(Hypertension. 1999;33:517-523.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Handling 22NaCl by the Blood-Brain Barrier and Kidney
Its Relevance to Salt-Induced Hypertension in Dahl Rats
From the Department of Medicine, Columbia University and New York University Medical Center, New York, NY.
Correspondence to Dr Shlomoh Simchon, National Hypertension Association, 324 E 30th St, New York, NY 10016.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Abstract—We previously reported that inappropriate renal vasoconstriction in Dahl salt-sensitive (DS) rats fed high NaCl diets may cause sodium retention. The present study examined the distribution and elimination of 22Na in DS and Dahl salt-resistant (DR) rats, and we determined whether an abnormality in renal function might also cause sodium retention in DS rats. Following an intravenous bolus of 4 µCi 22NaCl in prehypertensive DS and DR rats with similar blood pressures on low (0.23%) or high (8% for 4 days) NaCl diets, urinary clearance of 22Na in 1 hour was about 4 times less in DS than DR rats, and renal retention of 22Na was up to 8 times greater in DS than DR rats (P<0.01), suggesting that a renal functional defect may contribute to salt retention in DS rats; however, its uptake in tail artery, heart, lungs, liver, and spleen was similar in DS and DR rats. Uptake in brain was up to 5 times greater in DS than DR rats (P<0.01). Cerebrospinal fluid 22Na radioactivity (in counts per minute) revealed that the blood-brain barrier is 5 to 8 times more permeable to sodium in DS than DR rats (P<0.01). Cerebrospinal fluid volume and brain water content increased significantly (P<0.01) in DS but not DR rats on an 8% NaCl diet. Intracerebroventricular bolus injection of 0.06 mL of 4.5 mol/L NaCl acutely and transiently induced the same degree of hypertension in DR and DS rats, whereas similar volume injections of isotonic saline, 4.5 mol/L Na-acetate, or 4.5 mol/L NaBr did not produce hypertension in either strain. We conclude that functional abnormalities in DS rat kidneys may cause retention of NaCl and that an increased blood-brain barrier permeability to NaCl may enhance its access to sites in the brain that are then activated and induce hypertension.
Key Words: brain • cerebrospinal fluid • hemodynamics • ventricles, cerebral • kidney • rats, Dahl
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The mechanism of NaCl-induced hypertension in Dahl salt-sensitive (DS) rats and in salt-sensitive humans is unclear. Yet considerable evidence suggests that the renal abnormality that causes blood pressure (BP) elevation in acquired and inherited hypertension may be associated with a diminished sodium excretion.1 2 The cause of renal hemodynamic and/or functional abnormalities in DS rats that might play a role in the development of salt-sensitive hypertension is unknown; however, a number of biochemical derangements that might impair renal function have been implicated, including deficiency in the generation of cyclic GMP,3 20-hydroxyeicosatetraenoic acid,4 kallikrein,5 prostaglandin E2,6 or dopamine.7 It has also been postulated that hypertension develops in DS rats because of a decrease in nitric oxide production.8 9
DS rats appear to have a genetic functional derangement in the kidney that causes salt retention10 rather than a deficit of nephrons that Brenner et al11 12 13 postulated as a cause of hypertension. Although evidence suggests that sodium chloride (NaCl) is retained by kidneys of DS rats,14 15 16 17 accumulation of sodium in blood or tissues has not been conclusively demonstrated.
The DS rat is an excellent animal model for study of the mechanism of salt-induced hypertension. The moderate hypertension that develops after several months of a 1% NaCl diet may be the most appropriate model to study, because the hypertension results from increased total peripheral resistance (TPR) without detectable blood volume expansion,18 as occurs in most humans with essential hypertension. An 8% NaCl diet causes rapid onset of severe hypertension initially because of blood volume expansion and elevated cardiac output (CO); however, CO rapidly returns to normal and hypertension is maintained by increased TPR, even though hypervolemia persists.16 18
Our major objective was to determine how 22NaCl is handled in prehypertensive DS and Dahl salt-resistant (DR) rats on a low NaCl (0.23%) diet before hemodynamic or structural abnormalities related to hypertension have occurred. Furthermore, we studied the effects of hypertension induced by 8% NaCl on the handling of 22NaCl by the blood-brain barrier (BBB). We also investigated the BP effects of acute injection of hypertonic NaCl or other sodium compounds into cerebrospinal fluid (CSF) of DS and DR rats to determine any difference in BP response between prehypertensive DS and DR rats on a low NaCl diet.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Animals and Procedures
Ninety-five DR and 95 DS male rats (Brookhaven National Laboratory strain obtained from Harlan Sprague Dawley Inc, Indianapolis, Ind) were fed a low salt diet (0.23% NaCl) (Harlan TekLad) from weaning. Dietary sodium content was confirmed in our laboratory. All rats were housed in an animal facility with controlled temperature and lighting and were used according to National Institutes of Health and New York University Medical Center guidelines for animal care. Studies were performed on 3 groups of rats on the following diets: group A, 44 DR and 44 DS rats fed a 0.23% NaCl diet until 6 weeks of age; group B, 23 DR and 23 DS rats fed a 0.23% NaCl diet until 6 weeks of age and then fed an 8% NaCl diet for 4 days; and group C, 23 DR and 23 DS rats fed a 0.23% NaCl diet until 6 weeks of age and then fed an 8% NaCl diet for 3 or 4 weeks.
