(Hypertension. 1997;30:682.)
© 1997 American Heart Association, Inc.
Articles |
Role of Endothelin in Mediating the Attenuated Renal Hemodynamics in Dahl Salt-Sensitive Hypertension
From the Department of Physiology and Biophysics, University of Mississippi Medical Center (Jackson).
Correspondence to Joey P. Granger, PhD, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 N State St, Jackson, MS 39216-4505. E-mail JPG{at}fiona.umsmed.edu
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Abstract |
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Abstract The aim of this study was to evaluate the role of endothelin (ET) in the hypertension associated with giving a high sodium diet in Dahl salt-sensitive (DS) rats. To achieve this goal, we examined the effects of intravenous infusion of the nonspecific ETA-ETB antagonist on arterial pressure and renal function in conscious, chronically instrumented DS and Dahl salt-resistant (DR) rats. After 3 weeks on a high sodium (8%) diet, mean arterial pressure (MAP) in DS rats (166±3 mm Hg) was significantly higher than in DR rats (124±3 mm Hg). Baseline glomerular filtration rate (GFR) and renal plasma flow (RPF) in DS rats (1.92±0.25 mL/min and 7.07±0.80 mL/min) were lower than in DR rats (2.52±0.21 mL/min and 7.98±0.85 mL/min), respectively. Renal vascular resistance was significantly higher in DS rats (32.78±5.88 mm Hg · mL-1 · min-1) than in DR rats (24.60±5.04 mm Hg · mL-1 · min-1). Intravenous infusion of the ET antagonist SB 209670 at a dose of 30 µg · kg-1 · min-1 for 75 minutes caused a significant decrease in MAP in DS rats (from 166±3 to 144±4 mm Hg). In contrast, the effect of the ET antagonism on MAP in DR rats was not significant. ET-antagonist infusion tended to improve GFR and RPF in DS but not in DR rats. To determine the renal effects of ET antagonism independent of the systemic hemodynamic responses, we examined the effects of the same ET antagonist in rats chronically implanted with a renal interstitial catheter. Arterial pressure in DS rats (181±5 mm Hg) was significantly higher than in DR rats (135±3 mm Hg). Renal interstitial infusion of SB 209670 at a dose of 200 ng · kg-1 · min-1 for 60 minutes caused no change in MAP in DS or DR rats. Intrarenal ET antagonism significantly increased GFR (25%), RPF (30%), urine flow (32%), and urinary sodium excretion (25%) in DS rats, while it had no significant effect in DR rats. Fractional excretion of sodium was not significantly changed by renal interstitial infusion of the ET antagonist in DS rats, indicating that improved renal excretory function in DS rats is most likely due to the associated improvement in renal hemodynamics. We conclude that ET may play a role in the attenuated renal hemodynamics and possibly the development of Dahl salt-sensitive hypertension.
Key Words: endothelins • kidney • rats, Dahl • sodium
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Dahl salt-sensitive rats challenged with a high salt diet develop progressive and severe hypertension. Several lines of evidence support an important role for the kidneys in the pathogenesis and maintenance of hypertension in the DS rat.1 2 3 The severe hypertension in DS rats leads to target organ damage in the kidneys in the form of renal arteriolar and tubular injury and glomerulosclerosis and renal insufficiency.2 4 5 Although the exact mechanism responsible for the progressive deterioration in renal function in DS hypertensive rats is still unclear, it has been proposed that alterations in vascular endothelial function may be involved.6
ET-1 has been implicated in hypertension through its potent vasoconstrictor effects and by causing vascular smooth muscle hypertrophy and hyperplasia.7 Renal effects of ET-1 include a dose-dependent decrease in GFR and RPF mostly through stimulation of vascular smooth muscle and mesangial cell contraction.8 9 The renal endothelin system has been also shown to mediate renal injury in experimental models of progressive renal disease.10 The role of ET in DS hypertension is supported by previous studies demonstrating that isolated glomeruli obtained from prehypertensive DS rats exhibit an increased ouabain-induced production of ir-ET as well as an exaggerated responsiveness to ET-1 compared with DR rats.11 Uehara et al12 have also demonstrated a positive correlation between renal ET-1 production and the extent of renal injury in DS rats. Although these results indicate that ET may be involved in Dahl salt-sensitive hypertension, the importance of ET in mediating the renal hemodynamic alterations associated with this model of hypertension is unclear. Therefore, the aim of this study was to evaluate the role of ET in mediating the attenuated renal hemodynamics and hypertension in DS rats. To achieve this goal, we first investigated the effects of intravenous infusion of the nonspecific ET antagonist SB 209670 on arterial pressure and renal hemodynamic and excretory function in DS and DR rats placed on a high salt diet (8% NaCl) for 3 weeks. To further demonstrate the role of ET in the kidneys of hypertensive DS rats independent of the systemic hemodynamic effects of the ET antagonist, we examined the effects of renal interstitial infusion of SB 209670 on renal hemodynamic and excretory functions in DS and DR rats placed on a high salt (8% NaCl) diet for 3 weeks.
