(Hypertension. 1996;27:235-244.)
© 1996 American Heart Association, Inc.
Articles |
Role of Kinins in the Renal Response to Enalaprilat in Normotensive and Hypertensive Rats
Presented in part at the Southern and National Meetings of the American Federation of Clinical Research, New Orleans, La, January, 1990, and Washington, DC, May, 1990, and the American Society of Nephrology, Baltimore, Md, November, 1991, and published in abstract form (Clin Res. 1990;38:21A, Clin Res. 1990;38:428A, and J Am Soc Nephrol. 1991;2:475).
From the Divisions of Nephrology (W.R.F., D.W.P.) and Endocrinology (R.K.M.), Department of Medicine and Department of Pharmacology (A.A.J.), Medical University of South Carolina, Charleston, and the Ralph H. Johnson Veterans Affairs Medical Center (D.W.P., R.K.M.).
Correspondence to David W. Ploth, MD, Division of Nephrology, Department of Medicine, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC 29425-2220.
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Abstract |
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Abstract This study examined the role of endogenous kinins in the alteration of renal hemodynamics induced by low-dose converting enzyme inhibition in hydropenic normotensive rats and in the nonclipped kidney of hydropenic two-kidney, one clip hypertensive rats. Infusion of a bradykinin B2 receptor antagonist (D-Arg0,[Hyp3,Thi5,8,D-Phe7]-bradykinin, 1 or 10 µg · kg-1 · min-1) did not alter renal function of normotensive rats. In a second series of experiments, infusion of enalaprilat at 0.1 mg · kg-1 · h-1 increased renal blood flow (P<.01) and decreased renal vascular resistance (P<.01). The superimposition of the kinin antagonist at 1 µg · kg-1 · min-1 during the enalaprilat infusion decreased renal blood flow to a value similar to the preenalaprilat baseline and significantly different from the mean of the two enalaprilat periods before and after the addition of the kinin antagonist—the "mean effect of enalaprilat." The decrease in renal blood flow induced by the kinin antagonist was associated with an increase in renal vascular resistance above the mean effect of enalaprilat (P<.025). In two-kidney, one clip hypertensive rats, systemic infusion of enalaprilat augmented the hemodynamics of the nonclipped kidney by a degree similar to that in normotensive rats. In contrast to normotensive rats, superimposition of the kinin antagonist did not alter the enalaprilat-induced change in blood flow or vascular resistance of the nonclipped kidney. The results of this study suggest that endogenous kinins contribute to the increased renal function induced by low-dose converting enzyme inhibition in hydropenic normotensive rats but appear to contribute less to the enalaprilat-induced alterations of renal function in the nonclipped kidney of two-kidney, one clip hypertensive rats.
Key Words: angiotensin-converting enzyme inhibitors • bradykinin • enalapril • hypertension, renovascular • kinins • vasodilation
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Angiotensin-converting enzyme (kininase II) metabolizes the conversion of angiotensin I to angiotensin II and catabolizes kinins to inactive fragments.1 Converting enzyme is the major pathway for degradation of circulating kinins2 and is also an important kininase in renal tissue.3 CEI increase renal tissue kallikrein activity,4 plasma and renal kinin levels,5 and urinary kinin excretion.6 These observations support the possibility that the physiological effects of CEI could be mediated by alterations in kinin metabolism. Although studies using specific antagonists to bradykinin B2 receptors have indicated that kinins participate in the renal actions of CEI,7 8 9 10 the role of kinins in the whole-kidney hemodynamic effects of CEI has not been clarified.
In normotensive rats, the increase in RBF induced by the CEI captopril was not altered by treatment with the bradykinin B2 antagonist D-Arg0,[Hyp3,Thi5,8,D-Phe7]-bradykinin.9 The same kinin antagonist partially attenuated the increase in RBF induced by enalaprilat treatment in dogs11 but did not significantly attenuate the increase in RBF induced by captopril or lisinopril in rabbits.12 13 Furthermore, the bradykinin B2 antagonist Hoe 140 did not alter the increase in RBF induced by short-term treatment with either ramiprilat or captopril in rabbits14 or ramiprilat in rats.15
2K1C hypertension is a model of secondary hypertension in which the nonclipped kidney participates in the onset and development of the hypertension.16 The participation of the nonclipped kidney in the development phase (approximately the 4 weeks after placement of the renal artery clip) appears to be highly angiotensin dependent because the responses of the nonclipped kidney to CEI and angiotensin antagonists are qualitatively similar.16 However, a number of findings suggest that the kallikrein-kinin system may also contribute to the CEI-induced alteration in the hemodynamic and excretory functions of the nonclipped kidney of 2K1C hypertensive rats. Renal kallikrein gene expression17 18 and urinary kallikrein19 excretion from the nonclipped kidney are maintained at levels not different from normal levels, although tissue kallikrein level is reduced compared with normal kidneys20 and short-term treatment with CEI increased kinin excretion from the nonclipped kidney. Furthermore, studies using bradykinin B2 receptor antagonists indicate that endogenous kinins contribute to the hypotensive effect of CEI in renovascular hypertensive rats.21 22 23 24
Acute administration of low doses of CEI induce similar significant increases in the hemodynamics and excretory function of hydropenic normotensive rats and in the nonclipped kidney of hydropenic 2K1C hypertensive rats. The purpose of this study was to examine the hypothesis that endogenous kinins contribute to the CEI-induced alterations in hemodynamics and excretory function of kidneys of normotensive rats and of the nonclipped kidney of 2K1C hypertensive rats. We tested this hypothesis by assessing the effects of superimposing kinin receptor blockade during acute infusion of low-dose enalaprilat in hydropenic normotensive and 2K1C hypertensive rats. We also examined the effect of systemic kinin receptor blockade in the absence of enalaprilat on renal hemodynamics and excretory function of hydropenic normotensive rats. Superimposed low-dose B2 bradykinin receptor antagonist D-Arg0,[Hyp3,Thi5,8, D-Phe7]-bradykinin reversed the renal vasodilation induced by enalaprilat in the kidney of hydropenic normotensive rats but not the nonclipped kidney of 2K1C hypertensive rats. These observations suggest that endogenous kinins may play a major role in the renal hemodynamic responses induced by enalaprilat in hydropenic normotensive rats. In contrast, kinins appear to contribute less to the enalaprilat-induced alterations of renal function in the nonclipped kidney of 2K1C hypertensive rats.