Five DR and 5 DS rats were used for a preliminary study to detect any deterioration of rats during experiments. BPs were measured at regular intervals by the indirect tail-cuff method (Narco Bio-Systems). Rats from groups A and B were normotensive before experimental protocols.
Experimental Protocols
For each rat group, 6 different protocols were conducted.
Protocol 1
In protocol 1, we investigated 22Na uptake
in different organs. Fifteen DR and 15 DS rats (5 DR and 5 DS rats from
each group) were anesthetized with sodium pentobarbital (35
mg/kg IP, usually adequate for Dahl rats; supplemental doses used as
required), and a polyethylene catheter (PE-240) was inserted through an
incision into the trachea to ensure stable ventilation. A second
catheter (PE-50) was inserted into a femoral artery and connected to a
Statham transducer and a polygraph recorder (model 7, Grass
Instrument Co) for recording of arterial pressure.
A third catheter (PE-50) was inserted into the femoral vein for
intravenous injections. A dose of 4 µCi
22NaCl (NEN Research Products) in 0.4 mL
saline was injected intravenously, and 0.2-mL blood samples
were taken every 15 minutes to determine 22Na
radioactivity in counts per minute (cpm) in plasma. Fifty-five minutes
after the first injection, 10 µCi 24NaCl
(University of Missouri, Research Reactor Facility) in 0.1 mL saline
was injected intravenously. Five minutes after the
injection of 24NaCl, rats were decapitated and
blood was collected for estimation of 22Na
radioactivity. Several tissues (including part of the tail
artery, lungs, and liver as well as the entire heart, spleen, kidney,
and brain) were removed and weighed and their
22Na radioactivity determined.
22Na and 24Na
radioactivities were measured in plasma and tissues with a gamma
counter (well counter) connected to a multichannel analyzer.
The well counter is a scintillation crystal detector formed with a
central well into which the samples are inserted and their radioactive
emission counted. The major advantage of this arrangement is the
increased counting efficiency that results from surrounding the sample
with the detector. The well counter was connected to a PCA-P
computer-based program with a PCA-P card, which permits collection of
radioactivity data (Oxford Instruments Inc) and is installed in an
IBM-compatible personal computer. The radioactivity of each
isotope is corrected for any overlapping of isotopes. Relative uptake,
ie, tissue cpm/plasma cpm, of 22NaCl (60 minutes
after injection) to relative uptake of 24NaCl (5
minutes after injection) was determined. If the ratio
22Na/24Na equals 1, it
would indicate that the same volume is occupied by the 2 isotopes and
that the 55 minutes difference in time of injection did not affect
their distribution. If this ratio is greater than 1, it would indicate
the degree of tissue uptake of 22Na. The
radioactivity of 22Na in plasma was always
determined as the average between the extrapolated counts per minute at
zero time and the counts per minute 60 minutes after injection of
22NaCl.
Protocol 2
In protocol 2, we investigated the passage of
22Na across the BBB, its uptake by the brain,
urinary clearance, and renal retention. We also measured plasma volume
with 125I-albumin. Fifteen DR and 15 DS
rats (5 DR and 5 DS rats from each group) were anesthetized
with sodium pentobarbital (35 mg/kg IP), and catheters were placed as
in protocol 1. A fourth catheter (PE-190) was placed transabdominally
into the urinary bladder and secured so that all urine was collected.
The rat's head was placed in a stereotaxic
apparatus, and the dorsal surface of the skull was shaved.
