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(Hypertension. 1996;27:119-124.)
© 1996 American Heart Association, Inc.
Articles |
Blunted Pressure Natriuresis in Ovariectomized Dahl-Iwai Salt-Sensitive Rats
From the Department of Internal Medicine, School of Medicine, Keio University, Tokyo (K.O., H.S., T. Sasaki, T. Saruta), and the Department of Clinical Chemistry, School of Hygienic Sciences, Kitasato University, Kanagawa (N.I., H.I.), Japan.
Correspondence to Takao Saruta, MD, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160, Japan.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Abstract Our objective was to determine whether increased salt sensitivity after menopause precedes the development of overt hypertension. We investigated the effect of ovariectomy on pressure natriuresis in Dahl-Iwai salt-sensitive (DS) and salt-resistant (DR) rats by in vivo perfusion studies. Differences in the neural and hormonal backgrounds of the kidney were minimized by renal denervation and by holding plasma vasopressin, aldosterone, corticosterone, and norepinephrine levels constant by intravenous infusion. The pressure-natriuresis relationship was blunted in DS rats compared with DR rats (slope, 0.30 versus 0.63 µmol·min-1·g kidney wt-1·mm Hg-1, P<.01). The impaired pressure-natriuresis response of DS rats was further blunted by ovariectomy (from 0.30 to 0.14 µmol·min-1·g kidney wt-1·mm Hg-1, P<.05), and that of DR rats was not. The ovariectomized DS rats developed hypertension earlier than sham-operated DS rats by salt loading. These results show that ovariectomy enhances genetic salt sensitivity by blunting the pressure-natriuresis relationship, which precedes the development of overt hypertension in female DS rats.
Key Words: rats, Dahl • ovariectomy • hypertension, sodium-dependent • salt sensitivity • pressure-natriuresis
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Several epidemiological studies have shown that the risk of coronary heart disease rapidly increases when ovarian function ceases, such as after bilateral ovariectomy1 and natural menopause.2 In addition, some studies support the hypothesis that the postmenopausal use of estrogen reduces the risk of severe coronary heart disease.3 4
Hypertension is one of the main risk factors for cardiovascular disease, and there are gender differences in its prevalence and onset. The higher prevalence of hypertension in men has been confirmed in several epidemiological studies.5 Staessen et al6 reported that the prevalence of hypertension is 2.2 times higher in postmenopausal women than in premenopausal women. These authors also suggest that increased sodium reabsorption by the kidney may play an important role in the BP elevation after menopause. However, the underlying mechanisms of the sexual differences in hypertension are not completely understood. We previously reported that decreases in sex hormones and increases in sodium sensitivity are important factors in the genesis of postmenopausal hypertension.7 After menopause, urinary excretion of sodium with normal and high sodium diets is significantly lower in hypertensive patients than in normotensive control subjects.
The DS and DR rat strains developed by Dahl have been especially useful as an animal model for the study of hypertension related to sodium metabolism.8 Dahl's genetically selected salt-sensitive rat strain also shows effects of gonadal hormones on salt-induced hypertension, as do other hypertensive rats. BP increased in ovariectomized DS rats fed a high sodium diet,9 10 but it did not differ as a function of hormonal treatment.10
Our study had two purposes: (1) to investigate the effect of ovariectomy on pressure natriuresis in DS rats using in vivo perfusion studies, and (2) to determine whether increased salt sensitivity after ovariectomy precedes the development of overt hypertension in DS rats. Thus we examined whether ovariectomy might aggravate the development of salt-induced hypertension in DS rats.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Materials
Female DS and DR rats were obtained from Eisai's Laboratory Animal Research Center, Tsukuba, Japan, and maintained on tap water and 0.3% NaCl chow (Oriental Yeast) from the time of weaning. At the age of 12 weeks they were anesthetized with ether, and a small abdominal incision was made with the use of sterile techniques. Ovariectomy was performed on 11 DS and 4 DR rats; another 10 DS and 6 DR rats underwent a sham operation without ovariectomy.
