(Hypertension. 1995;25:1232-1237.)
© 1995 American Heart Association, Inc.
Articles |
Modulation of Tubuloglomerular Feedback by Angiotensin II Type 1 Receptors During the Development of Goldblatt Hypertension
From the Department Nephrology and Hypertension, University Hospital Utrecht, Netherlands (B.B.), and the Department of Physiology, Tulane University School of Medicine, New Orleans, La.
Correspondence to K.D. Mitchell, PhD, Department of Physiology, SL 39, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA 70112.
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Abstract |
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Abstract It has been suggested that the increased levels of angiotensin II (Ang II) in the contralateral kidney of two-kidney, one clip (2K1C) Goldblatt hypertensive rats act to enhance tubuloglomerular feedback responsiveness and proximal tubular reabsorption and thereby exert a substantial sodium-retaining influence on the nonclipped kidney. The current study investigated the Ang II dependency of tubuloglomerular feedback responsiveness in the nonclipped kidney during the early stages of development of 2K1C hypertension. Stop-flow pressure feedback responses were assessed in the nonclipped kidney of 2K1C rats during control conditions and after systemic administration of the Ang II type 1 receptor antagonist losartan (10 mg/kg). In 1-week clipped and sham-operated rats, losartan administration decreased mean arterial pressure (from 143±6 to 123±2 mm Hg, P<.01, and from 129±2 to 106±5 mm Hg, P<.01, respectively) and attenuated the magnitude of the maximal feedback responses (from -12.9±1.2 to -3.0±0.3 mm Hg, P<.01, and from -13.2±1.5 to -3.6±1.1 mm Hg, P<.01, respectively). The decreases in mean arterial pressure were not significantly different in sham-operated and 1-week clipped rats. In 3-week clipped rats, mean arterial pressure was further elevated (163±6 mm Hg) compared with sham-operated rats (134±4 mm Hg, P<.01). Although maximal tubuloglomerular feedback responses were similar in 3-week clipped and sham-operated rats, the late proximal perfusion rate eliciting a half-maximal response averaged 13±2 nL/min in the 3-week clipped and 18±1 nL/min in the sham-operated rats (P<.05), indicating enhanced tubuloglomerular feedback responsiveness in the nonclipped kidney. After losartan administration, mean arterial pressure decreased by 32±5 and 43±3 mm Hg, and the maximal tubuloglomerular feedback responses were markedly attenuated in both the sham-operated rats (from -12.3±1.9 to -2.4±0.9 mm Hg, P<.01) and clipped rats (from -9.6±0.6 to -1.8±0.5 mm Hg, P<.01). These data indicate that during the early stages of 2K1C Goldblatt hypertension, tubuloglomerular feedback responsiveness in the nonclipped kidney is maintained or slightly enhanced and highly dependent on Ang II type 1 receptor activation.
Key Words: renal circulation • receptors, angiotensin • hypertension, renovascular • rats, Sprague-Dawley • losartan
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Introduction |
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Previous studies have demonstrated a pathogenetic role for angiotensin II (Ang II) in the development of two-kidney, one clip (2K1C) Goldblatt hypertension.1 2 3 4 Administration of angiotensin-converting enzyme (ACE) inhibitors has been shown to prevent the development of hypertension and to reduce mean arterial pressure (MAP) during the maintenance phase of 2K1C hypertension.1 5 6 In addition, the Ang II content of the nonclipped kidney has been shown to be either normal7 or slightly elevated8 at a time (ie, 3 to 4 weeks after clipping) when plasma Ang II levels have returned to normal and renin content of the nonclipped kidney is reduced to barely detectable levels.8 9 By exerting a depressive influence on renal excretory function of the nonclipped kidney, such elevated Ang II levels would contribute to the inability of the nonclipped kidney to achieve normal rates of sodium excretion at normotensive pressures and thereby to the development and maintenance of hypertension in the 2K1C Goldblatt model.10
On the basis of previous observations that peritubular capillary infusion of Ang II, which mimics the effects of increases in intrarenal interstitial Ang II levels, increases proximal tubular reabsorption rate11 and tubuloglomerular feedback (TGF) responsiveness,12 one would predict that there would be an Ang II–dependent augmentation of TGF responsiveness in the nonclipped kidney. Although previous studies have demonstrated decreased13 or normal6 14 TGF responsiveness in the nonclipped kidney, these studies were performed at a time when MAP was already stabilized at substantially elevated levels. Consequently, factors other than Ang II, such as atrial natriuretic peptide or structural changes to the preglomerular vasculature, may have counteracted an initial Ang II–mediated increase in TGF responsiveness. We therefore performed the present study to determine the Ang II dependency of TGF responsiveness in the nonclipped kidney during the early development of 2K1C Goldblatt hypertension.
