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(Hypertension. 1997;29:1252-1259.)
© 1997 American Heart Association, Inc.
Articles |
Pressure Natriuresis in Salt-Sensitive and Salt-Resistant Sabra Rats
From the Franz Volhard Clinic and the Max Delbrück Center for Molecular Medicine, Virchow Klinikum, Humboldt University, Berlin, Germany, and Barzilai Medical Center, Faculty of Health Sciences, Ben Gurion University, Ashkelon, Israel.
Correspondence to Friedrich C. Luft, Franz Volhard Clinic, Wiltberg Strasse 50, 13122 Berlin, FRG. E-mail fcluft{at}orion.rz.mdc-berlin.de
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Abstract Salt-resistant (SBN/y) and salt-sensitive (SBH/y) Sabra rats are a useful model of salt-sensitive hypertension with incompletely explored renal mechanisms. We investigated their pressure-natriuresis curves, with and without deoxycorticosterone acetate (DOCA)–salt treatment. To differentiate between extrinsic neural and hormonal mechanisms and intrinsic renal influences, we performed experiments with neural denervation, adrenalectomy, and infusions of vasopressin, norepinephrine, 17-hydroxycorticosterone, and aldosterone as well as without these maneuvers. In untreated SBN/y without controlled neural and circulating hormonal factors, urine flow and sodium excretion increased from 32 to 95 µL/min per gram kidney weight (gkwt) and from 4 to 17 µmol/min per gkwt, respectively, as renal perfusion pressure was increased from 85 to 146 mm Hg. Renal blood flow and glomerular filtration rate were autoregulated and averaged 7.5 and 1.2 mL/min per gkwt. In untreated SBN/y with controlled neural and circulating factors, pressure-diuresis and -natriuresis curves were shifted toward the right, and renal blood flow and glomerular filtration rate ranged between 4.2 and 9.1 or 1 and 1.3 mL/min per gkwt as perfusion pressure was increased from 99 to 164 mm Hg. In both protocols, values in SBH/y did not differ. DOCA-salt increased blood pressure in SBH/y. In SBH/y without controlled neural and hormonal factors, pressure-diuresis and -natriuresis curves were shifted approximately 20 mm Hg toward the right. Fractional sodium and water excretion curves, renal blood flow, and glomerular filtration rate were shifted rightward in parallel. On the other hand, SBH/y with DOCA-salt and controlled neural and hormonal factors had lower sodium and water excretion rates only at the renal perfusion pressure of 150 mm Hg as well as decreased renal blood flow and glomerular filtration rate compared with DOCA-salt SBN/y. These data suggest that both extrinsic and intrinsic factors are responsible for reduced sodium and water excretory capacity in DOCA-salt SBH/y; however, the extrinsic factors may be more important.
Key Words: sodium • hypertension, sodium-dependent • natriuresis • rats, Sabra
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Introduction |
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The renal pressure-natriuresis mechanism is abnormal in all forms of chronic hypertension because sodium (chloride) excretion is the same as in normotension despite an increase in BP. A resetting of pressure natriuresis necessitates an increased BP to maintain sodium balance. By analyzing the characteristics of pressure natriuresis in hypertensive animals and by making comparisons with normotensive controls, it is possible to gain insight into BP-elevating mechanisms in experimental animal models. The underlying abnormality in sodium excretion may be either intrinsic or extrinsic to the kidneys.1 2 A parallel, rightward shift of the pressure-natriuresis relationship is characteristic for a non–salt-sensitive (resistant) form of hypertension. A decreased slope in the pressure-natriuresis relationship indicates the presence of a salt-sensitive form of hypertension.3 4 In hypertensive Dahl salt-sensitive rats, blunted pressure-natriuresis relationships exist and are intrinsic to the kidneys themselves.5 6 7 The Sabra rat model of hypertension is a different salt-sensitive model that is greatly augmented by DOCA and salt.8 9 10 11 Since renal sympathetic nerve activity and plasma vasopressin levels are increased in DOCA-salt hypertension,12 13 changes in the neurohormonal regulation of the kidneys could be responsible for an altered pressure-natriuresis relationship in the salt-sensitive strain, rather than a mechanism intrinsic to the kidneys. In the present study, we characterized the pressure-natriuresis relationships of SBN/y and SBH/y with and without DOCA-salt. We performed our studies under conditions in which neural and hormonal influences were controlled by renal denervation, adrenalectomy, and infusions of aldosterone, 17-hydroxycorticosterone, norepinephrine, and vasopressin and also under conditions without these maneuvers. This approach enabled us to differentiate between intrinsic and extrinsic renal mechanisms.