After a small scalp incision, a hole (2 mm diameter), 1 mm
caudal and 1.5 mm lateral to the bregma, was made in the skull
with a dental drill, and a stainless steel cannula (internal diameter,
1 mm; length, 5.5 mm) was inserted into the left lateral
ventricle. Doses of 4 µCi 22NaCl in 0.4 mL
saline and 4 µCi 125I-labeled albumin
(radioiodinated 125I serum
albumin, Mallinckrodt, Inc) in 0.2 mL saline were injected
intravenously. Sixty minutes after injection, samples of
blood and CSF were taken to determine 22Na and
125I activities (in counts per minute) in plasma
and CSF. After rats were decapitated, the brain was removed, weighed,
and 22Na and 125I
activities determined. 22Na and
125I-albumin activities were measured in
plasma, CSF, and tissues as in protocol 1. Passage of
22NaCl across the BBB was calculated from its
counts per minute in CSF and plasma and expressed as
22Na cpm in 1 g
CSF/22Na cpm in 1 mL plasma. Plasma volume was
determined from 125I-labeled albumin and
calculated as total 125I cpm
injected/125I cpm in 1 mL plasma and expressed
per 100 g body wt. Brain uptake was calculated as
22Na cpm in 1 g
brain/22Na cpm in 1 mL plasma. Urine was
collected for 1 hour, starting 15 minutes after injection of
22NaCl, and 22Na
radioactivity in urine was determined. For further study of urinary
clearance, plasma counts per minute of 22Na was
determined 15, 30, 45, and 60 minutes after
22NaCl injection. Urinary clearance (milliliters
per hour) was calculated as total 22Na cpm in
urine during 60 minutes collection/22Na cpm in 1
mL plasma. Renal retention was calculated as 22Na
cpm in 1 g kidney/22Na cpm in 1 mL
plasma.
Protocol 3
In protocol 3, we injected 22NaCl and
125I-albumin into the left cerebral
ventricle to measure CSF volume and uptake in brain. Nine DR and 9 DS
rats (3 DR and 3 DS rats from each group) were anesthetized
with sodium pentobarbital (35 mg/kg IP), and catheters were placed as
in protocol 1. A cannula was placed in the left cerebral ventricle as
described in protocol 2. Doses of 1 µCi
22NaCl in 60 µL saline and 1 µCi
125I-labeled albumin (which does not
penetrate cells or enter the circulation) in 60 µL saline were
injected into the cerebral ventricle. Sixty minutes after injection,
samples of CSF were taken to determine 22Na and
125I activities (in counts per minute) in CSF.
Volume distributions of 22NaCl and
125I-albumin in CSF were calculated from
counts per minute in CSF and total counts per minute injected and
expressed as total 22Na cpm
injected/22Na cpm in 1 mL CSF and total
125I cpm injected/125I cpm
in 1 mL CSF, respectively.
Protocol 4
In protocol 4, we injected hypertonic NaCl, Na-acetate, and NaBr
solutions into the left cerebral ventricle. Twenty-one DR and 21 DS
rats from group A were prepared as in protocol 2, and 60 µL of 4.5
mol/L NaCl, Na-acetate, or NaBr was injected into the left lateral
ventricle. BP and heart rate were monitored through a femoral artery as
described in protocol 1.
Protocol 5
In protocol 5, we studied systemic, renal, and cerebral
hemodynamic changes in 15 DR and 15 DS rats (5 DR and 5
DS rats from each group) using a transducer and polygraph as indicated
in protocol 1. CO (milliliters per minute) and blood flow distribution
(milliliters per minute per 100 g tissue) were determined by a
microsphere method previously validated in our laboratory by
comparison with electromagnetic flowmeter and
133Xe washout techniques,19 20 21
using 15.0±10.0-µm-diameter microspheres (New England
Nuclear Corp) labeled with 46Sc. The brain,
kidney, and heart and a section of thoracic aorta were immediately
removed. 46Sc radioactivity in tissues was
determined with a gamma counter (Packard Instrument Co) connected to a
multichannel analyzer (Tracor Northern Co). TPR was calculated
as the ratio of mean arterial BP (MABP) to CO. Renal
vascular resistance (RVR), coronary vascular resistance, or
cerebral vascular resistance (CVR) was calculated as the ratio of MABP
to renal, coronary, or cerebral blood flow, respectively.
Protocol 6
In protocol 6, we studied kidney and brain water content in 15
DR and 15 DS rats (5 DR and 5 DS rats from each group), calculated from
the difference between their wet and dry weights after placement in an
oven at 50°C for 24 hours, a period sufficient for drying.