Although both Ang II type 1 (AT1) and type 2 (AT2) receptor subtypes have been demonstrated in the kidney, previous studies on the Ang II dependency of TGF responsiveness showed that the modulatory influence of Ang II is mediated almost entirely by the AT1 receptor.15 16 This finding enabled a more complete evaluation of the Ang II dependency of TGF responsiveness in 2K1C rats with the use of a receptor antagonist that lacks the kinin-potentiating effects associated with ACE inhibitors and that has been reported to be devoid of agonist activity.17 In the present study, we used the nonpeptide AT1 receptor antagonist losartan to evaluate the Ang II dependency of TGF responses. This agent is the prototype of the class of compounds developed in recent years that selectively inhibits the AT1 receptor subtype.17
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Methods |
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Clipping Procedure
On the day of placement of the 0.25-mm silver clip, male Sprague-Dawley rats (Harlan Sprague Dawley, Houston, Tex) were anesthetized with sodium pentobarbital (45 mg/kg body wt IP). The right renal artery was clipped or sham operated as described previously.6 Immediately after surgery, all rats received penicillin G (30 000 U IM) to prevent postoperative infections. All rats were maintained on normal rat chow and had free access to tap water.
Micropuncture Protocol
On the day of the experiment, rats were anesthetized with sodium
pentobarbital (50 mg/kg body wt IP) and placed on a servo-controlled
surgical table that maintained body temperature at 37°C. After
intubation of the trachea, two catheters were inserted into the left
jugular vein for infusion of solutions and administration of additional
anesthetic. A catheter placed into the left femoral artery allowed us
to monitor MAP and obtain blood samples. MAP was measured with a
pressure transducer (Statham P23dB) and recorded on a polygraph (Grass
Instruments). The nonclipped left kidney was exposed through a flank
incision, freed from connective tissue, and placed in a Lucite cup.
Warm agar was dripped around the kidney to form a saline well. The left
ureter was cannulated and urine collected in preweighed tubes.
Immediately after insertion of the jugular vein catheter, an infusion
of 150 mmol/L NaCl containing 75 mg/mL polyfructosan (Inutest,
Laevosan) and 60 mg/mL bovine serum albumin (Sigma Chemical Co) was
started at a rate of 20 µL/min. After surgery, the intravenous
infusion solution was replaced by one containing 150 mmol/L NaCl, 75
mg/mL polyfructosan, and 10 mg/mL bovine serum albumin. The rate of
fluid administration was kept constant at 20 µL/min throughout the
experiment. Sixty minutes were allowed for equilibration before the
start of the experimental protocol.
The experimental protocol consisted of a 60-minute control period followed by a 60-minute experimental period. In each period, two urine samples and a plasma sample were obtained. Between the control and experimental periods, the pressor response to a bolus injection of 50 ng Ang II was evaluated, followed by intravenous administration of 10 mg/kg body wt of the nonpeptide Ang II receptor antagonist losartan to all clipped and sham-operated rats. Ten minutes after losartan administration and at the end of the experiment, the arterial pressor response to bolus injections of 50 ng Ang II was reevaluated.