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Methods |
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The rats used in the current study were sub-bred from the original colony and are referred to as SBH/y and SBN/y.8 Experiments were performed in 29 male salt-resistant SBN/y weighing 286±7 g and 25 male salt-sensitive SBH/y weighing 309±7 g. The animals were bred in the animal facility of the Barzilai Medical Center, Ashkelon, Israel. The rats were allowed free access to standard chow (0.3% NaCl, SSNIFF Specialitäten GmbH) and drinking water ad libitum. The experimental protocol was approved by the local council on animal care, which corresponds to the standards of the American Physiological Society.
The rats were prepared as previously described.14 Briefly, they were anesthetized with 35 mg/kg ketamine IM (Parke Davis GmbH) and 65 mg/kg thiobutabarbital IP (Res Biochemical Inc) and placed on a heated table to maintain body temperature at 37°C. A cannula was placed into the trachea to facilitate breathing, and catheters were placed into the carotid and femoral arteries and jugular vein for measurement of systemic BP and compound infusions, respectively. The left ureter was catheterized, and the right kidney and both adrenal glands were surgically removed. Adjustable clamps were placed around the abdominal aorta above and below the kidney, and ligatures were loosely placed around the celiac and mesenteric arteries for later occlusion so that RPP could be varied. During preparation, the rats received an intravenous infusion of a 0.9% NaCl solution containing 1% bovine albumin at a rate of 50 µL/min per 100 g body wt. Thereafter, the infusion rate was reduced to 33 µL/min per 100 g body wt. Inulin (20 mg/mL) (Sigma Chemical Co) and para-aminohippurate (1.2 mg/mL) (Merck Sharp & Dohme) were included in the infusion for measurement of GFR and RPF.
In the experiments of protocols 1 and 2, pressure-diuresis-natriuresis curves were obtained in rats with intact renal denervation and without controlled plasma hormone levels (vasopressin, norepinephrine, aldosterone, 17-hydroxycorticosterone). These rats were also not adrenalectomized. In the experiments of protocols 3 and 4 investigating intrinsic renal functions of Sabra rats, the right and left adrenal glands were acutely surgically removed to prevent changes in the release of adrenal steroids and catecholamines during the experiment. The remaining left kidney was denervated by stripping the visible nerves and swabbing the renal artery and vein with 10% phenol in ethanol to prevent reflex changes in sympathetic tone on kidney function when arterial pressure was changed. In these experiments, the circulating levels of sodium- and water-retaining hormones were also fixed by an infusion of norepinephrine (333 ng/kg per minute), aldosterone (66 ng/kg per minute), 17-hydroxycorticosterone (33 µg/kg per minute), and vasopressin (0.17 ng/kg per minute) (all from Sigma).
Animal Protocols
Protocol 1: Pressure Natriuresis and Diuresis Without
Controlled Neural and Hormonal Factors
Experiments were performed in seven SBN/y weighing 277±11 g and
eight SBH/y weighing 317±15 g. In these rats, the remaining left
kidney was not denervated and the hormone cocktail was not added to the
infusion solution. Otherwise, the rats were surgically prepared as
described above. After surgical preparation and an equilibration period
from 45 to 60 minutes, RPP was lowered to approximately 90 mm Hg
in both groups. After another 20- to 30-minute equilibration period,
urine flow, sodium excretion, GFR, and RBF were determined in two 15-
to 30-minute collection periods depending on the magnitude of the urine
flow. The supra-aortic occluder was then released to increase RPP to
120 mm Hg. After another 30-minute equilibration period, urine
and plasma samples were again collected during two 15-minute periods.