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Methods |
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General Surgical Procedures
Male Wistar rats weighing 210 to 350 g (Charles River, Wilmington, Mass) were fed standard rat chow (Wayne Rodent Blox [0.31% sodium], Teklad) ad libitum and given free access to tap water. Rats were anesthetized with pentobarbital (50 mg · kg-1 IP) and placed on a heated table for maintenance of body temperature at 37°C. After tracheotomy, a triple-lumen cannula was placed in a jugular vein for infusion of fluids, drugs, and anesthetic. A cannula was placed in the right femoral artery for measurement of blood pressure and for blood sampling. The bladder was cannulated to allow urine collection from the left kidney. The right kidney was exposed by a flank incision, freed of perirenal tissue, placed in a Lucite cup, and bathed in 0.9% NaCl. The ureter was then cannulated. In most rats, the right renal artery was freed from connective tissue, and a flow transducer (Carolina Medical Electronics) with either a 1.5- or 2-mm-circum lumen was fitted. The transducer was connected to a square-wave electromagnetic blood flowmeter (Carolina Medical Electronics). Hydropenic preparations were maintained by an intravenous bolus injection of 0.8 mL of 0.9% NaCl after cannulation of the jugular vein and a maintenance infusion of 1.2 mL · h-1 during the surgical procedures. A bolus injection of 0.4 mL of the 0.9% NaCl was given at the end of the surgery, and the infusion rate was set at 0.6 mL · h-1. The enalaprilat and kinin antagonist were delivered through this line. To allow the determination of GFR and in some rats estimated RPF, a 0.4-mL priming dose of 0.9% NaCl containing 12.5% polyfructosan (Inutest, Laevosan-Gesellschaft) and 1% PAH (Merck Sharp & Dohme) was given as a bolus through the other jugular line, followed by infusion at a rate of 0.6 mL · h-1. Consequently, during the experiment the total infusion rate was maintained at 1.2 mL · h-1. The flow transducers were calibrated to zero flow by momentary complete occlusion of the renal artery. Forty-five minutes was allowed for the preparation to reach a steady state before study. Timed urine collections were obtained, with blood (0.4 mL) collected between pairs of clearance periods. For maintenance of hematocrit, red blood cells from each blood sample were reconstituted to the same volume with 0.9% NaCl and reinjected through the arterial cannula.
Experimental Protocols
Protocol 1: Effect of the KA
D-Arg0,[Hyp3,Thi5,8,
D-Phe7]-Bradykinin
on Renal Function of Hydropenic Normotensive Rats
In group 1
(n=5), two 20-minute baseline clearance periods were
obtained. The KA
D-Arg0,[Hyp3,Thi5,8,D-Phe7]-bradykinin
(generously provided by Dr J.M. Stewart, Department of Biochemistry,
University of Colorado Health Sciences Center, Denver) was injected as
a bolus (20 µg · kg body wt-1) and
then infused at a rate of 1 µg · kg body
wt-1 · min-1. After 10
minutes, two 20-minute clearance periods were obtained. The KA was then
injected as a bolus of 200 µg · kg body
wt-1 and infused at a rate of 10
µg · kg body
wt-1 · min-1. After
another 10-minute stabilization period, two additional clearance
periods were taken. The KA infusion was discontinued; 20 minutes was
allowed for stabilization; and two further clearance (recovery) periods
were obtained.
In group 2 (n=5), similarly prepared rats served as time controls. They received equal volumes of vehicle (0.9% NaCl) instead of the KA.
Protocol 2: Effect of the KA
D-Arg0,[Hyp3,Thi5,8,
D-Phe7]-Bradykinin
on Enalaprilat-Induced Alterations in Renal
Hemodynamics and Excretory Function
Normotensive
rats. In group 3 rats (n=11), two baseline urine
collections were obtained, and enalaprilat (Vasotec, Merck Sharp &
Dohme) was then injected as a bolus of 0.3 mg · kg body
wt-1 and infused at 0.1 mg · kg body
wt-1 · h-1 throughout
the rest of the experiment. After 20 minutes of equilibration, two
20-minute urine collections were taken. The KA
D-Arg0,[Hyp3,Thi5,8,D-Phe7]-bradykinin
was injected as a bolus (20 µg · kg body
wt-1) and then infused at a rate of 1
µg · kg body
wt-1 · min-1. Again, 20
minutes was allowed for stabilization, and two 20-minute urine
collections were obtained during the superimposed infusion of the KA.
