(Hypertension. 1996;27:90-95.)
© 1996 American Heart Association, Inc.
Articles |
Blood Pressure and Its Regulation in Spontaneously Hypertensive Rats Bred on the Lowest Sodium Diet for Normal Growth
From the Third Department of Internal Medicine (S.T., K.F., N.K., Y.K.), University of the Ryukyus School of Medicine, Okinawa; the First Department of Internal Medicine (T.E.), Miyazaki Medical College, Miyazaki; the Second Department of Internal Medicine (Y.T.), Faculty of Medicine, Kyushu University, Fukuoka; the Research Laboratory (T.T.), Yoshitomi Pharmaceutical Industries, Ltd, Fukuoka; Seiwa Experimental Animals, Ltd (K.O.), Fukuoka; and the National Cardiovascular Center (S.T.), Osaka, Japan.
Correspondence to Shuichi Takishita, MD, Division of Hypertension and Nephrology, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka 565, Japan.
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Abstract |
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Abstract To investigate the effects of dietary sodium restriction from conception to adulthood on blood pressure and its regulatory mechanisms, male offspring were derived from inbreeding in spontaneously hypertensive rats fed a diet containing sodium of 175 µmol/g food (control) or 22 µmol/g (low sodium), which is the least sodium content for normal growth. While urinary sodium excretion was markedly less, the low sodium diet did not inhibit body growth and failed to blunt the development of hypertension. Neither plasma catecholamine concentration nor depressor response to hexamethonium was different between the two groups at any age examined (8, 12, and 20 weeks). Plasma renin concentration was not elevated, whereas urinary excretion of aldosterone was increased at any age in the low sodium group compared with that in the control group. Other sets of rats were fed a diet containing sodium of 175 µmol/g plus mefruside (a diuretic) of 0.001% in the same manner as in the other two groups. Urinary sodium excretion per creatinine was higher than in the other groups. The diuretic treatment inhibited body growth and suppressed adult blood pressure. While the sympathetic function was not affected, both plasma renin concentration and urinary excretion of aldosterone were elevated. These results indicate that dietary sodium restriction with the least sodium for normal growth from conception cannot blunt either the sympathetic nervous function or the development of hypertension in spontaneously hypertensive rats. Aldosterone appears to play an important role in maintaining sodium homeostasis under the dietary sodium restriction.
Key Words: aldosterone • catecholamines • diuretics • rats, inbred SHR • renin-angiotensin system • sodium, dietary
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Introduction |
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Increased sodium intake is widely assumed to be an important environmental triggering influence in primary hypertension.1 2 In young SHR, abnormalities of sodium intake,3 total body sodium,3 and renal handling of sodium4 have been detected. For the rapid development and full expression of hypertension in SHR, an early period of sodium retention was reported to be critical.5 Furthermore, perinatal exposure to high sodium increases adult BP in several genetic models of hypertension6 7 8 and in normotensive rats.9 10 On the other hand, dietary sodium restriction can affect the development of hypertension in SHR. To prevent or blunt the development of hypertension, a sodium-deficient diet11 12 13 14 (defined as a diet containing less than the 22 µmol sodium/g food required for normal growth of rats) or perinatal exposure15 to it is needed, which should result in a suppression of normal growth.11 12 13 14 15 Furthermore, suppressed growth itself may blunt the development of hypertension in SHR.15 16 However, moderate sodium restriction does not appear to affect the hypertension development when initiated at birth (26 µmol/g)12 14 or at 7 weeks of age (22 µmol/g).17 The influence of sodium restriction on BP was reported to be age dependent.18 The impact of sodium during development could be more pronounced than the impact in the later period. Furthermore, the perinatal period is thought to be a time in which there are important developmental changes in the structure and function of the cardiovascular and water and electrolyte systems, including both central and peripheral neural and hormonal mechanisms that regulate their function.10 19
In the present study, we used a 22 µmol/g sodium diet, the lowest amount consistent with normal growth.20 We aimed to investigate whether or not perinatal exposure to and subsequent placement on a 22 µmol/g sodium diet could affect the development and maintenance of hypertension and mechanisms regulating BP in SHR (F-1 generation). We also examined effects of a diuretic treatment started in breeders (F-0 generation) and continued in the F-1.