By ligating the mesenteric and celiac arteries and occluding the aorta
below the kidney, RPP increased to about 145 mm Hg. At this
pressure level, urine and plasma samples were collected during two
10-minute collection periods after an equilibration period from at
least 15 minutes.
Protocol 2: Pressure Natriuresis and Diuresis With
DOCA-Salt Treatment and Without Controlled Neural and Hormonal
Factors
Experiments were performed in eight SBN/y weighing 281±11 g and
six SBH/y weighing 299±15 g. A 25-mg DOCA tablet (Innovative Research
of America) was implanted into SBN/y and SBH/y below the skin at the
nape. The animals were provided with 1% NaCl solution to drink. After
3 weeks (20±1 days) of DOCA-salt treatment, the rats were surgically
prepared as described above, and pressure-natriuresis and
-diuresis relationships were determined as in protocol 1. In
DOCA-salt–treated SBN/y, RPP was lowered to approximately 80
mm Hg and thereafter in two steps increased to about 115 and 150
mm Hg. In DOCA-salt–treated SBH/y, RPP could be decreased only to a
level of 100 mm Hg. Thereafter, RPP was raised to about 120 and
150 mm Hg. At each level, two urine and plasma samples were
collected depending on the urine flow over 10 to 30 minutes.
Protocol 3: Pressure Natriuresis and Diuresis With
Controlled Neural and Hormonal Factors
Experiments were performed in six SBN/y weighing 305±21 g and
five SBH/y weighing 324±12 g. After surgical preparation and a 45- to
60-minute equilibration period, RPP was lowered to approximately 90 to
100 mm Hg in both groups. After another 20-minute equilibration
period, urine flow, sodium excretion, GFR, and RBF were determined in
two 15- to 20-minute collection periods. Thereafter, RPP was increased
in three steps to 164 mm Hg in SBN/y. In SBH/y, we were generally
able to increase RPP only to about 135 mm Hg. In two SBH/y (data
not shown), RPP was further increased to about 160 mm Hg. At each
pressure level, urine and plasma samples were collected during two
collection periods.
Protocol 4: Pressure Natriuresis and Diuresis With
DOCA-Salt Treatment and With Controlled Neural and Hormonal
Factors
Experiments were performed in eight SBN/y weighing 283±10 g and
six SBH/y weighing 296±6 g implanted with a 25-mg DOCA tablet and
provided with a 1% NaCl solution to drink. After 3 weeks (22±1 days)
of DOCA-salt treatment, pressure-natriuresis and -diuresis
relationships were determined. The rats were surgically prepared,
underwent renal denervation and adrenalectomy, and were infused with
the hormone mixture described above. In these experiments, RPP was
raised in four steps from 100 to 160 mm Hg. In DOCA-salt–treated
SBH/y, we were able to increase RPP only from 110 mm Hg in two
steps to 150 mm Hg. At each level, two urine and plasma samples
were collected, depending on the urine flow in 10- to 30-minute
periods. In three SBH/y, we succeeded in increasing the RPP to 170
mm Hg; however, these levels were not included in the
analysis.
General Procedures
BP was measured in each group by the tail-cuff method before the
final experiment and additionally in DOCA-salt–treated SBN/y and SBH/y
before DOCA-salt treatment was begun. Mean arterial
pressure was continuously measured throughout the experiment and
recorded on a computer system (TSE GmbH).
Representative mean arterial pressure
values were calculated for each urine collection period by averaging
all recorded values during that period. Urine flow was determined
gravimetrically. Inulin and para-aminohippurate concentrations of urine
and plasma samples were determined according to methods outlined
elsewhere.15 16 Urinary (FLM3, Radiometer) and plasma
(Cobas Mira Plus, Roche) sodium concentrations were determined by flame
photometry. GFR was calculated as the urine-to-plasma inulin
concentration ratio times urine flow. RBF was calculated as Renal
Plasma Flow/(1-Hematocrit). Urine flow, sodium excretion, GFR, and RBF
were normalized per gram kidney wet weight (gkwt). For conventional
morphology, one half of the contralateral right kidneys from SBH/y and
SBN/y without or with DOCA-salt was removed and prepared as described
earlier.17
Statistical Analysis
Data are presented as mean±SEM. Statistical
significance of differences in mean values were tested by two-way ANOVA
for repeated measures and the Duncan multiple range test. A value of
P<.05 was considered statistically significant.