Statistical significance of changes was evaluated by analysis of variance, followed by the Student-Newman-Keuls test for multiple comparisons.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
A preliminary study, to detect any deterioration of rats during experiments, revealed that 2 hours after anesthesia induction, intubation, and surgical procedures described in the protocols, arterial blood gases and pH were within normal ranges: PO2 from 80 to 90 mm Hg, PCO2 from 38 to 40 mm Hg, and pH from 7.34 to 7.40. Blood gases were determined with a blood gas analyzer.
Protocol 1
MABP in DS rats fed an 8% NaCl diet for 3 weeks increased
significantly (P<0.01) and was accompanied by an increase
in plasma volume (P<0.01), whereas DR rats on the same diet
remained normotensive without any increase in plasma volume (Table 1
). After an
intravenous bolus of 22NaCl and
24NaCl to 6-week-old prehypertensive DS and DR
rats with similar BPs and renal hemodynamics on low
(0.23%) or high (8% for 4 days) NaCl diets, as well as to
hypertensive, hypervolemic DS rats fed an 8% NaCl diet for 3 weeks,
renal tissue 22Na retention, calculated from the
relative volume distribution of 22NaCl (60
minutes after injection) to 24NaCl (5 minutes
after injection), was 6 to 8 times greater (P<0.01) in DS
than DR rats. One hour after an intravenous bolus of
22NaCl, its uptake in tail artery, heart, lungs,
liver, and spleen was similar in DS and DR rats, but its uptake in
brain was about 3 to 5 times greater (P<0.01) in DS than DR
rats (Table 1).
|
Protocol 2
Studies of 22Na excretion and its urinary
clearance in rats fed 0.23% or 8% NaCl diets (after 4 days or 3
weeks) revealed a progressive and markedly greater renal retention of
22Na and markedly less urinary clearance of
22Na in DS than DR rats (P<0.01),
whereas urinary clearance of 22Na increased
markedly (P<0.01) in DR rats, without any renal retention
(Figure 1). Increased permeability of the
BBB to 22NaCl caused 5 to 8 times greater
(P<0.01) accumulation of 22Na in the
CSF and about 3 to 5 times greater uptake in the brain of normotensive
DS than DR rats on 0.23% and 8% (4 days) NaCl diets (Figure 1). When the 8% NaCl diet was extended for 4 weeks, severe
hypertension developed in DS rats and 22Na
accumulation in CSF doubled when compared with normotensive DS rats;
however, uptake in brain did not increase significantly more but
remained greater (P<0.01) in DS than DR rats. Figure 2 reveals the rate of decrease in plasma
22Na radioactivity in normotensive DR and DS rats
fed 0.23% NaCl or 8% NaCl for 4 days. In DR rats fed 0.23% NaCl,
plasma 22Na radioactivity decreased at a rate of
166 (cpm/g plasma)/min, determined from the slope of the graph;
whereas in DR rats fed an 8% NaCl diet, 22Na
decreased at a greater rate of 244 (cpm/g plasma)/min
(P<0.01). In DS rats fed 0.23% NaCl,
22Na decreased at a rate of only 52 (cpm/g
plasma)/min and at only a slightly but not significantly greater rate
of 83 (cpm/g plasma)/min after an 8% NaCl diet, indicating sodium
retention in plasma in DS compared with DR rats.
|
|
Protocol 3
Table 2 shows that the volume of CSF
determined by dilution of 22NaCl and
125I-albumin was similar in normotensive
DS and DR rats on 0.23% NaCl. After an 8% NaCl diet for 4 days, MABP
remained normotensive, but CSF volume doubled in DS rats and did not
change in DR rats (Table 2). When 8% NaCl was continued for 4
weeks, severe hypertension (182±3 mm Hg) developed and CSF
increased further (P<0.01) to slightly more than 5 mL
(Table 2). The volumes of CSF determined by
22NaCl were similar to those determined by
125I-albumin, suggesting no significant
brain uptake of 22NaCl within 1 hour after
injection into CSF.
|
Protocol 4
Acute intracerebroventricular
(ICV) injection of a 0.06-mL bolus of 4.5 mol/L NaCl caused significant
(P<0.001) similar elevations of BP in DS and DR rats;
however, injection of 0.06 mL isotonic saline or 4.5 mol/L Na-acetate
or NaBr caused no change in BP. Figure 3
shows that the rate and magnitude of BP increase after a bolus
injection of 4.5 mol/L NaCl was similar in DS and DR rats; however,
heart rate increased more slowly in DS than DR rats.