To investigate the effect of ovariectomy on the pressure-natriuresis relationship, we divided the rats into four groups and fed them a 0.3% NaCl diet for a further 4 weeks: group 1, sham-operated DS rats (n=5); group 2, ovariectomized DS rats (n=6); group 3, sham-operated DR rats (n=6); and group 4, ovariectomized DR rats (n=4).
To investigate the effect of salt on BP, we fed two groups of DS rats an 8% NaCl diet (Oriental Yeast) from the age of 12 to 16 weeks: group 5, sham-operated DS rats (n=5); and group 6, ovariectomized DS rats (n=5).
BP Measurement
BP was measured in conscious rats by tail
plethysmography, and
body weight was determined at the ages of 12 and 16 weeks. Before BP
was recorded, the rat was housed in a small holding cage and warmed
at 40°C for 10 minutes. At least five BP and heart rate measurements
were obtained, and the median of three readings was taken as the rat's
BP. After clearance studies, uterus weight was measured in each rat for
evaluation of the state of estrogen deficiency.
Pressure-Natriuresis Relationship
Rats were prepared
according to the method of Roman and
Cowley11 and previous reports.12 13 The
right
kidney was removed 7 days before the experiment. The rats were
anesthetized with an intraperitoneal
injection of 70 mg/kg thiobutabarbital (Inactin, BYK-Gulden) and
tracheostomized to facilitate respiration. They were placed on a warm
plate for maintenance of body temperature at 37°C. The left
carotid and femoral arteries were cannulated (PE-50, Becton Dickinson
Co) for measurement of arterial BP above and below the left
renal artery. BP was monitored with a transducer (TP400T, Nihon Koden),
amplifier (AP601G, Nihon Koden), and writing recorder (Nihon
Koden). The left external jugular vein was cannulated (PE-50) for
administration of saline containing 1% bovine serum albumin,
1% inulin, 0.1% PAH, norepinephrine (5.9 µmol/L),
aldosterone (0.55 µmol/L), hydrocortisone (0.55 mmol/L),
and vasopressin (0.46 nmol/L). The infusion was started immediately
after the cannulation of the jugular vein at a rate of 100 µL/min and
continued throughout the experiments (Microliter Syringe Pump, special
model, Harvard Apparatus). With laparotomy, the bilateral
adrenal glands were removed, and the left kidney was denervated with a
10% solution of phenol in ethanol. Another cannula (PE-10, Becton
Dickinson Co) was placed in the left ureter for urine collection. Two
adjustable clamps were placed on the aorta, one above and one below the
left renal artery. Silk ligatures were placed loosely around the
superior mesenteric and celiac arteries. After a 60-minute
equilibration period, clearance studies were performed.
First, basal arterial BP was checked. Then urine was collected during the following 15 minutes for measurement of urinary excretion of sodium, inulin, and PAH. In this clearance study and the next, there were two 15-minute clearance periods, during which 400 µL of arterial blood was sampled at the middle of each period and BP measured. Immediately after each blood sampling an equal volume of arterial blood was transfused from a similarly treated littermate donor. Values obtained from the two clearance periods were averaged for analysis. The upper clamp was tightened to decrease RPP to approximately 130 mm Hg in DS rats because the basal BP in DR rats was approximately 130 mm Hg. After a 15-minute equilibration period, the first clearance study was performed. RPP was then adjusted to approximately 150 mm Hg in both DS and DR rats by releasing the aortic clamp above the renal artery and tightening the clamp below the renal artery, occluding the mesenteric or celiac artery, respectively.
Urine volume was measured with a gravimeter, and urine flow rate was factored per gram of kidney weight. Sodium concentrations were measured with a flame photometer. Inulin and PAH concentrations were measured by standard photometry. GFR and RPF were calculated as the ratio of urine per plasma concentration of inulin and PAH multiplied by urine flow rate. Filtration fraction was calculated as the ratio of GFR to RPF. Fractional sodium excretion was calculated by dividing the urinary sodium excretion rate by the product of GFR and plasma sodium concentration.