During both the control and experimental periods, stop-flow pressure (SFP) feedback responses to step increases in late proximal perfusion rate were obtained. A proximal tubule with several surface segments was localized with the use of a 4- to 6-µm tip diameter micropipette filled with artificial tubular fluid containing 2 mg/mL fast green (Sigma). The composition of the artificial tubular fluid was (mmol/L) NaCl 135, KCl 5, NaHCO3 10, MgSO4 1, CaCl2 1, Na2HPO4-NaH2PO4 1, and urea 4 (pH 7.40). A wax block was inserted upstream of the localization pipette with the use of a hydraulic microdrive (Trent Wells), and a 3- to 4-µm tip diameter pressure pipette was introduced in a segment upstream of the wax block. This pressure pipette was connected to a servo-null micropressure system (model 5A, Instruments for Physiology & Medicine) for continuous measurement of SFP. The localization pipette was then replaced by a 5- to 7-µm tip diameter perfusion pipette filled with stained (2 mg/mL fast green) isotonic artificial tubular fluid connected to a microperfusion pump system (Klaus Effenberger), with the perfusion rate set at 0 nL/min. SFP responses were then obtained at randomly selected late proximal perfusion rates of 10, 15, 20, 30, and 40 nL/min, and recovery of the zero-flow SFP was obtained. Generally, one to three complete SFP feedback curves could be obtained during both the control and experimental periods. We have previously demonstrated that no time-dependent alterations in TGF responsiveness occur throughout the time frame used in the present study.15
Two series of experiments were performed. For the first series, rats having a body weight of 175 to 200 g were clipped (n=5) or sham operated (n=5), and the micropuncture experiments were performed 5 to 10 days after the clipping or sham operation. For the second series, rats with a body weight of 100 to 125 g were clipped or sham operated and subjected to the micropuncture experiments 17 to 25 days after clipping (n=6) or sham operation (n=6). We used this experimental design so that the rats in both series would have approximately the same body and kidney weights at the time of the micropuncture experiment. This allowed direct comparison of renal function and TGF responsiveness in rats with similar body weight that had been exposed to unilateral renal artery stenosis or sham operation for 1 or 3 weeks. At the end of the experiment, the correct placement of the silver clip around the right renal artery was verified, and the left nonclipped kidney was removed, blotted dry, and weighed. All experiments were performed in accordance with institutional guidelines.
Analytical Methods
Urine volume was measured gravimetrically. Urine and plasma
sodium and potassium concentrations were measured with a flame
photometer (Instrumentation Laboratories). Urine and plasma inulin
concentrations were assessed with the use of the anthrone colorimetric
method. Clearances and excretions were calculated with the use of
standard formulas. For the analysis of the relationship between
late proximal perfusion rate and SFP, the perfusion rate eliciting a
half-maximal response (V
Max) was estimated
with the use of the logistic equation and a nonlinear curve-fitting
routine as described previously.18 For each individual
curve, VMax was estimated from the SFP at each
perfusion rate using the equation
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where VLP represents the late proximal
perfusion rate, SFPMax is the zero-flow SFP,
SFPMin is the minimal SFP during loop perfusion, and
c=4
/(SFPMax-SFPMin), with being the
slope of the curve at VMax. For each parameter,
the average was calculated per rat before means were calculated per
group. Statistical analyses were performed with the use of ANOVA for
repeated measurements followed by the least significant difference test
and Student's unpaired t test where appropriate.
Statistical significance was defined as a value of P<.05.
All data are expressed as mean±SEM.
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Results |
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1-Week Clipped Versus 1-Week Sham-Operated Rats
Body weight on the day of the experiment averaged 240±6 and 242±8 g in the sham-operated and clipped rats, respectively. MAP in the control period was significantly higher in the clipped compared with the sham-operated rats (143±6 versus 129±2 mm Hg, P<.01, n=5; Fig 1). As shown in Fig 1, the magnitude of pressor responses to bolus injections of 50 ng Ang II was not different between sham and clipped rats in the control period. In both groups, the pressor responses to Ang II were markedly attenuated 10 minutes after losartan administration and at the end of the experiment. In both groups, MAP decreased significantly after losartan administration but remained higher in the clipped rats (123±2 mm Hg) than in the sham-operated rats (106±5 mm Hg, P<.01, n=5; Fig 1). MAP was 82±2% and 87±3% of control MAP in sham-operated and 1-week clipped rats, respectively. Glomerular filtration rate (GFR) was not significantly different between the 1-week clipped and sham-operated control rats and did not change in either group after losartan administration (Table). Urine flow decreased significantly in the clipped rats and remained unchanged in the sham-operated rats after losartan administration (Table). No significant changes in fractional sodium excretion were observed after losartan administration.