|
Protocol 5
After a 0.23% NaCl diet, BP, CO, and TPR were similar in DS and
DR rats (Figure 4). After an 8% NaCl
diet for 4 days, although BP in DS and DR rats remained similar and
normotensive, CO increased significantly and TPR decreased
significantly (P<0.01) in DS rats, whereas CO and TPR
remained unchanged in DR rats. RVR and CVR (Figure 4) were
similar in DS and DR rats on 0.23% NaCl diets. After an 8% NaCl diet
for 4 days, RVR and CVR decreased significantly (P<0.01) in
DR rats but remained unchanged in DS rats. When rats ingested an 8%
NaCl diet for 4 weeks, RVR and CVR decreased further
(P<0.01) in DR rats, whereas they increased significantly
(P<0.01) in DS rats. There was no apparent change or
difference in coronary vascular resistance between DR
(13.51±1.7 [mm Hg/mL]/s per 100 g heart) and DS (11.51±3.5
[mm Hg/mL]/s per 100 g heart) rats.
|
Protocol 6
Dry and wet weights of brain and kidneys after a 0.23% NaCl
diet and 8% NaCl diet for 4 days were similar in DS and DR rats;
however, brain and kidney water contents increased in DS rats on an 8%
NaCl diet for 4 weeks (P<0.01). In DR rats water content of
the brain did not change significantly (Figure 5).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The present study suggests that both a renal functional defect and an inappropriate renal vasoconstriction, which occurs when DS rats are placed on a high NaCl diet, are responsible for salt retention. Other experimental studies provide evidence suggesting that the kidney retains NaCl in DS rats.14 15 16
It appears that the BBB is considerably more permeable to
22NaCl in DS than in DR rats, resulting in a
significantly greater increase in CSF and brain
22Na in DS than in DR rats. Furthermore, CSF
22Na was found to be significantly more elevated
in DS rats on an 8% NaCl diet for 4 days than on 0.23% NaCl even
though DS rats remained normotensive. It is uncertain whether increased
CO in DS rats on this high salt diet for 4 days enhanced passage of
22NaCl across the BBB. The fact that CSF volume
significantly expanded after 8% NaCl suggests that accumulation of
NaCl in CSF was accompanied by fluid retention in DS rats. The latter
finding is also consistent with the occurrence of increased
fluid in the brain of these DS rats (Figure 5
). Increased renal
sodium retention was also accompanied by fluid retention in kidneys of
DS rats on 8% NaCl for 4 weeks.
Nakamura and Cowley22 demonstrated that hypertensive DS rats fed a high salt diet exhibited a greater CSF concentration of sodium than DR rats; however, since the increase in CSF sodium followed the onset of hypertension, they concluded that this increase in sodium did not initiate NaCl-induced hypertension but might perpetuate it. After a high NaCl diet, plasma and CSF volume expansion might obscure an increase in total sodium content if only sodium concentration is determined. We observed that after an 8% NaCl diet, hypertension in DS rats was initiated by blood volume expansion and increased CO but was perpetuated by increased TPR,16 whereas prolonged ingestion of 1% NaCl caused hypertension by increasing TPR.18 Conceivably, increased access of NaCl to the brain of DS rats may be responsible for the increased TPR.
ICV administration of hypertonic NaCl solutions produces an increase in arterial BP.23 24 25 26 Furthermore, lesions in the anteroventral third ventricle abolish the acute hypertensive response of ICV NaCl and also prevent or attenuate development of salt-induced hypertension in rats on high NaCl diets.27 28 It is noteworthy that vasopressin injections blocked about half the antihypertensive effect of anteroventral third ventricle lesions in DS rats fed an 8% NaCl diet.28 Access of increased concentrations of NaCl to the brain may occur in DS rats ingesting excess NaCl and might activate the sympathetic nervous system or some other pressor system and increase TPR and BP. Leenen et al29 suggested that ouabainlike activity in the brain may mediate a sympathoexcitatory and hypertensive response to excess NaCl consumption in DS rats. Acute ICV injection of 1.5 mol/L NaCl in anesthetized dogs caused hypertension and tachycardia that coincided with elevation of plasma catecholamines; however, part of the pressor effect may be due to nonneurogenic activation, eg, secretion of vasopressin.25 Finally, in addition to effects on the brain, it is conceivable that chronic ingestion of excess NaCl by DS rats may alter vascular smooth muscle and in some way increase vasoconstriction and TPR.