The KA was discontinued, and after 20 minutes of stabilization, two
further 20-minute clearance periods were obtained.
Rats in group 4 (n=6) were used as time controls with the same protocol except they received equal volumes of vehicle (0.9% NaCl) instead of the KA.
2K1C hypertensive rats. The effect of the KA on enalaprilat-induced augmentation of renal hemodynamics and excretory function of the nonclipped kidney of 2K1C hypertensive rats (group 5, n=8) was examined 3 to 4 weeks after clip. Rats weighing 100 to 125 g were anesthetized with sodium pentobarbital (50 mg · kg-1 IP), and the left kidney was exposed via a retroperitoneal incision. The renal artery was partially freed from the renal vein, and a silver clip with a gap of 0.2 mm was placed around the artery. The rats were allowed to recover and received water and chow ad libitum during the next 3 to 4 weeks. On the day of the experiment, the rats were prepared as described for the general surgical procedure, with the nonclipped kidney (right) exposed and placed in the kidney cup. Only rats with MAP between 150 and 200 mm Hg were used in this study. The experimental protocol was exactly the same as that for group 3.
A second group of 2K1C hypertensive rats (group 6, n=5) was studied with the same protocol except they received equal volumes of vehicle (0.9% NaCl) instead of the KA.
The effectiveness of kinin blockade was evaluated by the vasodilator effect of bradykinin before and after KA administration. In five of the group 3 and four of the group 5 rats, bradykinin (Sigma Chemical Co) was injected as a bolus (0.05 mL IV) at doses of 5 and 10 ng during enalaprilat treatment before the superimposed KA infusion and then again 20 minutes after the start of the KA infusion.
Analytic Procedures
At the end of each experiment, the
kidneys were excised,
blotted, and weighed. Urine volume was determined gravimetrically.
Plasma and urinary sodium and potassium concentrations were determined
by flame photometry (model 943, Instrumentation Laboratories).
Polyfructosan and PAH concentrations were determined by modified
anthrone and colorimetric methods,
respectively.25 26 GFR was determined from the
clearance
of polyfructosan. To avoid a fixed bias of using only the
electromagnetic flowmeter to measure RBF, we determined RPF using the
clearance of PAH adjusted for the measured extraction of PAH in a
number of rats chosen randomly from each of the groups. There was no
difference in the extraction ratios between the normotensive and 2K1C
hypertensive rats; consequently, all values were combined and the
average value (0.55) was used. For these rats, RBF was calculated from
RPF and hematocrit. The values for RBF obtained directly were not
significantly different from the values determined with PAH. Filtration
fraction and RVR were then calculated with standard formulas. Clearance
data were normalized to kidney weight.
Statistical Analysis
Values are reported as mean±SEM.
For groups 1 through 4, data
from both kidneys were combined. Univariate two-factor
repeated measures ANOVA was used to test the group effect (two levels;
KA compared with vehicle) and the group by repeated measures
interaction. Differences between the two groups, at baseline or each
treatment level or in the change from baseline, were tested by the
relevant Scheffé contrasts, with the significance level adjusted
by the Bonferroni method. Data within each group were analyzed
by multivariate one-factor repeated measures ANOVA
with the Hunyh-Feldt correction or in a number of cases the
Greenhouse-Geisser correction. A limited number of comparisons between
pairs of means or combinations of means were established for most
variables (except MAP) and analyzed by the appropriate
Scheffé contrasts. The significance level for the comparisons was
modified with the appropriate Bonferroni adjustment. Differences
between single pairs of means were tested with the Wilcoxon
signed rank test or Student's t test, with a significance
level at a value of P<.05. Analyses were conducted
with either StatView 512+ (Brainpower) or SuperANOVA (Abacus
Concepts).
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Results |
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Protocol 1: Effect of the KA on Renal Function (Groups 1 and 2)
Mean body and kidney weights of the rats in groups 1 and 2 are presented in Table 1
. The effects of the kinin
antagonist (1 and 10
µg · kg-1 · min-1)
on arterial blood pressure and the renal
hemodynamics of hydropenic rats are shown in Fig 1. There was
no difference in the basal values of MAP,
GFR, or PAH clearance between the KA-infused rats and
vehicle-infused time controls. The MAP of the time control rats
remained stable during the experiment. In contrast, the blood pressure
of rats that received the KA decreased significantly
(P<.017) from baseline during the KA infusion at 10
µg · kg-1 · min-1
and decreased further during the recontrol period. Only during the
recontrol period was there a significant (P<.0125)
difference in MAP between the two groups. Systemic infusion of the KA
or vehicle did not alter either GFR or PAH clearance compared with
either baseline or the other group.