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P<.01,
losartan vs control; #P<.01, 2K1C vs sham-operated rats.
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Despite the difference in MAP, resting SFP (ie, SFP measured in the absence of late proximal perfusion) during control conditions was not different in the clipped rats (37.7±1.7 mm Hg, n=5) compared with the sham-operated rats (38.0±1.3 mm Hg, n=5). After losartan administration, resting SFP decreased by 8.1±0.8 mm Hg to 29.6±2.3 mm Hg (P<.01) in the sham-operated rats. However, resting SFP decreased by only 2.5±1.8 mm Hg to 35.5±1.7 mm Hg (P=NS versus control resting SFP; P<.05 versus sham-operated rats after losartan) in the clipped rats despite the fact that arterial pressure decreased to the same extent (-19±5 mm Hg) as in the sham-operated rats (-23±4 mm Hg). As a consequence, resting SFP decreased 0.38±0.04 and 0.13±0.13 mm Hg per millimeter of mercury decrease in MAP in the 1-week sham and clipped rats, respectively.
The SFP responses to step increases in late proximal perfusion
rate were similar in both groups in the control period (Fig 2). The maximal responses were -13.2±1.5 mm Hg
(35±3% of resting SFP) in the sham-operated rats and -12.9±1.2
mm Hg (34±4% of resting SFP) in the nonclipped kidneys of the 1-week
clipped rats. VMax was not different in the
sham-operated and clipped rats (20±1 and 20±2 nL/min, respectively;
Fig 3A). The TGF-mediated decreases in SFP were
significantly attenuated after losartan administration (Fig 2), with
the maximal SFP responses averaging -3.6±1.1 mm Hg (12±4% of
resting SFP) and -3.0±0.3 mm Hg (9±1% of resting SFP) in the
sham-operated and clipped rats, respectively.
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3-Week Clipped Versus 3-Week Sham-Operated Rats
Body weight averaged 272±10 g in the sham-operated controls and
273±15 g in the clipped group on the day of the micropuncture
experiment. MAP in rats 3 weeks after clipping was further elevated and
averaged 163±6 mm Hg, compared with 134±4 mm Hg in sham-operated
control rats (P<.01, Fig 4). The pressor
responses to injections of 50 ng Ang II were not different between
sham-operated and clipped rats before losartan administration (Fig 4).
Similar to the observation in the 1-week clipped and sham-operated
rats, the pressor responses to bolus injections of Ang II were almost
abolished after losartan administration and remained attenuated to the
end of the experiment (Fig 4). Losartan administration decreased MAP in
the clipped rats by 43±3 mm Hg to 122±5 mm Hg (P<.01)
and in the sham-operated rats by 32±5 mm Hg to 102±7 mm Hg
(P<.01, Fig 4). The absolute decrease in MAP was not
significantly different between groups. MAP was 74±3% and 74±2% of
control values in the sham-operated and clipped rats, respectively.
During control conditions, GFR in the nonclipped kidney of the 3-week
clipped rats was not different from that in sham-operated rats (Table).
After losartan administration, GFR decreased significantly in the
sham-operated group but did not change in the clipped rats (Table).
Neither fractional sodium excretion nor urine flow changed
significantly in the clipped or sham-operated rats (Table) after
losartan administration.
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Despite the increase in MAP, resting SFP under control conditions was not significantly different in the clipped rats (39.0±1.9 mm Hg, n=6) compared with the sham-operated rats (39.6±1.6 mm Hg, n=6). After losartan administration, resting SFP decreased by 9.4±2.4 mm Hg to 29.6±2.9 mm Hg (P<.01) in the clipped rats and by 13.3±2.0 mm Hg to 26.3±2.8 mm Hg in the sham-operated rats (P<.01). The decrease in resting SFP was not significantly different between 3-week sham-operated and clipped rats. From these values and the decrease in MAP, it was calculated that resting SFP decreased 0.42±0.07 and 0.24±0.07 mm Hg per millimeter of mercury decrease in MAP in the 3-week sham and clipped rats, respectively.