Our finding that acute ICV injection of 4.5 mol/L NaCl caused a rapid
similar rise in BP of DS and DR rats suggests that there is no
difference between the sensitivity of the brain of DS and DR rats to
stimulation by NaCl. Ikeda et al26 reported that an acute
ICV bolus injection of 2 µL of 0.3 mol/L NaCl induced a slight but
significant transient elevation of BP that was slightly greater in DS
than DR rats. We found no change in BP in DS or DR rats when we
repeated the bolus injection used by Ikeda et al.26
Explanation for these differences in results is unclear. Our findings
indicate that the brain responds specifically to stimulation by NaCl
and not to other sodium salts. It is noteworthy and perhaps relevant
that only increased dietary NaCl causes hypertension; addition of other
sodium compounds to the diet does not elevate BP.30 31 The
rapid increase in BP after acute ICV injection of 4.5 mol/L NaCl
suggests that the sympathetic nervous system may have been
activated to cause similar hypertension in DS and DR rats. The
reason for a less rapid increase of heart rate in DS rats remains
unclear. Miyajima and Bu
ag32 33 suggested that
chronic infusion of hypertonic sodium into the third ventricle of
Sprague-Dawley rats reduces hypothalamic inhibition of sympathetic
vasomotor tone and impairs the baroreflex, which then elevates BP.
Increased 22NaCl uptake by the brain of DS rats appeared to result from increased permeability of the BBB to sodium, whereas renal 22Na retention resulted from impaired excretion of 22Na. Uptake was similar in all other tissues studied in DS and DR rats. It seems unlikely that an abnormality of NaCl uptake in the arteries or the various organs studied is involved in the development of salt sensitivity of DS rats ingesting excessive amounts of NaCl. However, our studies could not determine whether there was any difference between an intracellular and extracellular location of 22Na in DS and DR rats.
Of particular interest was the finding that despite a decrease in TPR, resistance in renal and cerebral arteries of DS rats did not decrease when they ingested an 8% NaCl diet for 4 days. In contrast, RVR and CVR decreased significantly in DR rats on the same diet. After 4 weeks of 8% NaCl, RVR and CVR increased significantly in DS rats, whereas both resistances decreased significantly in DR rats. These results suggest that an abnormality in the vascular response to excess NaCl ingestion may be confined to renal and cerebral vessels of DS rats.
In summary, intravenous administration of 22NaCl to normotensive DS and DR rats on a 0.23% NaCl diet revealed similar 22NaCl uptake in the tail artery, aorta, heart, lungs, liver, and spleen. Renal retention of 22Na occurred in DS but not DR rats, and urinary clearance of 22Na was 4 times less in normotensive DS than DR rats, indicating impaired renal function, possibly due to increased tubular reabsorption of 22Na in DS rats, in agreement with Roman and Kaldunski15 and Sterzel et al.17 Increased permeability of the BBB caused significantly greater accumulation of 22Na in CSF and brain of DS than DR rats. Ingestion of 8% dietary NaCl for 4 days did not alter the normotensive BP, but CSF volume doubled in DS rats without changing brain water content. After 4 weeks on 8% NaCl, DS rats were markedly hypertensive and CSF volume increased further and was accompanied by an increased brain water content. Acute ICV administration of 4.5 mol/L NaCl induced a similar rapid, transitory hypertension and a tachycardia in both DS and DR rats, whereas other sodium compounds did not elevate BP or heart rate. An 8% NaCl diet for 4 days caused an inappropriate response of renal and cerebral arteries in DS rats. Unlike the decrease in vascular resistance occurring in DR rats, CVR and RVR did not decrease in DS rats. When rats ingested 8% NaCl for 4 weeks, CVR and RVR decreased further in DR rats, whereas these resistances increased significantly in DS rats.
In conclusion, it is hypothesized that a functional genetic abnormality of the kidneys causes impairment of NaCl excretion and inappropriate renal vasoconstriction in DS rats ingesting excess NaCl. Impairment of glomerular filtration rate and/or tubular function may also account for decreased NaCl excretion. This then causes retention of NaCl, which accumulates in CSF of DS rats because of an increased permeability of the BBB to NaCl. Increased access of NaCl to the brain may then activate the sympathetic nervous system and/or other pressor systems, which may cause and perpetuate hypertension.
|
Acknowledgments |
|---|
Supported by the National Hypertension Association. We acknowledge the excellent technical assistance of Ruth Johnston. We appreciate the consultation of Drs Kung-Ming Jan and Francis Haddy.