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Methods |
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Animals and Diets
Male and female SHR/Sea at weaning were shipped from Seiwa Experimental Animals, Ltd, Fukuoka, Japan. SHR/Sea are similar in genotype to SHR from Charles River, Japan (SHR/NCrj). All procedures were in accordance with institutional guidelines. The rats were randomly placed on one of three diets: 175 µmol sodium/g food (0.4%) diet (G1, control); 22 µmol/g (0.05%) diet (G2, low sodium); and control sodium plus 0.001% of mefruside21 (G3, diuretic). Potassium (192 µmol/g) and other constituents except chloride, which was less in G2, were the same for all diets. The diets were manufactured on special request by Oriental Yeast Co. All rats were placed four per cage in a specific pathogen-free room and allowed free access to their diet and to distilled water. The room was conditioned with constant temperature (24 to 25°C), humidity (45% to 75%), and lighting from 8 AM to 8 PM. At 13 weeks of age, two female and one male rat(s) of each group were placed per cage for mating. Dams were kept on the same diets as before until the weaning. Pups were not separated from the dams until 4 weeks of age; thereafter, male pups (F-1) were placed four per cage and fed their respective diets under the same conditions as parent rats (F-0). Only male rats of F-0 and F-1 were used in the following experiments.
Experiment 1
Rats (n=16 of each dietary group) in both
F-0 and F-1 were used
for the study. At 6, 8, 12, and 20 weeks of age (both groups) plus 30
weeks (F-0 only), each rat was separately housed in a
metabolic cage for 24 hours to examine food and water
consumption and to collect urine. On the second day after return to
their own cages, BW, SBP, and HR were measured. BP and HR were measured
by tail plethysmography after preheating at 38 to 39°C for 10 minutes
(PE-300, Narco Biosystems). Urinary excretion of sodium and potassium
was estimated by using flame-photometry and creatinine
by Jaffé reaction. AER was measured by
radioimmunoassay.22
Experiment 2
Blood sampling for determination of serum
concentrations of
electrolytes, total protein, creatinine, and urea nitrogen
was performed in 12 rats of all groups at 8, 12, and 20 weeks and 30
weeks (F-0 only) of age. Arterial blood was drawn from the
abdominal aorta under ether anesthesia. Thereafter, the
heart and kidneys were removed, cleaned, and weighed. Measurements of
HW and KW in F-0 were performed only in rats at 30 weeks of age. Serum
items were measured by the automatic analyzer (Hitachi
712).
In another set of 12 rats of each dietary group, plasma catecholamine and renin concentrations were determined at 8, 12, and 20 weeks of age. At least 4 hours after recovery from ether anesthesia, 1.5 mL of arterial blood was obtained through the catheter inserted into the common carotid artery of the rat in a conscious and unrestrained state. Blood was collected in ice-cold tubes that contained EGTA and reduced glutathione for plasma catecholamine determination or EGTA-2Na for PRC assay. Plasma catecholamine was assayed for free NE and E separately by a radioenzymatic method.23 The sensitivity was 2 pg for both NE and E in a plasma sample of 50 µL. The intra-assay CV was 8.0% and 10.4%, respectively, and the interassay CV was 9.9% and 11.6%, respectively. PRC was measured by a radioimmunoassay method.24 The intra-assay CV was 4.9% and interassay CV was 7.5%.
Experiment 3
BP responses to IV administration of NE and
hexamethonium were examined in 10 rats of each group of
F-1 at 8, 12, and 20 weeks of age. Under ether anesthesia,
rats received PE-10 catheters connected to PE-50 polyethylene tubing
(Clay Adams) inserted into the abdominal aorta via the femoral artery
for measurement of arterial BP and into the
inferior vena cava via the femoral vein for administration
of drugs. The catheters were filled with heparinized 5% dextrose
solution and were exteriorized by passing them subcutaneously through
the dorsal skin of the neck and fixing them to the skin. The
arterial line was connected to a pressure transducer (P50,
Gould) for continuous recording of MAP and HR triggered by
pulsatile pressure on a chart recorder (RM-6200, Nihon Koden). At
least 4 hours after the rats recovered from the anesthesia,
resting MAP and HR were recorded in a conscious and unrestrained
state. After baseline measurements, pressor responses to NE and
depressor responses to hexamethonium were monitored. NE
bitartrate was injected at doses of 0.3, 1.0, and 3.0 µg/kg BW.
Thereafter, 3.0 mg/kg hexamethonium bromide was
administered. The drugs were dissolved in 5% dextrose solution.
Each chemical assay was made in samples at the same points of age in the three dietary groups together in one assay procedure.
Statistical Analysis
All values were expressed as
mean±SEM. Statistical
analysis was performed by using one-way ANOVA and the
Bonferroni method25 to evaluate the difference of each
item between G1 and G2 or G3 at the corresponding age in each
generation. In the cases of BW, SBP, HR, urinary excretions of
electrolytes, and creatinine, repeated-measures ANOVA
was also used. A value of P<.05 was considered
statistically significant.