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, 1.0 and 10.0
µg · kg-1 · min-1,
n=5) or equal volumes of 0.9% NaCl (time control, 
, n=6) on
MAP
and renal hemodynamics in normotensive hydropenic
rats. Data are presented as mean±SEM.
P<.017 compared with baseline (differences tested
using contrasts, with the Greenhouse-Geisser correction, from
one-factor repeated measures ANOVA).
KA infusion did not alter UV
compared with baseline values or those
values obtained for the time control rats (Table 1
).
UNaV
and FENa were not significantly altered by KA infusion. In
contrast, UNaV and FENa were significantly less
(P<.017) than the baseline value during the recontrol
period (Table 1). The decreases in UNaV and
FENa from baseline during the recontrol period were
significantly larger (P<.0125) in the KA group compared
with the time control group. KA infusion abolished the increase in
UKV observed in the time control group.
Protocol 2: Effect of the KA on Enalaprilat-Induced Alterations in
Renal Hemodynamics and Excretory Function
In a subset of five
enalaprilat-infused hydropenic
normotensive rats, the superimposition of the KA (20
µg · kg-1 bolus and then infusion
at 1
µg · kg-1 · min-1)
for 20 minutes partially blocked the vasodepressor effect of bolus
systemic injections of 5 ng bradykinin by 39±10% (P<.05)
and 10 ng bradykinin by 30±7% (P<.05) (Fig
2). A similar degree of blockade was observed for 5 ng
bradykinin (31±9%, P<.05) and 10 ng bradykinin
(26±9%,
P=.06) in 2K1C hypertensive rats.
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P=.06, Wilcoxon rank sum test.
Normotensive
Rats (Groups 3 [KA] and 4 [Time Control])
Mean
body weights and mean combined kidney weights were similar
for the rats from groups 3 and 4.
Baseline MAP values did not differ
between the normotensive rats
that received the KA or those that received vehicle (Fig 3A).
Systemic infusion of a low dose of enalaprilat (0.3
mg · kg-1 bolus and infusion at 0.1
mg · kg-1 · h-1)
induced significant decreases in blood pressure in rats from both
groups 3 and 4 during the course of the experiment (Fig 3A).
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P<.0125,
ßP<.025 compared with baseline (differences
tested using contrasts with the Hunyh-Feldt correction, from
one-factor repeated measures ANOVA);
P<.025 compared
with
mean effect of CEI.
This experiment was designed to evaluate the effect of the KA on
changes in systemic blood pressure and renal function induced by CEI.
Thus, the period of superimposed infusion of the KA or vehicle was
bracketed by periods of enalaprilat infusion alone. Data from the two
periods of enalaprilat infusion alone were averaged, and the value
represented the mean effect of CEI. The effects of
superimposed infusion of either KA or vehicle were determined as
changes from this mean effect of CEI. For visual clarity, in Figs 3D
through 3F and 4D through 4F, the mean effects of CEI for each group
are presented as zero. The effects of superimposed infusion of
the KA or vehicle are thus presented as changes from zero. This
analysis allowed comparison of the changes observed for
superimposition of KA or vehicle during CEI treatment within and
between the groups. The changes in blood pressure observed during the
superimposed infusion of the KA or vehicle compared with the mean
effect of CEI are plotted in Fig 3D. Superimposition of the KA
did not
significantly alter MAP when compared with the effects of either
enalaprilat alone or the superimposed infusion of vehicle.
The effects
of KA on renal hemodynamics in these
enalaprilat-infused normotensive rats are presented in Fig 3.
For two of the KA-treated rats, inadequate measurements of either
RPF or RBF were made during the experiment; consequently, data from
these rats were not used for examination of the effect of KA on RPF,
RBF, or RVR. Although the baseline RPF of rats from group 3 (KA) was
higher than that of rats from group 4 (time control), the low dose of
enalaprilat significantly increased RPF by a similar extent in both
groups. In group 3 rats, enalaprilat infusion induced a significant
increase in mean effective RPF from a baseline value of 3.76±0.21 to
4.55±0.40 mL · min-1 · g
kwt-1 (P<.01, 21%) during
the first CEI period. Similarly, in group 4 rats, RPF increased from a
baseline of 2.74±0.36 to 3.53±0.39
mL · min-1 · g kwt-1
(P<.01, 31%) during the first CEI period. For group 3
rats, the mean RPF during the periods when enalaprilat was infused
without superimposed KA (the mean effect of CEI) was 4.40±0.40
mL · min-1 · g
kwt-1. During the superimposition of the
KA, RPF decreased significantly from the mean effect of CEI by
-0.66±0.20 mL · min-1 · g
kwt-1 (P<.01, -15%).
In group 4 rats, the mean RPF for the periods when enalaprilat was
infused without the superimposed infusion of vehicle was 3.40±0.35
mL · min-1 · g
kwt-1. In contrast to the KA group, the
effect of enalaprilat on RPF was not altered by the superimposed
infusion of the vehicle (the difference in RPF between the vehicle
infusion and the mean effect of CEI was 0.22±0.09
mL · min-1·g
kwt-1, P>.025). Also,
the change in RPF induced by the superimposition of the KA was
significantly (P<.01) greater than that observed during the
infusion of vehicle.