Received September 16, 1998; first decision October 19, 1998; accepted October 30, 1998.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. DeWardener HE. The primary role of the kidney and salt intake in the aetiology of essential hypertension, part I. Clin Sci. 1990;79:193–200.[Medline] [Order article via Infotrieve]
2. DeWardener HE. The primary role of the kidney and salt intake in the aetiology of essential hypertension, part II. Clin Sci. 1990;79:289–297.[Medline] [Order article via Infotrieve]
3.
Simchon S, Manger WM, Blumberg G, Brensilver J,
Cortell S. Impaired renal vasodilation and urinary cGMP excretion in
Dahl salt-sensitive rats. Hypertension. 1996;27:653–657.
4. Roman RJ, Alonso-Galicia M, Wilson TW. Renal P450 metabolites of arachidonic acid and the development of hypertension in Dahl salt-sensitive rats. Am J Hypertens. 1997;10:63S–67S.[Medline] [Order article via Infotrieve]
5. Sustarsic DL, McPharland RP, Rapp JP. Developmental patterns of blood pressure and urinary protein, kallikrein, and prostaglandin E2 in Dahl salt-hypertension-susceptible rats. J Lab Clin Med. 1981;98:599–606.[Medline] [Order article via Infotrieve]
6.
Limas C, Goldman P, Limas CJ, Iwai J. Effect of salt
on prostaglandin metabolism in
hypertension-prone and -resistant Dahl rats.
Hypertension. 1981;3:219–224.
7. Sakamoto T, Chen C, Lokhandwala MF. Lack of renal dopamine production during acute volume expansion in Dahl salt-sensitive rats. Clin Exp Hypertens. 1994;16:197–206.
8. Chen PY, Sanders PW. L-Arginine abrogates salt-sensitive hypertension in Dahl/Rapp rats. J Clin Invest. 1991;88:1559–1567.
9. Deng AY, Rapp JP. Locus for the inducible but not a constitutive nitric oxide synthetase co-segregates with blood pressure in the Dahl salt-sensitive rat. J Clin Invest. 1995;95:2170–2177.
10. Manger WM, Simchon S, Stokes MB, Gallo G. Renal morphology, hemodynamic, and biochemical studies of Dahl salt-sensitive (DS) and salt-resistant (DR) rats. FASEB J.. 1998;12:A42. Abstract.
11. Brenner BM, Garcia DL, Anderson S. Glomeruli and blood pressure: less of one, more the other. Am J Hypertens. 1988;1:335–347.[Medline] [Order article via Infotrieve]
12. Brenner BM, Chertow BM. Congenital oligonephropathy and the etiology of adult hypertension and progressive renal injury. Am J Kidney Dis. 1994;23:171–175.[Medline] [Order article via Infotrieve]
13. MacKenzie HS, Brenner BM. Fewer nephrons at birth: a missing link in the etiology of essential hypertension. Am J Kidney Dis. 1995;26:91–98.[Medline] [Order article via Infotrieve]
14. Roman RJ. Abnormal renal hemodynamics and pressure-natriuresis relationship in Dahl salt-sensitive rats. Am J Physiol. 1986;251:F57–F65.
15.
Roman RJ, Kaldunski ML. Enhanced chloride
reabsorption in the loop of Henle in Dahl salt-sensitive rats.
Hypertension. 1991;17:1018–1024.
16.
Simchon S, Manger WM, Carlin RD, Peeters LL, Rodriguez
JR, Batista D, Brown T, Merchant NB, Jan KM, Brinberg DE, Chien S.
Salt-induced hypertension in Dahl salt-sensitive rats:
hemodynamics and renal responses.
Hypertension. 1989;13:612–621.
17. Sterzel RB, Luft FC, GaoY, Schnermann J, Briggs JP, Ganten D, Waldherr R, Schnabel E, Kriz W. Renal disease and the development of hypertension in salt-sensitive Dahl rats. Kidney Int. 1988;33:1119–1129.[Medline] [Order article via Infotrieve]
18. Simchon S, Manger WM, Brown TW. Dual hemodynamic mechanisms for salt-induced hypertension in salt-sensitive Dahl rats. Hypertension. 1991;17(part 2):1063–1071.
19.
Chen RYZ, Fan F-C, Schuessler GB, Simchon S, Kim S,
Chien S. Regional blood flow and oxygen consumption of the canine brain
during hemorrhagic hypotension. Stroke. 1984;15:343–350.
20.
Simchon S, Jan KM, Chien S. Influence of reduced red
cell deformability on regional blood flow. Am J
Physiol. 1987;253:H898–H903.
21.
Simchon S, Jan KM, Chien S. Studies on the
sequestration of neuraminidase treated red blood cells. Am J
Physiol. 1988;254:H1167–H1171.