Statistical Methods
Values are given as mean±SEM. The
statistical significance of
differences in individual values was checked with ANOVA followed by
Scheffé's F test or unpaired t tests, as appropriate.
Linear regression ANOVA was used to calculate the slopes of the lines
relating sodium excretion and RPP. Differences in the slopes of these
lines were compared using an unpaired t test. A level of
P<.05 was accepted as statistically significant.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Pressure-Natriuresis Relationship
In DS rats elevation of RPP from 122 to 152 mm Hg increased urinary sodium excretion from 9.4 to 17.9 µmol·min-1·g kidney wt-1, and the slope of its linear regression was 0.30 µmol·min-1·g kidney wt-1 · mm Hg-1. In DR rats elevation of RPP from 124 to 144 mm Hg increased urinary sodium excretion from 17.5 to 30.7 µmol·min-1·g kidney wt-1, and the slope of its linear regression was 0.63 µmol·min-1·g kidney wt-1·mm Hg-1. In DS rats the pressure-natriuresis relationship was significantly blunted compared with that in DR rats (P<.01). The impaired pressure-natriuresis response of DS rats was further blunted by ovariectomy (slope, 0.30 to 0.14; P<.05), whereas that of DR rats was not blunted (Fig 1
). Urine flow and
fractional excretion of sodium showed a tendency similar to that of
urinary sodium excretion. GFR and RPF were well autoregulated in both
strains (Table 1).
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indicates sham-operated DS rats (n=5); 
, ovariectomized DS
rats (n=6); 
, sham-operated DR rats (n=6); and 
,
ovariectomized DR rats (n=4). In DS rats the pressure-natriuresis
relationship was blunted compared with DR rats (slope, 0.30 vs 0.63
µmol·min-1·g kidney
wt-1·mm Hg-1,
**P<.01). The impaired pressure-natriuresis response of
DS rats was further blunted by ovariectomy (0.30 to 0.14
µmol·min-1·g kidney
wt-1·mm Hg-1,
*P<.05), whereas that of DR rats was not
blunted.
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Blood Pressure
Systolic BP did not differ significantly at 12
weeks among
the four experimental groups of DS rats fed a 0.3% NaCl diet (Fig
2). BP tended to be increased in DS rats compared with
that in DR rats at 12 weeks (P=NS). Four weeks of salt
loading were not enough to increase BP in sham-operated DS rats,
whereas salt loading increased BP in ovariectomized DS rats at 16
weeks (Fig 2).
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Uterus and body weights at the end of the
study are shown in Table 2. The ovariectomized DS and DR rats
fed a 0.3% NaCl
diet attained significantly greater weights compared with
sham-operated rats fed a 0.3% NaCl diet. The increase in body
weight of DS rats tended to be suppressed by salt loading. Terminal BP
was unrelated to body weight. Uterus weights of ovariectomized DS and
DR rats were significantly decreased compared with those of
sham-operated rats when they were fed either a 0.3% or 8% NaCl
diet.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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Pressure-Natriuresis Relationship
In this study we describe for the first time the effect of ovariectomy on the pressure-natriuresis relationship in Dahl-Iwai rats. The blunted pressure-natriuresis relationship in DS rats after ovariectomy suggests that salt sensitivity increases in postmenopausal hypertensive women. According to our knowledge there have been no reports investigating the effect of ovariectomy on the pressure-natriuresis relationship in vivo in female hypertensive rats or women.
The kidneys play an important role in the long-term regulation of arterial pressure by maintaining sodium balance and extracellular fluid volume. Although it has been reported that the kidneys of DS rats have a reduced capacity to excrete sodium and water,12 14 the mechanisms for the abnormality have not been elucidated. In the present study GFR and RPF were well autoregulated in both rat strains with or without ovariectomy, whereas filtration fraction seemed to be rather high. We previously reported on the pressure-natriuresis relationship in male DS rats.12 The GFR and RPF of female DS rats seemed to be higher compared with those of male DS rats, and the GFR of female DS rats was increased more markedly than RPF. Therefore, filtration fraction might seem to be rather high in the present study. This increase of filtration fraction might be related to the gender difference in the kidney, not dependent on sex hormones, because ovariectomy had no significant effect on these renal function parameters.