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Results |
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Pressure Natriuresis and Diuresis Without Controlled Neural and Hormonal Factors (Protocols 1 and 2)
The tail-cuff BP measurements were slightly (P<.05) higher in SBH/y than SBN/y, averaging 135±1 and 105±2 mm Hg (protocol 1) or 123±4 and 99±3 mm Hg before the DOCA-salt protocol was started (protocol 2). Whereas in SBH/y BP increased about 40 mm Hg, BP in SBN/y after 3 weeks of DOCA-salt remained constant. Plasma sodium levels in SBN/y and SBH/y did not differ (144 to 146 mmol/L) and were not affected by DOCA-salt, whereas plasma potassium was decreased significantly in both strains with DOCA-salt from about 3.8 mmol/L to 2.3±0.1 in SBH/y and 2.7±0.2 in SBN/y.
Figs 1A
and 2A show
pressure-diuresis and -natriuresis responses of SBN/y and SBH/y
without and with DOCA-salt. In these experiments, the hormone cocktail
was not infused and the kidney was not denervated. Therefore, extrinsic
factors influencing sodium and water reabsorption were not eliminated.
In SBN/y, urine flow and sodium excretion increased from 31.9±7.2 to
95.1±11.7 µL/min per gkwt and from 4.2±1.1 to 16.9±1.7
µmol/min per gkwt, respectively, as RPP was increased from 85 to
146 mm Hg. Urine flow and sodium excretion of SBH/y at a similar
RPP of 87 mm Hg were slightly lower than in SBN/y. However, at
RPP levels of 118 and 144 mm Hg, these differences were no longer
discernible. In SBN/y given DOCA-salt for 3 weeks, increasing RPP from
81 to 149 mm Hg led to a similar increase in urine flow and
sodium excretion compared with untreated SBH/y or SBN/y.
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The pressure-diuresis-natriuresis relationship in DOCA-salt SBH/y was shifted to a higher range of RPP. Starting with a urine flow of 4.8±0.7 µL/min per gkwt and sodium excretion of 0.2±0.1 µmol/min per gkwt at an RPP of 98 mm Hg, increasing RPP to 147 mm Hg was followed by an increase of urine flow and sodium excretion to 51.8±6.0 µL/min per gkwt and 10.1±1.6 µmol/min per gkwt, respectively. In comparison, urine flow and sodium excretion of DOCA-salt SBN/y leveled at this RPP to 97.9±8.5 µL/min per gkwt and 20.0±1.6 µmol/min per gkwt, respectively.
RBF (Fig 3A) averaged 5.5±0.3 and 4.9±0.7 mL/min per
gkwt in SBN/y and SBH/y at the RPP level of 85 mm Hg; RBF
increased significantly to approximately 7.4 and 9.4 mL/min per gkwt as
RPP was raised to 120 mm Hg and remained unchanged thereafter.
The RBF response in DOCA-salt–treated SBN/y was similar. The RBF curve
of DOCA-salt SBH/y was shifted rightward. In these rats, increasing RPP
from 100 to 120 mm Hg was followed by a significant increase in
RBF from 4.3±0.5 to 6.9±0.5 mL/min per gkwt and remained stable
thereafter. The corresponding GFR responses for these rats over the
range of pressures studied are shown in Fig 4A. In SBN/y
and SBH/y, with and without DOCA-salt, GFR was well autoregulated over
120 mm Hg and was lower at all RPP levels in DOCA-salt SBH/y than
in the other groups.