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Methods |
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Experiments were performed on DS and DR inbred male rats of the Rapp strain (Harlan Sprague-Dawley, Indianapolis, Ind). All rats were placed on a high sodium chow (8% NaCl; ICN) for 3 weeks with free access to tap water. Surgeries were conducted with rats under anesthesia with sodium pentobarbital (40 mg/kg, IP); experimental procedures were executed in accordance with National Institutes of Health guidelines for use and care of animals, and the protocols were approved by the Animal Care and Use Committee at the University of Mississippi Medical Center.
All experiments were performed in rats that were chronically instrumented with catheters (PE-50) in the left femoral artery and right femoral vein for blood pressure monitoring, blood sampling, and infusions. During the same surgical session, a midline lower abdominal incision was made and the bladder was cannulated with flare-tipped PE-90 tubing for urine collection. All catheters were tunneled to the back of the neck and exteriorized, and animals were allowed to recover for at least 2 days before renal function measurements.
Intravenous Infusion Protocol in DS and DR
Rats
At the time of the experiment, DS (n=9) and DR (n=9) rats in the
conscious state with average weights of 280 g were placed in
individual restraining cages and prepared for intravenous
ET-antagonist infusion and renal function studies. The
femoral vein catheter was connected to an infusion pump that delivered
isotonic saline containing [125I]iothalamate (Isotex
Diagnostics; 0.05 µCi ·
kg-1 · min-1)
and [131I]iodohippurate (Syncor International Corp; 0.1
µCi · kg-1 ·
min-1) at a fixed rate of 3 mL ·
h-1. Arterial pressure was
monitored with a pressure transducer, and the data were displayed on a
chart recorder for continuous recording of
arterial pressure. After a 60-minute stabilization period,
two 15-minute control clearances and steady-state arterial
pressure measurements were obtained. At the end of each clearance
period, urine was collected and a blood sample was obtained.
Arterial pressure during each clearance period was the
average recording of four readings obtained at 0, 5, 10, and 15
minutes. After the control period, the rats were then infused
intravenously with the nonspecific
ETA-ETB antagonist SB 209670 at
dose of 30 µg · kg-1 ·
min-1 for 75 minutes. This dose has been
previously reported to be effective in blocking the effects of
exogenous ET and in reducing MAP in some hypertensive rat
models13 and reversing ischemia-induced acute
renal failure in rats.14 The ET antagonist was
diluted in saline and administered by intravenous infusion
at a rate of 3 mL · h-1. Forty-five
minutes after infusing the ET antagonist, two 15-minute
experimental clearances were obtained.