The effects of KA or vehicle on RBF are presented
in Fig 3B and 3E. The baseline RBF for group 3
rats was significantly higher
(P<.01) than that for group 4 rats (7.38±0.33 and
5.38±0.56 mL · min-1 · g
kwt-1, respectively). Enalaprilat
significantly increased RBF by a similar degree in both groups. The low
dose of enalaprilat increased the RBF of group 3 rats by 1.58±0.45
mL · min-1 · g kwt-1
(P<.01, 21%) during the first CEI period. For group 4
rats, RBF increased by 1.61±0.28
mL · min-1 · g
kwt-1 (P<.01, 32%) during
the first CEI period (Fig 3B). The changes in
enalaprilat-induced
increased RBF observed during the superimposition of either KA or
vehicle are plotted in Fig 3E. The superimposition of the KA
but
not vehicle significantly decreased RBF. Furthermore, the change in RBF
induced by the KA (-1.34±0.37
mL · min-1 · g
kwt-1, P<.01,
-16%) was significantly (P<.01) different from that
observed for the vehicle-infused rats (0.45±0.19
mL · min-1 · g
kwt-1, P>.05) (Fig 3E).
Low-dose enalaprilat infusion induced significant renal
vasodilation in both groups of hydropenic rats. For group 3 rats,
enalaprilat significantly decreased RVR by 23% from a mean baseline
value of 17.8±1.1 to 13.7±1.1
mm Hg · mL-1 · min-1 · g
kwt-1 during period 2 (P<.01)
and for group 4 rats, from a baseline value of 26.5±2.3 to
18.8±1.5
mm Hg · mL-1 · min-1 · g
kwt-1 (P<.001) during period
2. Superimposition of the low-dose KA reversed the vasodilator
effect of enalaprilat (RVR was increased significantly compared with
the mean effect of CEI by 2.8±1.3
mm Hg · mL-1 · min-1 · g-1,
P<.025, Fig 3F). In contrast, the superimposition
of
vehicle did not alter RVR (
RVR, -1.2±0.7, P>.05,
Fig 3F). Furthermore, the increase in RVR induced by the
superimposition of the KA was significantly greater than the change in
RVR observed during the superimposed infusion of vehicle
(P<.025).
Baseline GFR values obtained from group 3 and 4
rats were not
significantly different (Table 2). Enalaprilat infusion
initially increased GFR in group 3 from a baseline value of 0.96±0.04
to 1.15±0.04 mL · min-1 · g
kwt-1 (P<.001) during period
2 and in group 4 rats from a baseline of 1.00±0.04 to 1.28±0.08
mL · min-1 · g kwt-1
(P<.01). However, despite the continued presence of
enalaprilat, the increase in GFR was transitory. For group 4 rats, the
decrease was approximately linear; GFR during period 3 was not
significantly different from that during period 2, but during period 4,
GFR was similar to the baseline value (1.00±0.07
mL · min-1 · g
kwt-1). In contrast, superimposition of
the KA significantly (P<.01) decreased GFR to a value
similar to baseline (GFR was 1.01±0.07
mL · min-1 · g kwt-1
during period 3). Infusion of a low dose of enalaprilat into the
hydropenic rats induced significant (P<.01, natural
log–transformed data) increases in renal excretory function (Table
2). Superimposition of the KA did not alter UNaV
compared
with period 2. Similarly, the superimposition of vehicle (group 4) did
not alter the enalaprilat-induced natriuresis. Enalaprilat infusion
significantly increased UV and UKV of groups 3 and 4 rats
(Table 2). These increases were again transitory despite the
continued
presence of the CEI. The superimposition of the KA resulted in a
significant decrease in both UV (P<.01) and UKV
(P<.001) compared with period 2. In contrast, UV and
UKV were not significantly altered during the
superimposition of vehicle.
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2K1C Hypertensive Rats (Groups
5 and 6)
Mean body weights were not different between the two groups
of
hypertensive rats (301±11 and 289±12 g
[P>.05],
groups 5 [KA] and 6 [time control], respectively).
Baseline MAP was also not different between these two rat groups
(172±7 and 168±9 mm Hg, respectively). Enalaprilat infusion
resulted
in a marked decrease in MAP in both groups (Fig 4A).
Superimposition of the KA did not significantly alter MAP compared with
the effects of either enalaprilat alone or the superimposed infusion of
vehicle (Fig 4D).
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Baseline renal hemodynamics were not
different between
the two groups of hypertensive rats. The low dose of enalaprilat
increased RPF of the nonclipped kidney by a similar degree in the two
groups, although for group 6 rats, the increase in RPF did not reach
significance until period 3. The increase in RPF from baseline to
period 2 in group 5 rats was 0.72±0.16
mL · min-1 · g
kwt-1 (P<.025, 34%).
The superimposition of the KA did not alter RPF compared with either
the mean effect of enalaprilat alone or the effect of vehicle infusion.