22.
Nakamura K, Cowley AW. Sequential changes of
cerebrospinal fluid sodium during the development of hypertension in
Dahl rats. Hypertension. 1989;13:243–249.
23. Kawano Y, Barnes KLZ, Ferrario CM. Pressor effects of centrally administered sodium chloride: role of the ventral third ventricle region and the area postrema. J Auton Nerv Syst. 1991;35:153–160.[Medline] [Order article via Infotrieve]
24.
Nakamura K, Osborn JW Jr, Cowley AW. Pressor
responses to small elevations of cerebrospinal pressure in conscious
rats. Hypertension. 1987;10:635–641.
25. Kawano Y, Ferrario CM. Neurohumoral and characteristics of cardiovascular response due to intraventricular hypertonic NaCl. Am J Physiol. 1984;16:H422–H428.
26. Ikeda T, Tobian L, Iwai J, Goossens P. Central nervous system pressor responses in rats susceptible and resistant to sodium chloride hypertension. Clin Sci Mol Med. 1978;4(suppl):225s–227s.
27. Brody MJ, Fink GD, Buggy J, Haywood JR, Gordon FJ, Johnson AK. The role of anteroventral third ventricle (AV3V) region in experimental hypertension. Circ Res. 1978;43(suppl 1):2–13.
28. Goto A, Ganguli M, Tobian L, Johnson MA, Iwai J. Effect of an anteroventral third ventricle lesion on NaCl hypertension in Dahl salt-sensitive rats. Am J Physiol. 1982;243:H614–H618.
29. Leenen FHH, Harmsen E, Huilian Y. Dietary sodium and central vs peripheral ouabain-like activity in Dahl salt-sensitive vs salt-resistant rats. Am J Physiol. 1994;36:H1916–H1920.
30.
Kurtz TW, Morris RC Jr. Dietary chloride as a
determinant of "sodium-dependent" hypertension. Science. 1983;222:1139–1141.
31.
Whitescarver SA, Holtzclaw BJ, Downs JH, Ott CE, Sowers
JR, Kotchen TA. Effect of dietary chloride on salt-sensitive and
renin-dependent hypertension. Hypertension. 1986;8:56–61.
32.
Miyajima E, Buag RD. Chronic
cerebroventricular infusion of hypertonic sodium chloride
in rats reduces hypothalamic sympatho-inhibition and elevates blood
pressure. Circ Res. 1984;54:566–575.
33.
Buag RD, Miyajima E. Baroreflex impairment
precedes hypertension during chronic cerebroventricular
infusion of hypertonic sodium chloride in rats. J Clin
Invest. 1984;74:2065–2073.
This article has been cited by other articles:
 |
|
 |
|
  M. S. Amin, E. Reza, H. Wang, and F. H.H. Leenen Sodium Transport in the Choroid Plexus and Salt-Sensitive Hypertension Hypertension, October 1, 2009; 54(4): 860 - 867. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. S. Huang, M. Ahmad, A. Y. Deng, and F. H.H. Leenen Neuronal Responsiveness to Central Na+ in 2 Congenic Strains of Dahl Salt-Sensitive Rats Hypertension, June 1, 2007; 49(6): 1315 - 1320. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Amin, H.-W. Wang, E. Reza, S. C. Whitman, B. S. Tuana, and F. H. H. Leenen Distribution of epithelial sodium channels and mineralocorticoid receptors in cardiovascular regulatory centers in rat brain Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2005; 289(6): R1787 - R1797. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. S. Huang, B. N. Van Vliet, and F. H. H. Leenen Increases in CSF [Na+] precede the increases in blood pressure in Dahl S rats and SHR on a high-salt diet Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1160 - H1166. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Wang, R. White, and F. H. H. Leenen Stimulation of brain Na+ channels by FMRFamide in Dahl SS and SR rats Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H2013 - H2018. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Wang and F. H.H. Leenen Brain Sodium Channels Mediate Increases in Brain "Ouabain" and Blood Pressure in Dahl S Rats Hypertension, July 1, 2002; 40(1): 96 - 100. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. S. Huang, H. Wang, and F. H. H. Leenen Enhanced sympathoexcitatory and pressor responses to central Na+ in Dahl salt-sensitive vs. -resistant rats Am J Physiol Heart Circ Physiol, November 1, 2001; 281(5): H1881 - H1889. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. E. De Wardener The Hypothalamus and Hypertension Physiol Rev, October 1, 2001; 81(4): 1599 - 1658. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||