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Fractional water and sodium excretion curves are shown in Figs 5A and 6A. As with volume and sodium
excretion, these parameters were not different between
SBN/y and SBH/y without DOCA-salt and were shifted toward the right in
SBH/y after DOCA-salt over the range of RPP studied. Filtration
fractions of SBN/y and SBH/y without DOCA-salt ranged between 15% and
18%. Although the filtration fractions of SBN/y with DOCA-salt were in
the same range, the filtration fractions of SBH/y with DOCA-salt
ranged between 10% and 14%. All rats were well hydrated, as
determined from hematocrit levels (range, 0.44±0.1 to 0.40±0.1).
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Pressure Natriuresis and Diuresis With Controlled Neural
and Hormonal Factors (Protocols 3 and 4)
Arterial pressure (tail-cuff method) was
slightly (P<.05) higher in SBH/y than SBN/y, averaging
121±2 and 105±2 (protocol 3) or 118±4 and 105±2 (protocol
4) mm Hg, respectively. SBH/y increased their BP to 180±11
mm Hg after 3 weeks of DOCA-salt treatment, whereas in SBN/y, BP
remained unchanged (protocol 4). Plasma sodium concentrations increased
slightly from 141±1 to 145±1 mmol/L with DOCA-salt in SBH/y
(P<.05), whereas plasma potassium values decreased in both
rat strains from 4±0.1 to 2.6±0.2 mmol (P<.05).
Figs 1B
and 2B show the pressure-diuresis and
-natriuresis responses of SBN/y and SBH/y with controlled neural and
hormonal factors and with and without DOCA-salt. In control SBN/y,
urine flow and sodium excretion increased from 6.8±0.9 to 87.4±11.4
µL/min per gkwt and from 0.8±0.3 to 17.1±1.7 µmol/min per
gkwt, respectively, as RPP was increased from 99 to 164 mm Hg. As
RPP was increased in SBH/y from 90 to 135 mm Hg, urine flow and
sodium excretion were not different from values in SBN/y. When sodium
and water excretions were expressed as fractional excretion (Figs 5B and 6B), the responses of the two groups remained similar. DOCA-salt
treatment did not change the pressure-diuresis and -natriuresis
curves in SBN/y. At an RPP of 98 mm Hg, urine flow and sodium
excretion averaged 6.5±1.2 µL/min per gkwt and 0.7±0.2
µmol/min per gkwt and increased 15- and 23-fold, respectively, when
RPP was increased to 164 mm Hg. With DOCA-salt treatment, the
sodium and water excretions of SBH/y were not different from those in
SBN/y at a BP range between 109 to 131 mm Hg. As RPP was
increased further to 152 mm Hg, a decrease in the slope of the
pressure-diuresis and -natriuresis relationship was apparent so
that urine flow and sodium excretion at the given RPP level of 152
mm Hg averaged 49.9±3 µL/min per gkwt and 14.0±0.6 µmol/min
per gkwt, respectively, and were significantly lower than the
corresponding SBN/y values.
Figs 3B and 4B show the effects of changing RPP on RBF and GFR,
respectively. RBF increased from 4.2±0.5 to 9.1±1.1 mL/min per gkwt
in untreated SBN/y and from 4.8±0.2 to 8.5±0.9 in corresponding
SBH/y, respectively, as RPP was increased. DOCA-salt induced an RBF
decrease in both strains so that over the RPP range investigated, RBF
averaged between 2.7±0.1 and 5.6±0.5 mL/min per gkwt in SBN/y and
between 2.6±0.2 and 4.3±0.4 in SBH/y. DOCA-salt–treated SBH/y had a
significantly lower RBF at an RPP of 150 mm Hg than SBN/y. GFR
increased from 0.9±0.1 to 1.3±0.1 mL/min per gkwt in SBN/y as RPP was
increased from 99 to 123 mm Hg and was well autoregulated
thereafter. GFR of the corresponding control SBH/y group was not
significantly different. DOCA-salt resulted in a stronger GFR decrease
in SBH/y than in SBN/y and leveled between 0.7±0.1 and 1.0±0.1 mL/min
per gkwt.
Hematocrit values of all groups ranged between 0.36±0.01 and 0.40±0.1, indicating a good state of hydration. By light microscopy, the kidneys from SBH/y and SBN/y, with or without DOCA-salt, were normal and morphologically indistinguishable. We saw no chronic changes caused by disease in either the vessels, glomeruli, tubules, or interstitium (data not shown).