Fig 5 shows the SFP feedback responses to step increases
in late proximal perfusion rate in the 3-week clipped and sham-operated
rats. The clipped rats exhibited significant decreases in SFP at
perfusion rates of 15 to 40 nL/min. Furthermore, at 20 nL/min, SFP
almost reached the maximal response (Fig 5). However, the change in SFP
observed at 15 nL/min in the sham-operated rats was not significantly
different from that at zero perfusion, and the maximal response was
obtained at 30 nL/min (Fig 5). This difference in responsiveness can be
appreciated from the estimated VMax, which
averaged 13±2 nL/min in the clipped rats and 18±1 nL/min in the
sham-operated rats (P<.05, Fig 3B). The maximal response in
the clipped rats was -9.6±0.6 mm Hg (25±1% of resting SFP), a
value that was not significantly different from the maximal response in
the sham-operated rats, which averaged -12.3±1.9 mm Hg (32±5% of
resting SFP). After losartan administration, the SFP responses were
significantly attenuated to -1.8±0.5 mm Hg (6±2% of the resting
SFP) in the 3-week clipped rats and to -2.4±0.9 mm Hg (9±3% of
resting SFP) in the sham-operated rats (Fig 5).
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Discussion |
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The current study evaluated TGF responsiveness during the early development of 2K1C hypertension. In rats clipped 1 week before the experiment, MAP was modestly elevated and TGF responsiveness in the nonclipped kidney was maintained. In rats clipped 3 weeks before the experiment, MAP had increased further and TGF responsiveness, as assessed by V
Max, was slightly enhanced.
These results are consistent with the hypothesis that in this model of
hypertension Ang II continues to exert a stimulatory influence on TGF
responsiveness in the nonclipped kidney.
Acute reduction of renal perfusion pressure in one kidney is associated
with increased activity of the renin-angiotensin system. The resultant
increase in arterial pressure and the progressive renin depletion in
the nonclipped kidney would be expected to lead to attenuation of TGF
responsiveness in the nonclipped kidney.19 However, a
recent study reported that at 7 and 25 days after clipping, intrarenal
Ang II levels in the nonclipped kidney are elevated even at a time when
intrarenal renin levels are reduced to almost undetectable
levels.9 The data obtained in the 1-week clipped rats
indicate that TGF responsiveness in the nonclipped kidney is normal,
while in the 3-week clipped rats feedback responsiveness is slightly
enhanced, based on the significant decrease in
VMax. Previous studies have shown either
maintained or decreased TGF responsiveness in the contralateral kidney
3 and 4 weeks after clipping.6 13 14 Because hypertension
severity has been reported to be influenced by clip
size,20 it is possible that structural changes in the
glomerular microvasculature and the volume dependency of the
hypertension inducing depression of the renin-angiotensin system could
affect TGF responsiveness in these studies with the use of a clip
size13 14 smaller than that used in the current protocol.
It should also be emphasized that besides Ang II, several other
neurohumoral control systems that can modulate TGF responsiveness are
altered in 2K1C hypertension. Increased plasma atrial natriuretic
peptide levels, which have been shown to attenuate TGF
responsiveness,21 and increased atrial natriuretic peptide
receptor binding sites in the nonclipped kidney have been reported in
2K1C hypertension.22 Furthermore, alterations in products
of the prostaglandin system have been reported during 2K1C
hypertension2 ; in particular, prostaglandin E2
and thromboxane A2 have been identified as modulators of
TGF responsiveness.23 24 Thus, although the TGF function
curve must be considered to be influenced by several interrelated
modulators, it was possible in the present study to demonstrate a
slightly greater TGF responsiveness in the 3-week clipped group based
on a significant decrease in VMax in 3-week
clipped rats.