The change in RPF from the mean effect of CEI during the
superimposition of the KA was -0.07±0.12
mL · min-1 · g kwt-1
and during the superimposition of vehicle was 0.34±0.24
mL · min-1 · g
kwt-1. The effects of superimposition of
KA or vehicle during enalaprilat infusion on RBF and RVR of the
nonclipped kidney of the 2K1C hypertensive rats are presented
in Fig 4. The low dose of enalaprilat increased RBF of the
nonclipped
kidney by a similar degree in the two groups (Fig 4B). RVR (Fig
4C) was
significantly decreased in both groups during period 2 (the mean change
in RVR induced by enalaprilat was -10.87±3.02 and
-9.05±2.08
mm Hg · mL-1 · min-1 · g
kwt-1 for groups 5 [P<.025,
-29%] and 6 [P<.025, -31%],
respectively).
The superimposition of the KA did not alter RBF or RVR (Fig 4E
and 4F).
Baseline values of GFR were not significantly
different between groups
5 and 6 (Table 2). For group 6 rats, GFR was not significantly
increased by enalaprilat infusion. However, in group 5 rats,
enalaprilat increased the GFR of the nonclipped kidneys from a
baseline value of 0.63±0.05 to 0.78±0.07
mL · min-1 · g kwt-1
during period 2 (P<.025). As was observed for the
normotensive rats, the increase in GFR was transient despite the
continued presence of enalaprilat. Consequently, the effect of the
superimposition of KA or vehicle was examined by comparing the mean GFR
at period 3 (during the superimposition of KA or vehicle) with that
obtained during period 2 (enalaprilat alone). Compared with period 2,
the GFR of the nonclipped kidneys was not significantly altered by the
superimposition of the KA (0.71±0.06 versus 0.78±0.07
mL · min-1 · g
kwt-1) or vehicle (0.96±0.18 versus
0.86±0.16 mL · min-1 · g
kwt-1). The response to superimposition
of the KA was not different to that observed during the superimposition
of the vehicle (-0.07±0.04 and 0.1±0.09
mL · min-1 · g
kwt-1, for groups 5 and 6,
respectively).
Enalaprilat infusion induced significant increases in UV
and
UKV in both groups of 2K1C rats (Table 2).
Superimposition
of the KA did not alter the rate of either water or potassium excretion
compared with the mean effect of CEI (UV and UKV from
the mean effect of CEI, 0.2±0.4
µL · min-1 · g
kwt-1 and -26±93
nmol · min-1 · g
kwt-1, respectively) or with the
excretory rates obtained during the superimposition of vehicle (UV
and UKV from the mean effect of CEI, 1.2±1.1
µL · min-1 · g
kwt-1 and 249±128
nmol · min-1 · g
kwt-1, respectively). Low-dose
enalaprilat infusion did not significantly increase UNaV of
either group of hypertensive rats (Table 2). UNaV
during
the superimposition of the KA did not differ from either the mean
effect of CEI or UNaV during the superimposition of
vehicle.
|
Discussion |
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|
TopAbstractIntroductionMethods Results Discussion References |
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Studies that used the Stewart-Vavrek KA D-Arg0, [Hyp3,Thi5,8,D-Phe7]-bradykinin to investigate the contribution of endogenous kinins in control vascular tone and renal function in rats used relatively high doses of the antagonist to block kinin receptors. In contrast, Jaffa et al27 reported that a low systemic dose of this KA (at least 10-fold lower than used in other studies) prevented the increase in GFR and RBF induced by acute amino acid infusion, suggesting that renal bradykinin B2 receptors are effectively blocked by low doses of the KA. Consequently, we assessed the effects of superimposing a low dose of the KA during acute infusion of low-dose enalaprilat in hydropenic normotensive and 2K1C hypertensive rats.
Although very high doses of bradykinin receptor antagonists have been previously reported to alter baseline MAP28 29 or to reverse the hypotensive effect of CEI,24 30 basal vascular tone and CEI-induced vasodilation were not altered by lower doses of kinin receptor antagonists.9 10 30 31 In the present study, systemic infusion of two low doses of the KA did not alter the basal MAP of hydropenic normotensive rats. Treatment of normotensive rats with the CEI, enalaprilat, decreased systemic blood pressure and increased RBF. The superimposition of low-dose bradykinin B2 receptor antagonist intravenously during the enalaprilat treatment did not reverse the CEI-induced decrease in MAP. These findings are consistent with the above observations that suggest that in normotensive rats, endogenous kinins do not play a major role in either the maintenance of basal vascular tone or the vasodilation induced by CEI treatment. Although kinins participate at least partly in the renal actions of CEI,7 8 9 10 the role of kinins in the whole-kidney hemodynamic effects of CEI has not be clarified.