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The important findings in this study are that DOCA-salt altered the SBH/y pressure-diuresis-natriuresis relationship in that the slope of the relationship was flatter than that in SBN/y. This change is consistent with the salt sensitivity exhibited by these rats. Furthermore, since the pressure-diuresis-natriuresis relationship was more strongly affected under circumstances in which neural and circulating hormonal factors to the kidney were not controlled, we believe that external factors regulating renal sodium and water excretion are more important than intrinsic renal features for sodium and water reabsorption in hypertensive SBH/y.
SBH/y generally have only slightly but significantly higher resting BPs than SBN/y under conditions of usual salt intake.10 11 18 19 After DOCA-salt, arterial pressure increased by about 60 mm Hg in SBH/y, whereas in SBN/y it remained unchanged. We found that with and without neural and hormonal control, the pressure-diuresis-natriuresis relationships of SBH/y and SBN/y were not different before DOCA-salt administration. Therefore, we did not find evidence that sodium and water excretion of SBH/y is reduced before the onset of hypertension and that this difference disappears after DOCA-salt treatment.10 11 Our studies were done in anesthetized, hydrated, male SBN/y and SBH/y, which were developed as substrains with high genetic homogeneity of the original Sabra rat colony.8 The prehypertensive difference in sodium and water handling between conscious SBH and SBN in earlier studies may be related to some genetic differences from the original colony used in earlier studies as well as to different experimental conditions.10 11 Finally, it would be puzzling if increases in pressure, as found in DOCA-salt–treated SBH/y, were not manifested in terms of an altered pressure natriuresis.
With DOCA-salt, hypertensive SBH/y exhibited a decrease in the slope of the pressure-diuresis-natriuresis curves independent of external renal sodium excretory regulators. Furthermore, in kidneys without controlled neural and hormonal factors, the pressure-diuresis-natriuresis curves were shifted toward the right. A decrease in the slope of the pressure-natriuresis-diuresis curves is also described for the Dahl salt-sensitive rat5 6 7 and is generally accepted as a characteristic sign of salt sensitivity.3 4 In contrast to the Dahl salt-sensitive rats, in which both prehypertensive and hypertensive Dahl rats exhibit a blunted pressure-natriuresis relationship,5 6 7 we observed a disturbed relationship only after DOCA-salt administration. Since histologically SBH/y and SBN/y were indistinguishable both before and after DOCA-salt, structural differences do not appear to be responsible.
The fact that overt hypertension occurred after DOCA-salt administration suggests that the extrinsically and intrinsically altered renal salt and water excretion requires the DOCA-salt hypertensive stimulus to be functionally important. Thus, it appears that the decreased slopes of the pressure-diuresis-natriuresis relationships of SBH/y are more a factor maintaining the hypertension rather than an induction mechanism. An interesting notion is that the SBH/y possibly represents the "usual" response of rats to DOCA-salt, since in other DOCA-salt hypertensive rats, the arterial pressure–urinary output relationship is also shifted to higher BP ranges.20
Without controlling differences in the neural and hormonal factors to the kidney, DOCA-salt reduced RBF and GFR in SBH/y and shifted curves of fractional sodium and water reabsorption rightward. In denervated, hormonally controlled kidneys, DOCA-salt loading decreased RBF and GFR in both SBH/y and SBN/y and had no influence on fractional sodium and water reabsorption. This result is in agreement with earlier studies which showed that in DOCA-salt hypertensive rats, RBF and GFR were decreased.21 22 In animals with DOCA-salt hypertension, elevations in sympathetic nerve activity13 and increased vasopressin levels12 have been observed.