In both the 1- and 3-week clipped or sham-operated rats, TGF responsiveness in the nonclipped kidney was significantly attenuated after administration of the nonpeptide Ang II receptor antagonist losartan. Maximal TGF responses were attenuated by 73±8% and 76±3% in the 1-week sham-operated and clipped rats and by 72±13% and 80±6% in the 3-week sham-operated and clipped rats, respectively. No differences between groups in the degree to which TGF responses were attenuated by AT1 blockade could be demonstrated. The degree of attenuation of TGF responses observed in the present study is similar to that observed after administration of the ACE inhibitor enalaprilat.6 It is unlikely that the decreases in MAP per se elicited by losartan reduced the magnitude of the TGF response, because it has already been reported that direct reduction of MAP does not reduce the magnitude of TGF responses in either normal rats25 or the nonclipped kidney of 2K1C rats.6 Furthermore, peritubular capillary infusion of losartan, which does not cause discernible changes in MAP or resting SFP, has also been demonstrated to attenuate TGF responsiveness.16 Thus, the attenuation of TGF responsiveness observed after blockade of the renin-angiotensin system seems to reflect the effects of blockade of the modulatory influence of Ang II and does not seem to be related to the decrease in MAP or to the kinin- and prostaglandin-potentiating effects of ACE inhibition.26 Taken together, these data indicate that TGF responsiveness in the nonclipped kidney remains highly Ang II dependent during the early phases of the development of Goldblatt hypertension despite the elevated arterial pressure.
Losartan administration decreased MAP in all groups. Although the decrease in MAP tended to be more pronounced in 3-week 2K1C rats, the immediate effects of AT1 receptor blockade on arterial pressure were not significantly different between the clipped or sham-operated rats. Interestingly, after AT1 receptor blockade, arterial pressure in the clipped rats remained significantly higher than in the sham-operated rats, indicating a component of the elevation of arterial blood pressure, not directly reversible by Ang II blockade, that might be related to the long-term actions of Ang II on volume homeostasis. Despite the elevated MAP in the 1- and 3-week 2K1C rats, no differences in resting SFP between the clipped and sham-operated rats could be detected during control conditions. The absence of an increase in resting SFP in the 2K1C rats under control conditions is in accordance with previous data indicating pronounced preglomerular vasoconstriction in the nonclipped kidney in this model.4 6 In the 1-week clipped rats, losartan administration did not significantly decrease resting SFP, indicating that administration of the AT1 receptor antagonist was followed by a preglomerular vasodilation that allowed glomerular pressure to be maintained even in the face of the substantial decrease in arterial pressure. It is likely that both autoregulatory adjustments in afferent arteriolar tone and blockade of the preglomerular vasoconstrictor actions of Ang II contributed to the maintenance of resting SFP under these conditions. Although it has been demonstrated that autoregulation is attenuated in rats that have been clipped for 4 weeks,13 autoregulation in 1-week clipped rats may still be intact. Likewise, the decrease in SFP in the 3-week clipped rats was relatively small compared with the very large decrease in arterial pressure, also indicating a greater AT1-mediated afferent arteriolar vasoconstriction in the nonclipped kidney of 2K1C rats than in the sham-operated rats.
Interestingly, the nonclipped kidney did not exhibit increases in GFR or fractional sodium excretion after blockade of AT1 receptors by losartan. This is in contrast to the response of the nonclipped kidney to administration of ACE inhibitors.4 5 6 Although the reason for this apparent discrepancy remains unclear, it could be due to differences in the kinin- and prostaglandin-potentiating effects of ACE inhibitors and AT1 receptor antagonists. Indeed, the AT1 receptor antagonist losartan has been reported to be devoid of the kinin- and prostaglandin-potentiating effects associated with ACE inhibitors. An additional possibility is that ACE inhibitors will cause a gradual decline in Ang II levels, and thereby of the actions of Ang II, whereas losartan elicits a much more rapid blockade of the effects of Ang II. The almost instantaneous blockade of the actions of Ang II by losartan might be expected to lead to activation of fast compensatory mechanisms that would not be activated after the administration of an ACE inhibitor, in particular, renal sympathetic tone.27 Finally, the decrease in MAP observed after losartan administration in the present study exceeded the decreases in MAP observed during administration of the ACE inhibitor enalaprilat.6 Of note is the recent observation that long-term losartan administration to 2K1C rats increases GFR, urine flow, and sodium excretion.28 Nevertheless, further studies are required to evaluate the mechanism responsible for the differences between the effects elicited by ACE inhibitors and AT1 receptor blockers on renal hemodynamic and excretory functions of the nonclipped kidney of 2K1C Goldblatt hypertensive rats.