We report that a low dose of D-Arg0,[Hyp3,Thi5,8, D-Phe7]-bradykinin given systemically reversed the enalaprilat-induced changes in RVR and RBF in hydropenic normotensive rats. This effect of kinin receptor antagonism on CEI-induced changes in whole-kidney hemodynamics was observed at a KA dose substantially lower than that used by previous investigators to examine the effect of systemic bradykinin B2 receptor blockade on CEI-induced changes in renal hemodynamics and excretory function.8 9 Furthermore, this low systemic dose of the KA was similar to the doses used to examine the effect of intrarenal infusion on CEI-induced increases in RBF.12 13 These previous studies did not find a significant effect of the KA on changes in whole-kidney hemodynamics induced by CEI treatment. Thus, the KA dose used in the present study was markedly lower than the doses used in studies that failed to find an effect of systemic kinin receptor blockade on CEI-induced changes in whole-kidney hemodynamics. In the hydropenic normotensive rats, GFR and urinary excretory function increased after treatment with low-dose enalaprilat. This effect of enalaprilat was transient, as these renal function parameters returned to baseline values by the end of the experiment. Despite the transient effect of enalaprilat treatment, superimposition of the low dose of KA reduced GFR and UV but not UNaV to baseline levels. This finding suggests that blockade of kinin B2 receptors attenuated the CEI-induced changes in GFR and UV and is similar to those previously reported except that higher doses of KA attenuated the increase in UNaV after CEI treatment.7 8 9
Although the rats were housed and fed under the same conditions and had
similar hematocrit values (suggesting similar volume status) during the
clearance experiments, some baseline parameters of renal
function differed between the groups that received KA or vehicle.
Although these differences were unexpected, they do not appear to
compromise the findings of the study because they were negated by our
experimental design. The baseline values were obtained to ensure that
the effect of enalaprilat treatment was similar for all groups before
the superimposed KA or vehicle treatment. Despite differences in
baseline renal function between the two groups of normotensive rats,
the systemic infusion of enalaprilat induced similar changes in renal
function. Furthermore, the period of superimposed infusion of the KA
was bracketed by periods of enalaprilat infusion alone. The effect of
the KA was determined by the change observed during the superimposed KA
treatment from the periods of enalaprilat infusion alone. Data
presented in Fig 3E and 3F indicate that the
superimposition of
KA markedly attenuated enalaprilat-induced alterations in renal
hemodynamics within the same group of rats.
Infusion of low-dose KA during treatment with enalaprilat partially blocked the hypotensive effect of injected bradykinin (by 30% to 39%). This finding is consistent with other reports of partial blockade of the hypotensive action of exogenous bradykinin by the first generation of effective kinin antagonists, although most previous studies examined the completeness of kinin blockade in the absence of CEI. High doses of KA attenuated the hypotensive effect of intra-arterial bradykinin by 52%32 and 79%31 in conscious normal rats, 20% to 50% in anesthetized normotensive rats,33 and 39% to 72%23 and 45% to 55%21 in anesthetized 2K1C hypertensive rats. Although only partial blockade of systemically administered bradykinin was achieved for the normotensive rats in the present study, the KA abolished the enalaprilat-induced renal vasodilation. Despite the incomplete inhibition of exogenous bradykinin in the other studies, kinin antagonists reduced baseline RBF31 and UV,32 abolished the renal effects of kininase inhibition,33 and attenuated the hypotensive effects of CEI.21 23 Furthermore, D-Arg0,[Hyp3,Thi5,8,D-Phe7]-bradykinin almost completely blocked the renal hemodynamic effects of intrarenally infused bradykinin.12 13 Taken together, these observations suggest that blockade of renal bradykinin B2 receptors could be more complete than blockade of systemic receptors.
Our finding that infusion of low-dose KA reversed the renal hemodynamic effects of enalaprilat suggests that endogenous kinins acting on renal bradykinin B2 receptors control renal hemodynamics in normotensive hydropenic rats acutely treated with CEI. This role of kinins in the changes in renal hemodynamics induced by CEI treatment could simply be the result of increased kinin levels consequent to CEI.5 This possibility is supported by the findings that CEI potentiates the hypotensive action of exogenous systemic bradykinin by prolonging its activity.22 23 34 The present observations in hydropenic rats provide support for an action of CEI to augment kinin activity. Intravenous administration of low-dose bradykinin during enalaprilat infusion induced substantial decreases in systemic blood pressure in both the normotensive control and 2K1C hypertensive rats. These bradykinin-induced decreases in MAP were similar to the decreases in MAP reported for 5 to 10 times higher doses of intra-arterially injected bradykinin in the absence of CEI in normotensive and hypertensive rats.23 31 33
Since CEI results in both blockade of angiotensin formation and kinin degradation, the effects of superimposed KA during enalaprilat treatment on renal hemodynamics could also be due to an altered balance in angiotensin-induced vasoconstriction and kinin-mediated vasodilation. This interaction between angiotensin and kinins may be a major factor associated with the difficulty in fully elucidating the role of kinins in the regulation of renal function. Although the use of the Stewart-Vavrek antagonists and Hoe 140, a more potent antagonist, support a role for kinins in contributing to the regulation of sodium excretion, this role appears to be limited to circumstances when perturbations in the levels of both kinins and angiotensin are expected to occur, such as with deoxycorticosterone acetate–salt treatment32 or after treatment with CEI.7 8 9 Furthermore, the Stewart-Vavrek antagonist11 or Hoe 14035 attenuated CEI-induced increases in RBF in sodium-restricted dogs but not those fed a normal sodium diet.35 Since dietary sodium restriction markedly elevates renal interstitial kinin levels,36 these findings suggest that the renal hemodynamic effects of CEI are at least partly kinin dependent when basal kinin activity is elevated.