Renal Interstitial Infusion Protocol in DS and DR
Rats
In another group of DS (n=6) and DR (n=5) rats with an average
body weight of 305 g, the ET antagonist was infused
through a renal interstitial catheter that was surgically
implanted approximately 3 weeks before the experiment. The design and
surgical implantation of the renal interstitial catheter
have been previously described in detail.15 16 Briefly, a
hole was drilled into one end of a polyethylene matrix capsule, and
PE-50 tubing was inserted into the hole and fixed in place with a
combination of cement and Silastic glue. Rats were
anesthetized, the right kidney was surgically removed, and a
stainless steel wire was used to guide the PE-50 catheter into the
parenchyma of the left renal cortex. To reinforce surgical healing and
minimize leaking of catheter, the interstitial catheter was
anchored in place by a mersilene mesh (Ethicon) sutured to the renal
capsule. The catheter was then flushed with saline, sealed with a knot,
coiled, and placed in the abdominal cavity of the rat. Rats were then
left to recover and were placed on a high salt (8% NaCl) diet for 3
weeks. Two days before experimentation, rats were anesthetized
again and surgically instrumented with catheters in the femoral vessels
and urinary bladder; they were allowed to recover and in the conscious
state were prepared for clearance studies as described earlier in the
intravenous infusion protocol. The femoral vein catheter
was connected to an infusion pump that delivers isotonic saline
containing 125I and 131I at a rate of 3
mL · h-1, the renal interstitial
catheter was connected to an infusion pump that delivers isotonic
saline at a rate of 10 µL · min-1 and the
femoral artery catheter was connected to a pressure transducer to
monitor arterial pressure. We have previously reported that
saline infusion in the renal cortex at a rate of 10 µL ·
h-1 does not affect renal blood flow or renal
interstitial hydrostatic pressure.17 After a
60-minute period of equilibration and stable arterial
pressure recording, two control clearances of 15 minutes each
were obtained as described above. The ETA-ETB
antagonist SB 209670 was then infused into the renal
interstitium to deliver a dose of 200 ng ·
kg-1 · min-1
for 60 minutes. Thirty minutes after infusion of the
antagonist, two 15-minute experimental clearances were
obtained. The dose of ET antagonist was chosen to minimize
spillover into the systemic circulation. Preliminary studies
indicated that higher doses resulted in spillover into the systemic
circulation and led to significant decreases in blood pressure in DS
rats.
Materials
The antagonist (±) SB 209670
[(1RS-2SR,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic
acid] was synthesized at SmithKline Beecham Pharmaceuticals.
Analytical Procedures
Urine volume was determined gravimetrically. Sodium and
potassium concentrations in urine and plasma were measured by flame
photometry (IL-943, Instrumentation Laboratory). These measurements
allowed the calculation of UNaV, UKV,
UV, fFENa, and FEK. GFR and RPF
were calculated from concentrations of 125I and
131I in plasma and urine. Data representing the
control or experimental period are the average of two consequent
clearances. All data in the study are expressed as mean±SE.
Statistical significance within each group was determined with the
paired Student’s t test. Statistical significance between
groups was determined by using an unpaired t test. A value
of P<.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Intravenous Infusion Protocol in DS and DR Rats
After 3 weeks of an 8% sodium diet, MAP in DS rats (166±3 mm Hg) was significantly (P<.05) higher than in DR rats (124±3 mm Hg). GFR and RPF were lower and renal vascular resistance was significantly higher (P<.05) in DS rats than in DR rats. Intravenous infusion of the nonspecific ETA-ETB antagonist (SB 209670) at a dose of 30 µg · kg-1 · min-1 for 75 minutes significantly decreased arterial pressure in DS rats (from 166±3 to 144±4 mm Hg; P<.05) while having no significant effect in DR rats (Fig 1). As illustrated in Fig 2, intravenous infusion of the ET antagonist tended to increase GFR (from 1.92±0.25 to 2.09±0.34 mL/min) and RPF (from 7.07±0.80 to 7.27±1.24 mL/min) in DS rats. The ET antagonist tended to decrease GFR (from 2.52±0.21 to 2.22±0.22 mL/min) and RPF (from 7.98±0.85 to 6.0±0.71 mL/min) in DR rats. Renal vascular resistance tended to decrease in DS rats (32.78±5.88 to 28.1±6.3 mm Hg · mL-1 · min-1) as well as in DR rats (24.60±5.04 to 23.20±3.40 mm Hg · mL-1 · min-1). However, the renal hemodynamic responses to intravenous infusion of the ET antagonist in DS and DR did not achieve statistical significance. Fig 3 illustrates percent changes in renal excretory function in DS and DR rats in response to ET-antagonist infusion. Intravenous infusion of the ET antagonist in DS rats caused significant decreases in UNaV by 46.5% (8.51±0.87 to 3.98±0.10 mmol/min, P<.01), UV by 48.6% (30.52±4.05 to 13.2±2.2 µL/min, P<.01), and FENa by 61.6% (4.13±0.80 to 1.1±0.25%, P<.01). However, the renal excretory responses to intravenous infusion of the ET antagonist in DR rats were not statistically significant.