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Results |
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Body Weight
In experiment 1, food and water consumption were not different among the groups at respective ages. An average amount of food taken at 20 weeks of age for G1 (control), G2 (low sodium), and G3 (diuretic) in F-1 was 13.8±0.6, 13.2±0.7, and 14.9±0.8 g/24 h, respectively. In F-0, BW was not different between G1 and G2 up to 30 weeks of age. It was smaller in G3 than that in G1 at 12 weeks of age and thereafter (Fig 1
). In F-1, BW
in G2 tended to be larger than that in G1 at up to 12 weeks of age and
was similar to that at 20 weeks. BW in G3 was smaller than that in G1
at 12 and 20 weeks of age (P<.01).
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SBP and HR
In F-0, SBP became >170 mm Hg in all groups by
8 weeks of age
(Fig 1
). There was no significant difference in SBP between G1
and G2
throughout the observation period. Although SBP in G3 was not
significantly different from that in G1 up to 20 weeks of age, it was
lower than that at 30 weeks (P<.01). Average SBP at 30
weeks of age for G1, G2, and G3 was 192±3, 192±5, and
174±3 mm Hg,
respectively. In F-1, SBP became >160 mm Hg in all three groups by 8
weeks of age. The BP in G2 was higher than that in G1 at 8 weeks of age
(P<.05); thereafter, there was no difference between the
two groups. BP was significantly lower in G3 than in G1 at 12 and 20
weeks of age (P<.01). Average SBP at 20 weeks of age for
G1, G2, and G3 was 197±3, 200±3, and 177±2 mm Hg,
respectively.
HR decreased in association with an increase in SBP at 8 weeks of age in all the groups of both F-0 and F-1 and was restored gradually to the level measured at 6 weeks of age. There was no significant difference in HR among the groups (F=1.03 in F-0, 2.50 in F-2). The average HR at 20 weeks of age in F-1 for G1, G2, and G3 was 453±6, 458±7, and 468±4 beats per minute, respectively (F=1.88).
Urinary Excretion of Sodium, Potassium, and
Aldosterone
Twenty-four–hour excretion of urinary sodium and
potassium and the sodium-creatinine ratio are shown in
Table 1. Sodium excretion was markedly less in G2 than
in G1 and was slightly larger in G3 compared with that in G1 in both
F-0 and F-1. A consistent difference in potassium excretion was
not found among the three groups. While creatinine
excretion was less in G3 (F=2.55 in F-0, 12.51 in F-1), the
creatinine coefficient (mg/100 g BW per 24 hours) showed no
difference among the groups in both F-0 and F-1 (data not shown).
Urinary sodium per creatinine (µmol/mg
creatinine per 24 hours) was higher in G3 at all ages
examined except 8 weeks in F-0 and higher at 12 and 20 weeks in F-1
compared with that in G1 (Table 1).
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AER is shown in Fig
1 (bottom). It was highest in G2 among the three
groups in both F-0 and F-1 except at 12 weeks of age in F-0, when there
was no difference between G2 and G3. AER in G3 was higher than that in
G1 at all points of age examined.
Serum Concentrations of Protein, Electrolytes,
Creatinine, and Urea Nitrogen
There was no difference in serum total
protein among the three
groups in either F-0 or F-1. Serum concentrations of potassium and
chloride were significantly lower in G3 than in G1 at all ages examined
in both F-0 and F-1 (P<.01), whereas no difference was
found in serum sodium concentration between the two groups. There was
no difference in serum electrolytes between G1 and G2 in either F-0 or
F-1. Creatinine concentrations were similar among the three
groups in both F-0 and F-1. Blood urea nitrogen in G3, however, was
elevated throughout the observation periods in the two generations. The
values in F-1 at 20 weeks of age are shown in Table 2.
At 8 and 12 weeks of age, similar results were obtained (data not
shown).
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Plasma Concentrations of Catecholamine and
Renin
Neither plasma NE nor E was significantly different among the
three groups at any age examined in F-0 and F-1. PRCs are shown in Fig
2. In F-0, PRC at 8 weeks of age was
higher in G2 than in G1 (P<.01), whereas no significant
difference was found at 12 and 20 weeks of age between the two groups.
PRC in G3 was higher than that at corresponding ages in G1 and in G2
except at 8 weeks, when it did not differ from that in G2. In F-1, PRCs
in G1 and G2 were similar at all ages examined, whereas PRCs were
extremely higher in G3 compared with those in G1 and G2
(P<.01).