In contrast to the responses we observed in normotensive rats, superimposed low-dose KA did not alter the enalaprilat-induced increases in hemodynamics and excretory function of the nonclipped kidney of 2K1C hypertensive rats. Although we had previously observed qualitatively similar effects of CEI and angiotensin receptor antagonism on renal function in 2K1C hypertensive rats,16 we hypothesized that endogenous kinins could contribute to the CEI-induced increased function in the nonclipped kidney of 2K1C hypertensive rats. This hypothesis was derived from the findings that in 2K1C hypertensive rats, the hypotensive response to CEI could be attenuated by kinin antagonists,21 22 23 24 glomerular kinin receptors were upregulated in the nonclipped kidney of 2K1C hypertensive rats compared with kidney from normotensive rats,20 and renal kallikrein mRNA expression in the nonclipped kidney was not downregulated as it was in the clipped kidney.17 18 However, the present findings suggest that endogenous kinins contribute substantially less to the enalaprilat-induced alterations in renal hemodynamics for the nonclipped kidney during the early phase of 2K1C hypertension than for kidneys from normotensive rats.
In the present study, the KA attenuated the hypotensive effect of injected bradykinin similarly in the normotensive and hypertensive rats. Therefore, it would appear that the absence of a renal hemodynamic effect of superimposed KA in the hypertensive rats was not due to decreased blockade of kinin receptors. The same low systemic dose of D-Arg0,[Hyp3,Thi5,8,D-Phe7]-bradykinin as used in the present study is effective in elucidating the role of kinins in the altered renal hemodynamics of several rat models.27 37 38 This finding suggests that the low dose of the antagonist effectively blocks renal kinin receptors under a number of physiological and pathophysiological conditions, further supporting comparable kinin receptor blockade between the normotensive and hypertensive rats in the present study.
It seems unlikely that our observation that kinin receptor antagonism did not attenuate enalaprilat-induced renal hemodynamics in the nonclipped kidney of 2K1C hypertensive rats was due to the use of D-Arg0, [Hyp3,Thi5,8,D-Phe7]-bradykinin instead of the newer receptor antagonist Hoe 140. Although studies in vitro have found Hoe 140 to be more specific and more potent than the first-generation B2 receptor antagonists and in vivo to almost completely block the hypotensive effect of systemic bradykinin, both D-Arg0,[Hyp3,Thi5,8,D-Phe7]-bradykinin and Hoe 140 have suggested a role for kinins in CEI-induced alterations in renal hemodynamics in normal animals.7 10 11 35 Also, both D-Arg0,[Hyp3,Thi5,8,D-Phe7]-bradykinin and Hoe 140 effectively block renal bradykinin B2 receptors in rabbits.12 13 14 Interestingly, in contrast to the present study, Hoe 140 did not attenuate the action of CEI on RBF in rats.10 15 These findings suggest that D-Arg0,[Hyp3,Thi5,8,D-Phe7]-bradykinin may be as effective an agent as Hoe 140 in elucidating the role of kinins in CEI-induced renal hemodynamics.
Chronic CEI or increased tissue kinin levels have been reported to result in downregulation of bradykinin B2 receptors.6 However, it seems unlikely that acute CEI would downregulate kinin receptors to a greater extent in the nonclipped kidney of 2K1C hypertensive rats compared with kidneys from normotensive rats in the same short time frame.
Intrarenal angiotensin II levels are significantly elevated in the nonclipped kidneys of 2K1C hypertensive rats 4 weeks after clipping.39 This chronic increase in angiotensin activity may alter the responsiveness of the renal vasculature to kinins. Consequently, the nonclipped kidney of the 2K1C hypertensive rat may represent a situation in which the balance between angiotensin II and kinins is such that blockade of angiotensin II formation is the primary determinant of the action of CEI.
In summary, infusion of low doses of the bradykinin B2 receptor antagonist D-Arg0,[Hyp3,Thi5,8,D-Phe7]-bradykinin did not alter blood pressure, renal hemodynamics, or excretory function in hydropenic normotensive rats. Infusion of a low dose of the CEI enalaprilat resulted in decreased MAP, decreased RVR, and augmented excretory function. Superimposition of the KA during low-dose enalaprilat infusion reversed the CEI-induced increase in RBF and attenuated the increased excretory function in hydropenic normotensive rats. Infusion of low-dose enalaprilat resulted in decreased MAP and increased RBF for the nonclipped kidney of 2K1C hypertensive rats similar to that observed in normotensive rats. However, the superimposed infusion of the KA did not alter the CEI-induced increase in RBF or significantly change the CEI-induced alterations in excretory function for the nonclipped kidney in these rats. These observations suggest that endogenous kinins contribute to the increased renal function induced by low-dose CEI in hydropenic normotensive rats but appear to contribute less to the enalaprilat-induced alterations of renal function in the nonclipped kidney of 2K1C hypertensive rats.
|
Selected Abbreviations and Acronyms |
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|
|
Acknowledgments |
|---|
This investigation was supported by funds from Dialysis Clinics Inc and Merit Review Grants from the Research Service of the Department of Veterans Affairs (D.W.P., R.K.M.). Statistical consultation was provided by Dr Philip Rust, Department of Biometry, Medical University of South Carolina. We acknowledge the technical assistance of Emma S. Murner.
Received July 6, 1995; first decision August 2, 1995; accepted September 29, 1995.
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TopAbstractIntroductionMethods Results Discussion References |
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