to 22 of gestation resulted in sustained hypertension, proteinuria, thrombocytopenia, and intrauterine growth retardation (27). Similarly, pregnant baboons were studied after the administration of an oral NOS inhibitor (N-nitro-L-arginine; 5 or 10 mg/kg) at different periods of the pregnancy (19). Increased mean arterial blood pressure in nonpregnant animals and in mid and late pregnancy was observed following NOS inhibition. Reduction in PRA and significant proteinuria were also observed. These results show that NOS inhibition induces changes in blood pressure that are not specific to the pregnant condition. However, in these rat studies, high doses of L-NAME were used. With a low dose of 1 mg/day, Kassab et al. (20) showed that the increase in blood pressure was observed in pregnant rats only, suggesting a role for NO in the regulation of blood pressure during pregnancy. No information about fetal growth and well being was reported for this model.
Candidate genes for hypertensive diseases in pregnancy, that have been proposed, include those of RAAS and NOS. Pregnant mice that had four copies of the angiotensinogen gene (Agt2/2) and that were heterozygous (eNOS+/-) or homozygous (eNOS-/-) for mutation of the endothelial NOS (eNOS) gene had higher blood pressures compared with controls (18). This indicates that eNOS and Agt are important genes in the regulation of blood pressure. These mice showed a decrease of blood pressure during pregnancy. Therefore, this model is thought to represent chronic hypertension during pregnancy more than preeclampsia. The blood pressure of mice eNOS-/- did not decrease during pregnancy, but there is no evidence of renal dysfunction (18). Fetal characteristics were not studied in all of these mutant mice. In our experiments, we demonstrated that 1.8% sodium supplement given to pregnant rats caused proteinuria, indicating some renal dysfunction. In the rat, transgenic females for the gene of human angiotensinogen were mated with males made transgenic for the gene of human renin (8). In this model, an increase in blood pressure was observed on the twelfth day of gestation; however, a decrease in blood pressure still occurred toward the end of gestation.
In summary, we have observed that sodium supplements of 0.9 and 1.8% given to nonpregnant and pregnant rats induced inhibition of RAAS activity. Pregnant rats receiving 0.9% sodium supplement for the last week of gestation did not show the characteristic decrease in blood pressure, whereas the one on 1.8% NaCl did have an increase in blood pressure. This last effect of the 1.8% saline was accompanied by 1) an apparent reduction in blood volume expansion, 2) renal dysfunction as indicated by proteinuria, and 3) intrauterine growth restriction. All these findings resemble many clinical characteristics of preeclampsia in women (11, 24, 32, 37, 46). We believe that sodium supplementation during gestation, as described herein, represents an excellent tool that is specific to the pregnant condition. Furthermore, pregnant rats treated this way should contribute to better understand the links between RAAS and the regulation of blood pressure during pregnancy.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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