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BP Response to NE and Hexamethonium
In baseline measurements
there was no significant difference in
MAP between G1 and G2 at 8, 12, and 20 weeks of age in F-1. MAP in the
mefruside group (G3) tended to be lower than that in G1. The average
values of MAP at 20 weeks of age for G1, G2, and G3 were 155±10,
158±7, and 135±5 mm Hg, respectively. The pressor response to NE
was
substantially the same among the three groups at 8, 12, and 20 weeks of
age, and reflex bradycardia was also similar (data not shown).
Depressor response to hexamethonium at a fixed dose of
3.0 mg/kg was not different among the three groups at 8, 12, and 20
weeks of age in both absolute and percentage expression. At 20 weeks of
age depressor response in G1, G2, and G3 was -23.5±2.6%,
-22.4±2.9%, and -25.4±2.4%, respectively
(F=0.342).
Weights of Hearts and Kidneys
HW/BW and KW/BW are shown in
Table 3. Neither HW
nor the ratio of HW to BW was different between G1 and G2 at any age
examined in the two generations. On the other hand, these were
significantly smaller in G3 than those in G1 at 30 weeks of age in F-0
and at 12 and 20 weeks of age in F-1 (P<.01). KW-BW ratio
was smaller in G2 than in G1 in F-1, whereas it was larger in G3 than
in G1 at 30 weeks of age in F-0 and at 8 and 12 weeks of age in
F-1.
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Discussion |
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The minimal dietary sodium requirement for normal growth in rats has been shown to be 22 µmol sodium/g food.20 In SHR a sodium deficiency diet (less than 22 µmol/g) initiated at birth,12 14 weaning,11 or 5 weeks of age13 was reported to prevent or blunt the development of hypertension, which is associated with an inhibition of body growth.11 12 13 14 In the present study, we used 22 µmol/g sodium diet (low sodium diet) to avoid growth inhibition, which is not physiological and itself may blunt the development of hypertension in SHR.15 16 The low sodium diet was initiated at weaning in the breeders (F-0) and continued to 20 weeks of age in the second generation (F-1). Therefore, F-1 rats were exposed to the diet from conception to adulthood, resulting in normal body growth. The long-term sodium restriction in SHR that we used in the present study has not been performed in previous studies.
Perinatal exposure to a sodium-deficient diet (17 µmol/g)15 or high sodium diet (1.3 mmol/g)8 has been shown to suppress or increase the adult BP of SHR or borderline hypertensive rats, respectively. Furthermore, the effects of perinatal and adult exposure to high dietary sodium were additive.8 In the present study, however, exposure to the low sodium diet from conception to adulthood could not suppress the BP measured at 6, 8, 12, and 20 weeks of age in F-1 SHR.
It has been accepted that the sympathetic nervous system is hyperactive and essential to the development of hypertension in SHR.26 27 Therefore, the failure to blunt the development of hypertension in the present study might be attributed to the absence of suppression of the sympathetic function. We assessed the sympathetic activity by measuring (1) plasma catecholamine, (2) extent of BP decrease in response to hexamethonium, and (3) BP responsiveness to an IV injection of NE. The findings that there were no differences in the three items tested between the control and low sodium groups in F-0 and F-1 are consistent with results from other studies. Winternitz and Oparil17 reported that a dietary sodium restriction (22 µmol/g) for 3 weeks from 7 weeks of age had no influence on either plasma catecholamine levels or the depressor response to hexamethonium. Toal and Leenen14 also found no remarkable changes in sympathetic function in SHR on a 26 µmol/g sodium diet from birth to 16 weeks of age. More severe restriction or depletion of sodium, however, was reported to decrease the sympathetic nervous function.2 28 In dogs on sodium depletion induced by a low sodium diet and a diuretic, the pressor response to carotid occlusion was blunted29 and renal sympathetic nerve activities were suppressed by less of an increase in arterial pressure compared with a normal sodium group.30 In SHR, Toal and Leenen14 demonstrated that a sodium-deficient diet (9 or 17 µmol sodium/g food) started at birth prevented or blunted the development of hypertension with depressed body growth. Although plasma catecholamine levels were higher, the BP-lowering effect of ganglion blockade was significantly less compared with that in SHR on the control diet (101 µmol/g).14 They concluded that a decreased pressor effect of the sympathetic nervous system in SHR on a sodium-deficient diet contributed to the blunted development of hypertension. Folkow and colleagues2 13 also reported that 5 µmol/g sodium diet suppressed BP and the peripheral sympathetic function and altered central catecholamine metabolism in SHR.