In summary, the present study demonstrates that TGF responsiveness in the nonclipped kidney is maintained in 2K1C rats 1 week after clipping and is slightly enhanced 3 weeks after clipping. In addition, TGF responsiveness at both time points is highly dependent on the actions of Ang II. Collectively, the data support the hypothesis that Ang II, acting via AT1 receptors, contributes to the maintenance or even enhancement of TGF responsiveness in the nonclipped kidney of 2K1C Goldblatt hypertensive rats. Such Ang II dependency of TGF responsiveness might contribute to an inability of the nonclipped kidney to regulate its sodium excretion at normotensive pressures and attenuate the natriuretic response of the nonclipped kidney to the elevations in systemic arterial pressure. In this manner, the modulatory influence of Ang II on TGF responsiveness could play a role in the development and maintenance of the hypertension that occurs as a consequence of unilateral renal artery stenosis.
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Acknowledgments |
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This study was supported by grant HL-26371 from the National Heart, Lung, and Blood Institute and grant LA-91-G-24 from the American Heart Association, Louisiana Affiliate. B. Braam was a visiting postdoctoral fellow from the Netherlands and was supported by grant PGS-900-759-233 (Dutch Organization for Scientific Studies). Losartan was generously provided by Dr Ronald D. Smith of DuPont-Merck Inc. Pharmaceutical Co. The authors thank Anka A. Hymel and Lynn Lewis for technical assistance.
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Footnotes |
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This manuscript from Tulane University School of Medicine was sent to Theodore Kotchen, MD, Consulting Editor, for review by expert referees, for editorial decision, and for final disposition.
Received April 13, 1994; first decision May 27, 1994; accepted January 6, 1995.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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1. DeForrest JM, Knappenberger RC, Antonaccio MJ, Ferrone RA, Creekmore JS. Angiotensin II is a necessary component for the development of hypertension in the two kidney, one clip rat. Am J Cardiol. 1982;49:1515-1517. [Medline] [Order article via Infotrieve]
2.
Martinez-Maldonado M. Pathophysiology of
renovascular hypertension. Hypertension. 1991;17:707-719.
3. Mitchell KD, Braam B, Navar LG. Hypertensinogenic mechanisms mediated by renal actions of renin-angiotensin system. Hypertension. 1992;19(suppl I):I-18-I-27.
4.
Ploth DW. Angiotensin-dependent renal
mechanisms in two-kidney, one-clip renal vascular hypertension.
Am J Physiol. 1983;245:F131-F141.
5.
Huang W-C, Ploth DW, Navar LG.
Angiotensin-mediated alterations in nephron function in
Goldblatt hypertensive rats. Am J Physiol. 1982;243:F553-F560.
6. Huang W-C, Bell PD, Harvey D, Mitchell KD, Navar LG. Angiotensin influences on tubuloglomerular feedback mechanism in hypertensive rats. Kidney Int. 1988;34:631-637. [Medline] [Order article via Infotrieve]
7. Mendelsohn FAO. Failure of suppression of intrarenal angiotensin II in the contralateral kidney of one clip, two kidney Goldblatt hypertensive rats. Clin Exp Pharmacol Physiol. 1980;7:219-223. [Medline] [Order article via Infotrieve]
8.
Guan S, Fox J, Mitchell KD, Navar LG.
Angiotensin and angiotensin converting enzyme tissue levels in
two-kidney, one-clip Goldblatt hypertension.
Hypertension. 1992;20:763-767.
9. Jackson CA, Navar LG. Arterial pressure and renal function in two-kidney one-clip Goldblatt hypertensive rats maintained on a high-salt intake. J Hypertens. 1986;4:215-221. [Medline] [Order article via Infotrieve]
10. Mitchell KD, Navar LG. Interactive effects of angiotensin II on renal hemodynamics and tubular reabsorptive function. Kidney Int. 1990;30(suppl 38):S-69-S-73.