Previous work has demonstrated a central role for RIHP in the translation of changes in RPP to changes in urinary sodium excretion.15 Papillary hemodynamics play a critical role in the regulation of RIHP. Transmission of RPP into the interstitium has been shown to be abnormal in SHR, which show smaller changes in RIHP for a change in RPP than do normotensive Wistar-Kyoto rats. It is unclear whether a similar abnormality exists in DS rats.14 Recently, Kato et al16 reported that a reduced sensitivity of renal tubules to increases in RIHP in prehypertensive DS rats may contribute to their inability to excrete a sodium load.
Several possible mechanisms have been proposed for the pressure-natriuresis relationship. It has been said that the RAS may serve as an intrarenal hormonal system influencing renal hemodynamics and tubular reabsorptive processes17 18 and play a critical role in maintaining the pressure-natriuresis relationship. Therefore, manipulations that alter the RAS greatly influence the pressure-natriuresis relationship. In this regard, since administration of estrogen alters plasma angiotensinogen level, ovariectomy may also affect the RAS and thus might alter the pressure-natriuresis relationship through mechanisms associated with the RAS. However, the saline infusion rate in this protocol was high, 100 µL/min, which causes volume expansion in rats and may minimize the effect of the RAS. Furthermore, DS rats have significantly lower plasma and kidney renin activity compared with DR rats.19 Anesthesia may increase plasma levels of renin and cause sodium retention. However, we were unable to perform a pressure-natriuresis study in vivo without anesthesia because a sustained stable BP could not be obtained. Since anesthesia was continued at a constant degree throughout the protocol in every experiment, we believe that it is less likely that anesthesia modifies the observed differences in sodium reabsorption and pressure natriuresis among the rat groups.
There have been several reports that NO and prostaglandins also play an important role in the pressure-natriuresis relationship in hypertensive animals. They modulate autoregulatory control by afferent arterioles and renin release by the juxtaglomerular apparatus, which participates in the pressure-natriuresis response through regulation of intrarenal blood flow distribution.20 21 Chen and Sanders22 observed that administration of L-arginine, a precursor for endothelium-derived NO, prevents the development of hypertension in inbred DS rats exposed to a high sodium intake. Patel et al23 24 have shown that this effect is associated with normalization of blunted pressure natriuresis, which characterizes DS rats. We also have demonstrated that NO is important in the maintenance of the normal pressure-natriuresis response, and its dysfunction is responsible for the impairment of pressure natriuresis in SHR.13 The blockade of basal NO synthesis has been shown to result in decreases of renal blood flow and sodium excretion.25
Oophorectomy diminishes both circulating estradiol concentration and basal release of NO to levels seen in male rabbits.26 We have recently reported that NO synthase increases in response to 17ß-estradiol in human aortic endothelial cells.27 These data might establish that basal NO release from the endothelium depends on the circulating estradiol concentration and offer an explanation for the protective effect of estradiol against the pressure-natriuresis response. In another experiment we assessed platelet intracellular calcium of female DS rats treated identically to those of the present study. Intracellular calcium mobilization was decreased by ovariectomy, and stored intracellular calcium was also decreased by ovariectomy and salt loading. These results may relate to the decrease of NO synthase production by ovariectomy.
We have also reported the importance of the prostaglandin system in DS rats in their abnormal response.12 However, little is known about the relation between estrogen and prostaglandins in kidneys and vascular smooth muscle cells of hypertensive animals.
In the preliminary study when we administered the 17ß-estradiol with a silicone elastomer tube (0.5 mg per pellet) to ovariectomized DS rats fed a low sodium diet, the blunted pressure-natriuresis relationship did not reverse to that of sham-operated DS rats fed a low sodium diet (data not shown). This is probably due to the difference between endogenous estrogen and exogenously administered estrogen. It is generally accepted that higher doses of estrogen, such as contraceptives, may increase BP and the risk of cardiovascular disease in women. Therefore, a high dose of estrogen replacement might not restore the blunted pressure-natriuresis relationship by affecting vascular systems in the present experiment, because it did not mimic the endogenously released female hormones.