Therefore, it appears that the low sodium diet with minimal content of sodium for normal growth cannot suppress the sympathetic nervous function and the development of hypertension in SHR even in the present experimental conditions. We have reported31 32 that the same regimen of sodium as the current study suppressed the sympathetic function (lower plasma NE concentration and blunted depressor response to hexamethonium) and MAP in Wistar rats of the third generation (F-2) bred successively on the low sodium diet. A suppression of SBP measured by tail plethysmography and the tendency of a suppression of depressor response to ganglion blockade were found even in F-1.32 The inconsistency between SHR and Wistar normotensive rats might be due to the differences in basal activity of the sympathetic nervous system, strain, and/or the length of sodium restriction over the generations.
Dietary sodium restriction also has been known to enhance the renin-angiotensin-aldosterone system. It is possible that the hypotensive effects of the low sodium diet are offset by compensatory increased renin-angiotensin system. In the present study, however, PRC in the low sodium group was not elevated in F-0 and F-1 except at 8 weeks of age in F-0 compared with that in the control group. High PRC at 8 weeks of age in F-0 may be considered to be a short-term response to sodium restriction because the rats had been on the low sodium diet for only 3 weeks. Moderate sodium restriction with 26 µmol/g sodium from birth was also reported not to cause significant increases in plasma renin activity or the BP response to captopril at 16 weeks of age in SHR.33 The findings may be consistent with those of Morotomi et al,34 who noted that renal renin content was increased in both Wistar rats and SHR fed the low sodium food for 7 days but not in these rats on the food from weaning for 9 weeks. Normal PRC was also found in our previous study on Wistar rats bred on the low sodium diet, which was confirmed further by the pressure response to an infusion of saralasin, an angiotensin II analogue, that was similar to that in the control sodium group.32 Taken together, these results suggest that a readjustment of renin synthesis and release in the kidney may occur in rats on long-term dietary restriction of sodium. Severe sodium restriction, however, elicited a marked increase in plasma renin activity, an increased depressor response to captopril, and a marked decrease in pressor response to angiotensin II.33
In contrast to the findings of PRC in the present study, urinary AER increased in the low sodium group more than that in the diuretic group, where PRC was elevated. The dissociation between PRC and AER was also found in the aforementioned three generations (F-0, F-1, and F-2) of Wistar rats on the low sodium diet.31 32 Therefore, it may be reasonable to consider that the regulatory mechanisms of the renin-angiotensin system and aldosterone metabolism are not always in the same direction under long-term moderate sodium restriction but that aldosterone may play a more important role than angiotensin II in maintaining sodium homeostasis, at least in rats in this situation.
The diuretic treatment with mefruside21 decreased the adult BP, which was associated with the growth inhibition in both F-0 and F-1 SHR maintained on the control sodium diet. Suppressed BP was confirmed by the reduced HW-BW ratio. Although the sympathetic function was not influenced by long-term treatment, PRC was elevated at any age in both F-0 and F-1. Elevated PRC levels are consistent with the report that diuretic treatment causes an increase in granularity of juxtaglomerular cells in rats.35 While creatinine excretion was less in the diuretic group compared with that in the other two groups, the creatinine coefficient (mg/g BW per 24 hours) showed no difference among the three groups. Urinary sodium excretion and the excretion per creatinine were larger in the diuretic group compared with those in the control sodium group in both F-0 and F-1. Lower concentrations of serum chloride and potassium and higher urea nitrogen level were also reflections of diuretic effects of mefruside. These findings may explain the suppressed BP and high levels of PRC. Although the causes of reduced BW were not clear, it could not be attributed solely to a reduction in body fluid. Less urinary excretion of creatinine may indicate smaller muscle mass, which partly explains the reduced BW in the diuretic group. The KW-BW ratio was larger in the diuretic group than in the control group. We did not perform a pathological study of the kidney and have no explanation for the finding.
In summary, dietary sodium restriction with the least sodium for normal growth failed to blunt the development of hypertension in SHR placed on the diet from conception to adulthood, which was in contrast to the diuretic treatment. An enhanced urinary AER without an increase in PRC was demonstrated in association with normal sympathetic nervous function. The results in the present experimental conditions suggest that aldosterone played an important role in maintaining sodium homeostasis, which did not blunt the development of hypertension in conjunction with preserved sympathetic function.
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Selected Abbreviations and Acronyms |
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Footnotes |
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Reprint requests to Koshiro Fukiyama, MD, Third Department of Internal Medicine, University of the Ryukyus School of Medicine, 207 Uehara, Nishihara-cho, Okinawa 903-01, Japan.
Received April 18, 1995; first decision May 31, 1995; accepted September 6, 1995.
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