11.
Mitchell KD, Navar LG. Superficial nephron
responses to peritubular capillary infusions of angiotensins I and
II. Am J Physiol. 1987;252:F818-F824.
12.
Mitchell KD, Navar LG. Enhanced tubuloglomerular
feedback during peritubular infusions of angiotensins I and II.
Am J Physiol. 1988;255:F383-F390.
13. Ploth DW, Schnermann J, Dahlheim H, Hermle M, Schmidmeier E. Autoregulation and tubuloglomerular feedback in normotensive and hypertensive rats. Kidney Int. 1979;12:253-267.
14. Müller-Suur R, Gutsche HU, Samwer KF, Oelkers W, Hierholzer K. Tubuloglomerular feedback in rat kidneys with different renin contents. Pflugers Arch. 1975;359:33-56. [Medline] [Order article via Infotrieve]
15. Braam B, Mitchell KD, Navar LG. Modulation of tubuloglomerular feedback responsiveness by angiotensin AT1 receptors. In: MacGregor GA, Sever PS, eds. Current Advances in ACE Inhibition. 3rd ed. Tokyo, Japan: Churchill-Livingstone; 1994:155-158.
16. Mitchell KD, Braam B, Navar LG. Attenuation of tubuloglomerular feedback responses by the non-peptide angiotensin II receptor antagonist, DuP 753. J Am Soc Nephrol. 1991;2:524. Abstract.
17.
Wong PC, Price WA, Chiu AT, Duncia JV, Carini DJ,
Wexler RR, Johnson AL, Timmermans PBMWM. Nonpeptide angiotensin
II receptor antagonists, IX: antihypertensive activity in rats of DuP
753, an orally active antihypertensive agent. J Pharmacol
Exp Ther. 1990;252:726-732.
18. Briggs JP, Schubert G, Schnermann J. Quantitative characterization of the tubuloglomerular feedback response: effect of growth. Am J Physiol. 1984;247:F808-F815.
19.
Schnermann J, Briggs JP. Restoration of
tubuloglomerular feedback in volume-expanded rats by angiotensin
II. Am J Physiol. 1990;259:F565-F572.
20. Leenen FHH, De Jong W. Plasma renin and sodium balance during development of moderate and severe renal hypertension. Circ Res. 1975;36/37(suppl I):I-179-I-185.
21.
Pollock DM, Arendshorst WJ. Native tubular fluid
attenuates ANF-induced inhibition of tubuloglomerular feedback.
Am J Physiol. 1990;258:F189-F198.
22. Gaugelin GU, Schiffrin EL, Cantin M, Garcia R. Atrial natriuretic factor: specific binding to renal glomeruli during the development of two-kidney, one-clip hypertension in the rat. J Hypertens. 1988;6:587-592. [Medline] [Order article via Infotrieve]
23.
Welch WJ, Wilcox CS. Feedback responses during
sequential inhibition of angiotensin and thromboxane. Am
J Physiol. 1990;258:F457-F466.
24. Welch WJ, Wilcox CS. Potentiation of tubuloglomerular feedback in the rat by thromboxane mimetic: role of the macula densa. J Clin Invest. 1992;89:1857-1865.
25. Selén G, Persson AEG. Effects of reduced renal artery pressure on feedback control of glomerular filtration. Am J Physiol. 1983;244:F342-F348.
26. Gavras I. Bradykinin-mediated effects of ACE inhibition. Kidney Int. 1992;42:1020-1029. [Medline] [Order article via Infotrieve]
27.
Kumagai K, Reid IA. Angiotensin exerts
differential actions on renal nerve activity and heart rate.
Hypertension. 1994;24:451-456.
28. Imamura A, Mackenzie HS, Lacy ER, Hutchinson FN, Fitzgibbon WR, Ploth DW. Effects of chronic treatment with angiotensin converting enzyme inhibitor or an angiotensin receptor antagonist in two-kidney, one-clip hypertensive rats. Kidney Int. In press.
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