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Renal Interstitial Infusion Protocol in DS and DR
Rats
Arterial pressure in DS rats (181±5 mm Hg) was
significantly higher (P<.01) than in DR rats (135±3
mm Hg). Baseline GFR and RPF in DS rats were significantly lower
(P<.05) than in DR rats, and renal vascular resistance in
DS rats was markedly higher (P<.01) than in DR rats. Renal
interstitial infusion of the ET antagonist at a
dose of 200 ng · kg-1 ·
min-1 had no effect on MAP in DS or DR rats
(Fig 4). Renal interstitial
infusion of the ET antagonist significantly increased GFR
by 25% (1.37±0.18 to 1.72±0.13 mL/min, P<.05) and RPF by
30% (3.88±0.49 to 5.09±0.40 mL/min, P<.05) in DS rats.
Although renal interstitial ET antagonism tended to
increase GFR and RPF in DR rats as well, these changes were not
significant and were significantly smaller than the changes observed in
DS rats (Fig 5). In contrast to the renal
excretory responses to intravenous infusion, renal
interstitial infusion of the ET antagonist
significantly increased UNaV by 25% (from 5.80±0.91 to
7.26±1.21 mmol/min, P<.05) and UV
by 32% (from 29.20±4.35 to 38.54±5.63 µL/min, P<.05)
in DS rats while having no significant effect on renal excretory
function in DR rats (Fig 6). Renal
interstitial infusion of the ET antagonist did
not cause significant changes in FENa in DS rats
(3.11±0.51 to 3.20±0.56%) or in DR rats (3.91±0.63 to
3.70±0.86%), indicating that improved renal excretory functions in DS
rats in response to renal interstitial infusion of the ET
antagonist are most likely due to the associated increases
in renal hemodynamics.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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When DS rats are placed on a high salt diet, they develop malignant hypertension, vascular hypertrophy, extensive renal damage, and renal insufficiency.2 3 5 Results from recent studies indicate that ET-1 plays an important role in experimental animals with severe hypertension and small-artery hypertrophy such as DOCA-salt hypertensive rats, malignant DOCA-salt-SHR, one-kidney, one-clip hypertensive rats, and stroke-prone SHR.18 Furthermore, there is experimental evidence implicating ET in animal models of progressive renal failure. Pre-pro ET-1 gene expression19 and urinary excretion of ET20 have been shown to increase in a time-dependent fashion and to parallel the severity of proteinuria and hypertension following 5/6 nephrectomy in rats. Benigni et al21 also reported that chronic treatment with the ETA receptor antagonist FR 139137 significantly ameliorated the reduction in kidney function and attenuated the increase in blood pressure in rats with renal mass reduction.
Although the roles of ET in mediating the renal and cardiovascular changes in various experimental and genetic models of hypertension have been examined, the role of ET-1 in mediating the reduction in kidney function in Dahl salt-sensitive hypertension has not yet been fully elucidated. The main findings of this study were that acute ET antagonism by the intravenous infusion of the nonspecific ET antagonist SB 209670 was associated with a significant reduction in arterial pressure in DS rats and tendency to improve renal hemodynamics in DS but not in DR rats. More importantly, blocking the ET system within the kidneys significantly increased GFR and RPF and increased sodium and water excretion in DS rats while having no effect in DR rats.
The decrease in blood pressure observed after intravenous infusion of the ET antagonist SB 209670 in DS rats suggests that ET could be playing a role in the blood pressure elevation in this model. These observations are in agreement with a recently published study showing that an intravenous bolus injection of the ET antagonist bosentan decreased arterial pressure in DS but not DR rats.22 In addition, intravenous infusion of the ET antagonist SB 209670 for 2 hours produced a significant reduction in MAP in SHR, a response that was mostly due to systemic vasodilation.13 Whether the acute decrease in MAP in response to short-term ET receptor blockade can be sustained in DS rats during chronic administration is unknown. If the potent renal hemodynamic and natriuretic effects of the ET antagonist observed in this study are sustained over the long term in DS rats, theoretically, it should improve pressure-natriuresis and lead to a chronic reduction in arterial pressure. Ongoing studies in our laboratory are being conducted to assess the long-term role of ET-1 during the development of hypertension in DS rats and the possible underlying renal mechanisms.