Blood Pressure
BP increased in ovariectomized DS rats fed an
8% NaCl diet,
as other investigators have reported.9 10 Several
studies
have shown that hypertension is more severe and more rapid in
development in male than female SHR28 29 and more
rapid in
male DS rats.9 10 Female rats do not develop
deoxycorticosterone acetate–salt
hypertension30 31 as
rapidly or to the same extent as male rats. Some investigators have
reported that BP is reduced by estrogen in
SHR.32 33 34 These
reports suggest that there is a gender difference in the development of
hypertension in experimental hypertensive rats and that sex hormones
relate to its mechanism. Estrogen may play a protective role in the
development of hypertension. In the present study the blunted
pressure-natriuresis relationship showed an increase of salt
sensitivity in ovariectomized DS rats, which enhanced salt-induced
hypertension earlier than in sham-operated DS rats fed a high
sodium diet.
On the contrary, sham-operated DS rats did not develop hypertension after 4 weeks of salt loading. The duration of salt loading was not long enough to increase BP in sham-operated DS rats. In previous studies Dahl rats were often placed on a high sodium diet at the age of 3 to 5 weeks because the level of salt intake in young rats seemed to be a decisive factor for the susceptibility of adult animals to salt-induced hypertension.35 In the preliminary study male and female DS rats developed hypertension when they were fed a high sodium diet for 4 weeks from the age of 5 weeks. Consequently, BP increased less when we started feeding sodium to mature DS rats than to younger DS rats. The prepuberty and weaning periods might be critical for the induction of experimental hypertension in rats.36 There seemed to be a gender difference in the BP of intact male DS rats compared with their female counterparts at the same age; however, intact male DS rats also did not develop hypertension by 4 weeks of salt loading at the age of 12 weeks (data not shown). Thus, testosterone may contribute to the gender difference in BP through mechanisms independent of sodium retention. This hypothesis was supported by the report that in DS rats fed a high sodium diet, gonadectomy was without effect in males but enhanced hypertension in females.9 Although long-term salt restriction caused salt sensitivity to decrease in both male and female DS rats, only ovariectomized rats might restore the inherent increase of salt sensitivity compared with normal female and male DS rats. This finding suggests that estrogen may play a more important role than testosterone in salt-induced hypertension.
Furthermore, these distinct responses to salt intake at different ages may be associated with the difference of salt sensitivity between inbred DS rats and the Dahl salt-sensitive rats developed by John Rapp (S/JR). In the S/JR rats marked spontaneous hypertension with vascular and renal lesions developed even when they were fed a low sodium diet.37 On the other hand, DS rats did not develop hypertension on a low sodium diet.38 These reports suggest that there may be a genetic difference regarding salt sensitivity between these strains. Recently it has been reported that some inbred DS rats from Harlan Sprague Dawley are not salt sensitive because of genetic contamination. However, we used DS rats obtained from Eisai's Laboratory Animal Research Center, Tsukuba, Japan. These strains were introduced into Eisai's laboratory from the Brookhaven National Laboratory, courtesy of Dr J. Iwai in 1989.38 As far as we know, there have been no reports of genetic contamination in these strains.
In summary, ovariectomy enhanced genetic salt sensitivity by blunting the pressure-natriuresis relationship, which preceded the development of overt hypertension by salt loading in female DS rats. Estrogen may play a protective role in hypertension partly by modulating the pressure-natriuresis relationship in DS rats.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by a grant from the National Rice Association (Tokyo, Japan), a grant-in-aid from the Department of Education for encouragement of young scientists, and a grant from the Japan Foundation for Aging and Health (Tokyo, Japan).
Received April 10, 1995; first decision May 15, 1995; accepted September 5, 1995.
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