DOCA-salt induces a smaller increase in BP in female than male rats, which has been attributed to sex differences in the balance between vasopressin-induced vasoconstriction and vasodilator prostanoid release.23 In SBH, a decreased biosynthesis of vasodilator prostaglandins has been described compared with SBN.18 The decrease in renal prostaglandins plays a role in blunting the pressure natriuresis in Dahl salt-sensitive rats.24 Since prostaglandins are humoral mediators of pressure natriuresis and since an intact renal prostaglandin system is necessary for the full expression of natriuretic responses to increases in RPP,25 26 altered prostaglandin effects could have also augmented renal sodium and water reabsorption in SBH/y and may have shifted sodium and water excretion curves rightward. Moreover, bradykinin effects are decreased in DOCA-salt hypertension.27 Bradykinin is a vasodilator and increases RBF as well as salt and water excretion. Possibly, diminished activity of the kallikrein-kinin system was responsible for increasing BP and shifting pressure-natriuresis curves in SBH/y. Interestingly, kininogen-deficient rats react with a more rapid BP increase in response to DOCA-salt than normal rats.28 29
Clamping neural and hormonal factors shifted the pressure-diuresis-natriuresis curves of SBN/y rightward, compared with the curves of unclamped rats, but did not affect the slopes of the curves. The corresponding curves of SBH/y, on the other hand, were almost not affected. The reason for this difference is unknown. To our knowledge, this experiment is the first in which pressure-diuresis-natriuresis curves were determined with and without controlled neural and hormonal influences. In our study, extrinsic factors facilitating sodium excretion were more important in determining the position of the pressure-diuresis-natriuresis curves in SBN/y than SBH/y. In contrast, the decreased slopes of pressure-diuresis-natriuresis curves of hypertensive DOCA-salt SBH/y compared with DOCA-salt SBN/y that had their kidneys neurally and hormonally clamped cannot be attributed to increases in sympathetic nerve activity or vasopressin levels. Contrary to the experiments without this procedure, DOCA-salt reduced RBF and GFR in both SBN/y and SBH/y. DOCA-salt reduced plasma potassium concentrations in both SBN/y and SBH/y. Potassium depletion can lead to an increase in renal vascular resistance and can decrease RBF and GFR.30 31 Potassium depletion may have caused or contributed to the decrease in RBF and GFR we observed in both rat groups with DOCA-salt. Other factors are by no means excluded. For instance, DOCA-salt administration may also affect vascular reactivity by changing membrane permeability and transmembrane electrolyte flux.32 33
Hypokalemia also has an influence on sodium excretion and BP increases in response to salt loads. Potassium supplementation attenuated the increase in BP and facilitated sodium excretion in rats given DOCA-salt in an earlier study.34 Nevertheless, in SBH/y, potassium supplementation did not prevent the DOCA-salt–induced BP increase.19 We conclude that under conditions of controlled neural and hormonal input to the kidney, an impaired RBF and GFR regulation is responsible for the decreased sodium and water excretion at higher RPP levels in SBH/y compared with SBN/y. Supporting this conclusion is the fact that fractional sodium and water excretion were not different between the groups. This functional alteration is localized within the kidneys of SBH/y themselves and may be induced by DOCA-salt or DOCA-salt–dependent changes, such as hypokalemia.
In conclusion, we report results indicating that with and without controlled neural and hormonal influences, the natriuretic responses of normotensive SBN/y and SBH/y were not different. With the advent of DOCA-salt loading, SBH/y became progressively hypertensive in contrast to SBN/y. The hypertension was associated with a decrease in salt and water excretion at higher RPP values in neurally and hormonally controlled kidneys compared with the normotensive DOCA-salt SBN/y. In SBH/y without these maneuvers, we observed a rightward shift of 20 mm Hg of pressure-natriuresis-diuresis curves in SBH/y compared with SBN/y. Thus, both extrinsic and intrinsic influences on sodium and water renal excretory capacities are reduced in SBH/y. Factors extrinsic to the kidneys, apart from those we were able to control in this study, may be more important than intrinsic renal factors.
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Acknowledgments |
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This study was supported by a grant-in-aid from the Deutsche Forschungsgemeinschaft to Volkmar Gross. We are grateful to Regina Uhlmann, Edith Richter, and Christel Lipka for technical assistance.
Received September 20, 1996; first decision October 14, 1996; accepted November 19, 1996.
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