In agreement with previous studies,2 3 our data indicate that baseline measurements of GFR and RPF were lower and renal vascular resistance was higher in DS compared with DR rats fed a high sodium diet. Although several factors may account for the abnormal renal function in salt-sensitive hypertension, results from previous investigations suggest that ET may be involved in mediating the reduction in renal hemodynamic function in the DS rats. The renal vasculature is known to be extremely sensitive to the vasoconstrictor effects of ET-1 because of the abundance of ET receptors in renal blood vessels.23 Recent studies indicate that in the rat, this effect appears to be mediated through both ETA and ETB receptors.24 The improvement in kidney function after the renal ET system is blocked in our study suggests that ET may be playing an important role in mediating the reduction in renal hemodynamics in DS rats fed a high salt diet for 3 weeks. Whether increased renal production of ET or increased receptor density or affinity account for the enhanced role of ET in DS rats is unknown. However, a recent study has demonstrated a positive correlation between renal ET-1 production and the extent of renal injury in DS rats.5 Furthermore, isolated glomeruli obtained from prehypertensive DS rats exhibit an increased ouabain-induced production of ir-ET as well as an exaggerated responsiveness to ET-1 compared with DR rats, a response that was associated with increased intracellular calcium.11 Thus, there are several lines of experimental evidence indicating that renal ET production may be elevated in the DS rat. Although increased receptor density and affinity in the renal cortex has been reported in the SHR,23 the importance of altered receptor density and affinity in the DS rat model of hypertension still remains unclear.
Several lines of evidence support an important role for the kidneys in the pathogenesis and maintenance of hypertension in the DS rat.1 2 3 A common finding in DS rats is a hypertensive shift in the pressure-natriuresis relationship, indicating that the kidneys of DS rats have a reduced capability to excrete sodium and water.3 The altered pressure-natriuresis relationship exists in the prehypertensive DS rat and becomes progressively worse the longer the DS rats are exposed to a high sodium diet.2 3 Thus, it is likely that during the various stages of hypertension (prehypertensive to malignant), different factors may be involved in mediating the reduction in renal sodium excretory function. In the present study, we found that intrarenal blockade of ETA/ETB receptors significantly improves renal excretion of sodium and water in DS but not in DR rats. Our data suggest that ET may, in part, mediate the reduction in sodium excretory function in DS rats fed a high sodium diet for 3 weeks. Whether ET plays a role in mediating the altered pressure-natriuresis in the prehypertensive or early phases of salt-sensitive hypertension remains to be determined.
In summary, we found that DS rats fed a high sodium diet for 3 weeks had significantly higher arterial pressures and renal vascular resistance and lower RPFs and GFRs than DR rats. Intravenous infusion of the nonspecific ETA-ETB antagonist SB 209670 resulted in a significant decrease in arterial pressure in DS but not in DR rats. Intravenous administration of the ET antagonist had no significant effect on renal hemodynamics and decreased sodium excretory function, possibly as a result of the decrease in renal perfusion pressure. In contrast, intrarenal ET receptor blockade, via renal interstitial infusion of the ET antagonist, significantly improved RPF, GFR, and urinary excretion of sodium and water in DS rats while having no significant effects in DR rats. These data indicate that ET may play an important role in the attenuated renal hemodynamics and altered pressure-natriuresis in DS hypertensive rats.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by National Institutes of Health grants HL38499 and HL51971. We thank Gerry McAlpin for excellent secretarial assistance. The authors thank Dr David P. Brooks from SmithKline Beecham Pharmaceuticals for kindly supplying the ET antagonist (SB 209670).
Received March 17, 1997; first decision April 28, 1997; accepted April 28, 1997.
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References |
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